Patent Application
20140206741
The present invention relates to an N-substituted isopropyldimethyl azulene sulfonamide derivative, and preparation method and use thereof.
Guaiazulene, namely 1,4-dimethyl-7-isoproylazulene, is an active ingredient of Chrysanthemum plants, which has a structural formula as follows:
Guaiazulene has strong effect of anti pepsin, anti-inflammatory, anti-allergic and promoting mucosal metabolism. Its many derivatives also exhibit excellent biological activity. Compound Guaiazulene Ointment (Shanxi Tongsheng Pharmaceutical Co., Ltd.) can be used for burns, scalds, scorches, frostbite, chap, decubitus, radiation heat, dermatitis and etc.
Since the excellent pharmacological activities of guaiazulene, there have been many studies on structural modification of Guaiazulene. The resultant derivatives include azulene sodium sulphonate, 3-(2-substituted thiazole-4-yl)guaiazulene, 1-(2-benzofuran acyl)guaiazulene and etc. Among which, azulene sodium sulphonate is a water-soluble derivative of guaiazulene, has excellent anti-inflammatory and wound healing properties, and is used as the main ingredient of the currently available drug Glutamine Granules for treating gastric ulcer. Azulene sodium sulphonate can directly act on the inflammatory mucosa and has better therapeutic effect on various gastritis, as well as complications of gastritis and ulcers.
However, it is found by experiments that azulene sodium sulphonate has some stability issues, especially poor light stability and heat stability. In order to ensure the safety of products, the cost of product storage and transportation must be increased to prevent decomposition of the active ingredient and generation of impurities, leading to increased production costs.
Currently, there is no report about structural modification to improve the stability of azulene sodium sulphonate.
The object of the present invention is to provide an N-substituted isopropyldimethyl azulene sulfonamide derivative with excellent stability, and preparation method and use thereof.
The present invention provides an N-substituted isopropyldimethyl azulene sulfonamide derivative as represented by formula (I), having a structural formula as follows:
wherein R1 is an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, amino, or a substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and amino.
Further, R1 is 3-BrC6H4, 2,4-OCH3C6H3, iso-C3H7, 1-naphthyl, iso-C4H9, n-C3H7, 4-CH3C6H4, C2H5, cyclohexyl, CH2C6H5, 4-ClC6H4, 4-NH2C6H4 or NH2.
Wherein, the derivative has a structural formula as follows:
R2 is hydrogen or methoxyformyl; R3 is hydrogen, 2-methylpropyl, benzyl, indol-3-methyl, methyl, or methoxyformylmethyl; R4 is hydrogen, 2-methylpropyl, or indol-3-methyl; R5 is hydrogen or indol-3-methyl; R6 is 2-thienyl or 4-trifluoromethylphenyl.
Further, the derivative is selected from the group consisting of:
Wherein,
R1 is
wherein, R7, R8 represent mono- or multi-substituted groups, which are selected from the group consisting of hydrogen, hydroxy, carboxy, halogen, C1-4 alkoxyl, C1-4 alkyl, amino and aryl group.
Further, R2 is hydrogen, R3 is selected from the group consisting of hydrogen, halogen, C1-4 alkoxyl, C1-4 alkyl, amino and aryl group, or R3 together with a phenyl group which it is attached from an aromatic group.
Wherein, the halogen is Br.
Wherein, aryl represents a C1-10 aromatic compound; R3 together with a phenyl group which it is attached from a C1-10 aromatic compound.
Further, the derivative is selected from the group consisting of:
More further, said derivative is selected from the group consisting of:
More preferably, the derivative is N-(4-aminophenyl)-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide.
The present invention provides a preparation method of the N-substituted isopropyldimethyl azulene sulfonamide derivative, comprising the following steps of:
subjecting azulene sodium sulphonate to acetyl chlorination to generate azulene sulfonyl chloride, reacting the azulene sulfonyl chloride with an amine compound to obtain said derivative; azulene sodium sulphonate is 1,4-dimethyl-7-isopropylazulene-3-sodium sulfonate.
Wherein, said amine compound is selected from the groups consisting of an aliphatic amine and aromatic amine.
Further, it comprises the following steps of:
adding azulene sodium sulphonate under ice bath with CH2Cl2, then adding with DMF and pyridine; adding a small amount of CH2Cl2, and then (COCl)2, after completion of the reaction, slowly adding with a mixture solution of Et3N, pyridine and an amine compound, reacting at room temperature followed by separating and purifying, to obtain said derivative.
According to the present invention, the preparation method of the N-substituted isopropyldimethyl azulene sulfonamide derivative comprises: reacting guaiazulene and acetic anhydride and concentrated sulfuric acid at room temperature and neutralizing with NaOH to generate azulene sodium sulphonate, then reacting the resultant azulene sodium sulphonate with chloroglyoxylate in the presence of pyridine and DMF to generate azulene sulfonyl chloride, reacting azulene sulfonyl chloride with amine in the presence of weak base to obtain the derivative of guaiazulene, N-substituted-5-isopropyl-3,8-dimethyl azulene sulfonamide, the reaction route of which is as follows:
More further, it comprises the following steps:
(1) weighing raw materials according to the following ratios:
the molar ratio of azulene and oxalyl chloride being 1:2.5-3, the molar ratio of azulene and amine compound being 1:1.5-2;
(2) adding azulene sodium sulphonate under ice bath with CH2Cl2, then adding 3-5d DMF, adding pyridine; dropwise adding a small amount of CH2Cl2 and (COCl)2; after completion of the reaction, adding a mixture solution of 2 ml of Et3N, 1 ml of pyridine and an amine compound into the reaction solution; after completion of the dropwise addition, reacting the mixture at room temperature for 1 h, adding with an equal volume of water into the reaction flask, adjusting pH to 5-6 with dilute hydrochloric acid, extracting with CH2Cl2, and drying organic layer over anhydrous Na2SO4, removing the solvent by rotary evaporation, and purifying the crude product through column chromatography to obtain said derivative.
wherein, said aliphatic amine is one selected from the group consisting of isopropyl amine, isobutylamine, propylamine, ethylamine, cyclohexylamine and hydrazine hydrate; said aromatic amine is one selected from the group consisting of bromoaniline, 2,4-dimethoxy aniline, naphthylamine, toluidine, benzylamine, p-chloroaniline, and p-phenylenediamine.
The present invention also provides use of the N-substituted isopropyl dimethyl azulene sulfonamide derivative for preparing an anti digestive ulcer medicine.
Further, said medicine is an anti gastric ulcer medicine.
More further, said medicine is a medicine for treating alcohol-induced gastric ulcer.
The present invention also provides a pharmaceutical composition, which is a formulation that is prepared by one or a combination of two or more N-substituted isopropyldimethyl azulene sulfonamide derivatives as active ingredients, together with a pharmaceutically acceptable excipient or auxiliary component.
Wherein, said formulation is an oral or injectable formulation.
Further, said formulation is selected from the group consisting of tablets, pills, granules, capsules, powders, drop pills, and oral liquid.
The experiments demonstrate that N-(3-bromophenyl)-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide (4a), N-(2,4-dimethoxyphenyl)-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide(4b), N-(1-naphthyl)-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide (4d), N-cyclohexyl-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide (4i), N-(4-aminophenyl)-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide (4l) provided by the present invention, can significantly relieve the pathological degree of anhydrous ethanol-induced gastric ulcer in mice, the ulcer scores of which have significant difference compared to the model group, and can be used as active pharmaceutical ingredients to develop new drugs of anti gastric ulcer with better therapeutic effect.
The N-substituted isopropyldimethyl azulene sulfonamide derivatives prepared according to the present invention not only improve the stability of azulene sodium sulphonate and retain the therapeutic effect of azulene sodium sulphonate on gastric ulcer disease, but also enhance the activity of azulene sodium sulphonate and have excellent social and economic values. Meanwhile, the preparation method of the derivatives is very simple and low-cost, and is suitable for industrialization and large scale production.
Clearly, many other modifications, replacements and changes can be made according to ordinary technical knowledge and conventional technical means based on the above disclosure, without departing from the basic technical idea of the present invention.
The above disclosure of the present invention will be illustrated in detail through the following examples as embodiments. However it should not be construed as limiting the invention to the examples shown below. The techniques achieved based on the above disclosure are within the scope of the present invention.
The process steps of this example are as follows:
25 ml round-bottom flask was added with azulene sodium sulphonate (1 mmol), and then under ice bath added with 10 ml of CH2Cl2, 3-5 drops of DMF and 0.5 ml of pyridine. A dropping funnel was added with a small amount of CH2Cl2 and then added with (COCl)2 (2.5 mmol), which was then slowly dropwise added into the round-bottom flask. After completion of the reaction, a mixture solution of 2 ml of Et3N, 1 ml of pyridine and 3-bromoaniline (1.5 mmol) was slowly dropwise added into the reaction solution through a dropping funnel. After completion of dropwise addition, the mixture was reacted at room temperature for 1 h, and then added with an equal volume of water into the flask, and added with dilute hydrochloric acid to adjust pH to 5-6, extracted with CH2Cl2, and the organic layer was dried over anhydrous Na2SO4, then concentrated by rotary evaporation, and the resultant crude product was purified through column chromatography to obtain N-(3-bromophenyl)-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide (purple crystals). Yield: 25%. m.p. 172-174° C. 1H NMR (400 MHz, CDCl3) δ(ppm): 1.37 (d, J=7.2 Hz, 6H), 2.54 (s, 3H), 3.12 (q, J=7.2 Hz, J=7.2 Hz, 1H), 3.38 (s, 3H), 6.99 (d, J=8.0 Hz, 1H, PhH), 7.06 (t, J=8.0 Hz, 1H, PhH), 7.13 (d, J=8.0 Hz, 1H, PhH), 7.21 (s, 1H, PhH), 7.42 (d, J=10.4 Hz, 1H), 7.61 (d, J=11.2 Hz, 1H), 8.06 (s, 1H), 8.28 (d, J=2.0 Hz, 1H); IR (KBr) v: 3236, 2958, 2864, 1592, 1579, 1473, 1368, 1143, 775, 678, 587; HRMS (ESI) m/z calcd for C21H22BrNO2S [M+H]+432.0627, found 432.0622.
The process steps of this example are as follows:
25 ml round-bottom flask was added with azulene sodium sulphonate (1 mmol), and then under ice bath added with 10 ml of CH2Cl2, 3-5 drops of DMF and 0.5 ml of pyridine. A dropping funnel was added with a small amount of CH2Cl2 and then added with (COCl)2 (2.5 mmol), which was then slowly dropwise added into the round-bottom flask. After completion of the reaction, a mixture solution of 2 ml of Et3N, 1 ml of pyridine and 2,4-dimethoxy aniline (1.5 mmol) was slowly dropwise added into the reaction solution through a dropping funnel. After completion of dropwise addition, the mixture was reacted at room temperature for 1 h, and then added with an equal volume of water into the flask, and added with dilute hydrochloric acid to adjust pH to 5-6, extracted with CH2Cl2, and the organic layer was dried over anhydrous Na2SO4, then concentrated by rotary evaporation, and the resultant crude product was purified through column chromatography to obtain N-(2,4-dimethoxyphenyl)-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide (purple crystals). Yield: 27%. m.p. 114-116° C. 1H NMR (400 MHz, CDCl3) δ(ppm): 1.36 (d, J=6.8 Hz, 6H), 2.50 (s, 3H), 3.10 (q, J=6.4 Hz, J=6.4 Hz, 1H), 3.42 (s, 3H), 3.72 (s, 6H, OCH3), 6.31-6.37 (m, 2H, PhH), 7.00 (s, 1H, PhH), 7.37 (d, J=10.8 Hz, 1H), 7.56 (d, J=11.2 Hz, 1H), 8.02 (s, 1H), 8.22 (d, J=2.0 Hz, 1H); IR (KBr) v: 3349, 2963, 2843, 1511, 1458, 1369, 1145, 895, 834; HRMS (ESI) m/z calcd for C23H27NO4S [M+H]+ 414.1733, found 414.1746.
The process steps of this example are as follows:
25 ml round-bottom flask was added with azulene sodium sulphonate (1 mmol), and then under ice bath added with 10 ml of CH2Cl2, 3-5 drops of DMF and 0.5 ml of pyridine. A dropping funnel was added with a small amount of CH2Cl2 and then added with (COCl)2 (2.5 mmol), which was then slowly dropwise added into the round-bottom flask. After completion of the reaction, a mixture solution of 2 ml of Et3N, 1 ml of pyridine and isopropyl amine (1.5 mmol) was slowly dropwise added into the reaction solution through a dropping funnel. After completion of dropwise addition, the mixture was reacted at room temperature for 1 h, and then added with an equal volume of water into the flask, and added with dilute hydrochloric acid to adjust pH to 5-6, extracted with CH2Cl2, and the organic layer was dried over anhydrous Na2SO4, then concentrated by rotary evaporation, and the resultant crude product was purified through column chromatography to obtain N,5-diisopropyl-3,8-dimethyl-1-azulene sulfonamide (purple crystals). Yield: 34%. m.p. 128-130° C. 1H NMR (400 MHz, CDCl3) δ(ppm): 1.15 (d, J=7 Hz, 6H, CH3), 1.38 (d, J=7.2 Hz, 6H), 2.58 (s, 3H), 3.12 (q, J=6.8 Hz, J=6.8 Hz, 1H), 3.37 (s, 3H), 3.53 (m, 1H, CH), 7.37 (d, J=11.2 Hz, 1H), 7.57 (d, J=11.2 Hz, 1H), 8.16 (s, 1H), 8.26 (d, J=2.0 Hz, 1H); IR (KBr) v: 3274, 2967, 2866, 1368, 1133; HRMS (ESI) m/z calcd for C18H25NO2S [M+H]+320.1679, found 320.1693.
The process steps of this example are as follows:
25 ml round-bottom flask was added with azulene sodium sulphonate (1 mmol), and then under ice bath added with 10 ml of CH2Cl2, 3-5 drops of DMF and 0.5 ml of pyridine. A dropping funnel was added with a small amount of CH2Cl2 and then added with (COCl)2 (2.5 mmol), which was then slowly dropwise added into the round-bottom flask. After completion of the reaction, a mixture solution of 2 ml of Et3N, 1 ml of pyridine and naphthylamine (1.5 mmol) was slowly dropwise added into the reaction solution through a dropping funnel. After completion of dropwise addition, the mixture was reacted at room temperature for 1 h, and then added with an equal volume of water into the flask, and added with dilute hydrochloric acid to adjust pH to 5-6, extracted with CH2Cl2, and the organic layer was dried over anhydrous Na2SO4, then concentrated by rotary evaporation, and the resultant crude product was purified through column chromatography to obtain N-(1-naphthyl)-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide (purple crystals). Yield: 35%. m.p. 140-142° C. 1H NMR (400 MHz, CDCl3) δ(ppm): 1.37 (d, J=7.6 Hz, 6H), 2.49 (s, 3H), 3.12 (q, J=7.2 Hz, J=7.2 Hz, 1H), 3.45 (s, 3H), 7.17-7.60 (m, 5H, PhH), 7.39 (d, J=11.2 Hz, 1H), 7.58 (d, J=10.8 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 8.08 (s, 1H), 8.26 (d, J=2.0 Hz, 1H); IR (Mk) v: 3253, 2957, 2867, 1460, 1369, 1139, 773; HRMS (ESI) m/z calcd for C25H25NO2S [M+H]+ 404.1679, found 404.1691.
The process steps of this example are as follows:
25 ml round-bottom flask was added with azulene sodium sulphonate (1 mmol), and then under ice bath added with 10 ml of CH2Cl2, 3-5 drops of DMF and 0.5 ml of pyridine. A dropping funnel was added with a small amount of CH2Cl2 and then added with (COCl)2 (2.5 mmol), which was then slowly dropwise added into the round-bottom flask. After completion of the reaction, a mixture solution of 2 ml of Et3N, 1 ml of pyridine and isobutylamine (1.5 mmol) was slowly dropwise added into the reaction solution through a dropping funnel. After completion of dropwise addition, the mixture reacted at room temperature for 1 h, and then added with an equal volume of water into the flask, and added with dilute hydrochloric acid to adjust pH to 5-6, extracted with CH2Cl2, and the organic layer was dried over anhydrous Na2SO4, then concentrated by rotary evaporation, and the resultant crude product was purified through column chromatography to obtain N-isobutyl-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide (purple crystals). Yield: 20%. m.p. 117-118° C. 1H NMR (400 MHz, CDCl3) δ(ppm): 0.90 (d, J=6.8 Hz, 6H, CH3), 1.38 (d, J=6.8 Hz, 6H), 1.79 (m, 1H, CH), 2.58 (s, 3H), 2.89 (t, J=6.4 Hz, 2H, CH2), 3.12 (q, J=7.2 Hz, J=7.2 Hz, 1H), 3.37 (s, 3H), 7.37 (d, J=10.4 Hz, 1H), 7.57 (d, J=11.2 Hz, 1H), 8.07 (s, 1H), 8.27 (s, 1H); IR (KBr) v: 3316, 2955, 2865, 1461, 1370, 1149; HRMS (ESI) m/z calcd for C19H27NO2S [M+H]+ 334.1835, found 334.1910.
The process steps of this example are as follows:
25 ml round-bottom flask was added with azulene sodium sulphonate (1 mmol), and then under ice bath added with 10 ml of CH2Cl2, 3-5 drops of DMF and 0.5 ml of pyridine. A dropping funnel was added with a small amount of CH2Cl2 and then added with (COCl)2 (2.5 mmol), which was then slowly dropwise added into the round-bottom flask. After completion of the reaction, a mixture solution of 2 ml of Et3N, 1 ml of pyridine and n-propylamine (1.5 mmol) was slowly dropwise added into the reaction solution through a dropping funnel. After completion of dropwise addition, the mixture was reacted at room temperature for 1 h, and then added with an equal volume of water into the flask, and added with dilute hydrochloric acid to adjust pH to 5-6, extracted with CH2Cl2, and the organic layer was dried over anhydrous Na2SO4, then concentrated by rotary evaporation, and the resultant crude product was purified through column chromatography to obtain N-propyl-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide (purple powder). Yield: 31%. m.p. 60-62° C. 1H NMR (400 MHz, CDCl3) δ(ppm): 0.90 (t, J=7.2 Hz, 3H, CH3), 1.38 (d, J=6.8 Hz, 6H), 1.56 (m, 2H, CH2), 2.57 (s, 3H), 3.06 (m, 2H, CH2), 3.12 (q, J=7.2 Hz, J=7.2 Hz, 1H), 3.36 (s, 3H), 7.37 (d, J=11.2 Hz, 1H), 7.57 (d, J=11.2 Hz, 1H), 8.08 (s, 1H), 8.26 (s, 1H); IR (KBr) v: 3304, 2960, 2870, 1369, 1150; HRMS (ESI) m/z calcd for C18H25NO2S [M+H]+ 320.1688, found 320.1687.
The process steps of this example are as follows:
25 ml round-bottom flask was added with azulene sodium sulphonate (1 mmol), and then under ice bath added with 10 ml of CH2Cl2, 3-5 drops of DMF and 0.5 ml of pyridine. A dropping funnel was added with a small amount of CH2Cl2 and then added with (COCl)2 (2.5 mmol), which was then slowly dropwise added into the round-bottom flask. After completion of the reaction, a mixture solution of 2 ml of Et3N, 1 ml of pyridine and p-toluidine (1.5 mmol) was slowly dropwise added into the reaction solution through a dropping funnel. After completion of dropwise addition, the mixture was reacted at room temperature for 1 h, and then added with an equal volume of water into the flask, and added with dilute hydrochloric acid to adjust pH to 5-6, extracted with CH2Cl2, and the organic layer was dried over anhydrous Na2SO4, then concentrated by rotary evaporation, and the resultant crude product was purified through column chromatography to obtain N-(4-methylphenyl)-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide (purple powder). Yield: 33%. m.p. 146-148° C. 1H NMR (400 MHz, CDCl3) δ(ppm): 1.37 (d, J=6.8 Hz, 6H), 2.23 (s, 3H, PhCH3), 2.51 (s, 3H), 3.12 (q, J=7.2 Hz, J=7.2 Hz, 1H), 3.41 (s, 3H), 6.94 (d, J=8.4 Hz, 2H, PhH), 7.00 (d, J=8.4 Hz, 2H, PhH), 7.38 (d, J=11.2 Hz, 1H), 7.57 (d, J=11.2 Hz, 1H), 8.06 (s, 1H), 8.25 (d, J=2.0 Hz, 1H); IR (KBr) v: 3315, 2959, 2864, 1514, 1465, 1368, 1155, 811; HRMS (ESI) m/z calcd for C22H25NO2S [M+H]+ 368.1678, found 368.1693.
The process steps of this example are as follows:
25 ml round-bottom flask was added with azulene sodium sulphonate (1 mmol), and then under ice bath added with 10 ml of CH2Cl2, 3-5 drops of DMF and 0.5 ml of pyridine. A dropping funnel was added with a small amount of CH2Cl2 and then added with (COCl)2 (2.5 mmol), which was then slowly dropwise added into the round-bottom flask. After completion of the reaction, a mixture solution of 2 ml of Et3N, 1 ml of pyridine and ethylamine (1.5 mmol) was slowly dropwise added into the reaction solution through a dropping funnel. After completion of dropwise addition, the mixture was reacted at room temperature for 1 h, and then added with an equal volume of water into the flask, and added with dilute hydrochloric acid to adjust pH to 5-6, extracted with CH2Cl2, and the organic layer was dried over anhydrous Na2SO4, then concentrated by rotary evaporation, and the resultant crude product was purified through column chromatography to obtain N-ethyl-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide (blue floccule). Yield: 35%. m.p. 96-98° C. 1H NMR (400 MHz, CDCl3) δ(ppm): 1.17 (t, J=7.2 Hz, 3H, CH3), 1.37 (d, J=6.8 Hz, 6H), 2.58 (s, 3H), 3.09 (m, 2H, CH2), 3.16 (q, J=7.2 Hz, J=7.2 Hz, 1H), 3.37 (s, 3H), 7.37 (d, J=10.8 Hz, 1H), 7.58 (d, J=11.2 Hz, 1H), 8.09 (s, 1H), 8.27 (d, J=2.0 Hz, 1H); IR (KBr) v: 3314, 2965, 1365, 1153; HRMS (ESI) m/z calcd for C17H23NO2S [M+H]+306.1522, found 306.1526.
The process steps of this example are as follows:
25 ml round-bottom flask was added with azulene sodium sulphonate (1 mmol), and then under ice bath added with 10 ml of CH2Cl2, 3-5 drops of DMF and 0.5 ml of pyridine. A dropping funnel was added with a small amount of CH2Cl2 and then added with (COCl)2 (2.5 mmol), which was then slowly dropwise added into the round-bottom flask. After completion of the reaction, a mixture solution of 2 ml of Et3N, 1 ml of pyridine and cyclohexylamine (1.5 mmol) was slowly dropwise added into the reaction solution through a dropping funnel. After completion of dropwise addition, the mixture was reacted at room temperature for 1 h, and then added with an equal volume of water into the flask, and added with dilute hydrochloric acid to adjust pH to 5-6, extracted with CH2Cl2, and the organic layer was dried over anhydrous Na2SO4, then concentrated by rotary evaporation, and the resultant crude product was purified through column chromatography to obtain N-cyclohexyl-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide (purple floccule). Yield: 42%. m.p. 108-109° C. 1H NMR (400 MHz, CDCl3) δ(ppm): 1.38 (d, J=7.2 Hz, 6H), 1.91-1.50 (m, 10H), 2.58 (s, 3H), 3.12 (q, J=7.2 Hz, J=7.2 Hz, 1H), 3.27 (m, 1H, CH), 3.37 (s, 3H), 7.36 (d, J=10.4 Hz, 1H), 7.57 (d, J=10.4 Hz, 1H), 8.15 (s, 1H), 8.26 (d, J=2.0 Hz, 1H); IR (KBr) v: 3323, 2924, 2852, 1367, 1140; HRMS (ESI) m/z calcd for C21H29NO2S [M+H]+ 360.1992, found 360.1992.
The process steps of this example are as follows:
25 ml round-bottom flask was added with azulene sodium sulphonate (1 mmol), and then under ice bath added with 10 ml of CH2Cl2, 3-5 drops of DMF and 0.5 ml of pyridine. A dropping funnel was added with a small amount of CH2Cl2 and then added with (COCl)2 (2.5 mmol), which was then slowly dropwise added into the round-bottom flask. After completion of the reaction, a mixture solution of 2 ml of Et3N, 1 ml of pyridine and benzylamine (1.5 mmol) was slowly dropwise added into the reaction solution through a dropping funnel. After completion of dropwise addition, the mixture was reacted at room temperature for 1 h, and then added with an equal volume of water into the flask, and added with dilute hydrochloric acid to adjust pH to 5-6, extracted with CH2Cl2, and the organic layer was dried over anhydrous Na2SO4, then concentrated by rotary evaporation, and the resultant crude product was purified through column chromatography to obtain N-benzyl-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide (dark blue floccule). Yield: 48%. m.p. 124-126° C. m.p. 124-126° C. 1H NMR (400 MHz, CDCl3) δ(ppm): 1.39 (d, J=6.8 Hz, 6H), 2.58 (s, 3H), 3.14 (q, J=7.2 Hz, J=7.2 Hz, 1H), 3.37 (s, 3H), 4.23 (d, J=6.0 Hz, 2H, CH2), 7.22-7.24 (m, 5H, PhH), 7.38 (d, J=10.8 Hz, 1H), 7.57 (d, J=10.8 Hz, 1H), 8.13 (s, 1H), 8.28 (d, J=2.0 Hz, 1H); IR (KBr) v: 3327, 2958, 2863, 1542, 1366, 1147; HRMS (ESI) m/z calcd for C22H25NO2S [M+H]+ 368.1679, found 368.1683.
The process steps of this example are as follows:
A 25 ml round-bottom flask was added with azulene sodium sulphonate (1 mmol), and then under ice bath added with 10 ml of CH2Cl2, 3-5 drops of DMF and 0.5 ml of pyridine. A dropping funnel was added with a small amount of CH2Cl2 and then added with (COCl)2 (2.5 mmol), which was then slowly dropwise added into the round-bottom flask. After completion of the reaction, a mixture solution of 2 ml of Et3N, 1 ml of pyridine and p-chloroaniline (1.5 mmol) was slowly dropwise added into the reaction solution through a dropping funnel. After completion of dropwise addition, the mixture was reacted at room temperature for 1 h, and then added with an equal volume of water into the flask, and added with dilute hydrochloric acid to adjust pH to 5-6, extracted with CH2Cl2, and the organic layer was dried over anhydrous Na2SO4, then concentrated by rotary evaporation, and the resultant crude product was purified through column chromatography to obtain N-(4-chlorophenyl)-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide (purple powder). Yield: 22%. m.p. 134-135° C. 1H NMR (400 MHz, CDCl3) δ(ppm): 1.37 (d, J=6.8 Hz, 6H), 2.51 (s, 3H), 3.13 (q, J=7.2 Hz, J=7.2 Hz, 1H), 3.39 (s, 3H), 6.99 (d, J=8 Hz, 2H, PhH), 7.15 (d, J=8 Hz, 2H, PhH), 7.40 (d, J=11.2 Hz, 1H), 7.61 (d, J=10.8 Hz, 1H), 8.02 (s, 1H), 8.27 (d, J=2.0 Hz, 1H); IR (KBr) v: 3298, 2957, 2862, 1492, 1369, 1137, 820, 691; HRMS (ESI) m/z calcd for C21H22ClNO2S [M+H]+ 388.1132, found 388.1145.
The process steps of this example are as follows:
25 ml round-bottom flask was added with azulene sodium sulphonate (1 mmol), and then under ice bath added with 10 ml of CH2Cl2, 3-5 drops of DMF and 0.5 ml of pyridine. A dropping funnel was added with a small amount of CH2Cl2 and then added with (COCl)2 (2.5 mmol), which was then slowly dropwise added into the round-bottom flask. After completion of the reaction, a mixture solution of 2 ml of Et3N, 1 ml of pyridine and p-phenylenediamine (1.5 mmol) was slowly dropwise added into the reaction solution through a dropping funnel. After completion of dropwise addition, the mixture was reacted at room temperature for 1 h, and then added with an equal volume of water into the flask, and added with dilute hydrochloric acid to adjust pH to 5-6, extracted with CH2Cl2, and the organic layer was dried over anhydrous Na2SO4, then concentrated by rotary evaporation, and the resultant crude product was purified through column chromatography to obtain
N-(4-aminophenyl)-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide (purple crystals). Yield: 29%. m.p. 88-90° C. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 1.31 (d, J=6.4 Hz, 6H), 2.49 (s, 3H), 3.17 (q, J=6.8 Hz, J=6.8 Hz, 1H), 3.30 (s, 3H), 4.84 (s, 2H, NH2), 6.37 (d, J=8.0 Hz, 2H, PhH), 6.78 (d, J=8.0 Hz, 2H, PhH), 7.44 (d, J=10.8 Hz, 1H), 7.73 (d, J=10.4 Hz, 1H), 7.92 (s, 1H), 8.30 (s, 1H); IR (KBr) v: 3374, 3301, 2958, 2864, 1624, 1513, 1371, 1146, 824; HRMS (ESI) m/z calcd for C21H24N2O2S [M+H]+ 369.1631, found 369.1641.
The process steps of this example are as follows:
25 ml round-bottom flask was added with azulene sodium sulphonate (1 mmol), and then under ice bath added with 10 ml of CH2Cl2, 3-5 drops of DMF and 0.5 ml of pyridine. A dropping funnel was added with a small amount of CH2Cl2 and then added with (COCl)2 (2.5 mmol), which was then slowly dropwise added into the round-bottom flask. After completion of the reaction, a mixture solution of 2 ml of Et3N, 1 ml of pyridine and hydrazine hydrate (1.5 mmol) was slowly dropwise added into the reaction solution through a dropping funnel. After completion of dropwise addition, the mixture reacted at room temperature for 1 h, and then added with an equal volume of water into the flask, and added with dilute hydrochloric acid to adjust pH to 5-6, extracted with CH2Cl2, and the organic layer was dried over anhydrous Na2SO4, then concentrated by rotary evaporation, and the resultant crude product was purified through column chromatography to obtain N-amino-3,8-dimethyl-5-isopropyl-1-azulene sulfonamide (purple crystals).
The purified compound 4m deteriorated soon in the air and had a very poor stability, so the structural characterization and subsequent trials were not performed.
The structure formula is shown as follows:
The process steps of this example are as follows:
Under ice bath, 25 ml pear-shaped flask was sequentially added with 4 mmol of guaiazulene, 2 ml of Ac2O, and then added with a mixture of 1 ml of concentrated H2SO4 and 2 ml of Ac2O through constant pressure dropping funnel (with a drying tube on the top). After completion of dropwise addition, the mixture was stirred at room temperature for about 2 h and the reaction was tracked with TLC until the raw material disappears. The mixture solution was poured into 4 ml of water, and then dropwise added with NaOH solution to adjust pH to 8-9. Then the mixture solution was cooled to precipitate, leached, and washed with cold water and petroleum ether sequentially, dried, to obtain 1.05 g of blue solid. Yield: 87.5%. m.p. 106-107° C.
Under ice bath, 100 ml round-bottom flask was added with 60 ml of methanol, and then slowly added with 4 ml of SOCl2through constant pressure dropping funnel (with a drying tube on the top), and NaOH solution was used to absorb exhaust. After stirring for 1 h, 8 mmol of L-tryptophan (3d) was added and stirred at room temperature for 30 min, and then refluxed at 66° C. for 6 h. The reaction was tracked by TLC until the raw material disappears, with a solution of 2% ninhydrin in ethanol as chromogenic reagent. The solvent was evaporated out to obtain L-tryptophan methyl ester hydrochloride. Yield: 100%.
Under ice bath, 25 ml pear-shaped flask was sequentially added with 2 mmol of azulene sodium sulphonate, 0.8 ml of DMF, and 5 ml of CH2Cl2, 0.8 ml of Py, then added with a mixture of 5 mmol of (COCl)2 and 2.5 ml of CH2Cl2 through constant pressure dropping funnel (with a drying tube on the top). The produced acyl chloride was tested using n-propylamine. The reaction was tracked by TLC until the raw material disappears. Then the mixture was added with 2.5 mmol of L-tryptophan methyl ester hydrochloride, and slowly dropwise added with 3 ml of Et3N and 1 ml of Py through constant pressure dropping funnel. After completion of dropwise addition, the mixture was stirred at room temperature over night. The reaction solution was poured into a small beaker containing 15 ml of water, and added with an appropriate amount of dilute HCl to neutralize excessive Et3N and Py and adjust pH to 5-6, then extracted with CH2Cl2 for three times. The organic layers were combined and evaporated to remove the solvent. The residue was purified by column chromatography on silica gel (silica gel: 300-400 mesh; petroleum ether-ethyl acetate (V:V=4:1) as eluent) to obtain N-2-(indol-3-methyl)-2-methoxyformyl methylene-3′,8′-dimethyl-5′-isopropyl azulene-1′-sulfonamide (5d), purple crystals. Yield: 20%. m.p. 178-180° C. 1H NMR (CDCl3, 400 MHz) δ: 8.19 (s, 1H), 7.99 (s, 2H), 7.52 (d, J=11.6 Hz, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.25 (d, J=4.7 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 7.09 (t, J=7.2 Hz, 8.1 Hz, 1H), 6.98 (dd, J=4.4 Hz, 8.4 Hz, 2H), 5.28 (d, J=8.9 Hz, 1H), 4.32˜4.27, 3.30˜3.26 (m, 3H), 3.51 (s, 3H), 3.21 (s, 3H), 3.19˜3.08 (m, 1H), 2.47 (s, 3H), 1.37 (d, J=6.9 Hz, 6H). IR (KBr) v: 3304 (NH), 1744 (C═O), 1370 (as, S═O), 1145 (s, S═O) cm−1. HRMS (ESI) calcd for C27H30N2O4S [M+H]+ 479.1999 found 479.1990; [M+Na]+ 501.1818 found 501.1837; [M+K]+ 517.1558 found 517.1551.
The structure formula is shown as follows:
The process steps of this example are as follows:
Under ice bath, 25 ml pear-shaped flask was sequentially added with 4 mmol of guaiazulene, 2 ml of Ac2O, and then added with a mixture of 1 ml of concentrated H2SO4 and 2 ml of Ac2O through constant pressure dropping funnel (with a drying tube on the top). After completion of dropwise addition, the mixture was stirred at room temperature for about 2 h and the reaction was tracked with TLC until the raw material disappears. The mixture solution was poured into 4 ml of water, and then dropwise added with NaOH solution to adjust pH to 8-9. Then the mixture solution was cooled to precipitate, leached, and washed with cold water and petroleum ether sequentially, dried, to obtain 1.05 g of blue solid. Yield: 87.5%. m.p. 106-107° C.
Under ice bath, 100 ml round-bottom flask was added with 60 ml of methanol, and then slowly added with 4 ml of SOCl2 through constant pressure dropping funnel (with a drying tube on the top), and NaOH solution was used to absorb exhaust. After stirring for 1 h, 8 mmol of β-alanine was added and stirred at room temperature for 30 min, and then refluxed at 66° C. for 6 h. The reaction was tracked by TLC until the raw material disappears, with a solution of 2% ninhydrin in ethanol as chromogenic reagent. The solvent was evaporated out to obtain β-alanine methyl ester hydrochloride. Yield: 100%.
Under ice bath, 25 ml pear-shaped flask was sequentially added with 2 mmol of azulene sodium sulphonate, 0.8 ml of DMF, and 5 ml of CH2Cl2, 0.8 ml of Py, then added with a mixture of 5 mmol of (COCl)2 and 2.5 ml of CH2Cl2 through constant pressure dropping funnel (with a drying tube on the top). The produced acyl chloride was tested using n-propylamine. The reaction was tracked by TLC until the raw material disappears. Then the mixture was added with 2.5 mmol of β-alanine methyl ester hydrochloride, and slowly dropwise added with 3 ml of Et3N and 1 ml of Py through constant pressure dropping funnel. After completion of dropwise addition, the mixture was stirred at room temperature over night. The reaction solution was poured into a small beaker containing 15 ml of water, and added with an appropriate amount of dilute HCl to neutralize excessive Et3N and Py and adjust pH to 5-6, then extracted with CH2Cl2 for three times. The organic layers were combined and evaporated to remove the solvent. The residue was purified by column chromatography on silica gel (silica gel: 300-400 mesh; petroleum ether-ethyl acetate (V:V=4:1) as eluent) to obtain N-3-methoxyformylethyl-3′,8′-dimethyl-5′-isopropyl azulene-1′-sulfonamide (5h), purple crystals. Yield: 23%. m.p. 94-96° C. 1H NMR (CDCl3, 400 MHz) δ: 8.27 (s, 1H), 8.10 (s, 1H), 7.58 (d, J=11.8 Hz, 1H), 7.37 (d, J=11.0 Hz, 1H), 5.28 (t, J=8.4 Hz, 7.5 Hz, 1H), 3.65 (s, 3H), 3.36 (s, 3H), 3.30 (dd, J=6.3 Hz, 6.1 Hz, 2H), 3.16-3.09 (m, 1H), 2.59-2.56 (m, 2H), 2.58 (s, 3H), 1.37 (d, J=6.8 Hz, 6H). IR (KBr) v: 3314 (NH), 1728 (C═O), 1370 (as, S═O), 1154 (s, S═O) cm−1. HRMS (ESI) calcd for C19H25NO4S [M+H]+ 364.1577 found 364.1583; [M+Na]+ 386.1397 found 386.1405; [M+K]+402.1136 found 402.1151.
The structure formula is shown as follows:
The process steps of this example are as follows:
Under ice bath, 25 ml pear-shaped flask was sequentially added with 4 mmol of guaiazulene, 2 ml of Ac2O, and then added with a mixture of 1 ml of concentrated H2SO4 and 2 ml of Ac2O through constant pressure dropping funnel (with a drying tube on the top). After completion of dropwise addition, the mixture was stirred at room temperature for about 2 h and the reaction was tracked with TLC until the raw material disappears. The mixture solution was poured into 4 ml of water, and then dropwise added with NaOH solution to adjust pH to 8-9. Then the mixture solution was cooled to precipitate, leached, and washed with cold water and petroleum ether sequentially, dried, to obtain 1.05 g of blue solid. Yield: 87.5%. m.p. 106-107° C.
Under ice bath, 100 ml round-bottom flask was added with 60 ml of methanol, and then slowly added with 4 ml of SOCl2 through constant pressure dropping funnel (with a drying tube on the top), and NaOH solution was used to absorb exhaust. After stirring for 1 h, 8 mmol of L-leucine was added and stirred at room temperature for 30 min, and then refluxed at 66° C. for 6 h. The reaction was tracked by TLC until the raw material disappears, with a solution of 2% ninhydrin in ethanol as chromogenic reagent. The solvent was evaporated out to obtain L-leucine methyl ester hydrochloride. Yield: 100%.
Under ice bath, 25 ml pear-shaped flask was sequentially added with 2 mmol of azulene sodium sulphonate, 0.8 ml of DMF, and 5 ml of CH2Cl2, 0.8 ml of Py, then added with a mixture of 5 mmol of (COCl)2 and 2.5 ml of CH2Cl2 through constant pressure dropping funnel (with a drying tube on the top). The produced acyl chloride was tested using n-propylamine. The reaction was tracked by TLC until the raw material disappears. Then the mixture was added with 2.5 mmol of L-leucine methyl ester hydrochloride, and slowly dropwise added with 3 ml of Et3N and 1 ml of Py through constant pressure dropping funnel. After completion of dropwise addition, the mixture was stirred at room temperature over night. The reaction solution was poured into a small beaker containing 15 ml of water, and added with an appropriate amount of dilute HCl to neutralize excessive Et3N and Py and adjust pH to 5-6, then extracted with CH2Cl2 for three times. The organic layers were combined and evaporated to remove the solvent. The residue was purified by column chromatography on silica gel (silica gel: 300-400 mesh; eluent: petroleum ether-ethyl acetate (V:V=4:1)) to obtain N-2-(2-methylpropyl)-2-methoxyformyl methylene-3′,8′-dimethyl-5′-isopropyl azulene-1′-sulfonamide (5b), purple crystals. Yield: 21%. m.p. 68-70° C. 1H NMR (CDCl3, 400 MHz) δ: 8.26 (s, 1H), 8.14 (s, 1H), 7.58 (d, J=11.2 Hz, 1H), 7.39 (d, J=11.2 Hz, 1H), 5.13 (d, J=10.0 Hz, 1H), 3.97-3.90 (m, 1H), 3.43 (s, 3H), 3.38 (s, 3H), 3.13 (dd, J=7.1 Hz, 6.8 Hz, 1H), 2.56 (s, 3H), 1.74-1.67 (m, 1H), 1.50-1.40 ((m, 2H), 1.37 (d, J=6.8 Hz, 6H), 0.84 (d, J=6.6 Hz, 3H), 0.69 (d, J=6.6 Hz, 3H). IR (KBr) v: 3308 (NH), 1746 (C═O), 1370 (as, S═O), 1155 (s, S═O) cm−1. HRMS (ESI) calcd for C22H31NO4S [M+H]+ 406.2047 found 406.2048; [M+K]+ 444.1605 found 444.1652.
1 mmol of N-2-(2-methylpropyl)-2-methoxyformylmethylene-3′,8′-dimethyl-5′-isopropyl azulene-1′-sulfonamide (5b) was dissolved in 5 ml of methanol and 15 ml of water, and added with 0.8 ml of 5% NaOH solution, and extracted with CH2Cl2 for three times. The aqueous layers were retained, added with dilute HCl until reaching pH 5-6, then extracted with CH2Cl2 for three times. The organic layers were combined, evaporated to remove the solvent. The residue was purified by column chromatography on silica gel (silica gel: 300-400 mesh; Eluent: petroleum ether-ethyl acetate (V:V=4:1)) to obtain N-2-(2-methylpropyl)-2-carboxymethylene-3′,8′-dimethyl-5′-isopropyl azulene-1′-sulfonamide (6b), purple crystals. Yield: 95%. m.p. 44-46° C. 1H NMR (DMSO-d6, 400 MHz) δ: 10.80 (s, 1H), 10.52 (s, 1H), 10.39 (d, J=9.4 Hz, 1H), 10.22 (d, J=10.9 Hz, 1H), 9.93 (d, J=11.4 Hz, 1H), 6.13˜6.07 (m, 1H), 5.79 (s, 3H), 5.71˜5.64 (m, 1H), 5.03 (s, 3H), 4.14˜3.99 (m, 2H), 3.87˜3.84 (m, 1H), 3.82 (d, J=6.9 Hz, 6H), 3.28 (d, J=6.4 Hz, 3H), 3.06 (d, J=6.4 Hz, 3H). IR (KBr) v: 3329 (NH), 1726 (C═O), 1372 (as, S═O), 1151 (s, S═O) HRMS (ESI) calcd for C21H29NO4S [M+H]+ 392.1890 found 392.1898; [M+Na]+ 414.1710 found 414.1723; [M+K]+ 430.1449 found 430.1467.
The structure formula is shown as follows:
Under ice bath, 25 ml pear-shaped flask was sequentially added with 4 mmol of guaiazulene, 2 ml of Ac2O, and then added with a mixture of 1 ml of concentrated H2SO4 and 2 ml of Ac2O through constant pressure dropping funnel (with a drying tube on the top). After completion of dropwise addition, the mixture was stirred at room temperature for about 2 h and the reaction was tracked with TLC until the raw material disappears. The mixture solution was poured into 4 ml of water, and then dropwise added with NaOH solution to adjust pH to 8-9. Then the mixture solution was cooled to precipitate, leached, and washed with cold water and petroleum ether sequentially, dried, to obtain 1.05 g of blue solid. Yield: 87.5%. m.p. 106-107° C.
Under ice bath, 100 ml round-bottom flask was added with 60 ml of methanol, and then slowly added with 4 ml of SOCl2 through constant pressure dropping funnel (with a drying tube on the top), and NaOH solution was used to absorb exhaust. After stirring for 1 h, 8 mmol of L-tryptophan was added and stirred at room temperature for 30 min, and then refluxed at 66° C. for 6 h. The reaction was tracked by TLC until the raw material disappears, with a solution of 2% ninhydrin in ethanol as chromogenic reagent. The solvent was evaporated out to obtain L-tryptophan methyl ester hydrochloride. Yield: 100%.
Under ice bath, 25 ml pear-shaped flask was sequentially added with 2 mmol of azulene sodium sulphonate, 0.8 ml of DMF, and 5 ml of CH2Cl2, 0.8 ml of Py, then added with a mixture of 5 mmol of (COCl)2 and 2.5 ml of CH2Cl2 through constant pressure dropping funnel (with a drying tube on the top). The produced acyl chloride was tested using n-propylamine. The reaction was tracked by TLC until the raw material disappears. Then the mixture was added with 2.5 mmol L-tryptophan methyl ester hydrochloride, and slowly dropwise added with 3 ml of Et3N and 1 ml of Py through constant pressure dropping funnel. After completion of dropwise addition, the mixture was stirred at room temperature over night. The reaction solution was poured into a small beaker containing 15 ml of water, and added with an appropriate amount of dilute HCl to neutralize excessive Et3N and Py and adjust pH to 5-6, then extracted with CH2Cl2 for three times. The organic layers were combined and evaporated to remove the solvent. The residue was purified by column chromatography on silica gel (silica gel: 300-400 mesh; petroleum ether-ethyl acetate (V:V=4:1) as eluent) to obtain N-2-(indol-3-methyl)-2-methoxyformyl methylene-3′,8′-dimethyl-5′-isopropyl azulene-1′-sulfonamide (5d), purple crystals. Yield: 20%. m.p. 178-180° C. 1H NMR (CDCl3, 400 MHz) δ: 8.19 (s, 1H), 7.99 (s, 2H), 7.52 (d, J=11.6 Hz, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.25 (d, J=4.7 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 7.09 (t, J=7.2 Hz, 8.1 Hz, 1H), 6.98 (dd, J=4.4 Hz, 8.4 Hz, 2H), 5.28 (d, J=8.9 Hz, 1H), 4.32˜4.27, 3.30˜3.26 (m, 3H), 3.51 (s, 3H), 3.21 (s, 3H), 3.19˜3.08 (m, 1H), 2.47 (s, 3H), 1.37 (d, J=6.9 Hz, 6H). IR (KBr) v: 3304 (NH), 1744 (C═O), 1370 (as, S═O), 1145 (s, S═O) cm−1. HRMS (ESI) calcd for C27H30N2O4S [M+H]+ 479.1999 found 479.1990; [M+Na]+ 501.1818 found 501.1837; [M+K]+ 517.1558 found 517.1551.
1 mmol of N-2-(indol-3-methyl)-2-methoxyformyl methylene-3′,8′-dimethyl-5′-isopropyl azulene-1′-sulfonamide (5d) was dissolved in 5 ml of methanol and 15 ml of water, and added with 0.8 ml of 5% NaOH solution, and extracted with CH2Cl2 for three times. The aqueous layers were retained, added with dilute HCl until reaching pH 5-6, then extracted with CH2Cl2 for three times. The organic layers were combined, evaporated to remove the solvent. The residue was purified by column chromatography on silica gel (silica gel: 300-400 mesh; eluent: petroleum ether-ethyl acetate (V:V=4:1)) to obtain N-2-(indol-3-methyl)-2-carboxymethylene-3′,8′-dimethyl-5′-isopropyl azulene-1′-sulfonamide (6c), purple crystals. Yield: 98%. m.p. 107-108° C. 1H NMR (DMSO-d6, 400 MHz) δ: 13.35 (s, 1H), 10.69 (s, 1H), 10.52 (d, J=8.4 Hz, 1H), 10.00 (s, 1H), 9.81 (dd, J=11.2 Hz, 8.1 Hz, 2H), 9.74 (d, J=7.9 Hz, 1H), 9.68 (s, 1H), 9.50 (t, J=7.4 Hz, 7.6 Hz, 1H), 9.36 (t, J=7.6 Hz, 1H), 6.43˜6.37 (m, 1H), 5.66 (s, 3H), 5.61 (dd, J=6.4 Hz, 6.1 Hz, 2H), 5.51 (dd, J=8.4 Hz, 8.3 Hz, 1H), 5.00 (s, 3H), 3.81 (d, J=7.0 Hz, 6H). IR (KBr) v: 3409 (NH), 1736 (C═O), 1378 (as, S═O), 1146 (s, S═O) cm−1. HRMS (ESI) calcd for C26H28N2O4S [M+H]+ 465.1843 found 465.1841; [M+Na]+ 487.1662 found 487.1672; [M+K]+ 503.1401 found 503.1414.
The structure formula is shown as follows:
Under ice bath, 25 ml pear-shaped flask was sequentially added with 4 mmol of guaiazulene, 2 ml of Ac2O, and then added with a mixture of 1 ml of concentrated H2SO4 and 2 ml of Ac2O through constant pressure dropping funnel (with a drying tube on the top). After completion of dropwise addition, the mixture was stirred at room temperature for about 2 h and the reaction was tracked with TLC until the raw material disappears. The mixture solution was poured into 4 ml of water, and then dropwise added with NaOH solution to adjust pH to 8-9. Then the mixture solution was cooled to precipitate, leached, and washed with cold water and petroleum ether sequentially, dried, to obtain 1.05 g of blue solid. Yield: 87.5%. m.p. 106-107° C.
Under ice bath, 100 ml round-bottom flask was added with 60 ml of methanol, and then slowly added with 4 ml of SOCl2 through constant pressure dropping funnel (with a drying tube on the top), and NaOH solution was used to absorb exhaust. After stirring for 1 h, 8 mmol of glycine was added and stirred at room temperature for 30 min, and then refluxed at 66° C. for 6 h. The reaction was tracked by TLC until the raw materials disappeared, with a solution of 2% ninhydrin in ethanol as chromogenic reagent. The solvent was evaporated out to obtain glycine methyl ester hydrochloride. Yield: 100%.
Under ice bath, 25 ml pear-shaped flask was sequentially added with 2 mmol of azulene sodium sulphonate, 0.8 ml of DMF, and 5 ml of CH2Cl2, 0.8 ml of Py, then added with a mixture of 5 mmol of (COCl)2 and 2.5 ml of CH2Cl2 through constant pressure dropping funnel (with a drying tube on the top). The produced acyl chloride was tested using n-propylamine. The reaction was tracked by TLC until the raw material disappears. Then the mixture was added with 2.5 mmol of glycine methyl ester hydrochloride, and slowly dropwise added with 3 ml of Et3N and 1 ml of Py through constant pressure dropping funnel. After completion of dropwise addition, the mixture was stirred at room temperature over night. The reaction solution was poured into a small beaker containing 15 ml of water, and added with an appropriate amount of dilute HCl to neutralize excessive Et3N and Py and adjust pH to 5-6, then extracted with CH2Cl2 for three times. The organic layers were combined and evaporated to remove the solvent. The residue was purified by column chromatography on silica gel (silica gel: 300-400 mesh; eluent: petroleum ether-ethyl acetate (V:V=4:1)) to obtain N-methoxyformylmethyl-3′,8′-dimethyl-5′-isopropyl azulene-1′-sulfonamide (5a), purple crystals. Yield: 28%.
m.p. 70-72° C. 1H NMR (CDCl3, 400 MHz) δ: 8.28 (s, 1H), 8.11 (s, 1H), 7.59 (d, J=11.0 Hz, 1H), 7.39 (d, J=11.4 Hz, 1H), 5.17 (t, J=10.3 Hz, 1H), 3.84 (d, J=5.3 Hz, 2H), 3.67 (s, 3H), 3.38 (s, 3H), 3.13 (dd, J=6.9 Hz, 6.9 Hz, 1H), 2.57 (s, 3H), 1.38 (d, J=7.0 Hz, 6H). IR (KBr) v: 3315 (NH), 1735 (C═O), 1370 (as, S═O), 1155 (s, S═O) cm−1. HRMS (ESI) calcd for C18H23NO4S [M+H]+ 350.1421 found 350.1429; [M+Na]+ 372.1240 found 372.1226; [M+K]+ 388.0979 found 388.0989.
1 mmol of N-methoxyformylmethyl-3′,8′-dimethyl-5′-isopropyl azulene-1′-sulfonamide (5a), 60 ml of anhydrous ethanol, 3 mmol of 80% hydrazine hydrate were sequencially added into 100 ml bottom flask, and reacted under reflux at 80° C. for about 8 h. The reaction was tracked by TLC until the raw material disappears. The reaction solution was evaporated to remove the solvent and the residue was purified by column chromatography on silica gel (silica gel: 300-400 mesh; Eluent: petroleum ether-ethyl acetate-ethanol (V:V:V=4:1:0.5)) to obtain N-(2-hydrazo-2-oxoethyl)-3′,8′-dimethyl-5′-isopropyl azulene-1′-sulfonamide (7a), purple crystals. Yield: 80.5%. m.p. 71-73° C. 1H NMR (CDCl3, 400 MHz) δ: 8.28 (s, 1H), 8.02 (s, 1H), 7.61 (d, J=11.40 Hz, 1H), 7.56˜7.52 (m, 1H), 7.39 (d, J=10.9 Hz, 1H), 5.68˜5.60 (m, 1H), 3.40 (t, J=4.32 Hz, 3.61 Hz, 1H), 3.33 (s, 3H), 2.56 (s, 3H), 3.13 (dd, J=6.92 Hz, 2H), 2.04˜1.96 (m, 2H), 1.38 (d, J=6.93 Hz, 6H). IR(KBr) v: 3281 (NH2), 1660 (C═O), 1543 (C—N), 1375 (as, S═O), 1253 (s, S═O) cm−1. HRMS (ESI) calcd for C17H23N3O3S [M−H]− 348.1382 found 348.1392.
0.5 mmol of N-(2-hydrazo-2-oxoethyl)-3′,8′-dimethyl-5′-isopropyl azulene-1′-sulfonamide (7a), 15 ml of anhydrous ethanol, 0.6 mmol of 2-thiophene formaldehyde were added into 25 ml pear-shaped flask and stirred at 35° C. overnight. The reaction was tracked by TLC until the raw material disappears. The reaction solution was evaporated to remove the solvent and the residue was purified by column chromatography on silica gel (silica gel: 300-400 mesh; eluent: petroleum ether-ethyl acetate-ethanol (V:V:V=4:1:0.5)) to obtain N-(2-carbonyl-2-(2-(2-thienylmethylene)ethyl)-3′,8′-dimethyl-5′-isopropyl azulene-1′-sulfonamide (8a), purple crystals. Yield: 78%. m.p. 69-70° C. 1H NMR (CDCl3, 400 MHz) δ: 9.66 (s, 1H), 8.25 (d, J=2.10 Hz, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 7.56 (d, J=11.32 Hz, 1H), 7.40˜7.34 (d, J=3.27 Hz, 2H), 7.24 (d, J=3.63 Hz, 1H), 7.03 (dd, J=3.55 Hz, 3.55 Hz, 1H), 5.67 (t, J=4.34 Hz, 4.77 Hz, 1H), 4.27 (d, J=4.86 Hz, 2H), 3.41 (s, 3H), 3.11 (dd, J=7.22 Hz, 7.02 Hz, 1H), 2.56 (s, 3H), 1.36 (d, J=6.89 Hz, 6H). IR (KBr) v: 3396 (NH), 1685 (C═O), 1546 (C═N), 1381 (as, S═O), 1153 (s, S═O) cm−1. HRMS (ESI) calcd for C22H25N3O3S2 [M−H]− 442.1259 found 442.1250.
The advantages of the derivatives of the present invention will be illustrated by the following experimental examples.
Test Drugs:
(1) N-substituted isopropyldimethyl azulene sulfonamide derivatives prepared according to examples 1 to 18: 4a-4l
The test samples were open-stored in culture dishes at 60° C. for 10 days, and taken and detected on Day 5 and Day 10.
The test samples were open-stored in closed constant humidity desiccators under the condition of 25° C. and relative humidity of 90%+5% for 10 days, and taken and detected on Day 5 and Day 10. Meanwhile, each sample was accurately weighed before and after test.
The characteristics, especially colour change was observed.
Melting points were measured by an automatic melting point apparatus.
By self-reflection, TLC is used to observe whether the spot numbers were increased after 5 days and 10 days.
The test samples were open-stored in “adjustable light boxes” under the conditions of illumination of 4500LX±500LX for 10 days, and taken and detected on Day 5 and Day 10 with regards to dry items.
It can be seen from the above experiments of stability studies that the N-substituted isopropyldimethyl azulene sulfonamide derivatives such as 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j, 4k, 4l provided by the present invention have better light, humidity and heat stability than azulene sulfonate sodium and do not need special equipments or special treatment during the storage and transportation of the products, and thus reduce the product cost and increase the product safety.
Test Drugs:
(1) N-substituted isopropyldimethyl azulene sulfonamide derivatives prepared according to examples 1 to 18: 4a-4l
(2) Guaiazulene: Jiangxi East Flavor&Fragrance Co., Ltd, China
Omeprazole enteric-coated capsules: 20 mg/capsule, Lot: 100701, manufactured by Shangdong Laiyang Biochemistry Pharmaceutical Co. Ltd.
Kunming mice, half male and half female, weighing 18-22 g, provided by the West China Animal Center
(1) Electronic balance, manufactured by Changshu Shuangjie Test Instrument Factory, model T1000, Max=1000 g, d=0.1 g, manufactured by Beijing Sartorius balance Co., Ltd, model BS210S, Max=210 g, d=0.1 mg.
(1) Azulene sodium sulphonate was added with 0.5% CMC to prepare a suspension with concentration of 0.15 mg/ml.
(2) 20 mg of Omeprazole was added with 0.5% CMC to prepare a suspension with concentration of 0.67 mg/ml.
(3) The N-substituted isopropyldimethyl azulene sulfonamide derivatives 4a-4l prepared according to examples 1 to 12 were added with 0.5% CMC to prepare suspensions with concentration of 0.15 mg/ml.
Kunming mice were randomly grouped according the body weight (one model control group or negative control group, one Omeprazole control group or positive control group, one Azulene sodium sulphonate control group, twelve test drug groups), eight mice for each group, half male and half female.
Administration: Model control group was administrated intragastrically with 0.5% CMC solution at a dose of 0.4 m1/20 g; Omeprazole control group was administrated intragastrically with Omeprazole at a dose of 0.4 ml/20 g, Azulene sodium sulphonate control group and each test drug groups were administrated intragastrically with their respective drug at a dose of 0.4 ml/20 g. The mice in each group were administrated once a day for successive five days. 0.5 hour after final administration, the mice in each group were administrated intragastrically with 0.5 ml of anhydrous ethanol, one hour later the mice were executed and dissected, and their stomaches were taken, washed and scored according to the pathological degree. For local congestion and rubefaction, score was 1; for petechial hemorrhage or erosion, score was respectively 1, for each linear erosion, score was 3. Statistical analysis was performed. Ulcer scores were calculated, significant differences between the groups were compared and the inhibition rates of ulcer were calculated [Inhibition rate of ulcer=(ulcer score of model group−ulcer score of drug administration group)/ulcer score of model group]. Experiment results are shown in Tables 4-7.
Compared to the model group *P<0.05. The dose of each drug was calculated according to the same molar dose of azulene sulfonate sodium.
It can be seen from the data of Table 4, among the N-substituted isopropyldimethyl azulene sulfonamide derivatives prepared according to the present invention, compounds 4a, 4b, 4d and 4i can significantly relieve the pathological degree of ethanol-induced gastric ulcer disease in mice. Their ulcer scores are significant different from that of the model group and their pharmacodynamic activities are similar to and slightly superior than that of azulene sulfonate sodium.
Compared to the model group *P<0.05. The dose of each drug was calculated according to the same molar dose of azulene sulfonate sodium.
It can be seen from the data of Table 5, the N-substituted isopropyldimethyl azulene sulfonamide derivative 4l prepared according to the present invention can significantly relieve the pathological degree of ethanol-induced gastric ulcer disease in mice, the ulcer score of which is significant different from that of the model group.
Meanwhile, compared to azulene sulfonate sodium, the inhibition rate of the derivative 4l increased 38%; compared to Omeprazole, the inhibition rate of the derivative 4l increased 23%. Thus, the derivative 4l has better therapeutic effect on gastric ulcer than azulene sulfonate sodium and omeprazole.
Comparison of each drug group with the model group; *P<0.05.
Comparison of each drug group with the model group; *P<0.05.
It can be seen from the data of Tables 6 and 7, most of the derivatives 5a˜5h, 6a˜6c, 7a˜7b, 8a˜8b prepared according to the present invention have certain anti-gastric ulcer activity, wherein 5d, 5h, 6b, 6c and 8a have stronger and more significant anti-gastric ulcer capability, and have significant differences compared to the model group. The experiment results show that the derivatives of guaiazulene provided by the present invention can be used to develop new drugs with stronger pharmaceutical activity for treating gastric ulcer.
To sum up, the N-substituted isopropyldimethyl azulene sulfonamide derivatives prepared according to the present invention not only improve the stability of azulene sodium sulphonate and retain the therapeutic effect on gastric ulcer disease of azulene sodium sulphonate, but also enhance the pharmaceutical activity of azulene sodium sulphonate.
The N-substituted isopropyldimethyl azulene sulfonamide derivatives prepared according to the present invention have significant effect on treating gastric ulcer, the activity of which is comparable with or superior than that of azulene sulfonate sodium or Omeprazole, and have excellent light, moisture, heat stability, and can reduce the product cost and enhance the product safety. Meanwhile, the preparation method of the derivatives is simple and the raw materials are readily available. Thus, the N-substituted derivatives of isopropyl dimethyl azulene sulfonamides have good prospects in industrial applications.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201110164799.4 | Jun 2011 | CN | national |
| 201110175378.1 | Jun 2011 | CN | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/CN2012/073855 | 4/12/2012 | WO | 00 | 3/25/2014 |
