CN109912588A - The positive hexanoyl carboline carboxylate benzyl ester of 6- amino acylamino-, preparation, activity and application - Google Patents
The positive hexanoyl carboline carboxylate benzyl ester of 6- amino acylamino-, preparation, activity and application Download PDFInfo
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Abstract
The invention discloses (3S)-N- of following structure (the positive hexanoyl of 6- amino acylamino-) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate, (AA is selected from L-Lys in formula, L-Leu, L-Met, L-Asn, L-Pro, L-Ser, L-Thr and L-Trp residue).Their preparation method and its antitumor action are disclosed, their applications in the drug for preparing antitumor action are illustrated.
Description
Technical field
The present invention relates to following structure (3S)-N- (the positive caproyl of amino acylamino-) -2,3,4,9- tetrahydro-beta-carboline -3-
Benzyl carboxylate (AA is selected from L-Lys, L-Leu, L-Met, L-Asn, L-Pro, L-Ser, L-Thr and L-Trp residue in formula).It relates to
And its preparation method, it is related to its Anticancer effect in vivo.Thus the present invention relates to its answering in the preparation of antitumor drugs
With.The invention belongs to biomedicine fields.
Technical background
Malignant tumour seriously threatens human health.Wherein lung cancer is one of most invasive human cancer.For lung cancer
The patient in patient's advanced stage, the people of usual 10%-15% can only survive 5 years.The situation of this difficulty is not yet in past 30 years
Significantly make moderate progress.In many clinical cases, lung cancer is transferred into surrounding tissue before being diagnosed.Metastases, especially
It is the greateset risk that neoplasm lung metastasis is tumor patient death.So far, the antineoplastic of metastases still can not prevented
Object is for clinic.Inflammation then can further deteriorate the prognosis of tumour and metastases patient.So far, more not can prevention of inflammation and
The anti-tumor drug of metastases is for clinic.Invention have it is antitumor, the drug of anti-tumor metastasis and anti-inflammatory triple role is
The forward position of anti-tumor drug research.The early period of inventor invents (patent application publication CN 106349148A, application number CN
201510409682.6) it once discloses, double heteroauxin alcohol that amino-acid benzyl ester replaces under 0.2 μm of ol/kg dosage have anti-
Tumour, anti-tumor metastasis and anti-inflammatory triple role (levoform).Inventor plays this class double-indole alcohol amido acid acid benzyl ester anti-
The minimum effective dose of function of tumor is 0.2 μm of ol/kg dissatisfied.Dosage is higher.In past 2 years, inventor exists always
Find the low antitumor action compound of than 0.2 μm ol/kg of minimum effective dose.Finally inventors have found that aminoacyl -6- amino
The Tetrahydrocarboline benzyl carboxylate of caproic acid acid modification has antitumor action under 0.02 μm of ol/kg dosage.Because the poison of drug is secondary
Effect can be reduced with dosage and be disappeared, so 10 times of effective dose reduction shows this structural modification and has skill outstanding
Art effect.Then, the present invention is inventors herein proposed.
Summary of the invention
First content of the invention is to provide (3S)-N- (the positive caproyl of amino acylamino-) -2,3,4 of following structure,
(AA is selected from L-Lys, L-Leu, L-Met, L-Asn, L-Pro, L-Ser, L-Thr to 9- tetrahydro-β-carboline -3- benzyl carboxylate in formula
With L-Trp residue).
Second content of the invention is to provide (3S)-N- (the positive caproyl of amino acylamino-) -2,3,4,9- tetrahydro-β-click
The preparation method of quinoline -3- benzyl carboxylate, this method comprises:
(1) under the catalysis of dilute sulfuric acid, L-Trp benzyl ester and formaldehyde carry out Pictet-Spengler reaction and generate
(3S) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate；
(2) 6-aminocaprolc acid and two dimethyl dicarbonates in sodium hydrate aqueous solution (2M), water and dioxane mixed solution
Butyl ester (Boc)2O reaction generates 6- tert-butoxycarbonylamino caproic acid；
(3) in the presence of N, N- dicyclohexylcarbodiimide and N- hydroxy benzo triazole, in anhydrous tetrahydro furan, 6-
Tert-butoxycarbonylamino caproic acid and (3S) -2, the reaction of 3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylates, obtain (3S)-N- (tertiary fourth of 6-
The positive hexanoyl of oxygen carbonyl amino) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate；
(4) under ice bath in the ethyl acetate solution of hydrogen chloride (4M), (3S)-N- (6- t-butoxycarbonyl amino just oneself
Acyl) -2,3,4,9- Tetrahydrocarboline -3- benzyl carboxylate removing Boc obtain (3S)-N- (the positive hexanoyl of 6- amino) -2,3,4,9- tetrahydro -
B-carboline -3- benzyl carboxylate；
(5) in the presence of N, N- dicyclohexylcarbodiimide and N- hydroxy benzo triazole, in anhydrous tetrahydro furan,
(3S)-N- (the positive hexanoyl of 6- amino) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate and Boc-AA (AA is selected from L-Lys in formula,
L-Leu, L-Met, L-Asn, L-Pro, L-Ser, L-Thr and L-Trp residue) reaction, obtain (3S)-N- (6 tert-butoxycarbonylaminos
The positive hexanoyl of acylamino-) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate；
(6) under ice bath in the ethyl acetate solution of hydrogen chloride (4M), (6- tert-butoxycarbonylamino acylamino- is just by (3S)-N-
Hexanoyl) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate removing Boc obtain (3S)-N- (the positive hexanoyl of 6- amino acylamino-) -2,3,
4,9- tetrahydro-beta-carboline -3- benzyl carboxylate.
Third content of the invention is evaluation (3S)-N- (the positive hexanoyl of 6- amino acylamino-) -2,3,4,9- tetrahydro-β-click
Inhibiting effect of the quinoline -3- benzyl carboxylate to S180 mice tumors grew.
Detailed description of the invention
The synthesis of Fig. 1 (3S)-N- (the positive hexanoyl of 6- amino acylamino-) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate
Route I) HCHO, H2O,H2SO4；II) N, N- dicyclohexylcarbodiimide (DCC), N- hydroxy benzo triazole (HOBt), N-
Methyl morpholine, tetrahydrofuran；III) dioxane, sodium hydrate aqueous solution, di-tert-butyl dicarbonate (Boc)2O；IV) hydrogen chloride
Ethyl acetate solution (4M).
Specific embodiment
In order to which the present invention is further explained, a series of embodiments are given below.These embodiments be entirely it is illustrative, it
Only be used to the present invention is specifically described, be not construed as limitation of the present invention.
Embodiment 1 prepares (3S) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate (1)
The dense H of 1.5mL is slowly added to 300mL water under ice bath2SO4, stir 3min.5.00g (15.1mmol) is added later
L-Trp benzyl ester hydrochloride and 6mL formalin (40%).72h is stirred at room temperature, TLC shows that L-Trp benzyl ester hydrochloride disappears
It loses.Reaction solution is 7 with concentrated ammonia liquor tune pH value of solution under ice bath, filtering.Filter cake 100mL ethyl acetate dissolves, obtained solution
(40mL × 3) are washed with saturated sodium-chloride water solution, it is dry with anhydrous sodium sulfate later.Filtering, filtrate decompression concentration.Residue warp
Silica gel column chromatography purifies (methylene chloride: methanol=90:1) and obtains 1.9g (41%) target compound, is yellow oily solid.ESI-
MS (m/e): 307 [M+H]+。
Embodiment 2 prepares 6- tert-butoxycarbonylamino caproic acid (2)
5.00g (38.2mmol) 6-aminocaprolc acid (EACA) 50mL is distilled into aqueous suspension.Obtained suspension is in ice bath
Lower addition 10mL sodium hydrate aqueous solution (2M), stirring to dissolution.Add 9.2g (42.2 mmol) (Boc) into obtained solution2The solution of O and 20mL dioxane simultaneously adjusts pH to 9 with sodium hydrate aqueous solution (2M), stirs 30min.Remove ice bath, room temperature
Stirring shows that 6-aminocaprolc acid disappears to TLC.Reaction solution saturation KHSO under ice bath4Aqueous solution adjusts pH to 7, and reduced pressure removes
Remove dioxane.Reaction solution saturation KHSO under ice bath4Aqueous solution adjusts pH to 2, and (50mL × 3) are extracted with ethyl acetate.Second
Ethyl acetate layer washes (40mL × 3) with saturation NaCl aqueous solution, dry with anhydrous sodium sulfate.Filtering, filtrate decompression are concentrated to give 8.0g
(91%) target compound is colorless oil.ESI-MS (m/e): 232 [M+H]+。
Embodiment 3 prepares (3S)-N- (the positive hexanoyl of 6- tert-butoxycarbonylamino) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate
Ester (3)
4.15g (18mmol) tertbutyloxycarbonyl -6-aminocaprolc acid 80mL anhydrous tetrahydro furan is dissolved, is added under ice bath
2.46g (18.2mmol) N- hydroxyl benzotriazole (HOBt) and 4.04g (19.6mmol) N, N- dicyclohexylcarbodiimide
(DCC), it stirs 60 minutes.Later, add 5.06g (16.5mmol) (3S) -2,3,4,9- tetrahydro-beta-carbolines-toward obtaining reaction solution
The solution of 3- benzyl carboxylate and 80mL anhydrous tetrahydro furan.Reaction mixture adjusts pH extremely with N-methylmorpholine (NMM) under ice bath
9, it is stirred at room temperature 24 hours.TLC shows that (3S) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate disappears.Reaction solution filtering, filter
Liquid is concentrated under reduced pressure, and residue adds ethyl acetate to dissolve.Solution is successively with saturation NaHCO3Aqueous solution is washed (40mL × 3), saturation
NaCl aqueous solution is washed (40mL × 3), and KHSO is saturated4Aqueous solution is washed (40mL × 3), and saturation NaCl aqueous solution washes (40mL × 3),
It is saturated NaHCO3Aqueous solution is washed (40mL × 3), and saturation NaCl aqueous solution washes (40mL × 3).Ethyl acetate layer anhydrous Na2SO4It is dry
Dry, filtering, filtrate decompression is concentrated, and residue is purified by silica gel column chromatography (methylene chloride: methanol=160:1) and obtains 5.43g
(64%) target compound is yellow oily solid.ESI-MS (m/e): 520 [M+H]+。
Embodiment 4 prepares (3S)-N- (the positive caproyl of 6- amino) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate (4)
By 3.4g (6.6mmol) (3S)-N- (the positive caproyl of t-butoxycarbonyl amino) -2,3,4,9- tetrahydro-β-under ice bath
The ethyl acetate solution (4M) of carboline -3- benzyl carboxylate 40mL hydrogen chloride dissolves, and stirs 3 hours, TLC shows (3S)-N-
(the positive caproyl of t-butoxycarbonyl amino) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate disappears.Reaction is mixed under stirring
Object is concentrated to dryness.Residue adds anhydrous ethyl acetate to dissolve, and solution is concentrated to dryness again.The operation is in triplicate.It is residual
It stays object that anhydrous ether is added sufficiently to wash, obtains 2.8g (94%) target compound, be sepia solid.ESI-MS(m/e):420 [M+
H]+；Mp 223-226℃.1H NMR (300MHz, DMSO-d6: δ/ppm=10.963 (d, J=11.4Hz, 1H), 7.894 (s,
3H), 7.458 (d, J=7.5Hz, 1H), 7.327 (t, J=7.5Hz, 1H), 7.204 (dd, J1=1.5Hz, J2=7.2 Hz,
1H), 7.158-6.972 (m, 6H), 5.607 (d, J=4.7Hz, 1H), 5.059 (s, 2H), 4767 (d, J=15.6Hz, 1H),
4.610 (d, J=17.4Hz, 1H), 3.426 (m, 1H), 3.021 (m, 1H), 2.754 (m, 2H), 2.613 (m, 1H), 2.389
(m,1H),1.568-1.546(m,4H),1.399-1.323(m,2H)。
Embodiment 5 prepares (3S)-N- (the positive hexanoyl of 6- tertiary butyloxycarbonyl alanylamino) -2,3,4,9- tetrahydro-beta-carboline -3-
Benzyl carboxylate (5a)
By 1.14g (6mmol) Boc-Ala and 0.82g (6.1mmol) N- hydroxyl benzotriazole (HOBt) with 30mL without
Water tetrahydrofuran dissolves, and 1.36g (6.6mmol) N, N- dicyclohexylcarbodiimide (DCC) is added under ice bath, stirs 40 minutes.
Later, toward obtaining in reaction solution plus 2.50g (5.5mmol) (3S)-N- (the positive caproyl of 6- amino) -2,3,4,9- tetrahydro-β-click
It is small to be stirred at room temperature 12 with N-methylmorpholine tune pH to 8 under ice bath for the solution of quinoline -3- benzyl carboxylate and 30mL anhydrous tetrahydro furan
When.TLC shows that -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate of (3S)-N- (the positive caproyl of 6- amino) disappears, reaction solution mistake
Filter, filtrate decompression concentration, residue add 100mL ethyl acetate to dissolve.Solution is successively with saturation NaHCO3Aqueous solution wash (40mL ×
3), saturation NaCl aqueous solution is washed (40mL × 3), is saturated KHSO4Aqueous solution is washed (40mL × 3), and saturation NaCl aqueous solution washes (40mL
× 3), it is saturated NaHCO3Aqueous solution is washed (40mL × 3), and saturation NaCl aqueous solution washes (40 mL × 3).Ethyl acetate layer is with anhydrous
Na2SO4It dries, filters, filtrate decompression concentration, residue is purified by silica gel column chromatography (methylene chloride: methanol=60:1) and obtains 1.3g
(41%) target compound is faint yellow solid.ESI-MS (m/e): 591.3 [M+H]+。
Embodiment 6 prepares (3S)-N- (the bis- positive hexanoyls of tertiary butyloxycarbonyl lysylamino of 6-) -2,3,4,9- tetrahydro-beta-carboline -
3- benzyl carboxylate (5b)
According to the method for embodiment 5 from 0.86g (1.87mmol) Boc-Lys (Boc) and 0.42g (1.37mmol) (3S)-
N- (the positive hexanoyl of 6- amino) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate obtains 0.54g (39%) title compound, is
Faint yellow solid.ESI-MS(m/z):748[M+H]+。
Embodiment 7 prepares (3S)-N- (the positive hexanoyl of 6- tertiary butyloxycarbonyl leucylamino) -2,3,4,9- tetrahydro-beta-carboline -3-
Benzyl carboxylate (5c)
According to the method for embodiment 5, from 2.10g (4.6mmol) (3S)-N- (the positive hexanoyl of 6- amino) -2,3,4,9- tetrahydros -
B-carboline -3- benzyl carboxylate and 1.28g (5.5mmol) Boc-Leu obtain 1.62g (56%) title compound, are pale yellow colored solid
Body.ESI-MS(m/z):633[M+H]+。
Embodiment 8 prepares (3S)-N- (the positive hexanoyl of 6- tertiary butyloxycarbonyl methionyl amino) -2,3,4,9- tetrahydro-beta-carboline -
3- benzyl carboxylate (5d)
According to the method for embodiment 5, from 1.80g (4.0mmol) (3S)-N- (the positive hexanoyl of 6- amino) -2,3,4,9- tetrahydros -
B-carboline -3- benzyl carboxylate and 1.28g (5.1mmol) Boc-Met obtain 0.35g (14%) title compound, are pale yellow colored solid
Body.ESI-MS(m/z):651[M+H]+。
Embodiment 9 prepares (3S)-N- (the 6 positive hexanoyl of tertiary butyloxycarbonyl asparagine acylamino-) -2,3,4,9- tetrahydro-β-click
Quinoline -3- benzyl carboxylate (5e)
According to the method for embodiment 5, from 2.60g (5.7mmol) (3S)-N- (the positive hexanoyl of 6- amino) -2,3,4,9- tetrahydros -
B-carboline -3- benzyl carboxylate and 1.46g (6.3mmol) Boc-Asn obtain 0.72g (20%) title compound, are pale yellow colored solid
Body.ESI-MS(m/z):634[M+H]+。
Embodiment 10 prepares (3S)-N- (the positive hexanoyl of 6- tertiary butyloxycarbonyl prolinamidyl) -2,3,4,9- tetrahydro-beta-carboline -
3- benzyl carboxylate (5f)
According to the method for embodiment 5, from 2.00g (4.4mmol) (3S)-N- (the positive hexanoyl of 6- amino) -2,3,4,9- tetrahydros -
B-carboline -3- benzyl carboxylate and 1.04g (4.8mmol) Boc-Pro obtain 1.20g (44%) title compound, are pale yellow colored solid
Body.ESI-MS(m/z):617[M+H]+。
Embodiment 11 prepares (3S)-N- (the positive caproyl of 6- tertiary butyloxycarbonyl serylamino) -2,3,4,9- tetrahydro-β-click
Quinoline -3- benzyl carboxylate (5g)
According to the method for embodiment 5, from 1.5g (3.3mmol) (3S)-N- (the positive caproyl of 6- amino) -2,3,4,9- tetra-
Hydrogen-B-carboline -3- benzyl carboxylate and 0.74g (3.6mmol) Boc-Ser obtain 0.30g (15%) title compound, are faint yellow
Solid.ESI-MS(m/z):607[M+H]+。
Embodiment 12 prepares (3S)-N- (the positive caproyl of 6- tertiary butyloxycarbonyl threonyl amino) -2,3,4,9- tetrahydro-β-click
Quinoline -3- benzyl carboxylate (5h)
According to the method for embodiment 5, from 3.2g (7.0mmol) (3S)-N- (the positive hexanoyl of 6- amino) -2,3,4,9- tetrahydros -
B-carboline -3- benzyl carboxylate and 1.69g (7.7mmol) Boc-Thr obtain 0.36g (8.3%) title compound, are faint yellow
Solid.ESI-MS(m/z):621[M+H]+。
Embodiment 13 prepares (3S)-N- (the positive caproyl of 6- tertiary butyloxycarbonyl tryptophanyl amino) -2,3,4,9- tetrahydro-β-click
Quinoline -3- benzyl carboxylate (5i)
According to the method for embodiment 5, from 3.5g (7.7mmol) (3S)-N- (the positive hexanoyl of 6- amino) -2,3,4,9- tetrahydros -
B-carboline -3- benzyl carboxylate and 2.57g (8.5mmol) Boc-Trp obtain 1.80g (33%) title compound, are pale yellow colored solid
Body.ESI-MS(m/z):706[M+H]+。
Embodiment 14 prepares (3S)-N- (the positive hexanoyl of 6- lysylamino) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate
Ester (6a)
By 800mg (3S)-N- (the bis- positive hexanoyls of tertiary butyloxycarbonyl lysylamino of 6-) -2,3,4,9- tetrahydro-beta-carboline -3- carboxylic
The ethyl acetate solution (4M) of 16mL hydrogen chloride is added under ice bath and stirs 2h for sour benzyl, TLC (ethyl acetate: water: glacial acetic acid=
3:1:1.2) show (3S)-N- (double positive hexanoyls of tertiary butyloxycarbonyl lysylamino) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate
Ester disappears.Reaction solution is concentrated to dryness.Residue adds anhydrous ethyl acetate to dissolve, then is concentrated to dryness.The operation repeats
Three times.Residue adds anhydrous ether sufficiently to wash, after through C18Column chromatographic purifying (methanol: water=30:70) and be lyophilized obtain 430mg
(75%) title compound is faint yellow solid.ESI-MS(m/e):548[M+H]+.Mp 118-120 ℃；1H NMR
(300MHz, DMSO-d6: δ/ppm=10.990 (d, J=15.3Hz, 1H), 8.642 (m, 1H), 8.292 (s, 3H), 8.055
(s, 3H), 7.454 (d, J=7.8Hz, 1H), 7.331 (dd, J1=7.8Hz, J2=15.6Hz, 1H), 7.205 (dd, J1=
1.8Hz,J2=7.5Hz, 1H), 7.162-7.086 (m, 6H), 5.596 (d, J=4.8Hz, 1H), 5.061 (s, 2H), 4775
(d, J=15.6Hz, 1H), 4.634 (d, J=17.4Hz, 1H), 3.744 (m, 1H), 3.451 (m, 1H), 3.109-2.937
(m,3H),2.746(m,2H),2.584(m,1H),2.430(m,1H),1.742(m,2H),1.621-1.313(m,10H)。
Embodiment 15 prepares (3S)-N- (the positive caproyl of 6- leucylamino) -2,3,4,9- tetrahydro-beta-carboline -3- carboxylic acid
Benzyl ester (6b)
According to the method for embodiment 14, from 1000mg (3S)-N- (the positive hexanoyl of 6- tertiary butyloxycarbonyl leucylamino) -2,3,4,
9- tetrahydro-beta-carboline -3- benzyl carboxylate obtains 605mg (72%) title compound, is faint yellow solid.ESI-MS(m/e):
533 [M+H]+.Mp 111-113℃；1H NMR (300MHz, DMSO-d6: δ/ppm=10.998 (d, J=13.2Hz, 1H),
8.635(dd,J1=5.1Hz, J2=10.5Hz 1H), 8.281 (s, 3H), 7.455 (d, J=7.5Hz, 1H), 7.328 (t, J=
7.8 Hz,1H),7.200(dd,J1=2.1Hz, J2=7.5Hz, 1H), 7.158-7.072 (m, 6H), 5.613 (d, J=
4.5Hz, 1H), 5.057 (s, 2H), 4769 (d, J=15.6Hz, 1H), 4.630 (d, J=17.4Hz, 1H), 3.707 (m,
1H),3.447(m, 1H),3.174-3.030(m,3H),2.569(m,1H),2.419(m,1H),1.645-1.306(m,9H),
0.908 (d, J=6.0 Hz, 3H), 0.888 (d, J=6.0Hz, 3H).
Embodiment 16 prepares (3S)-N- (the positive hexanoyl of 6- methionyl amino) -2,3,4,9- tetrahydro-beta-carboline -3- carboxylic acid
Benzyl ester (6c)
According to the method for embodiment 14, from 1100mg (3S)-N- (the positive hexanoyl of 6- tertiary butyloxycarbonyl methionyl amino) -2,3,
4,9- tetrahydro-beta-carboline -3- benzyl carboxylates obtain 530mg (57%) title compound, are faint yellow solid.ESI-MS(m/e):
551.2 [M+H]+.Mp:108.8-110.4℃；1HNMR (300MHz, DMSO-d6: δ/ppm=10.962 (d, J=10.8Hz,
1H),8.599(q,J1=5.4Hz, J2=10.5Hz, 1H), 8.319 (s, 3H), 7.456 (d, J=7.5Hz, 1H), 7.329 (t,
J=7.5Hz, 1H), 7.206 (dd, J1=2.1Hz, J2=6.6Hz, 1H), 7.163-7.074 (m, 6H), 5.604 (d, J=
4.8Hz, 1H), 5.059 (s, 2H), 4769 (d, J=15.6Hz, 1H), 4.631 (d, J=17.4Hz, 1H), 3.818 (dd, J1
=5.4Hz, J2=11.7Hz, 1H), 3.427 (m, 1H), 3.186-3.050 (m, 3H), 2.568 (m, 1H), 2.466-2.401
(m,3H), 2.059-1.962(m,5H),1.596-1.520(m,2H),1.495-1.433(m,2H),1.384-1.308(m,
2H)。
Embodiment 17 prepares (3S)-N- (the positive hexanoyl of 6- asparagine acylamino-) -2,3,4,9- tetrahydro-beta-carboline -3- carboxylic
Acid benzyl ester (6d)
According to the method for embodiment 14, from 497mg (3S)-N- (the positive hexanoyl of tertiary butyloxycarbonyl asparagine acylamino-) -2,3,
4,9- tetrahydro-beta-carboline -3- benzyl carboxylates obtain 260mg (62%) title compound, are faint yellow solid.ESI-MS(m/e):
534.2 [M+H]+.Mp:124-125℃；1H NMR (300MHz, DMSO-d6: δ/ppm=10.986 (d, J=15.0Hz, 1H),
8.463 (m, 1H), 8.193 (s, 3H), 7.730 (s, 1H), 7.455 (d, J=7.8Hz, 1H), 7.330 (t, J=7.8Hz,
1H), 7.238(s,1H),7.205(dd,J1=1.8Hz, J2=7.2Hz, 1H), 7.160-6.972 (m, 6H), 5.603 (d, J
=4.5Hz, 1H), 5.060 (s, 2H), 4772 (d, J=15.6Hz, 1H), 4.632 (d, J=17.7Hz, 1H), 4.007 (m,
1H),3.451 (m,1H),3.137-3.045(m,3H),2.724-2.538(m,3H),2.428(m,1H),1.547(m,2H),
1.476-1.298(m,4H)。
Embodiment 18 prepares (3S)-N- (the positive hexanoyl of 6- prolinamidyl) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate
Ester (6e)
According to the method for embodiment 14, from 950mg (3S)-N- (the positive hexanoyl of 6- tertiary butyloxycarbonyl prolinamidyl) -2,3,4,
9- tetrahydro-β-carboline -3- benzyl carboxylate obtains 598mg (75%) title compound, is faint yellow solid.ESI-MS(m/e):
517.2 [M+H]+.Mp 116-117℃；1H NMR (300MHz, DMSO-d6: δ/ppm=10.975 (d, J=11.1Hz, 1H),
9.188(m,2H),8.610(dd,J1=5.4Hz, J2=11.1Hz, 1H), 7.456 (d, J=7.8Hz, 1H), 7.328 (t, J
=7.5Hz, 1H), 7.202 (dd, J1=2.1Hz, J2=7.5Hz, 1H), 7.159-7.085 (m, 6H), 5.605 (d, J=
4.5Hz 1H), 5.058 (s, 2H), 4767 (d, J=15.6Hz, 1H), 4.636 (d, J=17.7Hz, 1H), 4.21 (m, 1H),
3.421(m, 1H),3.224-3.099(m,5H),2.569(m,1H),2.438(m,1H),2.273(m,1H),1.889-
1.786(m,3H), 1.552(m,2H),1.457(m,2H),1.322(m,2H)。
Embodiment 19 prepares (3S)-N- (the positive hexanoyl of 6- serylamino) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate
Ester (6f)
According to the method for embodiment 14, from 825mg (3S)-N- (the positive hexanoyl of 6- tertiary butyloxycarbonyl serylamino) -2,3,4,
9- tetrahydro-beta-carboline -3- benzyl carboxylate obtains 448mg (65%) title compound, is faint yellow solid.ESI-MS(m/e):
507.2 [M+H]+.Mp 147-149℃；1H NMR (300MHz, DMSO-d6: δ/ppm=10.990 (d, J=14.1Hz, 1H),
8.501(dd,J1=5.1Hz, J2=10.2Hz, 1H), 8.185 (s, 3H), 7.454 (d, J=7.8Hz, 1H), 7.331 (t, J=
7.8 Hz, 1H), 7.243-7.191 (m, 1H), 7.162-7.085 (m, 6H), 5.602 (d, J=4.5Hz, 1H), 5.506 (t, J
=4.5 Hz, 1H), 5.060 (s, 2H), 4772 (d, J=15.6Hz, 1H), 4.634 (d, J=17.4Hz, 1H), 3.778-
3.700(m, 3H),3.426(m,1H),3.126-2.971(m,3H),2.574(m,1H),2.421(m,1H),1.553(m,
2H), 1.489-1.306(m,4H)。
Embodiment 20 prepares (3S)-N- (the positive hexanoyl of 6- threonyl amino) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate
Ester (6g)
According to the method for embodiment 14, from 479mg (3S)-N- (the positive hexanoyl of 6- tertiary butyloxycarbonyl threonyl amino) -2,3,4,
9- tetrahydro-beta-carboline -3- benzyl carboxylate obtains 172mg (43%) title compound, is faint yellow solid.ESI-MS(m/e):
521.2 [M+H]+.Mp 125-126℃；1H NMR (300MHz, DMSO-d6: δ/ppm=10.972 (d, J=11.1Hz, 1H),
8.570(dd,J1=5.1Hz, J2=9.9Hz, 1H), 8.142 (s, 3H), 7.456 (d, J=7.8Hz, 1H), 7.327 (t, J=
7.8 Hz, 1H), 7.236-7.188 (m, 1H), 7.158-7.050 (m, 6H), 5.602 (d, J=4.5Hz, 1H), 5.572 (s,
1H), 5.058 (s, 2H), 4766 (d, J=15.6Hz, 1H), 4.628 (d, J=17.4Hz, 1H), 3.870 (m, 1H), 3.490
(m, 1H),3.421(m,1H),3.184-2.966(m,3H),2.567(m,1H),2.420(m,1H),1.552(m,2H),
1.455 (m, 2H), 1.336 (m, 2H), 1.138 (d, J=6.3Hz, 3H).
Embodiment 21 prepares (3S)-N- (the positive hexanoyl of 6- tryptophanyl amino) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate
Ester hydrochloride (6h) according to embodiment 14 method, from 950mg (3S)-N- (the positive hexanoyl of 6- tertiary butyloxycarbonyl tryptophanyl amino) -2,
3,4,9- tetrahydro-β-carboline -3- benzyl carboxylate obtains 580mg (71%) title compound, is faint yellow solid.ESI-MS(m/
e):606.3 [M+H]+.Mp 144-146℃；1H NMR (300MHz, DMSO-d6: δ/ppm=11.067 (s, 1H), 10.994
(d, J=18.9Hz, 1H), 8.516 (dd, J1=5.1Hz, J2=10.8Hz, 1H), 8.240 (s, 3H), 7.659 (d, J=
7.8Hz, 1H), 7.458 (d, J=7.8Hz, 1H), 7.375-7.306 (m, 2H), 7.218-7.096 (m, 10H), 5.595 (d,
J=4.5Hz, 1H), 5.054 (s, 2H), 4764 (d, J=15.6Hz, 1H), 4.632 (d, J=17.1Hz, 1H), 3.931 (m,
1H),3.482(m, 1H),3.248-2.916(m,5H),2.545(m,1H),2.374(m,1H),1.48(m,2H),1.321
(m,2H),1.197 (m,2H)。
The anti-tumor activity of the evaluation of experimental example 1 compound 6a-h
1) compound 6a-h physiological saline solution, adriamycin use physiological saline solution as positive control, physiological saline
As negative control；
2) oral dose of compound 6a-h is 0.02 μm of ol/kg, and the oral dose of compound 4 is 0.2 μm of ol/kg, raw
The oral dose for managing salt water is 0.2mL/20g, and adriamycin intraperitoneal injection dosage is 2 μm of ol/kg.It is administered immediately after tumor inoculation,
It successive administration 10 days, is administered 10 times altogether.
3) experimental animal is ICR male mice (cleaning grade), 20 ± 2g of weight, every group of 12 mouse.
4) knurl source is mouse S 180 sarcoma, is purchased from Department Of Medicine, Peking University's animal experimental center, and voluntarily passage maintains.
5) it is extracted under aseptic condition and is inoculated with eugonic S180 ascites tumor tumor liquid, with normal saline dilution at (1:2)
Liquid is sufficiently mixed, and by 0.2% Trypan Blue of tumor cell suspension Fresh, white blood cell count(WBC) method is pressed after mixing
It counts, dye blue person is dead cell, and tinter is not living cells.By viable count/4 × 10 in cell concentration=4 block plaids4×
Extension rate=cell number/mL calculates cell concentration.By cell survival rate=viable count/(viable count+dead cell number) ×
100% calculates cell survival rate.
Tumor liquid by survival rate greater than 90% is prepared into 2.0 × 10 with homogenate method7The cell suspension of a/mL, in mouse armpit skin
Lower inoculation, 0.2mL/ only, manufacture S180 tumor-bearing mice.It is administered immediately after tumor inoculation.The daily oral administration of compound for the treatment of group mouse
4 dosage are 0.2 μm of ol/kg or compound 6a-h dosage is 0.02 μm of ol/kg.The daily oral normal saline agent of naive mice
Amount is 0.2mL/20g.It is 2 μm of ol/kg that doxorubicin dosages, which are injected intraperitoneally, in positive controls mouse daily.Successive administration ten days, the
11 days title mouse weights, etherization, cervical dislocation put to death mouse, then fix mouse right axillary tumor location with tweezers,
Cut off skin, exposure tumour, blunt separation, weighing.Experimental data is examined using t and variance analysis, and knurl weight is with (mean value ± SD
G) it indicates.It the results are shown in Table 1.As can be seen from Table 1, under 0.02 μm of ol/kg oral dose, compound 6a-h can be effectively inhibited
The knurl weight of mouse is grown.The present invention has significant technical effect.
The anti-tumor activity of 1 compound 6a-h of table
And physiological saline ratio p < 0.05, n=12 a).
Claims (3)
1. -2,3,4, the 9- tetrahydro-beta-carboline -3- benzyl carboxylate of (3S)-N- (the positive hexanoyl of 6- amino acylamino-) of structure below, formula
Middle AA be selected from L-Lys, L-Leu, L-Met, L-Asn, L-Pro, L-Ser and L-Val residue,
2. (3S)-N- (the positive hexanoyl of 6- amino acylamino-) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate system of claim 1
Preparation Method, this method are made of following steps:
(1) in dilute sulfuric acid (H2SO4) catalysis under, L-Trp benzyl ester and formaldehyde carry out Pictet-Spengler reaction and generate
(3S) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate；
(2) 6-aminocaprolc acid and di-tert-butyl dicarbonate in sodium hydrate aqueous solution (2M), water and dioxane mixed solution
(Boc)2O reaction generates 6- tert-butoxycarbonylamino caproic acid；
(3) in the presence of N, N- dicyclohexylcarbodiimide (DCC) and N- hydroxy benzo triazole (HOBt), in anhydrous tetrahydro furan
It mutters in (THF), 6- tert-butoxycarbonylamino caproic acid and (3S) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylates reaction obtain
(3S)-N- (the positive hexanoyl of 6- tert-butoxycarbonylamino) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate；
(4) under ice bath in the ethyl acetate solution of hydrogen chloride (4M), (3S)-N- (the positive hexanoyl of 6- t-butoxycarbonyl amino) -2,
3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate removing Boc obtains (3S)-N- (the positive caproyl of 6- amino) -2,3,4,9- tetrahydro-β -
Carboline -3- benzyl carboxylate；
(5) in the presence of N, N- dicyclohexylcarbodiimide (DCC) and N- hydroxy benzo triazole (HOBt), in dry tetrahydro furan
It mutters in (THF), -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate of (3S)-N- (the positive hexanoyl of 6- amino) and Boc-AA (AA in formula
Selected from L-Lys, L-Leu, L-Met, L-Asn, L-Pro, L-Ser, L-Thr and L-Trp residue) reaction, obtain (3S)-N- (6-
The positive hexanoyl of tert-butoxycarbonylamino acylamino-) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate；
(6) under ice bath in the ethyl acetate solution of hydrogen chloride (4M), (3S)-N- (6- tert-butoxycarbonylamino acylamino- just oneself
Acyl) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate removing Boc obtain (3S)-N- (the positive hexanoyl of 6- amino acylamino-) -2,3,4,
9- tetrahydro-beta-carboline -3- benzyl carboxylate.
3. (3S)-N- (the positive caproyl of 6- amino acylamino-) -2,3,4,9- tetrahydro-beta-carboline -3- benzyl carboxylate of claim 1
Application in preparation of anti-tumor drugs.
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| CN101597289A (en) * | 2008-06-02 | 2009-12-09 | 首都医科大学 | 2-tryptophyl-beta-tetrahydro carboline-3-formyol amino-acid benzyl ester and its production and application |
| CN101597291A (en) * | 2008-06-04 | 2009-12-09 | 首都医科大学 | 2-(aminoacyl tryptophyl)-beta-tetrahydro carboline-3-benzyl carboxylate and its production and application |
| CN105273053A (en) * | 2014-06-11 | 2016-01-27 | 首都医科大学 | Trp-Trp-Trp decapeptide modified beta-carboline, and preparation, nanometer structure, activity and application thereof |
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| 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 |
| CN101597289A (en) * | 2008-06-02 | 2009-12-09 | 首都医科大学 | 2-tryptophyl-beta-tetrahydro carboline-3-formyol amino-acid benzyl ester and its production and application |
| CN101597291A (en) * | 2008-06-04 | 2009-12-09 | 首都医科大学 | 2-(aminoacyl tryptophyl)-beta-tetrahydro carboline-3-benzyl carboxylate and its production and application |
| CN105273053A (en) * | 2014-06-11 | 2016-01-27 | 首都医科大学 | Trp-Trp-Trp decapeptide modified beta-carboline, and preparation, nanometer structure, activity and application thereof |
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| CN110551120A (en) * | 2018-06-04 | 2019-12-10 | 首都医科大学 | 6-amino amido n-hexanoyl carboline benzyl carboxylate, preparation, activity and application thereof |
| CN110551120B (en) * | 2018-06-04 | 2020-10-20 | 首都医科大学 | 6-amino amido n-hexanoyl carboline benzyl carboxylate, preparation, activity and application thereof |
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