CN112010926B - KGH and hydroxymethyl modified benzimidazole quinazolines, synthesis, activity and applications thereof - Google Patents
KGH and hydroxymethyl modified benzimidazole quinazolines, synthesis, activity and applications thereof Download PDFInfo
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- 230000015572 biosynthetic process Effects 0.000 title claims description 7
- 238000003786 synthesis reaction Methods 0.000 title claims description 7
- 230000000694 effects Effects 0.000 title description 7
- -1 hydroxymethyl modified benzimidazole quinazolines Chemical class 0.000 title description 3
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- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims abstract description 39
- 150000002460 imidazoles Chemical class 0.000 claims abstract description 26
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 239000003018 immunosuppressive agent Substances 0.000 claims abstract description 8
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- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 17
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 8
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
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- HKJZDEUEWZSNFY-UHFFFAOYSA-N imidazo[1,2-c]quinazoline Chemical compound C1=CC=C2C3=NC=CN3C=NC2=C1 HKJZDEUEWZSNFY-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
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- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
- 108010036949 Cyclosporine Proteins 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
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- KYVMQDVGHDCYLM-UHFFFAOYSA-N [6-(hydroxymethyl)-5H-benzimidazolo[1,2-c]quinazolin-6-yl]methanol Chemical compound OCC1(NC2=CC=CC=C2C=2N1C1=C(N2)C=CC=C1)CO KYVMQDVGHDCYLM-UHFFFAOYSA-N 0.000 description 3
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- 206010052779 Transplant rejections Diseases 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- YWNXHTNWOQHFRL-UHFFFAOYSA-N 2-(1H-benzimidazol-2-yl)aniline Chemical compound NC1=CC=CC=C1C1=NC2=CC=CC=C2N1 YWNXHTNWOQHFRL-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- JXYACYYPACQCDM-UHFFFAOYSA-N Benzyl glycinate Chemical compound NCC(=O)OCC1=CC=CC=C1 JXYACYYPACQCDM-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 240000001307 Myosotis scorpioides Species 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
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- 239000003814 drug Substances 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
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- 239000011521 glass Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000008376 long-term health Effects 0.000 description 1
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- 238000002616 plasmapheresis Methods 0.000 description 1
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- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- General Chemical & Material Sciences (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
The invention discloses a 6-hydroxymethyl-6- (His-Gly-Lys-OCH) with the following formula2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline, discloses a preparation method thereof, discloses immunosuppressive activity thereof, and discloses that the quinazoline can prolong the survival time of transplanted myocardium after ears of mice, so that the invention discloses application thereof in preparing immunosuppressant.
Description
Technical Field
The invention relates to 6-hydroxymethyl-6- (His-Gly-Lys-OCH2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline, to a process for its preparation, and to its immunosuppressive activity. The invention thus relates to the use of such compounds in the preparation of immunosuppressive drugs. The invention belongs to the field of biological medicine.
Background
The first example of organ transplant surgery was successful in the last 60 s of the century. Through decades of development, patients who lose organ functions are cured. However, the immune rejection of the human autoimmune system to foreign organs severely affects the recent and long-term health of patients. Ultimately, immune rejection affects the survival time of the patient after transplantation. How to avoid this immune rejection is of great importance. Although various measures are clinically implemented, the results are not ideal. In the case of kidney transplantation, although acute cellular and humoral rejection can be effectively controlled by plasmapheresis and intervention with potent immunosuppressive agents, the treatment is not as effective as chronic rejection. Thus, the present invention is directed to novel immunosuppressive agents. Also, the effects of the novel immunosuppressive agents of the present invention are not ideal. With the interest in the development of novel immunosuppressive agents, the inventors have been working on modifying N-containing heterocycles with peptides. After 3 years of exploration, the inventor finds thatThe inventors have designed this compound with the aim of combining two structures with immunosuppressive activity to obtain a novel immunosuppressive agent. The inventors found that hydroxymethyl and His-Gly-Lys-OCH were used2Modification of 5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline produced 6-hydroxymethyl-6- (His-Gly-Lys-OCH)2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline showed excellent activity in an experimental model of myocardial transplantation behind the mouse ear. Based on this finding, the inventors have proposed the present invention.
Disclosure of Invention
The first content of the invention is to provide 6-hydroxymethyl-6- (His-Gly-Lys-OCH2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline.
The second aspect of the present invention is to provide 6-hydroxymethyl-6- (His-Gly-Lys-OCH)2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A process for the preparation of a quinazoline, the process comprising:
1) synthesizing 6, 6-dihydroxymethyl-5, 6-dihydrobenzo [4,5] imidazole [1,2-c ] quinazoline;
2) synthesizing 6-hydroxymethyl-6- [ Boc-Lys (Fmoc) -OCH2] -5, 6-dihydrobenzo [4,5] imidazo [1,2-c ] quinazoline;
3) synthesizing 6-hydroxymethyl-6- [ Lys (Fmoc) -OCH2] -5, 6-dihydrobenzo [4,5] imidazo [1,2-c ] quinazoline;
4) synthesizing Boc-His (Boc) -Gly by using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst through a liquid phase method;
5) condensing 6-hydroxymethyl-6- [ Lys (Fmoc) -OCH2] -5, 6-dihydrobenzo [4,5] imidazo [1,2-c ] quinazoline with Boc-His (Boc) -Gly-OH by a liquid phase method using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst to obtain 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Lys (Fmoc) -OCH2] -5, 6-dihydrobenzo [4,5] imidazo [1,2-c ] quinazoline;
6) synthesizing 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Lys-OCH2] -5, 6-dihydrobenzo [4,5] imidazo [1,2-c ] quinazoline;
7) synthesis of 6-hydroxymethyl-6- (His-Gly-Lys-OCH2) -5, 6-dihydrobenzo [4,5] imidazo [1,2-c ] quinazoline.
The third aspect of the present invention is to evaluate the immunosuppressive effects of 6-hydroxymethyl-6- (His-Gly-Lys-OCH2) -5, 6-dihydrobenzo [4,5] imidazo [1,2-c ] quinazoline.
Drawings
FIG. 1.6-hydroxymethyl-6- (His-Gly-Lys-OCH2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Synthetic routes to quinazolines (i)2M hydrochloric acid solution, 1, 3-dihydroxyacetone; (ii) dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, Boc-Lys (Fmoc), N-methylmorpholine; (iii)4M ethyl acetate solution of hydrogen chloride; (iv) dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, N-methylmorpholine; (v) Pd/C, H2(ii) a (vi) 20% piperidine in dichloromethane.
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 (6, 6-dihydroxymethyl-5, 6-dihydrobenzo [4,5] imidazo [1,2-c ] quinazoline (1)
6.40g (30.6mmol) of 2- (2-aminophenyl) -1H-benzimidazole was suspended in 100mL of methanol, and 2.76g (30.7mmol) of 1, 3-dihydroxyacetone was added to the suspension. The reaction mixture was adjusted to pH 2 with 2M hydrochloric acid, at which time the reaction solution turned green. The reaction mixture was stirred at room temperature for 12 hours, TLC (dichloromethane/methanol ═ 20/1) showed the disappearance of the starting point and a large amount of yellow-green solid precipitated. The reaction was terminated, and a 4M aqueous solution of sodium hydroxide was added dropwise to the reaction solution to adjust the pH of the reaction solution to neutral, followed by filtration to obtain 7.03g of the title compound as a yellow-green solid. The filtrate was concentrated under reduced pressure and filtered to give 2.52g of the title compound as a dark green solid. The yield of the reaction of this step was 100%. ESI-MS (M/e):282[ M + H]+。
(c＝0.1CH3OH)。Mp 214-215℃。1H-NMR(300MHz,DMSO-d6):δ/ppm＝7.86(d,J＝7.2Hz,1H),7.69(m,1H),7.59(m,1H),7.15(m,3H),6.85(d,J＝8.1Hz,1H),6.70(m,2H),5.26(t,J＝5.4,2H),4.08(dd,J1＝6.0Hz,J2＝5.7Hz,2H),3.82(dd,J1＝5.7Hz,J2＝6.0Hz,2H)。
EXAMPLE 2 preparation of 6-hydroxymethyl-6- [ Boc-Lys (Fmoc) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (2)
468mg (1.00mmol) of Boc-Lys (Fmoc),250mg (1.20mmol) of DCC and 135mg (1.00mmol) of HOBt were dissolved in 20mL of DMF, and the resulting solution was stirred in an ice bath for 30 minutes, after which 1.12g (4.00mmol) of (6, 6-dihydroxymethyl-5, 6-dihydrobenzo [4,5] benzo [4,5] was added]Imidazole [1,2-c ]]Quinazoline (1), the reaction mixture was adjusted to pH 7-8 with NMM, after which the reaction mixture was stirred at room temperature for 12 hours and TLC monitoring (dichloromethane/methanol 20/1) showed the disappearance of Boc-lys (fmoc). The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 50mL of ethyl acetate, filtered, the filtrate was washed with a saturated aqueous solution of sodium bicarbonate (30 mL. times.3), a saturated aqueous solution of sodium chloride (30 mL. times.3), dried over anhydrous sodium sulfate for 12 hours, filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with dichloromethane, sonicated, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol ═ 70/1) to give 513mg (70.2%) of the title compound as a pale yellow-green solid. ESI-MS (M/e):732[ M + H]+。
(c＝0.1CH3OH)。Mp＝94-95℃。1H-NMR(300MHz,DMSO-d6):δ/ppm＝7.88(d,J＝6.6Hz,3H),7.68(m,4H),7.37(m,4H),7.17(m,4H),6.95(m,1H),6.84(t,J＝7.8Hz,1H),6.74(t,J＝7.5Hz,1H),5.53(m,1H),4.92(d,J＝11.7Hz,1H),4.53(m,1H),4.26(m,4H),4.03(m,2H),2.80(m,2H),1.31(s,9H),1.03(m,6H)。
EXAMPLE 3 preparation of 6-hydroxymethyl-6- [ Lys (Fmoc) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (3)
730mg (1.00mmol) of 6-hydroxymethyl-6- [ Boc-Lys (Fmoc) -OCH2]-5, 6-dihydroBenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (2) was dissolved in 1mL of dry ethyl acetate, 8mL of ethyl acetate hydrochloride solution (4M) was added under ice-bath, TLC monitoring of the reaction (dichloromethane/methanol ═ 20/1) showed disappearance of compound 2 after 4 hours of reaction, the reaction solution was concentrated under reduced pressure, the residue was dissolved in anhydrous ethyl acetate and concentrated under reduced pressure, and the residue was dissolved in anhydrous ethyl acetate again. This operation was repeated 3 times. The residue was dispersed in 10mL of anhydrous ether, allowed to stand, and ether was discarded, which was repeated 3 times to give 670mg (100%) of the title compound as a green solid. ESI-MS (M/e):632[ M + H [)]+。
EXAMPLE 4 preparation of Boc-His (Boc) -Gly-OBzl
5.23mg (14.7mmol) of Boc-His (Boc),3.70g (16.0mmol) of dicyclohexylcarbodiimide and 2.00g (15.0mmol) of 1-hydroxybenzotriazole were dissolved in 150mL of anhydrous tetrahydrofuran and stirred at 0 ℃ for 30 minutes. To the reaction mixture was added 3.00g (15.0mmol) Gly-OBzl, the reaction mixture was adjusted to pH 7-8 with N-methylmorpholine, stirred at room temperature for 12 hours, and TLC (dichloromethane/methanol ═ 20/1) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure, the residue was diluted with 100mL of ethyl acetate, filtered, the filtrate was washed with a saturated aqueous solution of sodium hydrogencarbonate (30mL × 3), saturated aqueous solution of sodium chloride (30mL × 3), dried over anhydrous sodium sulfate for 12 hours, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol ═ 80/1) to give 2.23g (30%) of the title compound as a yellow oil. ESI-MS (M/e) 503[ M + H]+。
EXAMPLE 5 preparation of Boc-His (Boc) -Gly
1.32g (2.64mmoL) of Boc-his (Boc) -Gly-OBzl was dissolved in 100mL of methanol, and 140mg of Pd/C was added to the resulting solution, followed by hydrogen gas introduction, stirring at room temperature for 12 hours, and TLC (dichloromethane/methanol ═ 20/1) showed completion of the reaction. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 1.16g (100%) of the title compound as a colorless solid. ESI-MS (M/e):413[ M + H]+。
EXAMPLE 6 preparation of 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Lys (Fmoc) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (4)
495mg (1.200mmol) of Boc-His (Boc) -Gly,250mg (1.20mmol) of dicyclohexylcarbodiimide and 115mg (1.20mmol) of 1-hydroxybenzotriazole were added with 10mL of anhydrous tetrahydrofuran under ice bathDissolving pyran, stirring for 30 min, adding 670mg (1.00mmol) of 6-hydroxymethyl-6- [ Lys (Fmoc) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (3). The reaction mixture was adjusted to pH 8 with N-methylmorpholine and stirred at room temperature for 6 hours, and TLC (dichloromethane: methanol ═ 15:1) showed disappearance of compound 3. The reaction solution was concentrated under reduced pressure, and the residue was diluted with 100mL of ethyl acetate, filtered, the filtrate was washed with a saturated aqueous solution of sodium hydrogencarbonate (30mL × 3), a saturated aqueous solution of sodium chloride (30mL × 3), dried over anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain a pale yellow solid, which was purified by silica gel column chromatography (dichloromethane/methanol ═ 30/1), to obtain 806mg (78.6%) of the title compound as a pale yellow solid. ESI-MS (M/e):1027[ M + H]+。
(c＝0.1CH3OH)。Mp＝104-105℃。1H-NMR(300MHz,DMSO-d6):δ/ppm＝8.02(m,2H),7.88(d,J＝7.8Hz,3H),7.694(m,4H),7.37(m,4H),7.19(m,5H),6.88(m,3H),6.74(t,J＝6.9Hz,1H),5.55(m,1H),4.96(d,J＝11.4Hz,1H),4.55(m,1H),4.29(m,2H),4.21(m,2H),4.08(m,1H),3.97(m,2H),3.64(m,2H),2.79(m,4H),1.53(d,J＝3.0Hz,9H),1.32(s,9H),1.02(m,6H)。13C-NMR(300MHz,DMSO-d6):δ/ppm＝171.9,169.3,157.7,155.7,144.4,143.6,143.5 143.0,139.9,137.9,137.0,133.4,133.3,131.9,129.4,127.7,124.9,122.5,122.4,121.8,120.5,119.2,118.1,114.8,114.6,113.1,112.7,111.2,110.1,78.7,76.5,66.5,65.8,64.1,63.7,55.5,54.2,52.2,49.1,46.5,32.9,30.4,29.6,22.8。
EXAMPLE 7 preparation of 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Lys-OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (5)
308mg (0.300mmoL) of 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Lys (Fmoc) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (4), dissolved in 5mL of 20% piperidine in dichloromethane, and after stirring for 2 hours at room temperature TLC (dichloromethane/methanol ═ 20/1) showed disappearance of compound 4. The reaction was concentrated under reduced pressure, and the residue was crystallized from 10mL of anhydrous ether under ice-bath and filtered to give 112mg (46.4%) of the title compound as a colorless solid. ESI-MS (M/e):804[ M + H]+。
EXAMPLE 8 preparation of 6-hydroxymethyl-6- [ His-Gly-Lys-OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (6)
112mg (0.139mmol) of 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Lys-OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (5) was dissolved with 3mL of hydrogen chloride in ethyl acetate (4M) and stirred for 4 hours. TLC (ethyl acetate/water/glacial acetic acid ═ 2/1/1) showed the disappearance of compound 5. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in anhydrous ethyl acetate, and the resulting solution was concentrated under reduced pressure. This operation was repeated 3 times. The residue was washed with dry ether 3 times. The resulting green solid was purified by C18 column (water/methanol 85/15) and the fractions were lyophilized to yield 51.4mg (28.4%) of the title compound as a green solid. ESI-MS (M/e) 604[ M + H]+。
(c＝0.1CH3OH)。Mp＝184-186℃。IR(cm-1):2930.98,1745.36,1649.53,1620.09,1532.77,1480.00,1449.23,1379.36,1329.47,1273.76,1150.69,842.42,750.17,656.21,625.76。1H-NMR(300MHz,DMSO-d6):δ/ppm＝8.85(m,1H),8.57(dd,J1＝8.4Hz,J2＝11.7Hz,1H),7.88(m,4H),7.65(m,1H),7.20(m,3H),7.09(s.1H),7.01(s,1H),6.86(m,1H),6.76(t,J＝6.9Hz,1H),5.63(m,1H),5.06(m,1H),4.58(m,1H),4.25(m,1H),4.09(m,2H),3.97-3.81(m,2H),3.65(m,1H),3.07(m,2H),1.30-0.93(m,6H)。13C-NMR(300MHz,DMSO-d6):δ/ppm＝171.8,171.7,169.1,168.5,148.0,144.3,143.7,143.7,135.4,133.3,132.0,125.0,122.7,122.5,122.4,119.2,113.1,112.9,111.0,76.6,66.0,63.7,52.6,52.1,42.1,31.6,29.7,26.7,22.5。
Example 9 evaluation of the immunosuppressive Effect of Compound 6
Male Balb/c mice (20. + -.2 g) were anesthetized with a 10% urethane (10mg/10g body weight) intraperitoneal injection. Mouse auricles were topically sterilized with 75% alcohol. A3-4 mm long incision perpendicular to the midline of the auricle was made at about 1/3 from the dorsal midline of the auricle, taking care not to damage the auricular veins. The subcutaneous tissue is bluntly separated in the direction of the ear tip through the opening to form an artificial lumen. The C57bl/6j heart-suckling mouse is frozen in crushed ice for one minute, the skin is disinfected by 75% alcohol, and the heart is taken after the chest is cut open. The heart is placed in a watch glass on which physiological saline-wetted gauze is laid to beat, so that the residual blood in the heart cavity is discharged. The heart of a suckling mouse is longitudinally cut into two petals of myocardium with basically equal-size muscle fibers and inclined planes. Myocardium was filled into the artificial lumen of Balb/c recipient mice. The isolated time of the myocardial tissue does not exceed 2 minutes during the operation. Lightly press the artificial lumen filled with myocardium to discharge excessive physiological saline and air bubbles, so that the transplanted myocardium is tightly adhered to the tissues around the ear of the recipient mouse. Compound 6 (at a dose of 0.1. mu. mol/kg/day) or cyclosporin A (at a dose of 2.5. mu. mol/kg/day) or normal saline was administered orally on the day of myocardial transplantation. The electrocardiogram continuously administered to the transplanted myocardium disappeared.
From the seventh day of myocardial transplantation, the electrocardiographic signals of the transplanted myocardial tissues were measured with a biosignal two-channel instrument every day (if no electrocardiographic signals were present from the seventh day to the following days, it was judged that the myocardial transplantation operation failed). When measuring the ectopic electrocardiogram, the positive and negative electrodes are respectively arranged at two sides of the transplanted myocardial tissue, and the grounding electrode is connected with the hind limb of the mouse. The measurement of the heterotropic electrocardiogram is finished after the electrocardiosignals of the transplanted myocardial tissue are completely disappeared, and the survival time (mean value +/-SD) of the transplanted myocardial tissue is counted, and the result is shown in table 1. It can be seen that the activity of compound 6 in prolonging survival of transplanted myocardium at 0.1 μmol/kg/day dose was not significantly different from cyclosporin a at 2.5 μmol/kg/day dose. The invention has outstanding technical effects.
TABLE 1 Effect of Compound 6 on myocardial transplant survival time in mice after ear
a) P <0.01 compared to saline; b) p <0.01 compared to saline, P >0.05 compared to cyclosporin A; n is 12.
Claims (3)
1. 6-hydroxymethyl-6- (His-Gly-Lys-OCH) of formula2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline in the form of a salt,
2. 6-hydroxymethyl-6- (His-Gly-Lys-OCH of claim 12) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A process for the preparation of a quinazoline, the process comprising:
2.1. synthesizing 6, 6-dihydroxymethyl-5, 6-dihydrobenzo [4,5] imidazole [1,2-c ] quinazoline;
2.2. synthesis of 6-hydroxymethyl-6- [ Boc-Lys (Fmoc) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline;
2.3. synthesis of 6-hydroxymethyl-6- [ Lys (Fmoc) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline;
2.4. synthesizing Boc-His (Boc) -Gly by adopting a liquid phase condensation method with dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst;
2.5. the liquid phase condensation method adopts dicyclohexylcarbodiimide as a condensation agent and 1-hydroxybenzotriazole as a catalyst to carry out liquid phase condensation on 6-hydroxymethyl-6- [ Lys (Fmoc) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Condensation of quinazoline with Boc-His (Boc) -Gly to 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Lys (Fmoc) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline;
2.6. synthesis of 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Lys-OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline;
2.7. synthesis of 6-hydroxymethyl-6- (His-Gly-Lys-OCH2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline.
3. 6-hydroxymethyl-6- (His-Gly-Lys-OCH of claim 12) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]The application of quinazoline in preparing immunosuppressant.
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