CN113754725B - Synthesis, biological activity and application of dimethyl dioxane-tetrahydro-beta-carboline-3-formyl-RGDV - Google Patents
Synthesis, biological activity and application of dimethyl dioxane-tetrahydro-beta-carboline-3-formyl-RGDV Download PDFInfo
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- CN113754725B CN113754725B CN202010500707.4A CN202010500707A CN113754725B CN 113754725 B CN113754725 B CN 113754725B CN 202010500707 A CN202010500707 A CN 202010500707A CN 113754725 B CN113754725 B CN 113754725B
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- 230000015572 biosynthetic process Effects 0.000 title claims description 4
- 238000003786 synthesis reaction Methods 0.000 title claims description 4
- 230000004071 biological effect Effects 0.000 title description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 title description 2
- -1 2, 2-dimethyl-1, 3-dioxane-5-yl Chemical group 0.000 claims abstract description 64
- 206010047249 Venous thrombosis Diseases 0.000 claims abstract description 30
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- 239000003814 drug Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 25
- ZHXOXUOJFRIQRZ-HMTLIYDFSA-N benzyl (3S)-1-(2,2-dimethyl-1,3-dioxan-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate Chemical compound CC(C)(OC1)OCC1C(C1=C(C2)C3=CC=CC=C3N1)N[C@@H]2C(OCC1=CC=CC=C1)=O ZHXOXUOJFRIQRZ-HMTLIYDFSA-N 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 16
- YTPNCKPHWVISQO-MLCCFXAWSA-N (3S)-1-(2,2-dimethyl-1,3-dioxan-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid Chemical compound CC(C)(OC1)OCC1C(C1=C(C2)C3=CC=CC=C3N1)N[C@@H]2C(O)=O YTPNCKPHWVISQO-MLCCFXAWSA-N 0.000 claims description 13
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 7
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- DIEPFYNZGUUVHD-UHFFFAOYSA-N 2-[(4-chlorophenyl)methyl]-3-hydroxy-7,8,9,10-tetrahydrobenzo[h]quinoline-4-carboxylic acid Chemical compound N=1C2=C3CCCCC3=CC=C2C(C(=O)O)=C(O)C=1CC1=CC=C(Cl)C=C1 DIEPFYNZGUUVHD-UHFFFAOYSA-N 0.000 claims 1
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- VGALFAWDSNRXJK-VIFPVBQESA-N L-aspartic acid beta-benzyl ester Chemical compound OC(=O)[C@@H](N)CC(=O)OCC1=CC=CC=C1 VGALFAWDSNRXJK-VIFPVBQESA-N 0.000 description 2
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- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
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- JXYACYYPACQCDM-UHFFFAOYSA-N Benzyl glycinate Chemical compound NCC(=O)OCC1=CC=CC=C1 JXYACYYPACQCDM-UHFFFAOYSA-N 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val, a synthesis method thereof, an anti-arterial thrombosis activity and an anti-venous thrombosis activity, and a targeting effect thereof on arterial thrombosis and venous thrombosis. Therefore, the invention discloses the application of the composition in preparing targeted anti-arterial thrombosis medicaments and targeted anti-venous thrombosis medicaments.
Description
Technical Field
The invention relates to a compound (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val, a synthesis method thereof, an anti-arterial thrombosis activity and an anti-venous thrombosis activity, and a targeting effect thereof on arterial thrombosis and venous thrombosis. The invention thus relates to its use in the preparation of targeted anti-arterial thrombosis medicaments and targeted anti-venous thrombosis medicaments. The invention belongs to the field of biological medicine.
Background
Thrombotic diseases have become one of the major diseases that endanger human health. Arterial thrombosis and venous thrombosis can be classified according to the site and mechanism of occurrence. Thrombus can cause serious harm to the body. Arterial thrombosis can lead to transient cerebral ischemia, acute coronary syndrome, myocardial infarction and atrial fibrillation. Among venous thrombosis, deep venous thrombosis of lower limbs, pulmonary embolism and cerebral apoplexy have serious influence on the life quality of patients. Venous thrombosis and arterial thrombosis are regarded as two different diseases under traditional ideas due to the different etiologies. In epidemiological studies, the association of venous and arterial thrombi is difficult to sever and is attributed to their overlapping risk factors. These knowledge has led the inventors to pay attention to the study of drugs having both anti-arterial and anti-venous thrombosis effects.
Clinically, oral anticoagulants are a popular strategy for treating thrombotic diseases. Although oral anticoagulants have definite therapeutic effects on thrombotic diseases, they all have bleeding side effects. For example, aspirin can induce gastrointestinal bleeding or intracranial bleeding at an effective oral dosage. Warfarin also presents a fatal bleeding risk. These knowledge has led the inventors to pay great attention to antithrombotic drug studies that do not alter clotting time or bleeding time.
Through extensive creative research, the inventor finds that (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid with the following formula has double functions of resisting arterial thrombosis and venous thrombosis, does not change clotting time and bleeding time, and reduces plasma P-selectin and GPIIb/IIIa level. However, the targeting research shows that the targeting agent has no arterial thrombosis targeting effect and no venous thrombosis targeting effect. This condition drives the structural modification of (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylic acid. Through repeated exploration, the inventor finds that (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val has both arterial thrombosis targeting effect and venous thrombosis targeting effect. Based on this knowledge, the inventors have proposed the present invention.
Disclosure of Invention
The first aspect of the present invention provides (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val of the formula.
The second aspect of the present invention is to provide a method for synthesizing (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val, comprising:
(A) Synthesizing (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-carboxylic acid benzyl ester;
(B) Synthesizing (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid benzyl ester;
(C) Synthesizing (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid;
(D) Liquid phase synthesis of Arg (NO 2) -Gly-Asp (OBzl) -Val-OBzl from N end to C end by using dicyclohexylcarbodiimide as condensing agent and 1-hydroxybenzotriazole as catalyst through gradual peptide grafting;
(E) Coupling (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid with Arg (NO 2) -Gly-Asp (OBzl) -Val-OBzl to prepare (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg (NO 2) -Gly-Asp (OBzl) -Val-OBzl by using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst;
(F) Deprotection of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg (NO 2) -Gly-Asp (OBzl) -Val-OBzl to prepare (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val.
The third aspect of the present invention is to evaluate the antithrombotic activity of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val.
The fourth aspect of the present invention is to evaluate the anti-venous thrombosis activity of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val.
The fifth aspect of the present invention is to evaluate the effect of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val on plasma P-selectin and GPIIb/IIIa content.
The sixth aspect of the present invention is to evaluate the effect of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val on clotting time and bleeding time.
The seventh aspect of the present invention is to evaluate the targeting effect of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val on arterial thrombosis.
The eighth aspect of the present invention is to evaluate the targeting effect of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val on venous thrombosis.
Drawings
FIG. 1 (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val is synthesized by i) trifluoroacetic acid, 1, 3-dihydroxyacetone; ii) H 2SO4, acetone, mgSO 4;iii)Pd/C,H2, methanol; iv) Dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine, anhydrous Tetrahydrofuran (THF); v) 2N NaOH, methanol; vi) ethyl acetate solution of hydrogen chloride (4M).
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention.
EXAMPLE 1 preparation of (3S) -1, 1-dihydroxymethyl-1, 2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid benzyl ester (1)
1.0G (3.6 mmol) of benzyl L-tryptophan was dissolved with 10mL of methylene chloride with stirring. To the resulting solution was slowly added dropwise 0.5mL of trifluoroacetic acid followed by 0.39g (4.3 mmol) of 1, 3-dihydroxyacetone under ice-bath cooling. The reaction mixture was stirred at room temperature for 7 hours, and TLC showed disappearance of benzyl L-tryptophan (dichloromethane: methanol, 30:1). To the reaction mixture was added 30mL of saturated aqueous NaHCO 3 under ice-bath cooling, and the dichloromethane layer was separated. Then, the solution was washed with saturated aqueous NaHCO 3 (30 mL. Times.2) and then with saturated aqueous NaCl (30 mL. Times.3). The separated dichloromethane layer was dried over anhydrous sodium sulfate for 12 hours. Filtration under reduced pressure, and concentration of the filtrate under reduced pressure gave 1.01g (81%) of the title compound as yellow powder .1H NMR(DMSO-d6,300MHz):δ/ppm＝2.52(m,2H),3.00(dd,J1＝15Hz,J2＝3Hz,1H),3.56(m,3H),3.77(m,1H),4.03(m,1H),4.81(s,2H),5.23(m,2H),6.98(dt,J1＝27Hz,J2＝6Hz,2H),7.40(m,7H),10.57(s,1H).
Example 2 preparation of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid benzyl ester (2)
0.8G (2.2 mmol) of (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-carboxylic acid benzyl ester (1) is dissolved in 16mL of acetone. To the resulting solution was slowly added dropwise 400. Mu.L of concentrated sulfuric acid followed by 316mg (2.6 mmol) of anhydrous MgSO 4 under ice-bath cooling. The reaction mixture was stirred at room temperature for 8 hours, TLC showed disappearance of compound 1 (petroleum ether: ethyl acetate, 4:1). The filtrate was filtered, the pH of the filtrate was adjusted to 7 with saturated aqueous NaHCO 3 under ice-bath cooling, acetone was removed by concentration under reduced pressure, the residue was extracted with ethyl acetate (20 mL. Times.3), the ethyl acetate layers were combined and washed with saturated aqueous NaCl solution (40 mL. Times.3). The ethyl acetate layer was dried over anhydrous sodium sulfate for 12h. Filtration, concentration of the filtrate under reduced pressure, and separation of the residue by silica gel column chromatography (petroleum ether: ethyl acetate, 4:1) gave 0.33g (37%) of the title compound as colorless powder .1H NMR(DMSO-d6,300MHz):δ/ppm＝1.38(s,3H),1.62(s,3H),2.72(m,1H),3.04(m,1H),3.52(d,J＝12Hz,1H),3.85(d,J＝12Hz,1H),3.99(m,2H),4.46(d,J＝12Hz,1H),5.26(s,2H),7.03(dt,J1＝30Hz,J2＝7.5Hz,2H),7.40(m,7H),11.05(s,1H).13C NMR(DMSO-d6,75MHz):δ/ppm＝19.3,25.6,29.1,51.8,63.8,66.5,68.8,98.1,108.7,111.7,118.3,119.1,121.7,126.7,128.3,128.6,129.0,133.2,136.5,136.6,172.9.ESI-MS(m/e):407[M+H]+.
Example 3 preparation of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid (3)
To 5mL of methanol were added 285mg (0.7 mmol) of benzyl (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylate (2) and 30mg palladium on carbon. The reaction was carried out at room temperature for 12 hours with hydrogen, and TLC showed disappearance of Compound 2 (Petroleum ether: ethyl acetate, 4:1). Filtration, concentration of the filtrate under reduced pressure, and trituration of the residue with diethyl ether afforded 201mg (91%) of the title compound as a colorless powder .1H NMR(DMSO-d6,300MHz):δ/ppm＝1.40(s,3H),1.63(s,3H),2.67(m,1H),3.02(dd,J1＝15Hz,J2＝3Hz,1H),3.56(d,J＝12Hz,1H),3.83(m,2H),4.03(d,J＝12Hz,1H),4.48(d,J＝12Hz,1H),7.04(dt,J1＝30Hz,J2＝7.5Hz,2H),7.40(dt,J1＝24Hz,J2＝9Hz,2H),11.07(s,1H).13C NMR(DMSO-d6,75MHz):δ/ppm＝19.5,25.6,29.1,51.8,52.0,63.8,68.7,98.2,109.2,111.7,118.3,119.1,121.7,126.7,133.0,136.7,174.3.ESI(-)-FT-ICR-MS(m/e):315.13382[M-H]-,( theory: 315.13393. HPLC purity 99.4%.
EXAMPLE 4 preparation of Boc-Arg (NO 2) -Gly-OBzl
960Mg (3.0 mmol) of Boc-Arg (NO 2) was suspended in 30mL of anhydrous tetrahydrofuran. 450mg (3.3 mmol) of 1-hydroxybenzotriazole (HOBt) and 751mg (3.6 mmol) of Dicyclohexylcarbodiimide (DCC) were added to the suspension in an ice bath, and the mixture was stirred for 30 minutes to give a reaction solution A. Under ice bath, 1.11g (3.3 mmol) of Gly-OBzl was dissolved in 10mL of anhydrous tetrahydrofuran, and the pH of the solution was adjusted to 8 with N-methylmorpholine to obtain a reaction solution B. The reaction solution B was added to the reaction solution A, the ice bath was removed, and the mixture was stirred at room temperature for 12 hours. TLC monitored the reaction to completion (CH 2Cl2/CH3 OH, 20/1) and concentrated under reduced pressure. The residue was dissolved with a small amount of ethyl acetate and insoluble matters were filtered off. The filtrate was washed successively with saturated aqueous NaHCO 3 (30 mL. Times.3), saturated aqueous NaCl (30 mL. Times.3), 5% aqueous KHSO 4 (30 mL. Times.3), saturated aqueous NaCl (30 mL. Times.3), saturated aqueous NaHCO 3 (30 mL. Times.3), and saturated aqueous NaCl (30 mL. Times.3). The ethyl acetate phase was dried over anhydrous sodium sulfate for 12h. Filtration and concentration of the filtrate under reduced pressure gave a pale yellow oil which was crystallized from 30mL of methylene chloride to give 1.23g (88%) of the title compound as a colorless solid .1H-NMR(300MHz,DMSO-d6):δ/ppm＝8.482(s,1H),8.260(t,J＝5.4Hz,1H),7.352(m,5H),6.872(d,J＝8.2Hz,1H),5.121(s,2H),3.888(m,3H),3.105(m,2H),2.448(m,2H),1.501(m,4H),1.378(s,9H).
EXAMPLE 5 preparation of Boc-Asp (OBzl) -Val-OBzl
Using the procedure of example 4, 1.33g (87%) of the title compound were obtained as colorless powder from 970mg (3.0 mmol) of Boc-Asp (OBzl) and 805mg (3.3 mmol) of Val-OBzl .1H NMR(DMSO-d6,300MHz):δ/ppm＝0.85(d,J＝6Hz,6H),1.38(s,9H),2.05(m,1H),2.65(m,2H),4.24(t,J＝6Hz,1H),4.45(m,1H),5.13(m,4H),7.29(m,11H),8.0 1(d,J＝9Hz,1H).
EXAMPLE 6 preparation of Boc-Arg (NO 2) -Gly
935Mg (2.0 mmol) of Boc-Arg (NO 2) -Gly-OBzl was dissolved in 10mL of methanol and the pH of the solution was adjusted to 12 with 2 molar NaOH in water under ice bath, stirred for 4h and TLC monitored for completion. The reaction mixture was pH adjusted to 7 with 5% khso 4 under a bath and concentrated under reduced pressure to remove methanol. The residue was adjusted to pH 2 with dilute hydrochloric acid under ice bath, extracted with ethyl acetate (30 mL. Times.3), washed with saturated aqueous NaCl solution (30 mL. Times.3), and dried over anhydrous sodium sulfate for 12h. Filtration and concentration of the filtrate under reduced pressure gave 635mg (84%) of the title compound as a colorless solid. ESI-MS (m/e): 375[ M-H ] -.
EXAMPLE 7 preparation of Asp (OBzl) -Val-OBzl
1.02G (2.0 mmol) of Boc-Asp (OBzl) -Val-OBzl are slowly dissolved in 10mL of 4 molar hydrogen chloride in ethyl acetate under ice-bath. The solution was stirred for 4h and TLC monitored for reaction completion (petroleum ether/ethyl acetate, 3/1). Concentrated under reduced pressure, and the residue was dissolved in 5mL of dried ethyl acetate. The solution was concentrated under reduced pressure and the residue was dissolved with 5mL of dried ethyl acetate. The solution was concentrated under reduced pressure and the residue was repeatedly washed with 5mL of dry diethyl ether to give 800mg (90%) of the title compound as a colorless solid. ESI-MS (m/e): 413[ M+H ] +.
EXAMPLE 8 preparation of Boc-Arg (NO 2) -Gly-Asp (OBzl) -Val-OBzl
Using the procedure of example 4, 1.01g (88%) of the title compound were obtained as colorless powder from 565mg (1.5 mmol) of Boc-Arg (NO 2) -Gly and 718mg (1.6 mmol) of Asp (OBzl) -Val-OBzl .1H NMR(DMSO-d6,300MHz):δ/ppm＝0.85(d,J＝6Hz,6H),1.37(s,9H),1.58(m,4H),2.07(m,1H),2.57(m,1H),2.76(m,1H),3.12(m,2H),3.71(m,2H),3.94(m,1H),4.18(t,J＝6Hz,1H),4.77(m,1H),5.09(m,4H),6.97(d,J＝6Hz,1H),7.35(m,10H),8.07(s,1H),8.15(d,J＝6Hz,1H),8.26(d,J＝9Hz,1H),8.49(s,1H).
EXAMPLE 9 preparation of Arg (NO 2) -Gly-Asp (OBzl) -Val-OBzl
Using the procedure of example 7, 435mg (88%) of the title compound are obtained as colorless solid from 470mg (0.7 mmol) of Boc-Arg (NO 2) -Gly-Asp (OBzl) -Val-OBzl. ESI-MS (m/e): 671[ M+H ].
EXAMPLE 10 preparation of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg (NO 2) -Gly-Asp (OBzl) -Val-OBzl (4)
Using the procedure of example 4 from 190mg (0.6 mmol) (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylic acid and 430mg (0.61 mmol) Arg (NO 2) -Gly-Asp (OBzl) -Val-OBzl gave 520g (90%) of the title compound as colorless powder .1H NMR(DMSO-d6,300MHz):δ/ppm＝0.85(d,J＝6Hz,6H),1.39(s,3H),1.62(m,7H),2.07(m,1H),2.27(s,1H),2.62(m,2H),2.67(m,1H),3.03(m,2H),3.16(m,2H),3.68(m,5H),3.99(d,J＝12Hz,1H),4.19(t,J＝6Hz,1H),4.38(m,2H),4.78(m,1H),5.08(m,4H),6.97(t,J＝6Hz,1H),7.07(t,J＝6Hz,1H),7.35(m,12H),8.02(d,J＝9Hz,1H),8.17(d,J＝6Hz,1H),8.31(m,2H),8.54(s,1H),10.92(s,1H).13C NMR(DMSO-d6,75MHz):δ/ppm＝18.6,19.4,20.3,26.3,28.2,29.6,30.3,36.6,42.4,49.6,51.6,52.7,53.0,55.5,58.1,64.7,66.1,66.4,66.5,68.5,98.1,109.0,111.7,118.1,119.1,121.6,126.7,128.3,128.4,128.5,128.6,128.8,128.9,133.8,136.3,136.4,136.5,159.7,169.2,170.3,171.1,171.5,172.2,173.4.
EXAMPLE 11 preparation of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val (5)
To 5mL of methanol were added 485mg (0.5 mmol) (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carbolin-3-formyl-Arg (NO 2) -Gly-Asp (OBzl) -Val-OBzl (4) and 50mg palladium on carbon. After stirring, hydrogen was introduced for 12h and TLC showed disappearance of Compound 4 (CH 2Cl2/CH3 OH, 50/1). Filtering, and concentrating the filtrate under reduced pressure. The residue was triturated with diethyl ether to give 340mg (92%) of the title compound as a colorless powder .1H NMR(DMSO-d6,300MHz):δ/ppm＝0.81(d,J＝6Hz,6H),1.40(s,3H),1.61(m,7H),2.06(m,2H),2.31(m,2H),2.60(m,2H),3.00(m,3H),3.58(m,2H),3.67(m,1H),3.79(d,J＝12Hz,1H),4.01(m,3H),4.39(m,3H),7.05(m,5H),7.40(dd,J1＝18Hz,J2＝6Hz,2H),8.06(d,J＝9Hz,1H),8.70(s,1H),9.03(d,J＝9Hz,1H),10.34(s,1H),10.92(s,1H);13C NMR(DMSO-d6,75MHz):δ/ppm＝18.2,19.6,20.5,24.9,26.3,28.2,31.2,37.8,42.9,49.1,50.6,51.6,52.5,52.9,58.3,64.8,66.5,68.5,98.1,109.1,111.7,118.2,119.1,121.5,126.7,133.9,136.5,157.9,169.0,170.8,172.7,173.0,173.8,175.6.ESI(+)-FT-ICR-MS(m/e):744.36409[M+H]+.HPLC% pure 97.60%.
Example 12 evaluation of anti-arterial thrombotic Activity
Male SD strain rats (250+ -20 g) purchased from Peking Vitre Liwa laboratory animal technologies Co.
The oral dosage of the compound (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val is 0.1 mu mol/kg, the oral dosage of positive control aspirin is 167 mu mol/kg, and the negative control is physiological saline.
The arterial thrombosis resistance was evaluated using the rat arterial venous bypass circulation silk-wire antithrombotic model. Rats were acclimatized and fasted for one day prior to surgery, male SD rats were randomized into physiological saline group (3 mL/kg) (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val group (0.1. Mu. Mol/kg) and aspirin group (167. Mu. Mol/kg). After 30 minutes of administration, the rats were anesthetized with 20% uratam solution (7 mL/kg, abdominal cavity). After sufficient anesthesia, the neck skin was cut and the right carotid artery and left jugular vein were separated. In a polyethylene tube, a precisely weighed 6cm long wire was added. The polyethylene tube was filled with a physiological saline solution (50 IU/mL) of heparin sodium, and the ends thereof were inserted into the left jugular vein and the right carotid artery, respectively, and blood was allowed to flow through the polyethylene tube for 15 minutes. Finally, the silk thread is taken out from the polyethylene tube, the weight increase of the silk thread is calculated to obtain the weight of thrombus, and the sample is reserved for measuring the arterial thrombus targeting effect. Blood from rats was left for the determination of plasma P-selectin and GPIIb/IIIa levels. To avoid the effect of the surgical time on the experimental results, the surgery was performed alternately in groups of three.
The measured antithrombotic activity is shown in Table 1. The thrombus weights of each group in Table 1 show that (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val can effectively inhibit arterial thrombosis of rats at an oral dose of 0.1 mu mol/kg, and the activity of the oral dose of 167 mu mol/kg of aspirin is not significantly different, namely, is equivalent to 1670 times of the activity of aspirin. It can be seen that the present invention has outstanding technical effects.
TABLE 1 antithrombotic Activity
A) Ratio to normal saline P <0.01, ratio to 167. Mu. Mol/kg aspirin P >0.05; compound 5 represents (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val; n=12.
EXAMPLE 13 evaluation of arterial thrombosis rat plasma P-selectin concentration
4ML of rat blood subjected to the anti-arterial thrombosis activity test is taken, EDTA is added for anticoagulation, 1000g is centrifuged for 15 minutes, and the supernatant plasma is taken for standby. The concentration of P-selectin in plasma of arterial thrombotic rats treated with rat P-selectin ELISA kit (rate P-SELECTIN ELISA KIT, CSB-E08776r, cusabio Biotech, USA) was determined with physiological saline (3 mL/kg) and (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val (0.1. Mu. Mol/kg). Balancing detection reagent in the kit for 30 minutes at room temperature, preparing standard solution, detection reagent and washing liquid under each concentration, setting 3 compound holes of the standard substance, taking 5 samples from a sample group to be detected, setting 2 compound holes of each sample, adding samples according to instructions, incubating, detecting and processing data. The data in Table 2 demonstrate that the concentration of P-selectin in plasma of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val treated arterial thrombosis rats is significantly lower than that of normal saline treated arterial thrombosis rats at an oral dose of 0.1. Mu. Mol/kg. It can be seen that the present invention has outstanding technical effects.
TABLE 2P-selectin concentration in arterial thrombosis rat plasma
A) Ratio P to physiological saline is less than 0.01; compound 5 represents (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val; n=12.
EXAMPLE 14 evaluation of arterial thrombosis rat plasma GPIIb/IIIa concentration
4ML of rat blood subjected to the anti-arterial thrombosis activity test is taken, EDTA is added for anticoagulation, 1000g is centrifuged for 15 minutes, and the supernatant plasma is taken for standby. The concentration of GPIIb/IIIa in plasma of arterial thrombotic rats treated with rat P-selectin ELISA kit (rate GPIIb/IIIA ELISA KIT, CSB-E08776r, cusabio Biotech, USA) was determined with physiological saline (3 mL/kg) and (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val (0.1. Mu. Mol/kg). Balancing detection reagent in the kit for 30 minutes at room temperature, preparing standard solution, detection reagent and washing liquid under each concentration, setting 3 compound holes of the standard substance, taking 5 samples from a sample group to be detected, setting 2 compound holes of each sample, adding samples according to instructions, incubating, detecting and processing data. The data in Table 3 demonstrate that the concentration of GPIIb/IIIa in plasma of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val treated arterial thrombosis rats is significantly lower than the concentration of GPIIb/IIIa in plasma of saline treated arterial thrombosis rats at an oral dose of 0.1. Mu. Mol/kg. It can be seen that the present invention has outstanding technical effects.
TABLE 3 GPIIb/IIIa concentration in arterial thrombosis rat plasma
A) Ratio P to physiological saline is less than 0.01; compound 5 represents (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val; n=12.
Example 15 evaluation of arterial thrombosis targeting
An arterial thrombus sample of an arterial thrombus rat treated with physiological saline and 0.1. Mu. Mol/kg oral dose of (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carbolin-3-formyl-Arg-Gly-Asp-Val was placed in a 5mL centrifuge tube, 1mL of chromatographic methanol was added, the thrombus tissue was crushed with a spatula, sonicated for 30min, the supernatant was sucked into the centrifuge tube after standing, the residue was soaked with ethyl acetate for 24 hours and sonicated for 30min, and the ethyl acetate supernatant was collected. The residue was added with 3mL of ethyl acetate, and after 30 minutes of sonication, the supernatant was collected and the above was repeated 3 times. The ethyl acetate phases were combined, concentrated under reduced pressure to remove ethyl acetate, and the residue was dissolved in 1mL of chromatographic methanol and the solution was subjected to ESI (+) -FT-ICR-MS analysis. The results show that the ESI (+) -FT-ICR-MS spectrum of arterial thrombus samples of arterial thrombus rats treated with (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val showed a peak of molecular ion addition H at 744.36630 for (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val-and a peak of molecular ion addition H at 317.14760 for (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-line-3-carboxylic acid. The ESI (+) -FT-ICR-MS spectra of arterial thrombus samples of saline-treated arterial thrombus rats had neither a peak of molecular ion addition H of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val nor a peak of molecular ion addition H of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid.
A homogenate extract sample was prepared from heart, liver, brain, spleen, lung and kidney of arterial thrombosis rats treated with 0.1. Mu. Mol/kg of oral dose (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carbolin-3-formyl-Arg-Gly-Asp-Val for ESI (+) -FT-ICR-MS analysis according to the procedure above. The results showed that they showed neither peaks of molecular ion of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val plus H nor peaks of molecular ion of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylic acid plus H in ESI (+) -FT-ICR-MS spectra.
It can be seen that (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val only entered rat arterial thrombosis and not into rat organs. It is apparent that this is arterial thrombotic targeting.
EXAMPLE 16 evaluation of anti-venous Thrombus Activity
Male SD strain rats (250+ -20 g) purchased from Peking Vitre Liwa laboratory animal technologies Co.
The oral dosage of the compound (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val is 0.1 mu mol/kg, the oral dosage of positive control warfarin is 4.87 mu mol/kg, and the negative control is normal saline.
The anti-venous thrombotic activity was evaluated using the rat inferior vena cava ligation model. The rats were acclimatized and fasted for one day prior to surgery, male SD rats were randomized into groups of 12. After 30min of administration, rats were anesthetized with 20% uratam solution (V/V) intraperitoneally. The rat which is completely in an anesthetic state is in a supine position and is fixed on a fixed plate, the abdomen is prepared and disinfected, the abdominal cavity is opened along the white line of the abdomen, the rat is lowered to the coagulation gland, and one corner of the liver is exposed. Organs such as small intestine in the abdominal cavity are removed, and the viscera of the abdominal cavity are gently pulled out and placed in clean gauze which is wetted by normal saline. Perivascular connective tissue is blunt-isolated, the inferior vena cava and its branches are exposed, and then the inferior vena cava is ligated at the junction of the inferior vena cava and the left renal vein with a suture wetted with physiological saline. The organs such as small intestine are moved back to the abdominal cavity according to the anatomical position, and the abdominal cavity is sutured layer by using suture lines.
The rats were then left to circulate in an environment at 25-28℃for 4 hours after surgery. After ether anesthesia, the branches were ligated one by one after the abdominal cavity was opened. The 2cm inferior vena cava was removed from the ligation site at the junction of the inferior vena cava and the left renal vein, from which thrombus was removed and weighed. Thrombus retention was used to evaluate targeting. To avoid the effect of the surgical time on the experimental results, the surgery was performed alternately in groups of three. Venous thrombosis for each group of rats and is summarized in Table 4.
The data in Table 4 shows that (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carbolin-3-formyl-Arg-Gly-Asp-Val is effective in inhibiting venous thrombosis in rats at an oral dose of 0.1. Mu. Mol/kg, with no significant difference in activity from that of warfarin at an oral dose of 4.87. Mu. Mol/kg, i.e. equivalent to 48.7 times the activity of warfarin. It can be seen that the present invention has outstanding technical effects.
TABLE 4 anti-venous thrombotic Activity
A) The ratio of P to normal saline is less than 0.01, and the ratio of P to warfarin of 4.87 mu mol/kg is more than 0.05; compound 5 represents (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val; n=12.
EXAMPLE 17 evaluation of venous thrombosis rat tail bleeding time
Rats for evaluation of anti-venous thrombosis activity were circulated in an environment of 25-28 ℃ for 4 hours, anesthetized with diethyl ether, and the tail tip was cut off 0.5 cm before opening the abdominal cavity to take venous thrombosis, and timing was started. The blood exuded from the wound was sucked off with filter paper and the timing was stopped when no blood was exuded from the wound. The time spent from starting to stopping the timing is the rat tail bleeding time. The data in Table 5 demonstrate that warfarin significantly prolonged tail bleeding time in venous thrombosed rats at an oral dose of 4.87. Mu. Mol/kg, that is to say warfarin was at risk of bleeding. In contrast, (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carbolin-3-formyl-Arg-Gly-Asp-Val did not extend the tail bleeding time in venous thrombosed rats at an oral dose of 0.1. Mu. Mol/kg, i.e. it did not have a bleeding risk. The bleeding risk of warfarin sample is not generated, which shows that the invention has outstanding technical effects.
TABLE 5 tail bleeding time in venous thrombosed rats
A) P >0.05 compared to normal saline, P <0.01 compared to warfarin; compound 5 represents (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val; n=12.
EXAMPLE 18 evaluation of clotting time in venous thrombosed rats
Rats for evaluation of anti-venous thrombosis activity were circulated in an environment of 25-28 ℃ for 4 hours, anesthetized with diethyl ether, and the abdominal cavity was opened to take venous thrombosis while dropping a drop of venous blood onto a clean glass plate and starting timing. The blood drop is stimulated with a needle tip and the timing is stopped when the drop forms a viscous film. The time spent from starting to stopping the timing is the clotting time of the rats. The data in Table 6 demonstrate that warfarin very significantly prolonged clotting time in venous thrombosed rats at an oral dose of 4.87. Mu. Mol/kg, that is to say that warfarin is at risk of bleeding. In contrast, (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carbolin-3-formyl-Arg-Gly-Asp-Val does not extend the clotting time of venous thrombosed rats at an oral dose of 0.1. Mu. Mol/kg, i.e. it does not have a bleeding risk. The bleeding risk of warfarin sample is not generated, which shows that the invention has outstanding technical effects.
TABLE 6 clotting time in venous thrombosed rats
A) P >0.05 compared to normal saline, P <0.01 compared to warfarin; compound 5 represents (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val; n=12.
Example 19 evaluation of venous thrombosis targeting
A sample of venous thrombosis from rats treated with physiological saline and 0.1. Mu. Mol/kg oral dose of (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carbolin-3-formyl-Arg-Gly-Asp-Val was placed in a 5mL centrifuge tube, 1mL of chromatographic methanol was added, the thrombus tissue was crushed with a spatula, sonicated for 30min, the supernatant was aspirated after standing in the centrifuge tube, the residue was soaked with ethyl acetate for 24 hours and sonicated for 30min, and the ethyl acetate supernatant was collected. The residue was added with 3mL of ethyl acetate, and after 30 minutes of sonication, the supernatant was collected and the above was repeated 3 times. The ethyl acetate phases were combined, concentrated under reduced pressure to remove ethyl acetate, and the residue was dissolved in 1mL of chromatographic methanol and the solution was subjected to ESI (+) -FT-ICR-MS analysis. The results show that the ESI (+) -FT-ICR-MS spectrum of venous thrombus samples of venous thrombus treated rats with (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val showed a peak of molecular ion addition H at 744.36635 for (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val-and a peak of molecular ion addition H at 317.14759 for (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-line-3-carboxylic acid. The ESI (+) -FT-ICR-MS spectrum of venous thrombosis samples of normal saline treated venous thrombosis rats has neither a peak of molecular ion of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val added with H nor a peak of molecular ion of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid added with H.
A0.1. Mu. Mol/kg oral dose of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carbolin-3-formyl-Arg-Gly-Asp-Val was used to prepare homogenate extract samples from heart, liver, brain, spleen, lung and kidney of ESI (+) -FT-ICR-MS treated venous thrombotic rats as described above. The results showed that they showed neither peaks of molecular ion of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val plus H nor peaks of molecular ion of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylic acid plus H in ESI (+) -FT-ICR-MS spectra.
It can be seen that (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg-Gly-Asp-Val only entered rat venous thrombosis and not into rat organs. It is apparent that this is venous thrombosis targeting.
It should be noted that the foregoing summary and the detailed description are intended to demonstrate practical applications of the technical solution provided by the present invention, and should not be construed as limiting the scope of the present invention. Various modifications, equivalent alterations, or improvements will occur to those skilled in the art, and are within the spirit and principles of the invention.
Claims (6)
1. A compound of (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val, having the structural formula:
2. a synthetic method for preparing the compound of (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val of claim 1, comprising:
(A) Synthesizing (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-carboxylic acid benzyl ester;
(B) Synthesizing (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid benzyl ester;
(C) Synthesizing (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid;
(D) Liquid phase synthesis of Arg (NO 2) -Gly-Asp (OBzl) -Val-OBzl from N end to C end by using dicyclohexylcarbodiimide as condensing agent and 1-hydroxybenzotriazole as catalyst through gradual peptide grafting;
(E) Coupling (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid with Arg (NO 2) -Gly-Asp (OBzl) -Val-OBzl to prepare (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-Arg (NO 2) -Gly-Asp (OBzl) -Val-OBzl by using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst;
(F) Deprotection of (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg (NO 2) -Gly-Asp (OBzl) -Val-OBzl to prepare (3S) -1- (2, 2-dimethyl-1, 3-dioxan-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val.
3. Use of a compound of (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val according to claim 1 for the preparation of a targeted anti-arterial thrombosis medicament.
4. Use of a compound of (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val according to claim 1 for the preparation of a targeted anti-venous thrombosis medicament.
5. Use of a compound of (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val according to claim 1 for the preparation of a P-selectin inhibitor.
6. Use of a compound of (3S) -1- (2, 2-dimethyl-1, 3-dioxane-5-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-Arg-Gly-Asp-Val according to claim 1 for the preparation of a GPIIb/IIIa inhibitor.
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| CN109134606A (en) * | 2017-06-16 | 2019-01-04 | 首都医科大学 | 1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-GRGDV, synthesis, activity and application |
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| CN109134606A (en) * | 2017-06-16 | 2019-01-04 | 首都医科大学 | 1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-GRGDV, synthesis, activity and application |
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