CN101591335A - N-(L-aminoacyl)-1,2,3,4-tetrahydrochysene carboline acyl aminoacid benzyl ester and synthetic method thereof and application - Google Patents

N-(L-aminoacyl)-1,2,3,4-tetrahydrochysene carboline acyl aminoacid benzyl ester and synthetic method thereof and application Download PDF

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CN101591335A
CN101591335A CNA2008101138564A CN200810113856A CN101591335A CN 101591335 A CN101591335 A CN 101591335A CN A2008101138564 A CNA2008101138564 A CN A2008101138564A CN 200810113856 A CN200810113856 A CN 200810113856A CN 101591335 A CN101591335 A CN 101591335A
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obzl
boc
tetrahydrocarboline
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benzyl ester
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CN101591335B (en
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彭师奇
赵明
张建伟
周冬初
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Capital Medical University
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Abstract

The invention discloses the N-(L-aminoacyl)-1,2,3 with antitumor action, 4-tetrahydrochysene carboline acyl aminoacid benzyl ester compound and preparation method thereof and they are as the application of antineoplastic agent.The present invention adopts S 180Mouse model has been estimated the anti-tumor activity of The compounds of this invention, and experimental result shows that compound of the present invention has outstanding antitumor action, can be used as antineoplastic agent clinically and uses.

Description

N-(L-aminoacyl)-1,2,3,4-tetrahydrochysene carboline acyl aminoacid benzyl ester and synthetic method thereof and application
Technical field
The present invention relates to have the compound of anti-tumor activity, relate in particular to N-(L-aminoacyl)-1 with anti-tumor activity, 2,3,4-tetrahydrochysene carboline acyl aminoacid benzyl ester compounds and preparation method thereof, the invention still further relates to the application of this compound in the preparation antitumor drug, belong to biomedicine field.
Background technology
Malignant tumour is a kind of common disease and frequently-occurring disease of serious threat human health, and the mortality ratio that the mankind cause because of malignant tumour is second of all disease death rates, is only second to cardiovascular and cerebrovascular diseases.The tumor treatment method has operative treatment, radiotherapy and pharmacological agent (chemotherapy).At present, chemotherapy remains the main means of clinical treatment tumour.Seeking antitumor drug is one of focus of new drug research.The contriver recognizes, introduces amino acid and 3 carboxyls at 2 N of β-Ka Lin-3-carboxylic acid and introduces the amino acid benzyls and may produce antitumor action.
Summary of the invention
One of the object of the invention provides the new compound with anti-tumor activity of a class.
Two of the object of the invention provides a kind of above-mentioned method with compound of anti-tumor activity for preparing.
Three of the object of the invention provides a kind of pharmaceutical composition with antitumor efficacy.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
Compound with anti-tumor activity, the structural formula of this compound are shown in general formula I or the general formula I I:
Figure A20081011385600051
General formula I
Wherein, AA 1Be selected from L-Ala (Ala) residue, glycine (Gly) residue, proline(Pro) (Pro), glutamine (Gln) residue, leucine (Leu) residue, phenylalanine (Phe) residue, Isoleucine (Ile) residue, methionine(Met) (Met) residue, tyrosine (Tyr) residue, tryptophane (Trp) residue, Xie Ansuan (Val) residue, Methionin (Lys) residue, Arg (NO 2), Thr (Bzl), Ser (Bzl) or Cys (CH 2-C 6H 4-OCH 3); AA 2Be selected from L-Ala (Ala) residue, glycine (Gly) residue, proline(Pro) (Pro) residue, glutamine (Gln) residue, leucine (Leu) residue, phenylalanine (Phe) residue, Isoleucine (Ile) residue, methionine(Met) (Met) residue, tyrosine (Tyr) residue, tryptophane (Trp) residue, Xie Ansuan (Val) residue, Methionin Lys (Z), Arg (NO 2), Thr (Bzl), Ser (Bzl) or Cys (But);
Figure A20081011385600061
General formula I I
Wherein, AA 1Be selected from Asp (OBZl) or Glu (OBZl); AA 2Be selected from Asp (OBZl) or Glu (OBZl);
A kind of method for preparing above-mentioned compound of Formula I, this method comprises:
(1) the L-tryptophan transfer is become 1,2,3,4-Tetrahydrocarboline carboxylic acid;
(2) with 1,2,3,4-Tetrahydrocarboline carboxylic acid changes carboline carboxylate benzyl ester into;
(3) in the presence of tosic acid and benzylalcohol, amino acid changed into amino-acid benzyl ester (2);
(4) at (Boc) 2O and NaOH exist down, and amino acid changes into N-t-butoxycarbonyl amino acid (1);
(5) with the acid of N-t-butoxycarbonyl amino and 1,2,3, the condensation of 4-Tetrahydrocarboline benzyl carboxylate generates N-t-butoxycarbonyl amino acyl-1,2,3,4-Tetrahydrocarboline benzyl carboxylate;
(6) with N-t-butoxycarbonyl amino acyl-1,2,3,4-Tetrahydrocarboline benzyl carboxylate hydrogenolysis generates N-t-butoxycarbonyl amino acyl-1,2,3,4-Tetrahydrocarboline carboxylic acid;
(7) with N-t-butoxycarbonyl amino acyl-1,2,3, the hydrolysis of 4-Tetrahydrocarboline benzyl carboxylate generates N-t-butoxycarbonyl amino acyl-1,2,3,4-Tetrahydrocarboline carboxylic acid;
(8) with N-t-butoxycarbonyl amino acyl-1,2,3,4-Tetrahydrocarboline carboxylic acid and amino-acid benzyl ester condensation generate N-t-butoxycarbonyl amino acyl-1,2,3, the 4-tetrahydrochysene carboline acyl aminoacid benzyl ester;
(9) with N-t-butoxycarbonyl amino acyl-1,2,3, the acidolysis of 4-tetrahydrochysene carboline acyl aminoacid benzyl ester, promptly.
Among the above-mentioned preparation method, the amino-acid benzyl ester described in the step (3) is selected from Ala-OBzl, Gly-OBzl, Pro-OBzl, Gln-OBzl, Leu-OBzl, Phe-OBzl, Ile-OBzl, Met-OBzl, Tyr-OBzl, Trp-OBzl, Val-OBzl, Lys (Z)-OBzl, Arg (NO 2)-OBzl, Thr (Bzl)-OBzl, Ser (Bzl)-OBzl, Cys (But)-OBzl, Asp (OBzl)-Obzl or Glu (OBzl)-OBzl;
N-t-butoxycarbonyl amino acid described in the step (4) is selected from N-Boc-Ala, N-Boc-Gly, N-Boc-Pro, N-Boc-Gln, N-Boc-Leu, N-Boc-Phe, N-Boc-Ile, N-Boc-Met, N-Boc-Tyr, N-Boc-Trp, N-Boc-Val, N-Boc-Lys, N-Boc-Arg (NO 2), N-Boc-Thr (Bzl), N-Boc-Ser (Bzl), N-Boc-Cys (CH 2-C 6H 4-OCH 3), N-Boc-Asp (OBzl) or N-Boc-Glu (OBzl);
A kind of method for preparing above-mentioned general formula I I compound, this method comprises:
(1) the L-tryptophan transfer is become 1,2,3,4-Tetrahydrocarboline carboxylic acid;
(2) with 1,2,3,4-Tetrahydrocarboline carboxylic acid is transformed into N-tertbutyloxycarbonyl-1,2,3,4-Tetrahydrocarboline carboxylic acid;
(3) with N-N-tertbutyloxycarbonyl-1,2,3,4-Tetrahydrocarboline carboxylic acid and amino-acid benzyl ester condensation generate N-N-tertbutyloxycarbonyl-1,2,3, the 4-tetrahydrochysene carboline acyl aminoacid benzyl ester;
(4) with N-N-tertbutyloxycarbonyl-1,2,3, the acidolysis of 4-tetrahydrochysene carboline acyl aminoacid benzyl ester generates 1,2,3, the 4-tetrahydrochysene carboline acyl aminoacid benzyl ester;
(5) with the acid of N-t-butoxycarbonyl amino and 1,2,3, the condensation of 4-tetrahydrochysene carboline acyl aminoacid benzyl ester generates N-N-t-butoxycarbonyl amino acyl-1,2,3, the 4-tetrahydrochysene carboline acyl aminoacid benzyl ester;
(6) with N-N-t-butoxycarbonyl amino acyl-1,2,3, the acidolysis of 4-tetrahydrochysene carboline acyl aminoacid benzyl ester, promptly.
Wherein, the amino-acid benzyl ester described in the step (3) is selected from Asp (OBZl)-OBzl or Glu (OBZl)-OBzl; N-t-butoxycarbonyl amino acid described in the step (5) is selected from N-Boc-Asp (OBZl) or N-Boc-Glu (OBZl)
Another purpose of the present invention provides a kind of medicinal compositions with anti-tumor activity, this medicinal compositions is gone up the general formula I of the present invention of effective dose or general formula I I compound and pharmaceutically acceptable carrier by treatment and is formed, after being about to the general formula I of the present invention of significant quantity or general formula I I compound and pharmaceutically acceptable carrier or thinner cooperating, it is prepared into any one appropriate drug composition by the formulation method of this area routine.Usually said composition is suitable for oral administration and drug administration by injection, also is fit to other medication.Said composition can be liquid preparation forms such as tablet, capsule, pulvis, granule, lozenge, suppository, or oral liquid.According to different medications, pharmaceutical composition of the present invention can contain 0.1%-99% weight, the The compounds of this invention of preferred 10-60% weight.
The present invention is at mouse S 180Estimate the anti-tumor activity of general formula I of the present invention and general formula I I compound on the sarcoma model, test-results shows that general formula I of the present invention and general formula I I compound have definite anti-tumor activity.
Description of drawings
The structure iron of Fig. 1 general formula compound of the present invention.
The synthetic route chart of Fig. 2 compound of Formula I; I) formaldehyde and the vitriol oil, stirring at room; Ii) benzylalcohol, polyphosphoric acid, oil bath are 90 ℃; Iii) Boc-AA 1, DCC, HoBt, NMM; Iv-1) Pd/C, H 2, ethanol AA 1Be selected from Ala, Gly, Pro, Gln, Leu, Phe, Ile, Tyr, Trp, Val, Lys (Boc); Iv-2) 2N NaOH, methyl alcohol AA 1Be selected from Met, Arg (NO 2), Thr (Bzl), Ser (Bzl), Cys (CH 2-C 6H 4-OCH 3); V) L-AA 2-OBzl, DCC, HoBt, NMM; Vi) 4N hydrogenchloride-ethyl acetate solution; AA among the 7a-p 1Be selected from Ala, Gly, Pro, Gln, Leu, Phe, Ile, Met, Tyr, Trp, Val, Lys (Boc), Arg (NO 2), Thr (Bzl), Ser (Bzl), Cys (CH 2-C 6H 4-OCH 3); AA 2Be selected from Ala, Gly, Pro, Gln, Leu, Phe, Ile, Met, Tyr, Trp, Val, Lys (Z), Arg (NO 2), Thr (Bzl), Ser (Bzl), Cys (But); AA among the 8a-p 1Be selected from Ala, Gly, Pro, Gln, Leu, Phe, Ile, Met, Tyr, Trp, Val, Lys, Arg (NO 2), Thr (Bzl), Ser (Bzl), Cys (CH 2-C 6H 4-OCH 3); AA 2Be selected from Ala, Gly, Pro, Gln, Leu, Phe, Ile, Met, Tyr, Trp, Val, Lys (Z), Arg (NO 2), Thr (Bzl), Ser (Bzl), Cys (But).
The synthetic route chart of Fig. 3 general formula I I compound; I) formaldehyde and the vitriol oil, stirring at room; Ii) (Boc) 2O, triethylamine, DMF; Iii) DCC, HOBt, AAOBzl, anhydrous THF; Iv) 4N HCl-EtoAC; V) DCC, HOBt, Boc-AA-OH, anhydrous THF; Vi) 4N HCl-EtoAC; 5q, AA is selected from Asp (OBzl) or Glu (OBzl) among the r; 6q, AA is selected from Asp (OBzl) or Glu (OBzl) among the r; 7q, AA among the r 1Be selected from Asp (OBzl) or Glu (OBZl), AA 2Be selected from Asp (OBzl) or Glu (OBZl); 8q, AA among the r 1Be selected from Asp (OBZl) or Glu (OBZl), AA 2Be selected from Asp (OBZl) or Glu (OBZl).
Embodiment
In order further to set forth the present invention, provide a series of examples 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.
Embodiment 11, and 2,3,4-Tetrahydrocarboline-3-carboxylic acid (2)
400ml water is placed the round-bottomed flask of 500ml, slowly adding the 0.2ml vitriol oil shakes up. in the dilution heat of sulfuric acid that obtains, add 5.0g (24.5mmol) L-tryptophane. dissolve fully with sonic oscillation to L-tryptophane, add 10ml concentration in the solution that obtains and be 35% formaldehyde, stir, the TLC plate detects L-tryptophane raw material point disappearance termination reaction. slow dropping ammonia accent pH value to 6 in the reaction solution, static half hour, decompression leaches the precipitation of generation, the colorless solid drying that water flushing the leaches 5.01g that weighs, productive rate: 95%.M.p.229-231℃，ESI-MS(m/z)：[M+H] +217。
Embodiment 2 2-Boc-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (3)
With 1g (4.63mmol) 1,2,3,4-Tetrahydrocarboline-3-carboxylic acid is suspended in and contains 1.2g (Boc) under the ice bath 2In the 10mlDMF solution of O (5.50mmol), add triethylamine then and transfer the PH8-9 reaction, along with the solution that carries out suspendible that reacts becomes clarification gradually, solution colour is yellow, TLC plate detection reaction (chloroform: raw material point disappearance stopped reaction methyl alcohol=10: 1), electric fan dries up DMF, the residue dissolving after will drying up with ethyl acetate, 5% KHSO 4Wash saturated NaCl washing 3 times, anhydrous Na 3 times 2SO 4Drying is filtered, and the evaporate to dryness residue obtains target compound 958mg with the chloroform washing, colorless solid, and productive rate: 65.5%, Mp:241-243 ℃; [α] D 25=64.43 (Cl; Methyl alcohol) .ESI-MS (m/z) 317[M+H] + 1HNMR (500MHz, DMSO-d 6): δ/ppm=12.794 (s, 1H), 10.887 (d, J=23.5Hz, 1H), 7.293-7.440 (m, J=8Hz, J=7.5Hz, 2H), 6.969-7.077 (m, J=7Hz, J=7.5Hz, 2H), 5.1245 (dd, J=5.5Hz, 1H), 4.742 (t, J=17Hz, J=19Hz, H), 4.4195 (dd, J=20Hz, 1H), 3.323 (m, J=7.5Hz, 1H), 2.985 (m, J=6.5Hz, 1H), 1.460 (s, 9H). 13CNMR (DMSO-d 6): δ/ppm=173.28,155.56,136.66,130.81,126.76,121.41,119.01,118.03,111.47,104.99,80.27,60.20,53.86,28.49,23.34.
Embodiment 31, and 2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (4)
Get 20ml benzylalcohol and the 2g polyphosphoric acid makes it to dissolve each other, 70 ℃ of oil baths, adding carboline carboxylate 1g begins insoluble, reaction solution is that yellow-green colour is warming up to 90 ℃ of reaction solutions and dissolves gradually and become the clarification color and turn brown gradually, TLC plate detection reaction, 24 hours raw material points disappear and carry out aftertreatment. cooling, adding 50ml ether and 70ml water fully stir and crystallization occurs, filter, ether water is washed the carboline carboxylate benzyl ester phosphoric acid salt that obtains yellow-white repeatedly. and the carboline carboxylate benzyl ester phosphoric acid salt DL that obtains in ethyl acetate, is dripped triethylamine to clarification, wash 6 times with 5% sodium bicarbonate, saturated sodium-chloride washing 3 times, anhydrous sodium sulfate drying filters, and is spin-dried for, obtain the carboline carboxylate benzyl ester 0.85g of yellow-white, productive rate 60%; Mp122-124 ℃; [α] D 25=53.4 (Cl; Methyl alcohol); ESI-MS (m/z): 307[M+H] + 1HNMR (500MHZ, DMSO-d 6): δ/ppm=7.275-7.401 (m, 7H), 6.951 (t, J=7.5Hz, 1H), 7.025 (t, J=10Hz, 1H), 5.191 (s, 2H), 3.9885 (q, J=15.5Hz, 2H), 3.824 (q, J=4.5Hz, J=8.5Hz, 1H), 2.9765 (dd, J=4.5Hz, J=15Hz, 1H), 2.815 (q, J=8.5Hz, J=15Hz). 13CNMR (DMSO-d 6): δ/ppm=173.21,136.57,136.23,133.46,128.90,128.71,128.46,128.21,127.30,120.97,118.79,117.73,111.33,105.83,66.15,55.63,41.7,25.26.
Embodiment 4 N-Boc-Ala-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (5a)
Ice bath dissolves 1.229g (6.5mmol) Boc-Ala with anhydrous THF down, add 0.921g (6.82mmol) N-hydroxy benzo triazole (HOBt), the dissolving back added 1.741g (8.45mmol) dicyclohexyl carbonyl diimine (DCC) after .10 minute fully, add anhydrous THF and 1.53g (5.0mmol) 1 inward, 2,3,4-Tetrahydrocarboline-3-benzyl carboxylate is also transferred solution between the pH value 8-9 with N-methylmorpholine.Reaction mixture stirs, and the detection of TLC plate (oil mystery/acetone, 3: 1, Rf=0.2).Raw material point leaches dicyclohexylurea (DCU) (DCU) after disappearing, and filtrate decompression concentrates, residue 40ml acetic acid ethyl dissolution.The solution that obtains is used saturated NaHCO successively 3, saturated NaCl, 5%KHSO 4, saturated NaCl, saturated NaHCO 3, saturated NaCl respectively gives a baby a bath on the third day after its birth time to neutral anhydrous Na 2SO 4Dry.Filter, filtrate decompression is concentrated into dried, obtains 1.761g (74%) title compound (faint yellow solid).Mp 87-90 ℃; [α] D 25=27.33 (C=1.0, methyl alcohol).ESI-MS(m/z)478[M+H] +。
Embodiment 5N-Boc-Gly-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (5b)
According to the operation of preparation 5a, from 0.91g (5.2mmol) Boc-Gly and 1.224g (4.0mmol) 1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 1.48g (79.9%) title compound (faint yellow solid).Mp 102-104 ℃; [α] D 25=19.47 (C=1.0, methyl alcohol); ESI-MS (m/z) 464[M+H] +
Embodiment 6N-Boc-Pro-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (5c)
According to the operation of preparation 5a, from 1.118g (5.2mmol) Boc-Pro and 1.224g (4.0mmol) 1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 0.372g (19%) title compound (yellow solid).Mp 88-90 ℃; [α] D 25=-2.70 (C=1.0, methyl alcohol); ESI-MS (m/z) 504[M+H] +
Embodiment 7N-Boc-Gln-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (5d)
According to the operation of preparation 5a, from 0.949g (6.5mmol) Boc-Gln and 1.53g (5.0mmol) 1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 1.0g (37%) title compound (colorless solid).Mp 102-104 ℃; [α] D 25=74 (C=1.0, methyl alcohol); ESI-MS (m/z) 535[M+H] +
Embodiment 8N-Boc-Leu-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (5e)
According to the operation of preparation 5a, from 1.201g (5.2mmol) Boc-Leu and 1.224g (4.0mmol) 1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 1.654g (80%) title compound (colorless solid).Mp 84-86 ℃; [α] D 25=38.5 (C=1.0; Methyl alcohol); ESI-MS (m/z) 520[M+H] +
Embodiment 9N-Boc-Phe-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (5f)
According to the operation of preparation 5a, from 1.378g (5.2mmol) Boc-Phe and 1.224g (4.0mmol) 1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 2.033g (92%) title compound (colorless solid).Mp 74-76 ℃; [α] D 25=53.0 (C=1.0, methyl alcohol); ESI-MS (m/z) 554[M+H] +
Embodiment 10N-Boc-Ile-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (5g)
According to the operation of preparation 5a, from 1.502g (6.5mmol) Boc-Ile and 1.53g (5.0mmol) 1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 1.90g (73%) title compound (colorless solid).Mp 78-81 ℃; [α] D 25=46.7 (C=1.0, methyl alcohol); ESI-MS (m/z) 542[M+H] +
Embodiment 11N-Boc-Met-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (5h)
According to the operation of preparation 5a, from 1.618g (6.5mmol) Boc-Met and 1.53g (5.0mmol) 1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 1.69g (63%) title compound (yellow solid).Mp 76-78 ℃; [α] D 25=46.9 (C=1.0, methyl alcohol); ESI-MS (m/z) 538[M+H] +
Embodiment 12N-Boc-Tyr-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (5i)
According to the operation of preparation 5a, from 1.826g (6.5mmol) Boc-Tyr and 1.53g (5.0mmol) 1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 0.747g (26%) title compound (yellow solid).Mp 102-103 ℃; [α] D 25=48.1 (C=1.0, methyl alcohol); ESI-MS (m/z) 592[M+H] +
Embodiment 13N-Boc-Trp-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (5j)
According to the operation of preparation 5a, from 1.58g (5.2mmol) Boc-Trp and 1.224g (4.0mmol) 1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 1.80g (76%) title compound (colorless solid).Mp 102-104 ℃; [α] D 25=56.5 (C=1.0, methyl alcohol); ESI-MS (m/z) 593[M+H] +
Embodiment 14N-Boc-Val-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (5k)
According to the operation of preparation 5a, from 1.128g (5.2mmol) Boc-Val and 1.224g (4.0mmol) 1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 1.403g (69%) title compound (yellow solid).Mp 72-74 ℃; [α] D 25=80.6 (C=1.0; Methyl alcohol); ESI-MS (m/z) 506[M+H] +
Embodiment 15N-Boc-Lys (Boc)-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (5l)
According to the operation of preparation 5a, from 1.799g (5.2mmol) Boc-Lys (Boc) and 1.224g (4.0mmol) 1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 2.298g (91%) title compound (yellow solid).Mp 78-79 ℃; [α] D 25=40.2 (C=1.0, methyl alcohol); ESI-MS (m/z) 635[M+H] +
Embodiment 16N-Boc-Arg (NO 2)-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (5m)
According to the operation of preparation 5a, from 0.957g (3.0mmol) Boc-Arg (NO 2) and 0.765g (2.5mmol) 1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 0.90g (59%) title compound (yellow solid).Mp 118-121 ℃; [α] D 25=42.1 (C=1.0, methyl alcohol); ESI-MS (m/z) 608[M+H] +
Embodiment 17N-Boc-Thr (Bzl)-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (5n)
According to the operation of preparation 5a, from 0.927g (3.0mmol) Boc-Thr (Bzl) and 0.765g (2.5mmol) 1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 0.90g (60%) title compound (colorless solid).Mp 148-150 ℃; [α] D 25=46.3 (C=1.0, methyl alcohol); ESI-MS (m/z) 598[M+H] +
Embodiment 18N-Boc-Ser (Bzl)-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (5o)
According to the operation of preparation 5a, from 0.885g (3.0mmol) Boc-Ser (Bzl) and 0.765g (2.5mmol) 1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 1.075g (74%) title compound (colorless solid).Mp 66-68 ℃; [α] D 25=38.9 (C=1.0, methyl alcohol); ESI-MS (m/z) 584[M+H] +
Embodiment 19N-Boc-Cys (CH 2-C 6H 4-OCH 3)-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate (5p)
According to the operation of preparation 5a, from 1.228g (3.6mmol) Boc-Cys (CH 2-C 6H 4-OCH 3) and 0.918g (3.0mmol) 1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 1.30g (69%) title compound (colorless solid).Mp 50-53 ℃; [α] D 25=13.0 (C=1.0, methyl alcohol); ESI-MS (m/z) 630[M+H] +
Embodiment 20N-Boc-1,2,3,4-Tetrahydrocarboline-3-formyl-Asp (OBzl)-OBzl (5q)
According to the operation of preparation 5a, from 0.632g (2.0mmol) N-Boc-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid and 1.067g (2.2mmol) Asp (OBzl)-OBz get 0.657g (54%) title compound (colorless solid).Mp 50-52 ℃; [α] D 25=29.7 (C=1.0, methyl alcohol); ESI-MS (m/z) 612[M+H] +
Embodiment 21N-Boc-1,2,3,4-Tetrahydrocarboline-3-formyl-Glu (OBzl)-OBzl (5r)
According to the operation of preparation 5a, from 0.632g (2.0mmol) N-Boc-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid and 1.10g (2.2mmol) Glu (OBzl)-OBzl get 0.671g (54%) title compound (colorless solid).Mp 53-56 ℃; [α] D 25=20.5 (C=1.0, methyl alcohol); ESI-MS (m/z) 626[M+H] +
Embodiment 22N-Boc-Ala-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (6a)
In the round-bottomed flask of 100ml, use the 20ml dehydrated alcohol with 1.6g (3.35mmol) N-Boc-Ala-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate dissolving adds 0.8gPd/C, feeds H 2Stirring reaction, TLC detect raw material point and disappear termination reaction; Filter Pd/C, the evaporate to dryness mother liquor gets 1.23g (95%) title compound (colorless solid).Mp148-150 ℃; [α] D 25=55.3 (C=1.0, methyl alcohol); ESI-MS (m/z) 386[M-H] -
Embodiment 23N-Boc-Gly-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (6b)
According to the operation of preparation 6a, from 1.2g (2.59mmol) N-Boc-Gly-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 0.956g (99%) title compound (colorless solid).Mp 142-144 ℃; [α] D 25=63.2 (C=1.0, methyl alcohol); ESI-MS (m/z) 370[M-H] -
Embodiment 24N-Boc-Pro-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (6c)
According to the operation of preparation 6a, from 0.370g (0.74mmol) N-Boc-Pro-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 0.364g (97%) title compound (colorless solid).Mp 167-169 ℃; [α] D 25=-12.5 (C=1.0, methyl alcohol); ESI-MS (m/z) 412[M-H] -
Embodiment 25N-Boc-Gln-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (6d)
According to the operation of preparation 6a, from 1.0g (1.873mmol) N-Boc-Gln-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 0.80g (96%) title compound (colorless solid).Mp 151-153 ℃; [α] D 25=71.7 (C=1.0, methyl alcohol); ESI-MS (m/z) 443[M-H] -
Embodiment 26N-Boc-Leu-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (6e)
According to the operation of preparation 6a, from 1.0g (1.93mmol) N-Boc-Leu-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 0.786g (95%) title compound (colorless solid).Mp 142-144 ℃; [α] D 25=64.1 (C=1.0, methyl alcohol); ESI-MS (m/z) 428[M-H] -
Embodiment 27N-Boc-Phe-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (6f)
According to the operation of preparation 6a, from 0.676g (1.222mmol) N-Boc-Phe-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 0.534g (94%) title compound (colorless solid).Mp 136-138 ℃; [α] D 25=58.8 (C=1.0, methyl alcohol); ESI-MS (m/z) 462[M-H] -
Embodiment 28N-Boc-Ile-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (6g)
According to the operation of preparation 6a, from 1.0g (1.222mmol) N-Boc-Ile-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 0.819g (99%) title compound (colorless solid).Mp 145-146 ℃; [α] D 25=55.0 (C=1.0, methyl alcohol); ESI-MS (m/z) 428[M-H] -
Embodiment 29N-Boc-Met-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (6h)
With 1.2g (2.235mmol) N-Boc-Met-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate is dissolved in 4ml methyl alcohol, splashes into the 3ml 2N NaOH aqueous solution and is stirred to the disappearance of raw material point, termination reaction to the solution that obtains under the ice bath.The saturated KHSO of compound of reaction 4Transfer pH6-7, concentrating under reduced pressure is removed steaming methyl alcohol.The saturated KHSO of residue 4Transfer pH1-2, ethyl acetate extraction 3 times, the combined ethyl acetate layer is washed 3 times with the saturated NaCl aqueous solution, the ethyl acetate layer anhydrous Na 2SO 4Drying is filtered, and is evaporated to dried 0.849g (85%) title compound (colorless solid).Mp 104-106 ℃; [α] D 25=48.7 (C=1.0, methyl alcohol); ESI-MS (m/z) 446[M+H] +
Embodiment 30N-Boc-Tyr-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (6i)
According to the operation of preparation 6a, from 0.720g (1.265mmol) N-Boc-Tyr-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 0.569g (94%) title compound (colorless solid).Mp 166-168 ℃; [α] D 25=51.7 (C=1.0, methyl alcohol); ESI-MS (m/z) 478[M-H] -
Embodiment 31N-Boc-Trp-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (6j)
According to the operation of preparation 6a, from 1.170g (1.976mmol) N-Boc-Trp-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 0.962g (97%) title compound (colorless solid).Mp 168-169 ℃; [α] D 25=72.5 (C=1.0, methyl alcohol); ESI-MS (m/z) 501[M-H] -
Embodiment 32N-Boc-Val-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (6k)
According to the operation of preparation 6a, from 1.403g (2.780mmol) N-Boc-Val-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 1.130g (98%) title compound (colorless solid).Mp 139-141 ℃; [α] D 25=66.2 (C=1.0, methyl alcohol); ESI-MS (m/z) 414[M-H] -
Embodiment 33N-Boc-Lys (Boc)-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (6l)
According to the operation of preparation 6a, from 1.0g (1.577mmol) N-Boc-Lys (Boc)-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 0.849g (99%) title compound (colorless solid).Mp 123-125 ℃; [α] D 25=18.6 (C=1.0, methyl alcohol); ESI-MS (m/z) 543[M-H] -
Embodiment 34N-Boc-Arg (NO 2)-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (6m)
According to the operation of preparation 6h, from 1.5g (2.479mmol) N-Boc-Arg (NO 2)-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 1.153g (90%) title compound (colorless solid).Mp 170-172 ℃; [α] D 25=27.7 (C=1.0, methyl alcohol); ESI-MS (m/z) 516[M-H] -
Embodiment 35N-Boc-Thr (Bzl)-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (6n)
According to the operation of preparation 6h, from 1.0g (1.675mmol) N-Boc-Thr (Bzl)-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 0.789g (93%) title compound (colorless solid).Mp 89-92 ℃; [α] D 25=39.1 (C=1.0, methyl alcohol); ESI-MS (m/z) 506[M-H] -
Embodiment 36N-Boc-Ser (Bzl)-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (6o)
According to the operation of preparation 6h, from 1.105g (1.895mmol) N-Boc-Ser (Bzl)-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 0.925g (99%) title compound (colorless solid).Mp 53-55 ℃; [α] D 25=30.9 (C=1.0, methyl alcohol); ESI-MS (m/z) 492[M-H] -
Embodiment 37N-Boc-Cys (CH 2-C 6H 4-OCH 3)-1,2,3,4-Tetrahydrocarboline-3-carboxylic acid (6p)
According to the operation of preparation 6h, from 1.20g (1.908mmol) N-Boc-Cys (CH 2-C 6H 4-OCH 3)-1,2,3,4-Tetrahydrocarboline-3-benzyl carboxylate gets 1.0g (97%) title compound (colorless solid).Mp 44-46 ℃; [α] D 25=-47.4 (C=1.0, methyl alcohol); ESI-MS (m/z) 538[M-H] -
Embodiment 381,2,3,4-Tetrahydrocarboline-3-acyl group-Asp (OBzl)-OBzl (6q)
In the round-bottomed flask of 100ml; with the 1ml ethyl acetate with 0.657g (1.075mmol) N-Boc-1; 2; 3; 4-Tetrahydrocarboline-3-acyl group-Asp (OBzl)-OBzl dissolving under the condition of ice bath, adds 2ml 4N HCl/ ethyl acetate stirring reaction; TLC plate detection reaction, termination reaction when raw material point disappears.Drain mother liquor, add ether and obtain 0.581g (98.6%) title compound (yellow solid) repeatedly for 3 times.M.p.93-95 ℃; [α] D 25=-55.5 (C=1.0, methyl alcohol); ESI-MS (m/z): 512.5[M+H] +
Embodiment 391,2,3,4-Tetrahydrocarboline-3-acyl group-Glu (OBzl)-OBzl (6r)
According to the operation of preparation 6q, from 0.671g (1.074mmol) N-Boc-1,2,3,4-Tetrahydrocarboline-3-acyl group-Glu (OBzl)-OBzl obtains 0.602g (99%) title compound (yellow solid).Mp 108-110 ℃; [α] D 25=-57.0 (C=1.0, methyl alcohol); ESI-MS (m/z): 526.5[M+H] +
Embodiment 40Boc-Ala-1,2,3,4-Tetrahydrocarboline-3-acyl group-Ala-OBzl (7a)
Ice bath descends with anhydrous THF 0.776g (2.0mmol) Boc-Ala-1,2,3, the dissolving of 4-Tetrahydrocarboline carboxylic acid, add 0.284g (2.104mmol) N-hydroxy benzo triazole (HOBt), dissolving back added 0.536g (2.60mmol) dicyclohexyl carbonyl diimine (DCC) after .10 minute fully, added anhydrous THF and 0.913g (2.60mmol) Ala-OBzl inward and with the solution between the N-methylmorpholine accent pH value 8-9.Reaction mixture stirs, and the detection of TLC plate (oil mystery/acetone, 3: 1, Rf=0.35).Raw material point leaches dicyclohexylurea (DCU) (DCU) after disappearing, and filtrate decompression concentrates, residue 40ml acetic acid ethyl dissolution.The solution that obtains is used saturated NaHCO successively 3, saturated NaCl, 5%KHSO 4, saturated NaCl, saturated NaHCO 3, saturated NaCl respectively gives a baby a bath on the third day after its birth time to neutral anhydrous Na 2SO 4Dry.Filter, filtrate decompression is concentrated into dried, obtains 0.709g (64.7%) title compound (colorless solid).M.p.:113-115.80 ℃; [α] D 25=-5.6 (C=1.0, methyl alcohol); ESI-MS (m/z): 549.4[M+H] +IR(KBr)：3313，2978，2931，1739，1678，1647，1520，1452，1246，1163，1065，744，693. 1HNMR(500MHz，DMSO-d 6)：δ/ppm＝10.806(s，1H)，8.374(t，J＝8.5Hz，1H)，7.094-7.439(m，7H)，7.05(t，J＝7Hz，1H)，6.9725(t，J＝6.5Hz，1H)，4.167-5.635(m，7H)，3.372(q，J＝15.5Hz，J＝46.5Hz，1H)，2.9285(m，J＝6Hz，1H)，1.405(s，9H)，1.225-1.338(m，6H). 13CNMR(DMSO-d 6)：δ/ppm＝172.58，172.43，171.10，156.22，155.50，136.34，130.17，128.79，128.35，128.07，126.93，121.26，118.90，111.43，105.03，79.00，78.63，66.22，48.63，33.81，28.62，24.92，23.41，17.15.
Embodiment 41Boc-Gly-1,2,3,4-Tetrahydrocarboline-3-acyl group-Gly-OBzl (7b)
According to the operation of preparation 7a, from 0.590g (1.582mmol) Boc-Gly-1,2,3,4-Tetrahydrocarboline carboxylic acid obtains 0.452g (54.95%) title compound (colorless solid).TLC (sherwood oil/acetone, 3: 1, Rf=0.4); Mp 114-116 ℃; [α] D 25=49.9 (C=1.0, methyl alcohol); ESI-MS (m/z): 521.6[M+H] +543.6[M+Na] +.IR (KBr): 3396,3302,2976,2931,1751,1685,1647,1521,1452,1390,1367,1161,744,690. 1HNMR (300MHz, DMSO-d 6): δ/ppm=10.817 (s, 1H), 8.4425 (m, J=5.4Hz, J=5.7Hz 1H), 7.3895 (d, J=7.5Hz, 1H), 7.258-7.377 (m, 6H), 7.047 (t, J=7.2Hz, 1H), 6.9655 (t, J=6.9Hz, 1H), and 4.329-5.021 (m, 5H), 3.739-4.164 (m, 4H), 3.3935 (m, J=2.7Hz, 1H), 2.9195 (dd, J=5.7Hz, J=15.9Hz, 1H), 1.404 (s, 9H). 13CNMR (DMSO-d 6): δ/ppm=171.04,170.61,170.56,156.22,136.77,136.52,130.58,129.85,128.84,128.46,128.35,126.98,118.93,111.54,105.39,78.58,66.34,65.36,54.25,42.96,41.51,28.70,22.74.
Embodiment 42Boc-Pro-1,2,3,4-Tetrahydrocarboline-3-acyl group-Pro-OBzl (7c)
According to the operation of preparation 7a, from 0.174g (0.421mmol) Boc-Pro-1,2,3,4-Tetrahydrocarboline carboxylic acid obtains 0.110g (43.5%) title compound (colorless solid).TLC (sherwood oil/acetone, 3: 1, Rf=0.2); Mp 100-103 ℃; [α] D 25=-156.2 (C=1.0, methyl alcohol); ESI-MS (m/z): 623.3[M+Na] +523.4[M+Na-Boc] +IR(KBr)：3330，2938，2850，1739，1689，1647，1452，1409，1165，743，693.
1HNMR(500MHz，CDCl3-d 6)：δ/ppm＝7.140-7.560(m，7H)，7.029-7.067(m，2H)，4.489-5.410(m，7H)，4.333(m，1H)，4.176(q，J＝4.5Hz，J＝11.5Hz，1H)，4.032(q，J＝3.5Hz，J＝6Hz，1H)，3.9125(q，J＝6.5Hz，J＝10.5Hz，1H)，3.430(m，J＝16Hz，1H)，2.827(dd，J＝6Hz，J＝5.5Hz，1H)，1.472(s，9H)，1.231-1.360(m，3H)，0.979-1.223(m.3H)，0.887-0.90(d，J＝6.5Hz，2H). 13CNMR(DMSO-d 6)：δ/ppm＝171.30，170.44，169.91，156.82，137.78，136.52，135.32，128.54，128.19，127.96，126.91，121.97，119.60，110.84，106.20，80.03，75.93，74.29，71.47，59.10，56.89，42.59，33.97，30.87，28.79，28.31，24.94，23.02，22.15.
Embodiment 43Boc-Gln-1,2,3,4-Tetrahydrocarboline-3-acyl group-Gln-OBzl (7d)
According to the operation of preparation 7a, from 0.707g (1.60mmol) Boc-Gln-1,2,3,4-Tetrahydrocarboline carboxylic acid obtains 0.325g (30.68%) title compound (colorless solid).TLC (chloroform/methanol, 10: 1, Rf=0.2); Mp 114-117 ℃; [α] D 25=16.7 (C=1.0, methyl alcohol); ESI-MS (m/z): 663.3[M+H] +.IR (KBr): 3334,2940,2856,1750,1662,1627,1520,1450,1166,743,697. 1HNMR (300MHz, CDCl 3-d 6): δ/ppm=7.207-7.487 (m, 7H), 7.037-7.085 (m, 2H), 4.493 (m, 1H), 4.908-5.120 (m, 4H), 5.711-5.811 (m, 2H), 3.5825 (m, J=5.4Hz, 1H), 3.087 (dd, J=5.5Hz, J=15.5Hz, 1H), 2.190-2.400 (m, 8H), 1.4195 (s, 9H). 13CNMR (DMSO-d 6): δ/ppm=174.56,173.97,172.83,171.87,170.34,156.72,136.77,136.56,130.19,128.80,128.36,128.12,127.96,126.84,121.26,118.90,118.03,111.49,105.00,79.64,66.25,65.37,52.74,51.43,31.68,31.04,29.44,28.67,27.62,26.79,23.04.
Embodiment 44Boc-Leu-1,2,3,4-Tetrahydrocarboline-3-acyl group-Leu-OBzl (7e)
According to the operation of preparation 7a, from 0.387g (0.902mmol) Boc-Leu-1,2,3,4-Tetrahydrocarboline carboxylic acid obtains 0.252g (44.2%) title compound (colorless solid).TLC (sherwood oil/acetone, 3: 1, Rf=0.3); Mp 81.9-83.2 ℃; [α] D 25=27.4 (C=1.0, methyl alcohol); ESI-MS (m/z): 633.6[M+H] +.IR (KBr): 3313,2956,2931,1739,1680,1643,1521,1435,1165,744,697. 1HNMR (500MHz, DMSO-d 6): δ/ppm=7.233-7.710 (m, 7H), 7.084-7.1475 (m, 2H), 4.436-4.895 (m, 2H), 4.90-5.230 (m, 4H), 5.255-5.524 (m, 1H), 3.505 (m, J=15Hz, J=15.3Hz, 1H), 2.8558 (dd, J=4.5Hz, J=5.1Hz, 1H), 2.191-2.193 (m, 6H), 1.444 (s, 9H), 0.668-1.276 (m, 12H). 13CNMR (DMSO-d 6): δ/ppm=173.30,172.54,169.20,168.26,156.83,136.31,135.56,128.64,128.57,128.32,127.86,121.90,119.58,110.83,106.24,80.52,66.81,66.65,55.60,41.25,40.50,30.88,28.44,23.33,22.83,21.91,21.38.
Embodiment 45Boc-Phe-1,2,3,4-Tetrahydrocarboline-3-acyl group-Phe-OBzl (7f)
According to the operation of preparation 7a, from 0.744g (1.61mmol) Boc-Phe-1,2,3,4-Tetrahydrocarboline carboxylic acid obtains 0.520g (46.14%) title compound (colorless solid).TLC (sherwood oil/acetone, 3: 1, Rf=0.3); Mp 94-97 ℃; [α] D 25=-10.9 (C=1.0, methyl alcohol); ESI-MS (m/z): 701.7[M+H] +.IR (KBr): 3292,2952,2890,1735,1685,1642,1521,1454,1166,1030,742,697. 1HNMR (500MHz, CDCl 3-d 6): δ/ppm=7.171-7.323 (m, 17H), 7.017-7.091 (m, 2H), 4.652-4.754 (m, 2H), 4.759-4.986 (m, H), 4.990-5.107 (m, 1H), 5.129-5.202 (m, 2H), 5.134-5.410 (m, 1H), 2.894-3.502 (m, 6H), 1.4795 (s, 9H). 13CNMR (DMSO-d 6): δ/ppm=172.06,171.34,168.98,156.16,154.63,136.89,136.26,135.81,129.63,128.96,128.66,127.92,126.96,126.65,122.40,122.08,119.61,110.64,106.24,80.27,67.45,66.93,53.48,52.44,38.77,37.59,36.81,28.56,21.13.
Embodiment 46Boc-Ile-1,2,3,4-Tetrahydrocarboline-3-acyl group-Ile-OBzl (7g)
According to the operation of preparation 7a, from 0.551g (1.284mmol) Boc-Ile-1,2,3,4-Tetrahydrocarboline carboxylic acid obtains 0.541g (66.65%) title compound (colorless solid).TLC (sherwood oil/acetone, 3: 1, Rf=0.3); Mp 96-98 ℃; [α] D 25=-1.0 (C=1.0, methyl alcohol); ESI-MS (m/z): 633.6[M+H] +.IR (KBr): 3315,2964,2856,1735,1680,1624,1521,1454,1431,1165,1020,743,699. 1HNMR (500MHz, DMSO-d 6): δ/ppm=7.488 (dd, J=8Hz, 1H), 7.258-7.467 (m, 6H), 7.151 (m, 1H), 7.1025 (t, J=7.5Hz, 1H), 4.436-5.239 (m, 7H), 3.4925 (m, J=9.3Hz, 1H), 2.958 (dd, J=5.7Hz, J=15HZ, 1H), 2.201 (s, 1H), 1.676 (s, 1H), 1.4395 (s, 9H), 1.067-1.399 (m, 4H), 0.756-0.973 (m, 12H). 13CNMR (DMSO-d 6): δ/ppm=173.29,172.85,169.07,156.22,155.45,136.41,135.29,128.59,128.54,128.39,126.82,125.06,119.62,111.47,109.87,80.24,67.19,66.96,55.90,52.19,38.78,37.92,36.53,28.33,25.42,24.85,23.41,22.82,22.42,16.01,15.89.
Embodiment 47Boc-Met-1,2,3,4-Tetrahydrocarboline-3-acyl group-Met-OBzl (7h)
According to the operation of preparation 7a, from 0.332g (0.743mmol) Boc-Met-1,2,3,4-Tetrahydrocarboline carboxylic acid obtains 0.090g (18.15%) title compound (colorless solid).TLC (sherwood oil/acetone, 3: 1, Rf=0.25); Mp 73-75 ℃; [α] D 25=-18.2 (C=1.0, methyl alcohol); ESI-MS (m/z): 691.4[M+Na] +591.1[M+Na-Boc] +.IR (KBr): 3315,2985,2917,1735,1691,1648,1526,1441,1167,1042,747,693. 1HNMR (500MHz, CDCl 3-d 6): δ/ppm=7.487 (dd, J=7.5Hz, J=8Hz, 1H), 7.251-390 (m, 6H), 7.054 (t, J=7.5Hz, 1H), 6.9815 (t, J=7.5Hz, 1H), 5.451 (m, 1H), 5.316 (dd, J=7Hz, J=5.5Hz, 1H), 5.006-5.164 (m, 3H), 4.8515 (m, 1H), 4.5725 (m, 1H), 3.3945 (dd, J=9.3Hz, J=9.5Hz, 1H), 2.976 (dd, J=4.5Hz, J=5.0Hz, 1H), 2.661 (t, J=7Hz, 1H), 2.5815 (t, J=6.5Hz, 1H), 2.413 (m, 1H), 2.2775 (t, J=7Hz, 1H), 2.136-2.200 (m, 4H), 1.997-2.100 (m, 2H), 1.889-1.967 (m, 4H), 1.3775 (s, 9H). 13CNMR (DMSO-d 6): δ/ppm=172.49,171.42,171.33,156.56,136.58,136.43,135.57,128.65,128.60,128.36,127.86,122.73,119.68,110.96,106.37,80.77,67.50,66.99,55.72,52.29,50.24,31.70,30.88,29.77,28.33,22.64,15.63,15.26.
Embodiment 48Boc-Tyr-1,2,3,4-Tetrahydrocarboline-3-acyl group-Tyr-OBzl (7i)
According to the operation of preparation 7a, from 0.586g (1.220mmol) Boc-Tyr-1,2,3,4-Tetrahydrocarboline carboxylic acid obtains 0.247g (27.66%) title compound (colorless solid).TLC (sherwood oil/acetone, 2: 1, Rf=0.25); Mp 135-139 ℃; [α] D 25=1.1 (C=1.0, methyl alcohol); ESI-MS (m/z): 733.4[M+H] +, 755.7[M+Na] +.IR (KBr): 3398,2970,2855,1730,1690,1640,1520,1448,1228,1168,1020,744,699. 1HNMR (500MHz, CDCl 3-d 6): δ/ppm=7.310-7.790 (m, 7H), 6.620-7.206 (m, 10H), 5.955 (m, 1H), 5.586 (m, 1H), and 4.955-5.360 (m, 3H), 4.410-4.80 (m, 2H), 3.215 (d, J=15Hz, 1H), 2.785-3.105 (m, 5H), 1.4045 (s, 9H). 13CNMR (DMSO-d 6): δ/ppm=173.39,171.69,168.94,155.88,155.35,136.11,135.60,130.57,128.64,128.55,128.08,127.34,126.51,125.25,121.43,118.97,115.77,110.90,105.94,80.81,67.09,56.20,54.23,52.52,41.37,38.75,37.84,28.42,22.64.
Embodiment 49Boc-Trp-1,2,3,4-Tetrahydrocarboline-3-acyl group-Trp-OBzl (7j)
According to the operation of preparation 7a, from 0.461g (0.918mmol) Boc-Trp-1,2,3,4-Tetrahydrocarboline carboxylic acid obtains 0.535g (74.9%) title compound (colorless solid).TLC (sherwood oil/acetone, 3: 1, Rf=0.25); Mp 128-130 ℃; [α] D 25=25.2 (C=1.0, methyl alcohol); ESI-MS (m/z): 801.9[M+Na] +701.5[M+Na-Boc] +.IR (KBr): 3404,3323,2956,2856,1735,1647,1624,1496,1456,1234,1163,1010,767,693. 1HNMR (500MHz, DMSO-d 6): δ/ppm=7.599 (dd, J=7.5Hz, J=5.4Hz, 1H), 6.877-7.510 (m, 18H), 5.1075 (d, J=17.1Hz, 1H), 4.360-5.098 (m, 6H), 3.590 (m, 1H), 2.950-3.395 (m, 4H), 2.892 (m, 1H), 1.3385 (s, 9H). 13CNMR (DMSO-d 6): δ/ppm=172.78,171.88,169.87,156.46,155.35,136.61,136.45,130.22,129.61,128.72,128.08,127.89,127.57,124.54,123.97,121.47,118.95,111.34,110.71,109.86,79.32,78.59,66.28,55.22,54.53,41.82,38.58,28.69,21.69.
Embodiment 50Boc-Val-1,2,3,4-Tetrahydrocarboline-3-acyl group-Val-OBzl (7k)
According to the operation of preparation 7a, from 0.550g (1.330mmol) Boc-Val-1,2,3,4-Tetrahydrocarboline carboxylic acid obtains 0.40g (43.8%) title compound (colorless solid).TLC (sherwood oil/acetone, 3: 1, Rf=0.3); Mp 99.6-101 ℃; [α] D 25=-4.7 (C=1.0, methyl alcohol); ESI-MS (m/z): 627.5[M+Na] +527.5[M+Na-Boc] +.IR (KBr): 3327,2966,2933,1732,1678,1624,1500,1456,1367,1236,1166,1020,740,699. 1HNMR (500MHz, DMSO-d 6): δ/ppm=7.033-7.510 (m, 7H), 7.103 (t, J=8.5Hz, 1H), 6.9645 (t, J=7.5Hz, 1H), 5.510 (m, 1H), 5.215 (m, 1H), 4.876-5.098 (m, 3H), 4.420 (m, 1H), 4.151 (m, 1H), 3.395 (m, 1H), 2.987 (m, 1H), 2.212-2.052 (m, 2H), 1.366 (s, 9H), 0.793-0.943 (m, 12H). 13CNMR (DMSO-d 6): δ/ppm=173.19,172.81,170.58,156.46,156.14,136.69,130.54,128.82,128.48,128.39,126.99,121.30,118.91,111.42,104.74,78.91,66.29,58.51,57.64,56.65,39.18,30.57,30.15,28.63,22.99,19.77,18.90.
Embodiment 51Boc-Lys (Boc)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Lys (Z)-OBzl (7l)
According to the operation of preparation 7a, from 0.493g (0.906mmol) Boc-Lys (Boc)-1,2,3,4-Tetrahydrocarboline carboxylic acid obtains 0.408g (50.24%) title compound (colorless solid).TLC (oil mystery/acetone, 2: 1, Rf=0.3); Mp 82.6-84.6 ℃; [α] D 25=1.3 (C=1.0, methyl alcohol); ESI-MS (m/z): 898.0[M+H] +.IR (KBr): 3313,2974,2935,1735,1678,1643,1517,1456,1365,1248,1168,1040,742,697. 1HNMR (500MHz, DMSO-d 6): δ/ppm=7.210-7.580 (m, 12H), 7.010-7.198 (m, 2H), 5.048-5.298 (m, 6H), 4.899 (m, 1H), 4.398-4.750 (m, 2H), 3.502 (m, 1H), 3.026-3.310 (m, 4H), 2.958 (m, 1H), 1.650-1.910 (m, 4H), 1.522-1.610 (m, 4H), 1.448 (s, 18H), 0.8-1.391 (m, 4H). 13CNMR (DMSO-d 6): δ/ppm=172.92,171.91,169.94,156.57,156.21,155.77,136.64,135.16,128.64,128.56,128.07,123.01,121.78,119.75,118.21,110.90,80.35,67.36,66.84,66.32,55.83,52.42,42.22,40.89,31.86,30.89,29.88,28.40,22.59,21.85.
Embodiment 52Boc-Arg (NO2)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Arg (NO2)-OBzl (7m)
According to the operation of preparation 7a, from 1.14g (2.220mmol) Boc-Arg (NO 2)-1,2,3,4-Tetrahydrocarboline carboxylic acid obtains 0.770g (42.9%) title compound (yellow solid).TLC (chloroform/methanol, 10: 1, Rf=0.2); Mp131-133.2 ℃; [α] D 25=4.2 (C=1.0, methyl alcohol); ESI-MS (m/z): 809.3[M+H] +.IR (KBr): 3304,2939,2856,1735,1624,1533,1445,1259,1161,740,693. 1HNMR (300MHz, DMSO-d 6): δ/ppm=7.137-7.405 (m, 7H), 7.0425 (t, J=7.8Hz, 1H), 6.9635 (m, 1H), 4.610-5.810 (m, 5H), and 4.12-4.528 (m, 2H), 3.3975 (q, J=7.2Hz, J=14.1Hz, 1H), 3.03-3.270 (m, 4H), 2.932 (m, 1H), 1.374-1.980 (m, 8H), 1.3675 (s, 9H). 13CNMR (DMSO-d 6): δ/ppm=172.93,172.42,170.24,159.8,156.61,155.94,136.74,130.22,128.81,128.39,127.46,121.27,118.92,118.01,111.45,105.06,79.17,66.33,65.36,52.86,51.42,50.82,29.05,28.62,25.30,23.81,21.20.
Embodiment 53Boc-Thr (Bzl)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Thr (Bzl)-OBzl (7n)
According to the operation of preparation 7a, from 0.777g (1.53mmol) Boc-Thr (Bzl)-1,2,3,4-Tetrahydrocarboline carboxylic acid obtains 0.416g (34.5%) title compound (colorless solid).TLC (sherwood oil/acetone, 3: 1, Rf=0.2); Mp 184-186 ℃; [α] D 25=6.4 (C=1.0, methyl alcohol); ESI-MS (m/z): 811.8[M+Na] +711.6[M+Na-Boc] +.IR (KBr): 3305,2974,2856,1735,1678,1647,1525,1452,1286,1163,1104,736,697. 1HNMR (500MHz, CDCl 3-d 6): δ/ppm=7.160-7.387 (m, 17H), 7.045-7.092 (m, 2H), 4.767-5.128 (m, 9H), 4.466-4.667 (m, J=4.5Hz, 2H), and 3.805-4.210 (m, 2H), 3.310 (m, 1H), 2.6335 (m, J=15.5Hz, 1H), 1.541 (s, 9H), 1.447-1.462 (m, 6H). 13CNMR (DMSO-d 6): δ/ppm=172.96,171.73,169.91,156.94,153.79,137.77,136.65,135.31,129.33,128.81,128.73,128.20,127.96,126.71,123.96,121.83,119.46,110.99,104.29,79.99,79.64,74.52,71.49,67.09,66.89,59.93,33.89,28.80,24.99,23.61,22.63,16.12.
Embodiment 54Boc-Ser (Bzl)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Ser (Bzl)-OBzl (7o)
According to the operation of preparation 7a, from 0.951g (1.93mmol) Boc-Ser (Bzl)-1,2,3,4-Tetrahydrocarboline carboxylic acid obtains 0.733g (49.97%) title compound (colorless solid).TLC (sherwood oil/acetone, 3: 1, Rf=0.3); Mp 105-108 ℃; [α] D 25=6.5 (C=1.0, methyl alcohol); ESI-MS (m/z): 784.6[M+Na] +684.3[M+Na-Boc] +.IR (KBr): 3330,2985,2856,1736,1685,1620,1520,1452,1165,1110,744,693. 1HNMR (500MHz, CDCl 3-d 6): δ/ppm=7.236-7.528 (m, 17H), 7.086-7.111 (m, 2H), 5.5005 (dd, J=8Hz, J=6Hz, 1H), 4.899-5.327 (m, 4H), 4.54-4.890 (m, 2H), 4.265-4.50 (m, 4H), 3.587-3.930 (m, 4H), 3.433 (m, 1H), 2.828 (dd, J=4.5Hz, J=5Hz, 1H), 1.430 (s, 9H). 13CNMR (DMSO-d 6): δ/ppm=171.72,170.17,169.78,155.71,154.68,137.53,136.47,135.33,129.78,128.52,128.33,128.13,128.00,127.91,127.83,127.65,122.70,121.86,119.73,111.47,107.62,80.35,73.63,73.08,70.95,69.72,69.25,67.88,53.04,52.83,38.98,28.79,22.59.
Embodiment 55Boc-Cys (CH2-C6H4-OCH3)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Cys (But)-OBzl (7p)
According to the operation of preparation 7a, from 1.426g (2.65mmol) Boc-Cys (CH 2-C 6H 4-OCH 3)-1,2,3,4-Tetrahydrocarboline carboxylic acid obtains 0.687g (32.9%) title compound (colorless solid).TLC (sherwood oil/acetone, 3: 1, Rf=0.3); Mp 72.3-74 ℃; [α] D 25=-14.7 (C=1.0, methyl alcohol); ESI-MS (m/z): 789.4[M+H] +811.6[M+Na] +.IR (KBr): 3330,2985,2857,1735,1685,1640,1526,1450,1256,1165,1040,743,693. 1HNMR (500MHz, DMSO-d 6): δ/ppm=7.317-7.450 (m, 7H), 7.098-7.288 (m, 5H), 6.992 (m, 1H), 5.149 (d, J=4Hz, 2H), 4.854 (m, 1H), 4.752 (m, 1H), 4.651 (m, 1H), 4.411-4.448 (m, 2H), 3.905 (s, 3H), 3.7735 (d, J=4.5Hz, 2H), 3.503 (m, 1H), 2.935-3.215 (m, 4H), 2.893 (m, 1H), 1.474 (s, 9H), 1.1945 (m, 9H). 13CNMR (DMSO-d 6): δ/ppm=172.23,171.53,170.03,168.78,158.42,154.89,136.56,130.73,130.15,128.55,128.12,127.22,126.70,122.10,121.92,119.64,114.43,110.89,107.25,80.14,67.37,67.15,55.81,55.29,55.23,50.49,42.66,36.25,34.54,33.96,28.33,24.94,21.41.
Embodiment 56Boc-Asp (OBzl)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Asp (OBzl)-OBzL (7q)
According to the operation of preparation 7a, from 0.588g (1.074mmol) 1,2,3,4-Tetrahydrocarboline-3-acyl group-Asp (OBzl)-OBzl obtains 0.385g (43.93%) title compound (colorless solid).TLC (sherwood oil/acetone, 2: 1, Rf=0.3); Mp 62-65 ℃; [α] D 25=4.5 (C=1.0, methyl alcohol); ESI-MS (m/z): 817.5[M+H] +.IR (KBr): 3331,2986,2855,1735,1685,1620,1521,1452,1160,1010,744,697. 1HNMR (500MHz, DMSO-d 6): δ/ppm=7.115-7.450 (m, 17H), 7.106 (m, 1H), 7.0895 (m, J=8.5Hz, 1H), 5.610 (m, 1H), and 5.007-5.410 (m, 8H), 4.820 (d, J=12.5Hz, 1H), 4.630 (m, 1H), 3.725 (m, 1H), 2.842-3.305 (m, 4H), 2.645 (m, 1H), 1.401 (s, 9H). 13CNMR (DMSO-d 6): δ/ppm=172.12,171.86,170.71,170.19,169.96,154.89,136.52,135.47,129.55,128.78,128.52,128.30,127.98,122.72,122.10,119.65,111.46,107.54,80.72,67.67,66.24,49.44,48.96,41.97,37.96,36.44,28.24,22.41.
Embodiment 57Boc-Glu (OBzl)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Glu (OBzl)-OBzL (7r)
According to the operation of preparation 7a, from 0.465g (1.38mmol) 1,2,3,4-Tetrahydrocarboline-3-acyl group-Glu (OBzl)-OBzl obtains 0.323g (36.13%) title compound (colorless solid).TLC (sherwood oil/acetone, 2: 1, Rf=0.3); Mp 156-158 ℃; [α] D 2 5=14.9 (C=1.0, methyl alcohol); ESI-MS (m/z): 845.2[M+H] +.IR (KBr): 3320,3200,1724,1680,1630,1520,1452,1230,1168,744,693. 1HNMR (500MHz, DMSO-d 6): δ/ppm=7.230-7.502 (m, 17H), 7.092-7.1165 (m, 2H), 5.215-5.610 (m, 2H), 5.110-5.205 (m, 2H), 4.995-5.055 (m, 5H), 5.714 (m, 1H), 5.510 (m, 1H), 3.510 (m, 1H), 2.899 (m, 1H), 2.087-2.634 (m, 8H), 1.4105 (m, 9H). 13CNMR (DMSO-d 6): δ/ppm=171.72,170.17,169.78,155.71,154.68,137.53,136.47,135.33,129.78,128.52,128.33,128.13,128.00,127.91,127.83,127.65,122.70,121.86,119.73,111.47,107.62,80.35,73.63,73.08,70.95,69.72,69.25,67.88,53.04,52.83,38.98,28.99,22.59.
Embodiment 58 HClNH2Ala-1,2,3,4-Tetrahydrocarboline-3-acyl group-Ala-OBzl (8a)
0.10g Boc-Ala-KLSS-Ala-OBzl (0.18mmol) is dissolved in the 2ml ethyl acetate, adds hydrogenchloride-ethyl acetate solution of 1ml again in the solution that obtains.TLC (oil mystery/acetone, 3: 1, Rf=0.3) detect, raw material point disappearance stopped reaction, drain solvent after, add the 10ml ether and drain, repeats 3 times after the grinding of adding 10ml ether filter 0.085g (96.14%) title compound (yellow solid).M.p.:146-148 ℃; [α] D 25=1.4 (C=1.0, methyl alcohol); ESI-MS (m/z): 449.5[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=10.99 (m, 1H), 8.75 (m, 1H), 8.40 (m, 2H), 7.75-7.50 (m, 7H), 7.05 (m, 1H), 6.95 (m, 1H), 5.65 (m, J=5Hz, 1H), 5.15 (m, 1H), 4.85-5.05 (m, 2H), 4.65 (m, 1H), 4.30 (m, 1H), 3.70 (m, 1H), 3.35 (m, J=10Hz, 1H), 3.05 (m, J=5Hz, 1H), 1.45-1.50 (m, 3H), 1.30-1.38 (m, 3H). 13CNMR (DMSO-d 6): δ/ppm=172.48,170.75,169.76,136.79,136.30,130.18,129.67,128.78,128.11,126.88,121.41,119.15,118.01,111.62,104.48,67.42,66.29,50.92,47.98,33.80,28.64,21.54,17.42.
Embodiment 59HClNH2Gly-1,2,3,4-Tetrahydrocarboline-3-acyl group-Gly-OBzl (8b)
According to the operation of preparation 8a, from 0.089g (0.17mmol) Boc-Gly-1,2,3,4-Tetrahydrocarboline-3-acyl group-Gly-OBzl obtains 0.077g (97.8%) title compound (yellow solid).Mp 148-151 ℃; [α] D 25=52.8 (C=1.0, methyl alcohol); ESI-MS (m/z): 421.4[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=11.120 (s, 1H), 8.75 (m, J=9.5Hz, 1H), 8.35 (s, 2H), 7.21-7.51 (m, 7H), 7.05 (t, J=11.5Hz, 1H), 6.95 (t, J=15.5Hz, 1H), 5.68 (m, J=9.5Hz, 1H), 5.05 (m, 2H), 4.85 (s, 1H), 4.05-4.51 (m, 2H), 3.75-3.98 (m, 3H), 3.45 (m, J=11.5Hz, 1H), 2.98 (m, J=10.5Hz, 1H). 13CNMR (DMSO-d 6): δ/ppm=172.45,170.28,167.76,136.77,136.29,129.87,129.36,128.66,128.35,126.76,121.45,118.97,118.04,111.55,105.14,66.38,54.46,51.38,23.27,21.56.
Embodiment 60HClNH2Pro-1,2,3,4-Tetrahydrocarboline-3-acyl group-Pro-OBzl (8c)
According to the operation of preparation 8a, from 0.13g (0.22mmol) Boc-Pro-1,2,3,4-Tetrahydrocarboline-3-acyl group-Pro-OBzl obtains 0.110g (94.63%) title compound (yellow solid).Mp 113-115 ℃; [α] D 25=-61.4 (C=1.0, methyl alcohol); ESI-MS (m/z): 501.4[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=10.45 (m, 1H), 8.56 (s, 1H), 7.21-7.46 (m, 7H), 7.05 (t, 1H), 6.98 (t, J=10Hz, 1H), 5.55 (m, 1H), 5.15 (m, 1H), 4.15-4.95 (m, 2H), 4.18-4.52 (m, 2H), 4.05 (m, 1H), and 3.60-3.85 (m, 2H), 2.89-3.35 (m, 4H), 2.25 (m, 1H), 1.5-2.05 (m, 7H). 13CNMR (DMSO-d 6): δ/ppm=171.81,169.77,169.10,136.74,136.25,129.53,129.34,128.97,128.15,126.72,121.76,118.98,118.01,111.64,104.05,67.73,66.20,59.15,58.94,47.97,42.18,33.80,29.58,28.21,25.29,24.91,21.98.
Embodiment 61HClNH2Gln-1,2,3,4-Tetrahydrocarboline-3-acyl group-Gln-OBzl (8d)
According to the operation of preparation 8a, from 0.08g (0.12mmol) Boc-Gln-1,2,3,4-Tetrahydrocarboline-3-acyl group-Gln-OBzl obtains 0.072g (98.92%) title compound (yellow solid).Mp 147-149 ℃; [α] D 25=14.3 (C=1.0, methyl alcohol); ESI-MS (m/z): 563.4[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=10.99 (d, J=10Hz, 1H), 8.75 (m, J=10Hz, 1H), 8.45-8.55 (m, 4H), 7.15-7.52 (m, 7H), 7.05 (t, J=10Hz, 1H), 6.89 (t, J=5Hz, 1H), 5.65 (m, J=5Hz, 1H), 5.15 (m, J=15Hz, 1H), 4.75-4.92 (m, 2H), 4.45-4.65 (m, 2H), 4.20 (m, 1H), 3.38 (m, J=10Hz, J=5Hz, 1H), 3.05 (m, J=5Hz, 1H), 2.05-2.30 (m, 8H). 13CNMR (DMSO-d 6): δ/ppm=174.13,172.40,171.78,170.96,169.97,136.80,136.31,130.10,129.60,128.79,128.15,126.87,121.40,118.95,117.92,111.92,104.71,66.31,54.20,52.71,50.09,31.88,31.65,30.43,30.04,26.69,21.54.
Embodiment 62HClNH2Leu-1,2,3,4-Tetrahydrocarboline-3-acyl group-Leu-OBzl (8e)
According to the operation of preparation 8a, from 0.155g (0.245mmol) Boc-Leu-1,2,3,4-Tetrahydrocarboline-3-acyl group-Leu-OBzl obtains 0.131g (93.95%) title compound (yellow solid).Mp 101-103 ℃; [α] D 25=28.9 (C=1.0, methyl alcohol); ESI-MS (m/z): 533.5[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=11.05 (m, 1H), 8.30-8.89 (m, 3H), 7.16-7.37 (m, 7H), 6.89-7.09 (m, J=5Hz, 2H), 5.65 (m, J=5Hz, 1H), and 4.95-5.15 (m, 2H), 4.85 (m, J=10Hz, 1H), 4.65 (m, 1H), 4.33 (m, 1H), 4.05 (m, 1H), 3.46 (m, 1H), 2.95 (m, 1H), 1.25-1.71 (m, 6H), 0.57-0.99 (m, 12H). 13CNMR (DMSO-d 6): δ/ppm=172.72,172.38,170.60,136.80,136.20,129.88,128.95,128.77,128.30,126.64,121.30,118.97,117.97,111.40,104.67,66.47,51.65,51.06,50.80,49.45,42.30,33.80,28.64,25.81,24.90,24.64,22.03,21.53.
Embodiment 63HClNH2Phe-1,2,3,4-Tetrahydrocarboline-3-acyl group-Phe-OBzl (8f)
According to the operation of preparation 8a, from 0.12g (0.17mmol) Boc-Phe-1,2,3,4-Tetrahydrocarboline-3-acyl group-Phe-OBzl obtains 0.108g (99.44%) title compound (yellow solid).Mp 122-124 ℃; [α] D 25=10.5 (C=1.0, methyl alcohol); ESI-MS (m/z): 601.4[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=11.01 (m, 1H), 8.25-8.81 (m, 3H), 7.16-7.44 (m, 17H), and 6.88-7.10 (m, 2H), 5.67 (m, 1H), 5.21 (m, J=5Hz, 1H), 5.05 (m, J=5Hz, 1H), 4.89-5.01 (m, 2H), 4.68 (m, J=15Hz, 1H), 3.81 (m, 1H), 2.89-3.36 (m, 6H). 13CNMR (DMSO-d 6): δ/ppm=172.70,171.37,169.90,137.75,136.20,136.12,130.36,129.89,129.70,129.06,128.89,128.80,129.68,128.21,127.78,127.00,126.86,126.76,121.30,118.88,117.94,111.45,104.35,66.62,66.52,65.36,54.70,54.37,36.74,36.61,21.53.
Embodiment 64HClNH2-Ile-1,2,3,4-Tetrahydrocarboline-3-acyl group-Ile-OBzl (8g)
According to the operation of preparation 8a, from 0.12g (0.19mmol) Boc-Ile-1,2,3,4-Tetrahydrocarboline-3-acyl group-Ile-OBzl obtains 0.105g (97.28%) title compound (yellow solid).Mp 94-96 ℃; [α] D 25=-0.8 (C=1.0, methyl alcohol); ESI-MS (m/z): 533.5[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=11.00 (m, 1H), 8.70 (m, 1H), 8.20-8.45 (m, 2H), 7.15-7.54 (m, 7H), 6.89-7.12 (m, J=10Hz, 2H), 5.87 (m, J=5Hz, 1H), 5.01-5.29 (m, J=10Hz, 2H), 4.81-5.00 (m, J=15Hz, 2H), 4.15-4.4 (m, J=5Hz, 2H), and 2.89-3.45 (m, J=15Hz, 3H), 2.05 (m, 1H), 1.25-1.40 (m, 4H), 0.75-0.98 (m, 12H). 13CNMR (DMSO-d 6): δ/ppm=172.36,171.42,169.76,136.76,136.18,129.97,128.95,128.90,128.37,126.70,121.40,119.02,117.83,111.61,104.24,66.43,57.11,55.00,50.76,36.90,36.63,36.01,28.63,25.42,25.03,23.73,21.25,15.59,11.75.
Embodiment 65HClNH2-Met-1,2,3,4-Tetrahydrocarboline-3-acyl group-Met-OBzl (8h)
According to the operation of preparation 8a, from 0.10g (0.15mmol) Boc-Met-1,2,3,4-Tetrahydrocarboline-3-acyl group-Met-OBzl obtains 0.089g (98.91%) title compound (yellow solid).Mp 103-105 ℃; [α] D 25=-7.5 (C=1.0, methyl alcohol); ESI-MS (m/z): 569.4[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=11.00 (m, 1H), 8.40-8.99 (m, 3H), 7.16-7.44 (m, 7H), 6.97-7.05 (m, J=5Hz, 1H), and 7.08-7.11 (m, 1H), 5.47 (m, J=10Hz, 1H), 5.17 (m, 1H), 4.82-5.05 (m, 2H), 4.63 (m, J=5Hz, 1H), 4.38 (m, 1H), 3.58 (m, 1H), 3.35 (m, 1H), 3.05 (m, J=5Hz, 1H), 2.58-2.80 (m, 2H), 2.26-2.48 (m, 2H), 2.11-2.20 (m, 2H), 2.03-2.09 (m, 2H), 1.84-2.02 (m, 6H). 13CNMR (DMSO-d 6): δ/ppm=171.61,171.15,169.92,136.80,136.22,130.10,129.54,128.88,128.21,126.85,121.46,119.04,118.04,111.62,104.48,67.66,66.40,54.33,51.24,33.80,30.84,30.35,30.13,29.92,23.92,14.99.
Embodiment 66HClNH2-Tyr-1,2,3,4-Tetrahydrocarboline-3-acyl group-Tyr-OBzl (8i)
According to the operation of preparation 8a, from 0.15g (0.205mmol) Boc-Tyr-1,2,3,4-Tetrahydrocarboline-3-acyl group-Tyr-OBzl obtains 0.134g (97.67%) title compound (yellow solid).Mp 157-159 ℃; [α] D 25=8.1 (C=1.0, methyl alcohol); ESI-MS (m/z): 633.5[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=10.96 (m, 1H), 9.45 (m, 2H), 8.25-8.65 (m, 3H), and 7.25-7.45 (m, 5H), 7.11-7.25 (m, 3H), 6.89-7.10 (m, 5H), 6.65-6.78 (m, 4H), 5.69 (m, J=10Hz, 1H), 5.05 (m, 1H), 4.45-4.95 (m, 3H), and 4.21-4.35 (m, 2H), 3.30 (m, J=15Hz, 1H), 2.89-3.15 (m, 5H). 13CNMR (DMSO-d 6): δ/ppm=172.40,171.48,169.85,157.30,156.56,136.74,136.53,131.24,130.48,129.83,128.76,127.54,126.76,124.67,121.42,119.00,115.92,115.70,111.61,104.41,66.39,60.21,55.01,54.65,42.04,36.18,24.09,21.53.
Embodiment 67HClNH2-Trp-1,2,3,4-Tetrahydrocarboline-3-acyl group-Trp-OBZl (8j)
According to the operation of preparation 8a, from 0.07g (0.0899mmol) Boc-Trp-1,2,3,4-Tetrahydrocarboline-3-acyl group-Trp-OBzl obtains 0.064g (98.77%) title compound (brown solid).Mp 160-162 ℃; [α] D 25=45.0 (C=1.0, methyl alcohol); ESI-MS (m/z): 679.5[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=10.89-11.15 (m, 3H), 8.52-8.79 (m, 2H), 8.25 (s, 1H), 7.15-7.57 (m, 10H), 6.89-7.11 (m, 9H), 5.12 (m, 1H), 4.99 (m, 1H), 4.67-4.89 (m, 2H), 4.25-4.62 (m, 2H), 3.40 (m, 1H), 2.89-3.35 (m, 6H). 13CNMR (DMSO-d 6): δ/ppm=172.44,171.43,169.97,136.80,136.74,136.10,130.02,129.80,128.85,128.11,127.53,126.73,121.57,119.02,118.34,112.05,111.45,109.60,104.39,66.36,60.22,54.49,50.91,41.91,27.65,26.22,21.23.
Embodiment 68HClNH2-Val-1,2,3,4-Tetrahydrocarboline-3-acyl group-Val-OBzl (8k)
According to the operation of preparation 8a, from 0.15g (0.25mmol) Boc-Val-1,2,3,4-Tetrahydrocarboline-3-acyl group-Val-OBzl obtains 0.030g (96.96%) title compound (yellow solid).Mp 131-133 ℃; [α] D 25=-1.7 (C=1.0, methyl alcohol); ESI-MS (m/z): 505.5[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=11.02 (m, 1H), 8.30-8.44 (m, 3H), 7.15-7.35 (m, 7H), 6.89-7.08 (m, J=5Hz, 2H), 5.68 (m, J=10Hz, 1H), 5.14 (m, J=5Hz.J=10Hz, 1H), 4.84-5.01 (m, 3H), 4.61 (m, 1H), 4.15 (m, J=5Hz, 1H), 3.85 (m, 1H), 3.16-3.33 (m, J=15Hz, 1H), 3.05-3.15 (m, J=10Hz, 1H), 2.15 (m, 1H), 0.81-1.19 (m, 12H). 13CNMR (DMSO-d 6): δ/ppm=171.63,171.40,169.70,136.76,136.21,130.45,129.96,128.79,128.47,126.85,121.39,119.02,117.91,111.63,104.24,66.45,66.32,58.03,50.75,30.58,30.17,29.88,24.42,19.05,17.35.
Embodiment 69HClNH2-Lys-1,2,3,4-Tetrahydrocarboline-3-acyl group-Lys (Z)-OBzl (8l)
According to the operation of preparation 8a, from 0.10g (0.11mmol) Boc-Lys (Boc)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Lys (Z)-OBzl obtains 0.084g (97.86%) title compound (yellow solid).Mp 118-120 ℃; [α] D 25=7.9 (C=1.0, methyl alcohol); ESI-MS (m/z): 697.6[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=11.0485 (m, 1H), 8.35-8.75 (m, 3H), 8.05-8.25 (m, 3H), 7.15-7.51 (m, 12H), 7.05 (t, J=12Hz, 1H), 6.98 (t, J=12.5Hz, 1H), 5.56 (m, J=8.3Hz, 1H), 5.15 (m, 1H), 5.0 (s, 2H), 4.73-4.95 (m, 2H), 4.51 (m, 1H), 4.15 (m, 1H), 3.35 (m, 1H), 2.72-3.15 (m, 6H), 1.55-1.85 (m, 6H), 1.15-1.45 (m, 6H). 13CNMR (DMSO-d 6): δ/ppm=172.357,171.235,170.020,156.551,137.767,136.244,130.243,129.722,128.937,128.147,126.668,121.394,118.967,117.869,111.584,104.334,66.389,65.593,53.883,52.907,51.036,50.616,42.213,38.699,38.373,30.909,30.597,29.422,26.796,23.184,21.159.
Embodiment 70HClNH2-Arg (NO2)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Arg (NO2)-OBzl (8m)
According to the operation of preparation 8a, from 0.12g (0.148mmol) Boc-Arg (NO 2)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Arg (NO 2)-OBzl obtains 0.110g (99.48%) title compound (yellow solid).Mp 163-165 ℃; [α] D 25=5.4 (C=1.0, methyl alcohol); ESI-MS (m/z): 709.5[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=10.93 (m, 1H), 7.89-8.65 (m, 7H), 7.25-7.51 (m, 7H), 7.05 (t, J=5Hz, 1H), 6.89 (t, J=10Hz, J=5HZ, 1H), 5.53-5.83 (m, 2H), 4.85-5.25 (m, 3H), 4.35 (m, 1H), 3.05-3.45 (m, 7H), 1.92 (s, 2H), 1.45-1.85 (m, 8H). 13CNMR (DMSO-d 6): δ/ppm=172.36,171.73,170.13,159.79,136.76,136.19,130.13,129.67,128.18,127.55,126.67,121.30,118.96,118.02,111.60,104.43,66.38,60.19,54.05,52.63,33.74,28.66,27.49,25.26,24.29,21.51.
Embodiment 71HClNH2-Thr (Bzl)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Thr (Bzl)-OBzl (8n)
According to the operation of preparation 8a, from 0.15g (0.19mmol) Boc-Thr (Bzl)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Thr (Bzl)-OBzl obtains 0.130g (94.26%) title compound (yellow solid).Mp 98-100 ℃; [α] D 25=-7.1 (C=1.0, methyl alcohol); ESI-MS (m/z): 689.6[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=11.00 (m, 1H), 8.78 (m, 1H), 8.23-8.56 (m, 2H), and 7.15-7.409 (m, 17H), 6.89-7.11 (m, J=13Hz, 1H), 5.68 (m, J=12Hz, 1H), 4.88-5.25 (m, 3H), and 4.21-4.80 (m, 8H), 4.15 (m, J=5Hz, 1H), 3.35 (m, J=12.5Hz, 1H), 3.05 (m, J=13Hz, 1H), 1.05-1.45 (m, 6H). 13CNMR (DMSO-d 6): δ/ppm=171.83,170.30,168.39,138.57,136.14,136.01,129.77,128.87,128.76,128.50,128.47,128.34,128.00,127.89,126.71,123.37,119.87,119.01,112.61,109.10,74.50,72.14,70.74,70.62,66.88,64.91,63.04,57.02,33.79,25.82,16.99,16.70.
Embodiment 72HClNH2-Ser (Bzl)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Ser (Bzl)-OBzl (8o)
According to the operation of preparation 8a, from 0.15g (0.1974mmol) Boc-Ser (Bzl)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Ser (Bzl)-OBzl obtains 0.136g (98.93%) title compound (yellow solid).Mp 136-138 ℃; [α] D 25=-3.6 (C=1.0, methyl alcohol); ESI-MS (m/z): 661.5[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=11.00 (m, 1H), 8.45-8.98 (m, 3H), 7.165-7.42 (m, 17H), 7.55 (m, J=10Hz, 1H), 6.99 (m, J=5Hz, 1H), 5.56 (m, J=5Hz, 1H), 5.23 (m, 1H), 4.89-5.04 (m, 2H), 4.25-4.89 (m, 6H), and 3.48-3.91 (m, 5H), 3.35 (m, J=20Hz, 1H), 2.99 (m, J=5Hz, 1H). 13CNMR (DMSO-d 6): 171.07,170.27,167.83,138.22,137.95,137.69,136.50,130.09,129.64,128.74,128.59,128.40,128.14,126.89,121.43,119.00,117.96,111.62,104.46,72.86,72.73,69.47,67.98,67.43,66.54,53.77,51.21,28.21,24.24.
Embodiment 73HClNH2-Cys (CH2-C6H4-OCH3)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Cys (But)-OBzl (8p)
According to the operation of preparation 8a, from 0.15g (0.19mmol) Boc-Cys (CH 2-C 6H 4-OCH 3)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Cys (But)-OBzl obtains 0.136g (98.62%) title compound (yellow solid).Mp 1132-134 ℃; [α] D 25=-12.2 (C=1.0, methyl alcohol); ESI-MS (m/z): 689.5[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=10.99 (m, 1H), 8.45-8.95 (m, 3H), 7.15-7.47 (m, 9H), and 6.55-7.15 (m, 4H), 5.35 (m, J=5Hz, 1H), 4.85-5.15 (m, 3H), 4.65 (m, 1H), 4.35 (m, J=5Hz, J=10Hz, 1H), 3.84 (m, 1H), 3.58-3.78 (m, 5H), 2.75-3.35 (m, 6H), 1.10-1.28 (m, 9H). 13CNMR (DMSO-d 6): δ/ppm=170.49,169.54,169.11,158.89,136.84,136.23,130.77,129.80,129.55,128.80,128.19,126.92,121.44,118.97,117.92,114.41,111.63,104.69,66.67,66.61,55.56,55.45,53.98,49.75,42.64,35.59,31.81,31.10,30.94,21.53.
Embodiment 74HClNH2-Asp (OBzl)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Asp (OBzl)-OBzl (8q)
According to the operation of preparation 8a, from 0.15g (0.184mmol) Boc-Asp (OBzl)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Asp (OBzl)-OBzl obtains 0.137g (99.04%) title compound (yellow solid).Mp 90-92 ℃; [α] D 25=-6.2 (C=1.0, methyl alcohol); ESI-MS (m/z): 717.5[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=10.98 (m, 1H), 8.35-8.39 (m, 3H), 7.11-7.573 (m, 17H), 7.05 (t, J=11.5Hz, 1H), 6.99 (t, J=12Hz, 1H), 5.565 (m, J=9.5Hz, 1H), 5.05-5.21 (m, 4H), 4.83-5.00 (m, 4H), 4.65 (m, J=11Hz, 1H), 4.35 (m, 1H), 3.45 (m, J=25Hz, 1H), 2.67-3.25 (m, 5H). 13CNMR (DMSO-d 6): δ/ppm=172.40,171.48,169.85,157.30,156.56,136.74,136.53,131.24,130.48,129.83,128.76,127.54,126.76,124.67,121.42,119.00,115.92,115.70,111.61,104.41,66.39,60.21,55.01,54.65,42.04,36.18,24.09,21.53.
Embodiment 75HClNH2-Glu (OBzl)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Glu (OBzl)-OBzl (8r)
According to the operation of preparation 8a, from 0.20g (0.24mmol) Boc-Glu (OBzl)-1,2,3,4-Tetrahydrocarboline-3-acyl group-Glu (OBzl)-OBzl obtains 0.180g (97.32%) title compound (yellow solid).Mp 76-78 ℃; [α] D 25=7.5 (C=1.0, methyl alcohol); ESI-MS (m/z): 745.5[M+H] +. 1HNMR (500MHz, DMSO-d 6): δ/ppm=10.94 (m, 1H), 8.35-8.90 (m, 3H), 7.15-7.40 (m, 17H), 6.88-7.08 (m, 2H), 5.56 (m, J=5Hz, 1H), 4.89-5.25 (m, 6H), 4.85 (m, 1H), 4.61 (m, 1H), 4.25 (m, 1H), 3.65 (m, 1H), 3.38 (m, J=10Hz, 1H), 3.05 (m, J=10Hz, 1H), 2.55-2.79 (m, 6H), 1.81-2.46 (m, 2H). 13CNMR (DMSO-d 6): δ/ppm=172.54,172.33,171.46,171.06,169.89,136.85,136.27,130.07,129.53,128.88,128.44,126.88,121.47,119.05,118.05,111.64,104.54,66.55,54.32,52.34,50.09,42.08,30.55,30.36,30.21,29.08,26.44,26.00,25.55,23.83.
Experimental example 1 The compounds of this invention anti-tumor in vivo activity experiment
1) experiment material
The compound 8a-r that test-compound: embodiment of the invention 58-75 is prepared;
Positive reference substance is a cytosine arabinoside
Laboratory animal: the ICR mouse, male, body weight 20 ± 2g (± s); Provide by experimentation on animals center, Department Of Medicine, Peking University.One group of per 10 mouse, each one group of blank and positive control.
The knurl source: mouse S180 sarcoma, provide by experimentation on animals center, Department Of Medicine, Peking University, go down to posterity voluntarily and keep.
Solvent: 0.5%CMC-Na solution.
2) experimental technique
1. dosage setting
Test-compound 8a-r and positive control are made as 8.9 μ mol/kg, all adopt the abdominal cavity single-dose.
2. medicine preparation
Test-compound 8a-r indissoluble in water adds the wetting hydrotropy of a spot of tween 80 during experiment, add 0.5%CMC-Na solution to required concentration gradually and get final product.The positive reference substance cytosine arabinoside is water-soluble, adopts the 0.5%CMC-Na dissolving to get final product.
3) dosage and dosage regimen
Test-compound 8a-r is all with the abdominal cavity single-dose.By corresponding dosage once a day, the 0.2ml/ mouse, successive administration 7 days, administration is 7 times altogether.
Negative control is with isopyknic corresponding solution, all with intraperitoneal administration.By corresponding dosage once a day, the 0.2ml/ mouse, successive administration 7 days, administration is 7 times altogether.
The positive reference substance cytosine arabinoside is by the dosage of 8.9 μ mol/kg, intraperitoneal administration.Once a day, the 0.2ml/ mouse, successive administration 7 days, administration is 7 times altogether.
4) foundation of animal model
Adopt anti-tumor in vivo armpit subcutaneous vaccination model: under aseptic condition, extract inoculation and get the vigorous S180 ascitic tumor knurl liquid of growth after 5 days, be diluted to the liquid thorough mixing of (1: 2) with physiological saline, the tumour cell suspension is calculated as follows cell concn and cell survival rate with freshly prepared substratum dilution counting.
Viable count/4 * 10 in the big grid in cell concn=4 4* extension rate=cell count/ml
Cell survival rate=viable count/(viable count+dead cell number) * 100%
Survival rate is prepared into 1 * 10 greater than 90% knurl liquid with the homogenate method 7The cell suspension of individual/ml in corresponding host's armpit subcutaneous vaccination 0.2ml/ mouse, is made the solid tumor animal model.
5) detect index and method
Neurotoxicity is observed in a body
Observe autonomic activities, the mental status, hair, breathing, the diet of the reaction mouse of each treated animal of administration every day, the ight soil proterties.
The mensuration of b solid tumor tumour inhibiting rate and body weight gain
After each organizes successive administration 7d, take off cervical vertebra in 8d and put to death mouse, take by weighing body weight (execution body weight), with the fixing right armpit tumor location of mouse of tweezers, cut off skin then, the exposure tumour, blunt separation is weighed, and is calculated as follows tumour inhibiting rate.
The average knurl of the average knurl weight-administration of tumour inhibiting rate %=[(negative control group group is heavy)/the average knurl of negative control group is heavy] * 100%
Body weight gain (g)=execution body weight-original body weight-knurl is heavy
The c statistical method
This experimental data statistics all adopts t check and variance analysis, with (x ± SD) expression.
6) experimental result
Compound 8a-r lists table 1 in to the tumour inhibiting rate of S180 tumor-bearing mice and the influence of body weight.
Table 1 compound 8a-r is to the tumour inhibiting rate of S180 tumor-bearing mice and the influence of body weight a
Group Tumour inhibiting rate % Knurl heavy (g) Weight increase (g)
NS 0 1.47±0.39 8.56±2.37
Arc 49.49±4.38 c 0.78±0.22 c 8.13±1.83
8a 54.24±8.4 c 0.60±0.03 c 8.38±1.49
8b 26.54±9.24 1.08±0.37 9.60±2.93
8c 15.21±9.04 1.22±0.24 7.24±3.89
8d 31.56±5.56 b 1.01±0.26 b 8.69±2.64
8e 48.99±4.46 c 0.72±0.24 c 9.08±1.54
8f 61.68±5.81 e 0.54±0.08 e 10.94±2.82
8g 75.12±7.76 f 0.38±0.21 f 2.53±3.92 b
8h 45.8±4.66 c 0.70±0.17 c 9.96±1.64
8i 57.41±5.48 d 0.62±0.15 d 0.05±2.72 d
8j 30.76±9.42 1.08±0.38 8.31±1.50
8k 27.65±10.91 1.15±0.42 8.74±2.58
8l 22.57±7.02 1.13±0.27 8.31±4.13
8m 49.84±11.59 c 0.67±0.29 c 8.71±2.47
8n 53.58±4.35 d 0.69±0.21 d 8.56±3.92
8o 27.59±12.24 1.08±0.41 6.82±2.94
8p 43.04±9.46 b 0.86±0.34 b 8.15±3.28
8q 25.26±10.21 b 1.07±0.18 b 8.65±2.69
8r 16.68±8.34 1.21±0.29 7.93±2.57
A) Arc (cytosine arabinoside) and 8a-r dosage are 8.9 μ mol/kg, NS=physiological saline, and n=10, knurl weighs and weight increase is expressed as x ± SDg; Inhibiting rate is expressed as x ± SD%; After the administration each treated animal do not observe occur the trembling of bibliographical information, jump, tic, tetanic, lie on the back, the symptom of accelerated breathing; B) compare p＜0.05 with NS; C) compare p＜0.01 with NS; D) compare p＜0.001 with NS; E) compare p＜0.05 with cytosine arabinoside; F) compare p＜0.05. with cytosine arabinoside
Experimental result shows that The compounds of this invention has definite anti-tumor activity.
According to the result of test of significance, the compound 8f and the 8g that choose p＜0.001 carry out dose-effect relationship research, and the result is referring to table 2.
Table 2 various dose 8f and 8g are to the influence of S180 tumor-bearing mice tumour inhibiting rate, tumor weight and body weight a
Figure A20081011385600311
A) Arc=cytosine arabinoside, NS=physiological saline, n=10, knurl weighs and weight increase is expressed as x ± SDg; Inhibiting rate is expressed as x ± SD%; B) compare p＜0.05 with 0.89 μ mol/kg group; C) compare p＜0.01 with 0.089 μ mol/kg group; D) compare p＜0.01 with 0.89 μ mol/kg and 0.089 μ mol/kg group.

Claims (10)

1, the compound of Formula I that has anti-tumor activity:
General formula I
Wherein, AA 1Be selected from alanine residue, glycine residue, proline residue, glutamine residue, leucine residue, phenylalanine residue, Isoleucine residue, methionine residues, tyrosine residues, tryptophan residue, Xie Ansuan residue, lysine residue, Arg (NO 2), Thr (Bzl), Ser (Bzl) or Cys (CH 2-C 6H 4-OCH 3); AA 2Be selected from alanine residue, glycine residue, proline residue, glutamine residue, leucine residue, phenylalanine residue, Isoleucine residue, methionine residues, tyrosine residues, tryptophan residue, Xie Ansuan residue, Lys (Z), Arg (NO 2), Thr (Bzl), Ser (Bzl) or Cys (But).
2, the general formula I I compound that has anti-tumor activity:
Figure A2008101138560002C2
General formula I I
Wherein, AA 1Be selected from Asp (OBZl) or Glu (OBZl); AA 2Be selected from Asp (OBZl) or Glu (OBZl).
3, a kind of method for preparing the described compound of Formula I of claim 1, this method comprises:
(1) the L-tryptophan transfer is become 1,2,3,4-Tetrahydrocarboline carboxylic acid;
(2) with 1,2,3,4-Tetrahydrocarboline carboxylic acid changes carboline carboxylate benzyl ester into;
(3) amino acid is changed into amino-acid benzyl ester;
(4) amino acid is changed into the acid of N-t-butoxycarbonyl amino;
(5) with the acid of N-t-butoxycarbonyl amino and 1,2,3, the condensation of 4-Tetrahydrocarboline benzyl carboxylate generates N-t-butoxycarbonyl amino acyl-1,2,3,4-Tetrahydrocarboline benzyl carboxylate;
(6) with N-t-butoxycarbonyl amino acyl-1,2,3,4-Tetrahydrocarboline benzyl carboxylate hydrogenolysis generates N-t-butoxycarbonyl amino acyl-1,2,3,4-Tetrahydrocarboline carboxylic acid;
(7) with N-t-butoxycarbonyl amino acyl-1,2,3, the hydrolysis of 4-Tetrahydrocarboline benzyl carboxylate generates N-t-butoxycarbonyl amino acyl-1,2,3,4-Tetrahydrocarboline carboxylic acid;
(8) with N-t-butoxycarbonyl amino acyl-1,2,3,4-Tetrahydrocarboline carboxylic acid and amino-acid benzyl ester condensation generate N-t-butoxycarbonyl amino acyl-1,2,3, the 4-tetrahydrochysene carboline acyl aminoacid benzyl ester;
(9) with N-t-butoxycarbonyl amino acyl-1,2,3, the acidolysis of 4-tetrahydrochysene carboline acyl aminoacid benzyl ester, promptly.
4, in accordance with the method for claim 2, it is characterized in that: the amino-acid benzyl ester described in the step (3) is selected from Ala-OBzl, Gly-OBzl, Pro-OBzl, Gln-OBzl, Leu-OBzl, Phe-OBzl, Ile-OBzl, Met-OBzl, Tyr-OBzl, Trp-OBzl, Val-OBzl, Lys (Z)-OBzl, Arg (NO 2)-OBzl, Thr (Bzl)-OBzl, Ser (Bzl)-OBzl, Cys (But)-OBzl, Asp (OBzl)-Obzl or Glu (OBzl)-OBzl.
5, in accordance with the method for claim 2, it is characterized in that: the N-t-butoxycarbonyl amino acid described in the step (4) is selected from N-Boc-Ala, N-Boc-Gly, N-Boc-Pro, N-Boc-Gln, N-Boc-Leu, N-Boc-Phe, N-Boc-Ile, N-Boc-Met, N-Boc-Tyr, N-Boc-Trp, N-Boc-Val, N-Boc-Lys, N-Boc-Arg (NO 2), N-Boc-Thr (Bzl), N-Boc-Ser (Bzl), N-Boc-Cys (CH 2-C 6H 4-OCH 3), N-Boc-Asp (OBzl) or N-Boc-Glu (OBzl).
6, a kind of method for preparing the described general formula I I of claim 2 compound, this method comprises:
(1) the L-tryptophan transfer is become 1,2,3,4-Tetrahydrocarboline carboxylic acid;
(2) with 1,2,3,4-Tetrahydrocarboline carboxylic acid is transformed into N-tertbutyloxycarbonyl-1,2,3,4-Tetrahydrocarboline carboxylic acid;
(3) with N-N-tertbutyloxycarbonyl-1,2,3,4-Tetrahydrocarboline carboxylic acid and amino-acid benzyl ester condensation generate N-N-tertbutyloxycarbonyl-1,2,3, the 4-tetrahydrochysene carboline acyl aminoacid benzyl ester;
(4) with N-N-tertbutyloxycarbonyl-1,2,3, the acidolysis of 4-tetrahydrochysene carboline acyl aminoacid benzyl ester generates 1,2,3, the 4-tetrahydrochysene carboline acyl aminoacid benzyl ester;
(5) with the acid of N-t-butoxycarbonyl amino and 1,2,3, the condensation of 4-tetrahydrochysene carboline acyl aminoacid benzyl ester generates N-N-t-butoxycarbonyl amino acyl-1,2,3, the 4-tetrahydrochysene carboline acyl aminoacid benzyl ester;
(6) with N-N-t-butoxycarbonyl amino acyl-1,2,3, the acidolysis of 4-tetrahydrochysene carboline acyl aminoacid benzyl ester, promptly.
7, according to the method for claim 6, it is characterized in that: the amino-acid benzyl ester described in the step (3) is selected from Asp (OBZl)-OBzl or Glu (OBZl)-OBzl; N-t-butoxycarbonyl amino acid described in the step (5) is selected from N-Boc-Asp (OBZl) or N-Boc-Glu (OBZl).
8, a kind of pharmaceutical composition for the treatment of tumour is gone up the described compound of Formula I of claim 1 of significant quantity and pharmaceutically acceptable carrier or auxiliary material by treatment and is formed.
9, a kind of pharmaceutical composition for the treatment of tumour is gone up the claim 2 described general formula I I compound of significant quantity and pharmaceutically acceptable carrier or auxiliary material by treatment and is formed.
10, described compound of Formula I of claim 1 or the described general formula I I of the claim 2 compound purposes in the preparation antitumor drug.
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