CN109912588B - 6-amino amido n-hexanoyl carboline benzyl carboxylate, preparation, activity and application thereof - Google Patents
6-amino amido n-hexanoyl carboline benzyl carboxylate, preparation, activity and application thereof Download PDFInfo
- Publication number
- CN109912588B CN109912588B CN201711315843.0A CN201711315843A CN109912588B CN 109912588 B CN109912588 B CN 109912588B CN 201711315843 A CN201711315843 A CN 201711315843A CN 109912588 B CN109912588 B CN 109912588B
- Authority
- CN
- China
- Prior art keywords
- carboline
- tetrahydro
- hexanoyl
- benzyl ester
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses (3S) -N- (6-amino acylamino n-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-benzyl carboxylate (wherein AA is selected from L-Lys, L-Leu, L-Met, L-Asn, L-Pro, L-Ser, L-Thr and L-Trp residue).
Description
Technical Field
The invention relates to (3S) -N- (aminoacylamino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-benzyl carboxylate with the following structure (wherein AA is selected from L-Lys, L-Leu, L-Met, L-Asn, L-Pro, L-Ser, L-Thr and L-Trp residues), a preparation method thereof, and in-vivo anti-tumor effect thereof.
Technical Field
Malignant tumors seriously threaten human health. Among them lung cancer is one of the most aggressive human cancers. For patients with advanced lung cancer, 10% -15% of the patients typically survive for only 5 years. The situation of this difficulty has not improved significantly over the last 30 years. In many clinical cases, lung cancer has metastasized to surrounding tissues before it is diagnosed. Tumor metastasis, especially tumor lung metastasis, is the greatest risk of death in tumor patients. To date, there is no antitumor drug that can prevent tumor metastasis for clinical use. Inflammation further worsens the prognosis of patients with tumors and tumor metastases. To date, no antitumor drug that can prevent inflammation and tumor metastasis has been used clinically. The invention relates to a medicament with triple effects of resisting tumor, tumor metastasis and inflammation, which is the leading edge of research on anti-tumor medicaments. The inventor's prior invention (patent application publication No. CN 106349148A, application No. CN201510409682.6) has disclosed that amino acid benzyl ester substituted bisindole acetic acid alcohol has triple effects of anti-tumor, anti-tumor metastasis and anti-inflammatory at 0.2 mu mol/kg (left formula). The minimum effective dose of benzyl bisindoloethanol amino acid to exert an antitumor effect by the inventors was unsatisfactory at 0.2. mu. mol/kg. The dosage is higher. Over the past two years, the inventors have been searching for compounds with an anti-tumour effect at a minimum effective dose of less than 0.2. mu. mol/kg. Finally, the inventor finds that the aminoacyl-6-amino caproic acid modified tetrahydrocarboline benzyl carboxylate has an anti-tumor effect at a dosage of 0.02 mu mol/kg. Because the toxic and side effects of the medicine can disappear along with the reduction of the dosage, the reduction of the effective dosage by 10 times shows that the structure modification has outstanding technical effect. Thus, the inventors have proposed the present invention.
Disclosure of Invention
The first aspect of the present invention provides benzyl (3S) -N- (aminoamido N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate of the structure (wherein AA is selected from the group consisting of L-Lys, L-Leu, L-Met, L-Asn, L-Pro, L-Ser, L-Thr and L-Trp residues).
In a second aspect, the present invention provides a process for the preparation of benzyl (3S) -N- (aminoamido N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate, which comprises:
(1) under the catalysis of dilute sulfuric acid, performing Pictet-Spengler reaction on L-tryptophan benzyl ester and formaldehyde to generate (3S) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(2) 6-aminocaproic acid and di-tert-butyl dicarbonate (Boc) in aqueous sodium hydroxide (2M), mixed solution of water and dioxane2O reaction to produce 6-tert-butyloxycarbonylaminohexanoic acid;
(3) reacting 6-tert-butoxycarbonylamino caproic acid with (3S) -2,3,4, 9-tetrahydro- β -carboline-3-benzyl carboxylate in anhydrous tetrahydrofuran in the presence of N, N-dicyclohexylcarbodiimide and N-hydroxybenzotriazole to obtain (3S) -N- (6-tert-butoxycarbonylamino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-benzyl carboxylate;
(4) removing Boc from (3S) -N- (6-amino-N-hexanoyl) -2,3,4, 9-tetrahydrocarboline-3-benzyl carboxylate in ethyl acetate solution of hydrogen chloride under ice bath to obtain (3S) -N- (6-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-benzyl carboxylate;
(5) reacting (3S) -N- (6-amino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester with Boc-AA (wherein AA is selected from L-Lys, L-Leu, L-Met, L-Asn, L-Pro, L-Ser, L-Thr and L-Trp residue) in anhydrous tetrahydrofuran in the presence of N, N-dicyclohexylcarbodiimide and N-hydroxybenzotriazole to obtain (3S) -N- (6-tert-butoxycarbonylamino-acylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(6) removing Boc from (3S) -N- (6-tert-butoxycarbonylamino-acylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester in hydrogen chloride ethyl acetate solution under ice bath to obtain (3S) -N- (6-amino-acylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester.
The third aspect of the present invention is to evaluate the inhibition of tumor growth in S180 mice by (3S) -N- (6-aminoacyl-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester.
Drawings
FIG. 1. scheme for the synthesis of (3S) -N- (6-Aminoacylamido-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester i) HCHO, H2O,H2SO4(ii) a Ii) N, N-Dicyclohexylcarbodiimide (DCC), N-hydroxybenzotriazole (HOBt), N-methylmorpholine, tetrahydrofuran; iii) dioxane, aqueous sodium hydroxide solution, di-tert-butyl dicarbonate (Boc)2O; iv) a solution of hydrogen chloride in ethyl acetate (4M).
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
EXAMPLE 1 preparation of benzyl (3S) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (1)
To 300mL of water under ice bath was slowly added 1.5mL of concentrated H2SO4And stirring for 3 min. Thereafter 5.00g (15.1mmol) L-tryptophan benzyl ester hydrochloride and 6mL formaldehyde solution (40%) were added. After stirring at room temperature for 72h, TLC showed disappearance of L-tryptophan benzyl ester hydrochloride. The reaction solution was adjusted to pH 7 with concentrated ammonia water in an ice bath and filtered. The filter cake was dissolved in 100mL of ethyl acetate, and the resulting solution was washed with a saturated aqueous solution of sodium chloride (40 mL. times.3), followed byDried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 90:1) to give 1.9g (41%) of the objective compound as a yellow oily solid. ESI-MS (m/e): 307[ M + H]+。
EXAMPLE 2 preparation of 6-tert-Butoxycarbonylaminohexanoic acid (2)
5.00g (38.2mmol) 6-aminocaproic acid (EACA) were suspended in 50mL distilled water. The resulting suspension was added with 10mL of aqueous sodium hydroxide (2M) under ice-bath and stirred until dissolved. To the resulting solution was added 9.2g (42.2 mmol) (Boc)2A solution of O and 20mL dioxane was adjusted to pH 9 with aqueous sodium hydroxide (2M) and stirred for 30 min. The ice bath was removed and stirred at room temperature until TLC showed disappearance of 6-aminocaproic acid. The reaction solution was saturated KHSO in ice bath4The pH of the aqueous solution was adjusted to 7 and the dioxane was removed by concentration under reduced pressure. The reaction solution was saturated KHSO in ice bath4The pH of the aqueous solution was adjusted to 2, and the mixture was extracted with ethyl acetate (50 mL. times.3). The ethyl acetate layer was then washed with saturated aqueous NaCl solution (40 mL. times.3), and was dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave 8.0g (91%) of the title compound as a colorless oil. ESI-MS (m/e): 232[ M + H ]]+。
EXAMPLE 3 preparation of benzyl (3S) -N- (6-tert-butoxycarbonylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (3)
Dissolving 4.15g (18mmol) of tert-butoxycarbonyl-6-aminocaproic acid in 80mL of anhydrous tetrahydrofuran, adding 2.46g (18.2mmol) of N-hydroxybenzotriazole (HOBt) and 4.04g (19.6mmol) of N, N-Dicyclohexylcarbodiimide (DCC) under ice bath, stirring for 60 min, adding a solution of 5.06g (16.5mmol) of (3S) -2,3,4, 9-tetrahydro- β -carboline-3-benzyl carboxylate and 80mL of anhydrous tetrahydrofuran to the obtained reaction solution, adjusting pH of the reaction mixture to 9 with N-methylmorpholine (NMM) under ice bath, stirring at room temperature for 24 h, TLC (3S) -2,3,4, 9-tetrahydro- β -carboline-3-benzyl carboxylate disappearance, filtering the filtrate, concentrating the filtrate under reduced pressure, adding ethyl acetate to the residue to dissolve the solution, and sequentially dissolving the saturated NaHCO in saturated NaHCO solution3Washing with an aqueous solution (40 mL. times.3), washing with a saturated aqueous NaCl solution (40 mL. times.3), and saturating KHSO4Aqueous solution (40 mL. times.3), saturated aqueous NaCl solution (40 mL. times.3), saturated aqueous NaHCO solution3Aqueous solution (40 mL. times.3), saturated aqueous NaCl solution(40 mL. times.3). Anhydrous Na for ethyl acetate layer2SO4Drying, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography (dichloromethane: methanol 160:1) gave 5.43g (64%) of the title compound as a yellow oily solid. ESI-MS (m/e): 520 [ M + H ]]+。
EXAMPLE 4 preparation of benzyl (3S) -N- (6-amino-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (4)
3.4g (6.6mmol) of benzyl (3S) -N- (tert-butoxycarbonylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate were dissolved in 40mL of hydrogen chloride in ethyl acetate (4M) under ice-bath, stirred for 3 hours, TLC showed disappearance of benzyl (3S) -N- (tert-butoxycarbonylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate, the reaction mixture was concentrated to dryness under reduced pressure with stirring, the residue was dissolved in anhydrous ethyl acetate, the solution was concentrated to dryness under reduced pressure, the operation was repeated three times, the residue was washed well with anhydrous ether to give 2.8g (94%) of the title compound as a tan solid, ESI-MS (M/e):420 [ M + H ] (M + H): 420]+；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)。
EXAMPLE 5 preparation of benzyl (3S) -N- (6-tert-butoxycarbonylalanylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5a)
Dissolving 1.14g (6mmol) of Boc-Ala and 0.82g (6.1mmol) of N-hydroxybenzotriazole (HOBt) in 30mL of anhydrous tetrahydrofuran, adding 1.36g (6.6mmol) of N, N-Dicyclohexylcarbodiimide (DCC) under ice bath, stirring for 40 minutes, adding 2.50g (5.5mmol) of a solution of (3S) -N- (6-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-benzyl carboxylate and 30mL of anhydrous tetrahydrofuran to the obtained reaction solution, adjusting pH to 8 with N-methylmorpholine under ice bath, stirring at room temperature for 12 hours, TLC (TLC shows that the (3S) -N- (6-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-benzyl carboxylate disappears, filtering the reaction solution, and decompressing the filtrateConcentrate and dissolve the residue in 100mL of ethyl acetate. The solution was sequentially saturated NaHCO3Washing with an aqueous solution (40 mL. times.3), washing with a saturated aqueous NaCl solution (40 mL. times.3), and saturating KHSO4Aqueous solution (40 mL. times.3), saturated aqueous NaCl solution (40 mL. times.3), saturated aqueous NaHCO solution3The resulting mixture was washed with an aqueous solution (40 mL. times.3) and with a saturated aqueous NaCl solution (40 mL. times.3). Anhydrous Na for ethyl acetate layer2SO4Drying, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography (dichloromethane: methanol ═ 60:1) gave 1.3g (41%) of the title compound as a pale yellow solid. ESI-MS (m/e): 591.3[ M + H]+。
EXAMPLE 6 preparation of benzyl (3S) -N- (6-bis-tert-butoxycarbonyllysylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5b)
From 0.86g (1.87mmol) of Boc-Lys (Boc) and 0.42g (1.37mmol) of benzyl (3S) -N- (6-aminon-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate according to the method of example 5, 0.54g (39%) of the title compound is obtained as a pale yellow solid ESI-MS (M/z):748[ M + H ] 748]+。
EXAMPLE 7 preparation of benzyl (3S) -N- (6-tert-butoxycarbonylleucylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5c)
Following the procedure of example 5, from 2.10g (4.6mmol) of benzyl (3S) -N- (6-aminon-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate and 1.28g (5.5mmol) of Boc-Leu, 1.62g (56%) of the title compound were obtained as a pale yellow solid ESI-MS (M/z):633[ M + H ]: 633]+。
EXAMPLE 8 preparation of benzyl (3S) -N- (6-tert-butoxycarbonylmethionyl-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5d)
According to the method of example 5, 0.35g (14%) of the title compound was obtained as a light yellow solid from 1.80g (4.0mmol) of benzyl (3S) -N- (6-aminon-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate and 1.28g (5.1mmol) of Boc-Met ESI-MS (M/z):651[ M + H ] 651]+。
EXAMPLE 9 preparation of benzyl (3S) -N- (6-tert-butoxycarbonylasparaginyl-amido-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5e)
Following the procedure of example 5, from 2.60g (5.7mmol) of (3S) -N- (6-aminon-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester and 1.46g (6.3mmol) Boc-Asn to give 0.72g (20%) of the title compound as a pale yellow solid ESI-MS (M/z):634[ M + H: -M]+。
EXAMPLE 10 preparation of benzyl (3S) -N- (6-tert-butoxycarbonylprolylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5f)
Following the procedure of example 5, from 2.00g (4.4mmol) of benzyl (3S) -N- (6-aminon-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate and 1.04g (4.8mmol) of Boc-Pro, 1.20g (44%) of the title compound was obtained as a pale yellow solid ESI-MS (M/z):617[ M + H ]: 617%]+。
EXAMPLE 11 preparation of benzyl (3S) -N- (6-tert-butoxycarbonylserylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5g)
Following the procedure of example 5, from 1.5g (3.3mmol) of benzyl (3S) -N- (6-aminohexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate and 0.74g (3.6mmol) of Boc-Ser, 0.30g (15%) of the title compound was obtained as a pale yellow solid ESI-MS (M/z):607[ M + H)]+。
EXAMPLE 12 preparation of benzyl (3S) -N- (6-tert-butoxycarbonylthreonyl-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5h)
Following the procedure of example 5, from 3.2g (7.0mmol) of benzyl (3S) -N- (6-aminon-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate and 1.69g (7.7mmol) of Boc-Thr, 0.36g (8.3%) of the title compound was obtained as a pale yellow solid ESI-MS (M/z):621[ M + H ] 621]+。
EXAMPLE 13 preparation of benzyl (3S) -N- (6-tert-butoxycarbonyltryptophanylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5i)
Following the procedure of example 5, from 3.5g (7.7mmol) of benzyl (3S) -N- (6-aminon-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate and 2.57g (8.5mmol) of Boc-Trp, 1.80g (33%) of the title compound was obtained as a light yellow solid ESI-MS (M/z):706[ M + H: 706: [ M + H ])]+。
EXAMPLE 14 preparation of benzyl (3S) -N- (6-lysylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (6a)
800mg of (3S) -N- (6-bis-tert-butoxycarbonyllysylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid are benzyl16mL of hydrogen chloride in ethyl acetate (4M) was added under ice-bath and stirred for 2h, TLC (ethyl acetate: water: glacial acetic acid ═ 3: 1: 1.2) showed disappearance of (3S) -N- (di-tert-butoxycarbonyllysylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester, the reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in anhydrous ethyl acetate and concentrated to dryness under reduced pressure, the operation was repeated three times, the residue was thoroughly washed with anhydrous ether, and then washed with C18Column chromatography purification (methanol: water ═ 30:70) and lyophilization gave 430mg (75%) of the title compound as a pale 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)。
EXAMPLE 15 preparation of benzyl (3S) -N- (6-leucylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (6b)
Following the procedure of example 14, from 1000mg of benzyl (3S) -N- (6-tert-butoxycarbonylleucylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate, 605mg (72%) of the title compound was obtained as a pale yellow solid ESI-MS (M/e):533 [ M + H ] ESI-MS (M/e)]+.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)。
EXAMPLE 16 preparation of benzyl (3S) -N- (6-methionyl-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (6c)
Pressing to realThe procedure of example 14 was followed to give from 1100mg of (3S) -N- (6-tert-butoxycarbonylmethionyl-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester 530mg (57%) of the title compound as a pale yellow solid ESI-MS (M/e):551.2 [ M + H ] 551.2]+.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)。
EXAMPLE 17 preparation of benzyl (3S) -N- (6-asparaginamidon-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (6d)
Following the procedure of example 14, from 497mg of (3S) -N- (tert-butoxycarbonylasparaginyl amido N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl, 260mg (62%) of the title compound was obtained as a light yellow solid ESI-MS (M/e):534.2 [ M + H ] ESI-MS (M/e):534.2]+.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)。
EXAMPLE 18 preparation of benzyl (3S) -N- (6-prolylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (6e)
Following the procedure of example 14, from 950mg of benzyl (3S) -N- (6-tert-butoxycarbonylprolyl-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate 598mg (75%) of the title compound are obtained as a pale yellow solid ESI-MS (M/e):517.2 [ M + H ] ESI-MS (M/e)]+.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)。
EXAMPLE 19 preparation of benzyl (3S) -N- (6-serylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (6f)
Following the procedure of example 14, from 825mg of benzyl (3S) -N- (6-tert-butoxycarbonylserylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate, 448mg (65%) of the title compound was obtained as a pale yellow solid ESI-MS (M/e):507.2 [ M + H ] ESI-MS (M/e)]+.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)。
EXAMPLE 20 preparation of benzyl (3S) -N- (6-threonyl-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (6g)
Following the procedure of example 14, from 479mg of benzyl (3S) -N- (6-tert-butoxycarbonylthreonyl amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate, 172mg (43%) of the title compound was obtained as a pale yellow solid ESI-MS (M/e):521.2 [ M + H ] ESI-MS (M/e)]+.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)。
EXAMPLE 21 preparation of (3S) -N- (6-Tryptophan-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester hydrochloride (6H) 580mg (71%) of the title compound as a light yellow solid was obtained from 950mg of (3S) -N- (6-tert-butoxycarbonyl-tryptophanyl-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester according to the procedure of example 14 ESI-MS (M/e):606.3 [ M + H ] ESI-MS (M/e):606.3]+.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)。
Experimental example 1 evaluation of antitumor Activity of Compounds 6a-h
1) Dissolving the compound 6a-h by using normal saline, dissolving the adriamycin by using the normal saline as a positive control, and using the normal saline as a negative control;
2) the oral dose of the compounds 6a-h is 0.02 mu mol/kg, the oral dose of the compound 4 is 0.2 mu mol/kg, the oral dose of physiological saline is 0.2mL/20g, and the intraperitoneal injection dose of adriamycin is 2 mu mol/kg. The administration was carried out immediately after tumor inoculation, 10 days continuously, and 10 times in total.
3) The experimental animals were ICR male mice (clean grade) weighing 20 + -2 g, 12 mice per group.
4) The tumor source is mouse S180 sarcoma purchased from animal experiment center of department of medicine of Beijing university and maintained by self passage.
5) Inoculating S180 ascites tumor liquid which grows vigorously under aseptic condition, diluting the liquid into liquid (1:2) by using normal saline, fully mixing, staining tumor cell suspension by using freshly prepared 0.2% trypan blue, uniformly mixing, counting according to a white cell counting method, wherein the blue stained cells are dead cells, and the non-stained cells are live cells. The cell concentration is 4-large-grid viable cell number/4 × 104The cell concentration was calculated by x dilution factor ═ cell number/mL. Survival rate of cellsCell viability was calculated as the number of cells/(number of live cells + number of dead cells). times.100%.
Preparing tumor solution with survival rate of more than 90% into 2.0 × 10 by homogenizing method7One cell/mL of the cell suspension was inoculated subcutaneously to the mouse axilla, and 0.2 mL/mouse was prepared as S180 tumor-bearing mice. Administration was immediately after tumor inoculation. The treatment group mice were orally administered compound 4 at a dose of 0.2. mu. mol/kg or compound 6a-h at a dose of 0.02. mu. mol/kg per day. The daily oral physiological saline dose of the blank group of mice is 0.2mL/20 g. The dose of the positive control group of mice injected with adriamycin into the abdominal cavity every day is 2 mu mol/kg. The administration was continued for ten days, and on the eleventh day, the mice were weighed, anesthetized with ether, sacrificed by removing the cervical vertebrae, then the right axillary tumor growth sites of the mice were fixed with forceps, the skin was cut open, the tumors were exposed, blunt-stripped, and weighed. Experimental data were expressed as (mean ± SDg) tumor weights using t-test and analysis of variance. The results are shown in Table 1. As can be seen from Table 1, compounds 6a-h were effective in inhibiting tumor regrowth in mice at an oral dose of 0.02 μmol/kg. The invention has obvious technical effect.
TABLE 1 antitumor Activity of Compounds 6a-h
a) P <0.05, n-12 with saline.
Claims (3)
1.(3S) -N- (6-aminoacyl-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester compound with the following structure, wherein AA is selected from L-Lys or L-Leu or L-Met or L-Asn or L-Pro or L-Ser or L-Thr or L-Trp residue,
2. a process for preparing a benzyl (3S) -N- (6-aminoacylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate compound of the structure of claim 1, which comprises the steps of:
(1) in dilute sulfuric acid (H)2SO4) Under the catalysis of the (3S) -benzyl 2,3,4, 9-tetrahydro- β -carboline-3-carboxylate is generated by the Pictet-Spengler reaction of L-tryptophan benzyl ester and formaldehyde;
(2) 6-aminocaproic acid and di-tert-butyl dicarbonate (Boc) in a 2M aqueous solution of sodium hydroxide, a mixed solution of water and dioxane2O reaction to produce 6-tert-butyloxycarbonylaminohexanoic acid;
(3) reacting 6-tert-butoxycarbonylaminocaproic acid with (3S) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester in anhydrous Tetrahydrofuran (THF) in the presence of N, N-Dicyclohexylcarbodiimide (DCC) and N-hydroxybenzotriazole (HOBt) to obtain (3S) -N- (6-tert-butoxycarbonylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(4) removing Boc from (3S) -N- (6-tert-butoxycarbonylamino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester in 4M hydrogen chloride ethyl acetate solution under ice bath to obtain (3S) -N- (6-amino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(5) reacting (3S) -N- (6-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester with Boc-AA in the presence of N, N-Dicyclohexylcarbodiimide (DCC) and N-hydroxybenzotriazole (HOBt) in dried Tetrahydrofuran (THF) to obtain (3S) -N- (6-tert-butoxycarbonylaminoacylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester, wherein AA is selected from L-Lys or L-Leu or L-Met or L-Asn or L-Pro or L-Ser or L-Thr or L-Trp residue;
(6) removing Boc from (3S) -N- (6-tert-butoxycarbonylamino-acylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester in 4M hydrogen chloride ethyl acetate solution under ice bath to obtain (3S) -N- (6-amino-acylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester.
3. The use of a (3S) -N- (6-aminoacylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester compound of the structure of claim 1 in the preparation of an anti-tumor medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711315843.0A CN109912588B (en) | 2017-12-12 | 2017-12-12 | 6-amino amido n-hexanoyl carboline benzyl carboxylate, preparation, activity and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711315843.0A CN109912588B (en) | 2017-12-12 | 2017-12-12 | 6-amino amido n-hexanoyl carboline benzyl carboxylate, preparation, activity and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109912588A CN109912588A (en) | 2019-06-21 |
| CN109912588B true CN109912588B (en) | 2020-06-19 |
Family
ID=66957262
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711315843.0A Active CN109912588B (en) | 2017-12-12 | 2017-12-12 | 6-amino amido n-hexanoyl carboline benzyl carboxylate, preparation, activity and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109912588B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2017
- 2017-12-12 CN CN201711315843.0A patent/CN109912588B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109912588A (en) | 2019-06-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109912587B (en) | Side chain protection amido n-hexanoyl carboline benzyl carboxylate, preparation, activity and application thereof | |
| CN109111501B (en) | Fatty amino acid modified indole ethanol derivative, and synthesis, activity and application thereof | |
| CN109912590B (en) | Amino acid and amino n-hexanoic acid modified carboline benzyl carboxylate, and preparation, activity and application thereof | |
| CN109912588B (en) | 6-amino amido n-hexanoyl carboline benzyl carboxylate, preparation, activity and application thereof | |
| CN108976159A (en) | The indoles alcohol derivative of ArAA modification, synthesis, activity and application | |
| CN109912589B (en) | Glutamine amido n-hexyl carboline carboxylic acid benzyl ester, preparation, activity and application thereof | |
| CN110551119B (en) | 6-Aminoacylamino n-hexanoyl carboline carboxylic acid benzyl ester, preparation and application thereof | |
| CN110551121B (en) | Glutamine amido n-hexyl carboline carboxylic acid benzyl ester, preparation, activity and application thereof | |
| CN112175014B (en) | Nitric oxide donor type tetravalent platinum derivative, preparation method and medical application thereof | |
| CN108929320B (en) | 3R-indolylmethyl-6R-oxazolidinone modified piperazine-2, 5-dione, synthesis, activity and application thereof | |
| CN114315930A (en) | Compound or pharmaceutically acceptable salt thereof, pharmaceutical composition and application | |
| CN108948137B (en) | 3S-indolylethyl-6S-polar amino acid modified piperazine-2, 5-diketone and synthesis, activity and application thereof | |
| CN110551120B (en) | 6-amino amido n-hexanoyl carboline benzyl carboxylate, preparation, activity and application thereof | |
| CN109134595B (en) | Theanyl amino acid benzyl ester modified curcumin, and synthesis, activity and application thereof | |
| CN110577568B (en) | Methyl indole and amide side chain amino acid modified diketopiperazine, synthesis, activity and application thereof | |
| CN110577518B (en) | Methyl indole and amide side chain amino acid modified diketopiperazine, synthesis and application thereof | |
| CN108976204B (en) | 3S-indolylmethyl-6R-aspartic acid modified piperazine-2, 5-dione, and synthesis, activity and application thereof | |
| CN109456311B (en) | 3R-indolylmethyl-6R-aromatic amino acid modified piperazine-2, 5-diketone and synthesis, activity and application thereof | |
| CN109081802B (en) | Indole ethanol derivative modified by basic amino acid, and synthesis, activity and application thereof | |
| CN110577516B (en) | Amino acid and tranexamic acid modified diketopiperazines, their preparation and use | |
| CN108976207B (en) | 3S-indolylmethyl-6R-fatty side chain amino acid modified piperazine-2, 5-diketone, synthesis, activity and application | |
| CN108948141B (en) | 3R-indolylmethyl-6S-Pro modified piperazine-2, 5-dione, synthesis, activity and application thereof | |
| CN108947978B (en) | 3R-indolylmethyl-6R-Tyr modified piperazine-2, 5-diketone and synthesis, activity and application thereof | |
| CN108947977B (en) | Piperazine-2, 5-diketone modified by 3R-indolylmethyl-6R-amide side chain amino acid, and synthesis, activity and application thereof | |
| CN108947979B (en) | 3R-indolylmethyl-6R-polar amino acid modified piperazine-2, 5-dione, and synthesis, activity and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |