CN107827849B - 6- [ 2-hydroxy-3- (alkylamino) propoxy ] benzofuran compound and application thereof - Google Patents
6- [ 2-hydroxy-3- (alkylamino) propoxy ] benzofuran compound and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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Abstract
The invention belongs to the technical field of medicines, and relates to 6- [ 2-hydroxy-3- (alkylamino) propoxy group]Benzofuran compounds and their application are provided. 6- [ 2-hydroxy-3- (alkylamino) propoxy group]Benzofuran compounds comprise stereoisomers and pharmaceutically applicable salts of the compounds, and the structural general formula of the compounds is as follows: wherein R is as described in the claims and specification. 6- [ 2-hydroxy-3- (alkylamino) propoxy groups of the invention]The benzofuran compound and the pharmaceutically applicable acid addition salt thereof can be combined with the existing medicines or used independently, and can be used as medicines for treating vascular smooth muscle spastic diseases.
Description
The technical field is as follows:
the invention belongs to the technical field of medicines, and relates to a 6- [ 2-hydroxy-3- (alkylamino) propoxy ] benzofuran compound and application thereof. The compound can be used as a medicine for treating vascular smooth muscle spastic diseases.
Background art:
hypertension is one of the most major public health problems in the world today, and the awareness rate, treatment rate and control rate of hypertension diagnosis and treatment are low. In the adult population of developed countries in the west, the incidence of hypertension is 30% to 40% and increases with age. The incidence of hypertension is higher in developing countries. The epidemiological survey data of China records the prevalence rate of hypertension in the last 50 years, and the prevalence rate is increased by about 4 times from 5% in 1959, 7% in 1979, 18.8% in 2008 to about 21% reported in recent years, and the number of patients reaches 2 hundred million. At present, about 1.3 hundred million of hypertension patients in China do not know that the patients suffer from hypertension, and about 3000 thousands of patients do not have treatment in the population known to suffer from hypertension; of the patients receiving the hypotensive treatment, 75% of patients had blood pressure that did not achieve the control goal. Therefore, the task of hypertension control still faces great difficulty.
The pathogenic factors of hypertension are more, and the unchangeable risk factors include age, gender, race, geographical region, family heredity and the like; modifiable risk factors include high sodium low potassium diet, smoking and drinking, overweight and obesity, mental stress and dyslipidemia, insulin resistance and other health conditions. As for the pathogenesis of hypertension, the following theories are currently available: (1) vascular endothelial dysfunction leads to hypertension, including endothelial-dependent vasodilator/contractile factor system disorders, NO/NO synthase system, and the like. (2) The renin-angiotensin-aldosterone system is unbalanced. (3) Activation of the sympathetic nervous system. (4) The proliferation of vascular smooth muscle cells under stimulation by various factors leads to the development of hypertension. (5) The inflammatory reaction is related to the occurrence and development of hypertension.
Treatment of hypertension can be controlled by a number of targets, the major of which include calcium and potassium channels, renin, angiotensin converting enzyme, angiotensin II receptor, mineralocorticoid receptor, α -adrenergic receptor and β -adrenergic receptor, 5-hydroxytryptamine receptor, dopamine receptor and imidazoline receptor, as well as prostacyclin, endothelin, phosphodiesterase, β -hydroxy- β -methylglutaryl coenzyme a reductase and the like.
The most commonly used five types of first-line antihypertensive drugs at present comprise calcium antagonists, diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists and β -receptor blockers.
The strong contraction and spasm of the vascular smooth muscle can cause various diseases, such as hypertension and various complications brought by the hypertension, so that the research on the vascular smooth muscle vasodilating agent has great practical significance. Has guiding significance and reference value for treating hypertension, further reducing the damage to target organs, and reducing the morbidity of diseases such as severe complications such as cerebral apoplexy, angina pectoris, myocardial infarction, heart failure, renal failure and the like. Clinically, a combined administration mode is often adopted to replace a treatment method which can not achieve a good blood pressure reduction effect by only using a single target medicament. The burden on the liver and kidney caused by a single compound in the metabolic process is obviously smaller than that caused by a plurality of compounds. Is safer than the combined medication and can avoid the interaction of the drugs.
Therefore, the development of a single compound with better activity is a hot spot of research by those skilled in the art.
The invention content is as follows:
the invention provides a novel antihypertensive drug in order to overcome the defects of the prior art, and the compound and the derivative thereof can be combined with the existing drugs or used independently. The present invention relates to compounds of formula I, and stereoisomers, prodrugs and pharmaceutically active metabolites thereof, and pharmaceutically acceptable salts of the above compounds:
wherein the content of the first and second substances,
r can be independently selected from H, halogen, substituted or unsubstituted C1-C10 alkyl, C1-C10 alkoxy, and the substituent is C1-C10 alkyl, C1-C10 alkoxy and halogen.
R' may be independently selected from C3-C8 cycloalkyl, substituted or unsubstituted C1-C10 alkyl, C1-C10 alkoxy, said substituents being: phenoxy, C1-C4 alkoxy-substituted phenoxy.
Further, the air conditioner is provided with a fan,
r can be independently selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, and the substituent is C1-C6 alkyl, C1-C6 alkoxy and halogen.
Preferably, the first and second electrodes are formed of a metal,
r can be independently selected from H, halogen, substituted or unsubstituted C1-C4 alkyl, C1-C4 alkoxy, and the substituent is C1-C4 alkyl, C1-C4 alkoxy and halogen.
More preferably still, the first and second liquid crystal compositions are,
r may be independently selected from H, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo.
Further, in the present invention,
r' may be independently selected from C5-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, said substituents being: phenoxy, C1-C6 alkoxy-substituted phenoxy.
Preferably, the first and second electrodes are formed of a metal,
r' may be independently selected from C5-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkyl, said substituents being phenoxy, C1-C4 alkoxy-substituted phenoxy.
More preferably still, the first and second liquid crystal compositions are,
r' may be independently selected from propyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, phenoxyethyl, 2-methoxyphenoxyethyl.
"pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts that retain the biological potency and properties of the compounds of formula I and are formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid addition salts include malate, maleate, sulfanate, hydrochloride, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, p-toluenesulfonate, hydrogensulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids, such as arginine, lysine, and the like, and basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides and the like. Preferred acids for forming acid addition salts include hydrochloric acid and acetic acid.
"pharmaceutically acceptable" such as pharmaceutically acceptable carriers, excipients, prodrugs, etc., means pharmacologically acceptable and substantially non-toxic to a patient to whom a particular compound is administered.
"pharmaceutically active metabolite" refers to a pharmaceutically acceptable and effective metabolite of a compound of formula I.
The invention also relates to an antihypertensive pharmaceutical composition containing formula I or its stereoisomer or its pharmaceutically acceptable acid addition salt and a pharmaceutically acceptable carrier.
The present invention also relates to a method of lowering blood pressure comprising administering to a mammal a blood pressure lowering effective amount of a compound of formula I or a stereoisomer thereof or a pharmaceutically acceptable acid addition salt thereof.
The term "halogen" as used in the present invention includes chlorine, bromine or fluorine.
"substituted," unless otherwise specified, means that the substituent may be present at one or more positions, the substituents being independently selected from a particular choice.
The invention also relates to the application of the 6- [ 2-hydroxy-3- (alkylamino) propoxy ] benzofuran compound in preparing a medicament for treating vascular smooth muscle spastic diseases. Unlike the combination of drugs to achieve multi-target therapeutic effects, the 6- [ 2-hydroxy-3- (isopropylamino) propoxy ] benzofuran derivative is a monomeric compound, whereas the combination of drugs is apparently a plurality of compounds.
The compound of the invention is used as a medicine with a brand new structure type for treating vascular smooth muscle spastic diseases, has the characteristics of novel structure type, equivalent or superior drug effect to the existing medicine, and has good application value and development and application prospects.
The compounds of the invention can be administered to a patient by various methods, such as orally in capsules or tablets, as sterile solutions or suspensions, and in some cases, intravenously in the form of solutions. The free base compounds of the present invention may be formulated and administered in the form of their pharmaceutically acceptable acid addition salts. The compound provided by the invention is simple in preparation method and stable in yield, and the prepared compound can be used for preventing and treating hypertension diseases better.
The specific implementation mode is as follows:
the following reaction scheme outlines the synthetic procedures for preparing the compounds of the present invention.
Reaction scheme
Wherein the content of the first and second substances,
r can be independently selected from H, halogen, substituted or unsubstituted C1-C10 alkyl, C1-C10 alkoxy, and the substituent is C1-C10 alkyl, C1-C10 alkoxy and halogen.
R' may be independently selected from C3-C8 cycloalkyl, substituted or unsubstituted C1-C10 alkyl, C1-C10 alkoxy, said substituents being: phenoxy, C1-C4 alkoxy-substituted phenoxy. The specific implementation mode is as follows:
the compound provided by the invention is simple in preparation method and stable in yield, and the prepared compound can be used for preventing and treating hypertension diseases better.
The present invention is described in detail by the following examples. It should be understood, however, that the present invention is not limited to the following examples which are specifically set forth.
Example 1: preparation of 2-benzoyl-3-methyl-6- [ 2-hydroxy-3- (isopropylamino) propoxy ] benzofuran (T-01)
Step A: preparation of 2 '-hydroxy-4' -benzyloxyacetophenone
2 ', 4' -dihydroxy acetophenone (7.60g,0.05mol), anhydrous potassium carbonate (8.00g,0.06 mol), potassium iodide (1.00g,0.006mol), 100mL of acetone were placed in a 250mL eggplant-shaped bottle and stirred at room temperature. After diluting benzyl chloride (7.87g,0.06mol) with 10mL of acetone, the mixture is dropped into the reaction solution at a constant speed for about 10 min. The reaction was heated to reflux for 6h and monitored by TLC for completion. After the reaction, the mixture is cooled to room temperature, and the organic solvent is evaporated under reduced pressure to obtain light yellow solid. 50mL of ethanol was recrystallized to obtain 10.45g of white crystals, and the yield was 86.4%. m.p. 101.6-103.4 deg.C; EI-MS:243.0([ M + H ]]+),264.9([M+Na]+)；IR:3030.4,2940.4,1622.9, 1569.9,1507.3,1494.2,1466.2,1452.7,1430.5,1388.2,1364.6,1247.1, 1183.2,1132.7；1H-NMR(400MHz,CDCl3)δ12.75(1H,s),7.64(1H,d,J＝ 8.4Hz),7.44-7.32(5H,m),6.55-6.48(2H,m),5.09(2H,s),2.56(3H,s)。
And B: preparation of 2-benzoyl-3-methyl-6-benzyloxybenzofuran
Placing 2 '-hydroxy-4' -benzyloxyacetophenone (6.05g,25mmol), α -bromoacetophenone (25 mmol), tetrabutylammonium bromide (4.03g,12.5mmol) and 80mL of dichloromethane in a 250mL eggplant-shaped bottle, adding 40mL of 30% potassium carbonate aqueous solution, heating and refluxing for 12H under stirring, monitoring by TLC to complete the reaction, removing the water layer, washing the organic layer with 100mL of 1mol/L hydrochloric acid aqueous solution for three times, washing with 100mL of water once, removing the solvent by organic phase decompression, recrystallizing the obtained solid with 60mL of ethanol, standing to separate out crystals, filtering by suction, and drying to obtain 6.43g of 2-benzoyl-3-methyl-6-benzyloxybenzofuran white powdery solid with 75.2% yield m.p: 76.8-79.2 ℃, EI-MS:343.1([ M + H ])]+),365.1([M+Na]+)；IR:3060.5,2923.0, 1628.2,1598.7,1563.3,1500.9,1447.7,1383.0,1268.5,1167.9；1H-NMR (400MHz,CDCl3)δ8.06(2H,d,J＝7.2Hz),7.61-7.55(2H,m),7.52(2H,t), 7.47(2H,d,J＝7.2Hz),7.41(3H,t),7.06(2H,dd,J1＝10.6Hz,J2＝1.8Hz), 5.14(2H,s),2.61(3H,s)。
Step C preparation of 2-benzoyl-3-methyl-6-hydroxybenzofuran
2-benzoyl-3-methyl-6-benzyloxybenzofuran (0.015mol) was dissolved in 100mL of dichloromethane, and boron tribromide (5.64g, 0.023mol) diluted with 5mL of dichloromethane was added dropwise with stirring at-10 ℃ after the addition was completed, the temperature was maintained for reaction for 10min, and the completion of the reaction was monitored by TLC. The reaction solution was poured into 80mL of water and quenched, the insoluble material was dissolved in dichloromethane, the organic phase was washed three times with 100mL of water, the organic solvent was removed by distillation under reduced pressure to give a dark green solid, which was filtered, the filter cake was washed with 5mL of dichloromethane and dried to give 3.55g of a yellow green solid of 2-benzoyl-3-methyl-6-hydroxybenzofuran in a yield of 94.0%. m.p. 150.8-153.0 deg.C; EI-MS 253.0([ M + H ]]+), 274.8([M+Na]+),290.8([M+K]+)；IR:3228.8,2923.2,1612.6,1549.1, 1501.2,1474.3,1446.7,1377.1,1353.5,1311.9,1242.3,1224.1,1162.2；1H-NMR(400MHz,CDCl3)δ8.07-8.02(2H,m),7.63-7.47(4H,m),6.99(1H,d,J＝2.1Hz),6.90(1H,dd,J1＝8.5,J2＝2.2Hz),2.59(3H,s)。
Step D: preparation of 2-benzoyl-3-methyl-6- (2, 3-epoxypropoxy) benzofuran
2-benzoyl-3-methyl-6-hydroxybenzofuran (0.016mol), anhydrous potassium carbonate (4.50 g,0.033mol), potassium iodide (0.27g,0.0016mol) and 2mL of polyethylene glycol were put in a 100mL eggplant-shaped bottle, 30mL of acetonitrile was poured, and stirred at room temperature for 15 min. Then epichlorohydrin (7.50g,0.081mol) diluted with 2mL of acetonitrile was added dropwise to the reaction solution, and after completion of the addition, the reaction was refluxed for 5 hours, and the progress of the reaction was monitored by TLC. After the reaction is finished, the potassium carbonate is removed by suction filtration, the filtrate is distilled under reduced pressure to obtain brown oily matter, 4mL of ethanol is added for standing at room temperature, yellow solid is separated out by suction filtration, the filter cake is recrystallized by 10mL of absolute ethanol, the filter cake is filtered by suction filtration, the filter cake is washed by the absolute ethanol and dried to obtain 4.18 g of white powdery solid of the 2-benzoyl-3-methyl-6- (2, 3-epoxypropoxy) benzofuran, and the yield is 84.9%. m.p. 84.0-85.7 ℃; eI-MS:309.0([M+H]+),331.0([M+Na]+)； IR:3424.4,2919.6,1801.7,1636.4,1619.3,1564.5,1495.1,1449.7,1383.0, 1349.4,1305.0,1271.3,1127.3,1019.9；1H NMR(400MHz,CDCl3)δ8.06 (2H,d,J＝7.2Hz),7.62-7.48(4H,m),7.06-6.96(2H,m),4.32(1H,dd,J1＝ 11.0,J2＝2.9Hz),4.00(1H,dd,J1＝11.0,J2＝5.8Hz),3.45-3.37(1H,m), 2.94(1H,t,J＝4.5Hz),2.80(1H,dd,J1＝4.8,J2＝2.6Hz),2.61(3H,s)。
Step E: preparation of 2-benzoyl-3-methyl-6- [ 2-hydroxy-3- (isopropylamino) propoxy ] benzofuran (T-01)
Placing 2-benzoyl-3-methyl-6- (2, 3-epoxypropoxy) benzofuran (4.04mmol) in a 50mL eggplant-shaped bottle, adding 15mL methanol, adding 15mL isopropylamine or 15mL tert-butylamine while stirring, heating and refluxing for 1h, and monitoring the reaction completion by TLC. Separating by column chromatography to obtain 2-benzoyl-3-methyl-6- [ 2-hydroxy-3- (isopropylamino) propoxy group]Benzofuran pale yellow solid 0.98g, yield 66.0%. m.p. 86.9-88.0 deg.C; EI-MS 368.7([ M + H)]+),390.2 ([M+Na]+)；IR:3421.5,3278.4,3071.8,2963.9,2922.3,2854.5,1634.8, 1622.5,1598.2,1555.2,1497.4,1462.4,1447.3,1382.3,1357.9,1236.2, 1122.9,1058.9；1H NMR(400MHz,CDCl3)δ8.10-8.02(2H,m),7.53(4H, ddd,J1＝14.9,J2＝10.4,J3＝7.3Hz),7.04-6.94(2H,m),4.22-3.92(3H,m), 2.93-2.88(1H,m),2.88-2.79(1H,m),2.74(1H,dd,J1＝12.2,J2＝7.3Hz), 2.60(3H,s),1.10(6H,dd,J1＝6.2,J2＝3.2Hz)。
Example 2: preparation of 2- (4-methylbenzoyl) -3-methyl-6- [ 2-hydroxy-3- (isopropylamino) propoxy ] benzofuran (T-02)
Referring to the preparation method of example 1, 1.01g of pale yellow solid was obtained with a yield of 65.6%. m.p. 100.0-101.5 deg.C; EI-MS:382.8([ M + H ]]+),404.2([M+Na]+)；IR:3407.4, 3272.5,2961.6,2922.9,2854.2,1622.3,1553.8,1498.0,1464.1,1382.5, 1360.5,1318.6,1304.6,1237.8,1176.5,1162.9,1120.0；1H NMR(400MHz, CDCl3)δ7.98(2H,d,J＝8.2Hz),7.54(1H,d,J＝8.6Hz),7.31(2H,d,J＝ 8.0Hz),7.02(1H,d,J＝2.0Hz),6.98(1H,dd,J1＝8.7,J2＝2.2Hz),4.06(3H,dd,J1＝11.2,J2＝7.6Hz),2.91(1H,dd,J1＝12.1,J2＝3.5Hz),2.84 (1H,dt,J1＝12.5,J2＝6.3Hz),2.77-2.70(1H,m),2.59(3H,s),2.45(3H,s), 1.10(6H,d,J＝6.3Hz)。
Example 3: preparation of 2- (4-methoxybenzoyl) -3-methyl-6- [ 2-hydroxy-3- (isopropylamino) propoxy ] benzofuran (T-03)
Referring to the preparation method of example 1, off-white solid 1.09g was obtained in 68.0% yield. m.p. 105.1-106.0 deg.C; ESI-MS:398.9([ M + H ]]+)；IR:3420.1,3267.0,3098.9,2966.6, 2925.0,2837.3,1625.5,1599.0,1550.3,1510.0,1464.4,1382.4,1360.8, 1323.2.1303.4,1260.4,1176.3,1164.01121.3；1H NMR(400MHz,CDCl3)δ 8.12(2H,d,J＝8.9Hz),7.54(1H,d,J＝8.6Hz),7.09-6.90(4H,m), 4.14-4.00(3H,m),3.90(3H,s),2.95-2.88(1H,m),2.84(1H,dt,J1＝12.5,J2＝6.3Hz),2.78-2.71(1H,m),2.60(3H,s),1.10(6H,d,J＝6.3Hz)。
Example 4: preparation of 2-benzoyl-3-methyl-6- [ 2-hydroxy-3- (tert-butylamino) propoxy ] benzofuran (T-04)
Referring to the preparation method of example 1, light yellow solid 0.88g was obtained in 57.0% yield. m.p. 100.7-102.1 deg.C; EI-MS:383.6([ M + H ]]+),404.2([M+Na]+)；IR:3409.0, 3281.6,3069.8,2966.7,2923.6,2870.4,1631.8,1621.6,1596.9,1549.5, 1494.0,1447.1,1379.9,1357.5,1297.1,1267.9,1235.5,1167.6,1127.0, 1105.3；1H NMR(400MHz,CDCl3)δ8.05(2H,d,J＝7.1Hz),7.61-7.47 (4H,m),7.01(2H,dd,J1＝13.3,J2＝5.0Hz),4.11-3.93(3H,m),2.88(1H, dd,J1＝11.9,J2＝3.7Hz),2.70(1H,dd,J1＝11.9,J2＝7.6Hz),2.60(3H,s), 1.13(9H,d,J＝3.2Hz)。
Example 5: preparation of 2- (4-methylbenzoyl) -3-methyl-6- [ 2-hydroxy-3- (tert-butylamino) propoxy ] benzofuran (T-05)
Referring to the preparation method of example 1, 1.03g of pale yellow solid was obtained in a yield of 64.7%. m.p. 105.2-106.5 deg.C; EI-MS 396.6([ M + H)]+),418.3([M+Na]+)；IR:3424.2, 3299.0,2962.7,2917.1,2865.0,1636.9,1623.4,1608.6,1558.5,1495.6, 1454.5,1381.4,1353.4,1275.0,1237.7,1161.0,1060.3；1H NMR(400MHz, CDCl3)δ7.98(2H,d,J＝8.2Hz),7.54(1H,d,J＝8.6Hz),7.34-7.23(2H,m), 7.05-6.92(2H,m),4.13-3.84(3H,m),2.87(1H,dd,J1＝11.9,J2＝3.8Hz), 2.70(1H,dd,J1＝11.9,J2＝7.5Hz),2.59(3H,s),2.45(3H,s),1.13(9H,s)。
Example 6: preparation of 2- (4-methoxybenzoyl) -3-methyl-6- [ 2-hydroxy-3- (tert-butylamino) propoxy ] benzofuran (T-06)
Referring to the preparation method of example 1, 1.11g of pale yellow solid was obtained in a yield of 67.0%. m.p. 92.5-94.0 deg.C; ESI-MS:412.4([ M + H ]]+)；IR:3423.1,2965.1,2927.7,1624.8, 1604.5,1509.8,1495.1,1455.6,1382.5,1357.6,1264.4,1161.1,1126.4；1H NMR(400MHz,CDCl3)δ8.13(2H,d,J＝8.9Hz),7.55(1H,d,J＝8.7Hz), 7.06-6.95(4H,m),4.10-4.03(2H,m),4.02-3.96(1H,m),3.91(3H,s),2.89 (1H,dd,J1＝12.0,J2＝4.0Hz),2.70(1H,dd,J1＝11.9,J2＝7.6Hz),2.61(3H,s),1.14(9H,s)。
Example 7: preparation of 2-benzoyl-3-methyl-6- { 2-hydroxy-3- [2- (2-methoxyphenoxy) ethylamino ] propoxy } benzofuran (T-07)
Referring to the preparation method of example 1, 0.77g of white solid was obtained with a yield of 40.1%. m.p. 82.5-83.9 deg.C; EI-MS of 476.2([ M + H)]+),498.4([M+Na]+)；IR:3447.9,2917.9, 2847.8,1738.4,1641.1,1624.2,1594.4,1563.4,1507.4,1453.6,1383.1, 1357.1,1276.6,1254.7,1168.4,1125.4；1H NMR(600MHz,CDCl3)δ8.06 (2H,d,J＝7.6Hz),7.59(1H,t,J＝7.2Hz),7.55(1H,d,J＝8.6Hz),7.51 (2H,t,J＝7.5Hz),7.02(1H,s),6.99(1H,d,J＝8.7Hz),6.91(4H,dt,J1＝ 20.8,J2＝7.9Hz),4.14(2H,t,J＝4.8Hz),4.12-4.09(1H,m),4.06(2H,d,J ＝3.7Hz),3.84(3H,s),3.09(2H,t,J＝4.9Hz),2.98(1H,dd,J1＝12.2,J2＝ 3.5Hz),2.87(1H,dd,J1＝12.1,J2＝8.0Hz),2.61(3H,s)。
Example 8: preparation of 2- (4-methylbenzoyl) -3-methyl-6- { 2-hydroxy-3- [2- (2-methoxyphenoxy) ethylamino ] propoxy } benzofuran (T-08)
Referring to the preparation method of example 1, 0.69g of a white solid was obtained in 34.9% yield. m.p. 80.3-82.0 deg.C; EI-MS:491.0([ M + H ]]+),512.4([M+Na]+)；IR:3448.9,2907.0, 2841.1,1627.0,1605.8,1592.4,1552.9,1506.8,1464.0,1376.5,1354.8, 1274.9,1254.1,1223.9,1184.7,1126.2,1058.7；1H NMR(400MHz,CDCl3) δ7.98(2H,d,J＝8.2Hz),7.54(1H,d,J＝8.6Hz),7.31(2H,d,J＝8.0Hz), 7.02(1H,d,J＝1.9Hz),6.98(1H,dd,J1＝8.6,J2＝2.0Hz),6.91(4H,td,J1＝5.9,J2＝1.9Hz),4.14(2H,t,J＝5.2Hz),4.10(1H,dd,J1＝7.8,J2＝3.9 Hz),4.08-4.04(2H,m),3.84(3H,s),3.09(2H,t,J＝5.0Hz),2.98(1H,dd,J1＝12.3,J2＝3.8Hz),2.87(1H,dd,J1＝12.3,J2＝7.8Hz),2.60(3H,s),2.45 (3H,s)。
Example 9: preparation of 2- (4-methoxybenzoyl) -3-methyl-6- { 2-hydroxy-3- [2- (2-methoxyphenoxy) ethylamino ] propoxy } benzofuran (T-09)
Referring to the preparation method of example 1, yellow crystals 0.51g were obtained in 24.8% yield. m.p. 88.0-89.7 deg.C; ESI-MS:506.1([ M + H ]]+),528.1([M+Na]+)；IR:3417.9,3273.4, 3077.3,2929.8,2835.9,1634.4,1602.0,1554.6,1507.5,1453.9,1380.9, 1346.4,1317.8,1299.1,1251.1,1162.8,1123.9,1023.9；1H NMR(600MHz, CDCl3)δ8.13(2H,d,J＝8.9Hz),7.53(1H,d,J＝8.6Hz),7.02(1H,d,J＝ 2.0Hz),7.01-6.96(3H,m),6.93(3H,ddd,J1＝13.1,J2＝7.0,J3＝3.5Hz), 6.89(1H,s),4.14(2H,t,J＝5.2Hz),4.11(1H,dd,J1＝8.2,J2＝4.2Hz),4.06 (2H,d,J＝4.8Hz),3.90(3H,s),3.84(3H,s),3.09(2H,t,J＝5.2Hz),2.98 (1H,dd,J1＝12.2,J2＝3.9Hz),2.87(1H,dd,J1＝12.2,J2＝8.0Hz),2.60 (3H,s)。
Table 1 Structure of the Compounds
Example 10: vasodilation Activity test
The method comprises the steps of firstly, knocking out rabbits (for both male and female purposes, the weight is 2.0-2.5 kg), then, quickly splitting the thoracic cavity, stripping off descending aorta, cutting off connective tissues and surrounding adipose tissues, then, cutting into blood vessel rings of 3-5 mm, then, penetrating the blood vessel rings through a thin iron hook, fixing one end of the thin iron hook on a ventilation hook, connecting the other end of the thin iron hook to a tension transducer, placing the thin iron hook in a bath tube filled with 20mL of nutrient solution, and recording tension change through a recorder. Introducing mixed gas (95% O) into the bath tube at a rate of 1-2 bubbles per second2+5％CO2). After the tension of rabbit isolated thoracic aorta ring specimen is stable, recording a section of waveform, adding spasmolytic epinephrine (10) into the bathtub-5mol/L) or high potassium solution (K)+60mmol/L), fully washing the specimen after the maximum contraction is reached, changing K-H nutrient solution every 20min, balancing for 60min, inducing secondary contraction by using a spasmodic agent with the same concentration after the specimen is recovered to be stable, accumulating and adding the target compound when the secondary contraction is basically consistent with the previous contraction, recording the relaxation curve of the target compound, and calculating the percentage of relaxation:
plotting dose-effect curve with maximum contraction amplitude of spasmolytic 100%, relaxation percentage of target compound as ordinate, and concentration negative logarithm of target compound as abscissa, and calculating logEC50The value is obtained. The results are shown in tables 2 and 3.
TABLE 2 Ex vivo vascular smooth muscle relaxation of adrenalin preshrunk rabbits with the object Compounds (n ═ 8)
TABLE 3 vasodilation of isolated vascular smooth muscle of rabbits preshrinked with high potassium by the target compound (n ═ 8)
The experimental result shows that the target compound has the relaxation effect on isolated vascular smooth muscle of rabbits preshrunk by epinephrine or high potassium solution.
In the following formulations, "active ingredient" means a compound of formula 1, or a salt or solvate thereof.
Example 11: gelatin capsule
Example 12: tablet formulation
Example 13: tablet formulation
The active ingredient, starch and cellulose were passed through a 45 mesh u.s. sieve and mixed thoroughly, the resulting powder was mixed with polyvinylpyrrolidone, then passed through a 14 mesh u.s. sieve, and the granules thus obtained were dried at 50-60 ℃ and passed through an 18 mesh u.s. sieve. The sodium carboxymethylcellulose, the magnesium stearate and the talc are firstly sieved by a 60-mesh U.S. sieve, then added into the granules, mixed and pressed into tablets on a tablet machine.
Example 14: suspending agent
The drug is passed through a 45 mesh u.s. screen and mixed with sodium carboxymethylcellulose and syrup to form a uniform paste, the benzoic acid solution, flavoring and coloring agents are diluted with some water and added with stirring, then sufficient water is added to achieve the desired volume.
Example 15: aerosol and method of making
The active ingredient is mixed with ethanol and the resulting mixture is added to propellant 22, cooled to 30 ℃ and transferred to a container. The required amount was then added to the stainless steel vessel and diluted with the remaining propellant before the valve assembly was installed.
Example 16: suppository
The active ingredient was passed through a 60 mesh u.s. sieve and suspended in a pre-melted saturated fatty acid glyceride compound, and the mixture was poured into a standard 2g cavity suppository mold and cooled.
Example 17: injectable formulations
The above solution was administered to the patient by intravenous injection at a rate of about 1mL per minute.
The foregoing is directed to preferred embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the protection scope of the technical solution of the present invention.
Claims (5)
1. A compound or a pharmaceutically acceptable salt thereof having an effect of treating a vascular smooth muscle spastic disease:
2-benzoyl-3-methyl-6- [ 2-hydroxy-3- (isopropylamino) propoxy ] benzofuran;
2- (4-methylbenzoyl) -3-methyl-6- [ 2-hydroxy-3- (isopropylamino) propoxy ] benzofuran;
2- (4-methoxybenzoyl) -3-methyl-6- [ 2-hydroxy-3- (isopropylamino) propoxy ] benzofuran;
2-benzoyl-3-methyl-6- [ 2-hydroxy-3- (tert-butylamino) propoxy ] benzofuran;
2- (4-methylbenzoyl) -3-methyl-6- [ 2-hydroxy-3- (tert-butylamino) propoxy ] benzofuran;
2- (4-methoxybenzoyl) -3-methyl-6- [ 2-hydroxy-3- (tert-butylamino) propoxy ] benzofuran;
2-benzoyl-3-methyl-6- { 2-hydroxy-3- [2- (2-methoxyphenoxy) ethylamino ] propoxy } benzofuran;
2- (4-methylbenzoyl) -3-methyl-6- { 2-hydroxy-3- [2- (2-methoxyphenoxy) ethylamino ] propoxy } benzofuran;
2- (4-methoxybenzoyl) -3-methyl-6- { 2-hydroxy-3- [2- (2-methoxyphenoxy) ethylamino ] propoxy } benzofuran;
the vascular smooth muscle spastic diseases are cerebral ischemic diseases and myocardial ischemic diseases caused by vasospasm; renal dysfunction and peripheral vasospastic disorders due to renal vasospasms.
2. The process for the preparation of a compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein 2, 4-dihydroxyacetophenone is reacted with benzyl chloride in Williamson to give 2-hydroxy-4-benzyloxyacetophenone, which is then cyclized with α -haloacetophenone to give 2-aroyl-3-methyl-6-benzyloxybenzofuran, which is then deprotected to give 2-aroyl-3-methyl-6-hydroxybenzofuran, which is then reacted with epichlorohydrin in Williamson to give 2-aroyl-3-methyl-6- (2, 3-epoxypropoxy) benzofuran, which is finally reacted with isopropylamine, tert-butylamine or 2- (2-methoxyphenoxy) ethylamine to give 6- [ 2-hydroxy-3- (alkylamino) propoxy ] benzofuran.
3. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
4. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 3 for the manufacture of a medicament for the treatment of a vascular smooth muscle spastic disorder.
5. The use according to claim 4, characterized in that: the vascular smooth muscle spastic diseases are cerebral ischemic diseases and myocardial ischemic diseases caused by vasospasm; renal dysfunction and peripheral vasospastic disorders due to renal vasospasms.
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