CN108586445A - Amide derivatives and its application as endothelin-receptor antagonists in the diseases such as cardiovascular and cerebrovascular, pulmonary hypertension - Google Patents

Amide derivatives and its application as endothelin-receptor antagonists in the diseases such as cardiovascular and cerebrovascular, pulmonary hypertension Download PDF

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CN108586445A
CN108586445A CN201810560186.4A CN201810560186A CN108586445A CN 108586445 A CN108586445 A CN 108586445A CN 201810560186 A CN201810560186 A CN 201810560186A CN 108586445 A CN108586445 A CN 108586445A
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endothelin
amide derivatives
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曾庆强
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Abstract

A kind of application the invention discloses amide derivatives formula I and its as endothelin-receptor antagonists in the diseases such as cardiovascular and cerebrovascular, pulmonary hypertension,Wherein：R1、R2It is independently selected from H, F, OH or CH3.It finds that amide derivatives formula I of the present invention has preferable endothelin receptor antagonizing activity in the contraction experiment for inhibiting Endothelin to induce isolated rabbit aortic annulus, can be used to prepare that treat cardiovascular and cerebrovascular, hypertension, pulmonary hypertension, myocardial infarction, tumour, diabetic complication, nephrosis, asthma and thyroid gland hyperfunction etc. as endothelin-receptor antagonists.

Description

Amide derivatives and its dynamic in cardiovascular and cerebrovascular, lung as endothelin-receptor antagonists Application in the diseases such as arteries and veins high pressure
Technical field
The invention belongs to chemical medicine, it is related to a kind of amide derivatives formula I and its as endothelin receptor antagonism Application of the agent in the diseases such as cardiovascular and cerebrovascular, pulmonary hypertension.
Background technology
Cardiovascular and cerebrovascular disease (cardiovascular and cerebrovascular diseases, CCVd) is heart The general designation of blood vessel and cranial vascular disease refers to hyperlipidemia, blood is sticky, caused by atherosclerosis, hypertension etc. Heart, brain and the body tissue ischemic or hemorrhagic disease that occur.The death rate of cardiovascular and cerebrovascular disease occupies various diseases First of, the final cause of the death overwhelming majority is myocardial hypertrophy, heart failure, cerebral apoplexy and fatal arrhythmia.Especially in recent years The case fatality rate of serious heart failure is high, has formed a problem of international the world of medicine.These diseases lack effective at present Medicine.
Endothelin (endothelin, ET) be made of 21 amino acid discoveries such as Yanagisawa within 1988 it is more Peptide is synthesized and is secreted by vascular endothelial cell, cardiac muscle, smooth muscle etc., belongs to sarafotoxin (sarafotoxin) family, has Powerful contracting blood vessel and rush vascular smooth muscle cells, is a kind of endogenous damage factor, in many hearts, brain, lung, kidney It is all of great significance in the morbidity of vascular diseases.ET has the shaped body of 3 kinds of forms, is referred to as ET-1, ET-2 and E-3, ET is acted on through Endothelin-converting Enzyme (ECEs) and activate, the ET of activation and its receptor in conjunction with and play a role, wherein ET1 is existing by force Strong and lasting vasoconstrictor effects, and be the inflammatory for causing a variety of diseases with cell growth and mitosis characteristic is promoted The factor.Due to the potential therapeutic value that endothelin antagonist is contained, major drugmaker of the world all energetically puts into endothelium In the research and development of plain antagonist, the research of endothelin antagonist has become hot spot.The stronger peptides of effect having found ET antagonists have BQ123, BQ160, FR2139317 etc., but are limited since the oral bioavailability rate of peptide agonist is low Its application in the angiocardiopathy of palpus long-term administration.Many drugmakers are dedicated to the non-peptides ET antagonisms for having Orally active The research of agent.The endothelin-receptor antagonists listed have Bosentan, tezosentan, enrasentan, sitaxentan, A Qusheng Smooth and ambrisentan, in treatment hypertension, pulmonary hypertension, tumour, diabetic complication, myocardial infarction and cerebral angiospasm etc. Aspect obtains very good effect.
Used in test example of the present invention control drug Bosentan chemical structural formula for：
Invention content
The invention discloses a kind of amide derivatives formula I, structure is：
Wherein：R1、R2It is independently selected from H, F, OH or CH3.The invention further relates to The pharmaceutically acceptable salt or solvate of the amide derivatives formula I.
Further, amide derivatives formula I described in some preferred schemes is
The synthetic route that another object of the present invention discloses the amide derivatives formula I is：
Specifically synthetic method is：
1) 3- sulfamoyls propionic acid (compound 1) occurs into the presence of a base with 2,4- dihydroxy-benzoic acids (compound 2) Ring reacts, and generates (7- hydroxyl -2- oxo -2H- chromene -3- bases) Methanesulfomide (compound 3)；
2) in a suitable solvent, compound 3 reacts with iodomethane, generates (7- methoxyl group -2- oxo -2H- colors Alkene -3- bases) Methanesulfomide (compound 4)；
3) in a suitable solvent, compound 4 and iodide react generation (7- methoxyl groups -2,2- dimethyl - 2H- chromene -3- bases) Methanesulfomide (compound 5)；
4) compound 5 again with hexichol [b, d] thiophene reaction generate (4- (hexichol [b, d] thiene-3-yl) methoxyl group-2-7-, 2- lutidines -3- bases) Methanesulfomide (compound 6)；
5) in a suitable solvent, compound 6 and corresponding acyl chloride reaction, generate corresponding amide product.
Further, the alkali of the use in the step 1) can use potassium carbonate, and cesium carbonate, triethylamine, sodium hydroxide is molten Liquid or potassium hydroxide solution, sodium carbonate liquor, preferably triethylamine.
Further, the solvent in the step 2) can use n,N-Dimethylformamide (DMF), Dioxane, DMSO, DMF, acetone etc., preferably acetone；
Further, the solvent in the step 3) can use n,N-Dimethylformamide (DMF), Dioxane, DMSO, DMF, THF, acetone etc., preferably THF.
Further, solvent can be absolute ethyl alcohol, second eyeball, benzene, toluene, dimethylbenzene, ether, diformazan in the step 5) Base sulfoxide, n,N-Dimethylformamide (DMF), acetone, pyridine etc., preferably absolute ethyl alcohol.
Another object of the present invention discloses application of the amide derivatives formula I as endothelin-receptor antagonists. With the relevant disease of endothelin-receptor antagonists such as cardiovascular and cerebrovascular, hypertension, pulmonary hypertension, myocardial infarction, tumour, diabetes Complication, nephrosis, asthma and thyroid gland are hyperfunction etc..
Pharmaceutically acceptable salt of the present invention refers to the organic salt and inorganic salts of the compounds of this invention.Pharmaceutically may be used The salt that the nontoxic acid received is formed includes, but is not limited to, inorganic acid salt, such as hydrochloride, hydrobromate, phosphate, sulfuric acid Salt, perchlorate；Acylate, such as acetate, oxalates, maleate, tartrate, citrate, succinate, the third two Hydrochlorate；Or these salt are obtained by other methods described in the books or literature such as ion-exchange.Other can pharmaceutically connect The salt received includes adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, Borate, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, second Sulfonate, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, Caproate, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl sulfate, apple Hydrochlorate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfuric acid Salt, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, 11 Hydrochlorate, valerate, etc..By including alkali metal, alkaline-earth metal, ammonium and N+ (C1-4 alkane with alkali appropriate salt obtained by the reaction Base) 4 salt.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Can with the alkali metal of forming salt or Alkaline-earth metal includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises appropriate, nontoxic ammonium, season The amine cation that ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitre Acidulants, C1-8 azochlorosulfonate acid compounds and aromatic sulphonic acid compound.
Solvate of the present invention refers to that one or more solvent molecules are formed by with the compound of the present invention and form Close object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, Acetic acid and ethylaminoethanol.
Specific implementation mode
Embodiment 1：N- (((4- (hexichol [b, d] thiene-3-yl) -7- methoxyl group -2,2- lutidines -3- bases) first Base) sulfonyl) isoxazole -5- formamides synthesis
The synthesis of 1-1, (7- hydroxyl -2- oxo -2H- chromene -3- bases) Methanesulfomide
By 3- sulfamoyls propionic acid (compound 1) (15.0g, 97.94mmol) and 2,4- dihydroxy-benzoic acids (compound 2) (10.2g, 66.18mmol) is dissolved in acetic anhydride (22.6mL), the careful addition triethylamine (13.2mL) into mixture, and Mixture is heated 4 hours.After having reacted, cooling is simultaneously diluted with water.The product of precipitation is filtered and is washed with methanol aqueous solution, Obtain (7- hydroxyl -2- oxo -2H- chromene -3- bases) Methanesulfomide (compound 3), 21.2g, yield 85%.1H-NMR (400MHz,CDCl3)δ:4.08(s,2H),5.14(s,2H),5.26(s,1H),6.74(s,1H),6.81(d,1H),7.51 (dd,1H),7.60(s,1H).13C-NMR(125MHz,CDCl3)δ:63.62,102.58,112.85,114.47,119.70, 129.31,140.10,156.42,157.32,160.10.LC-MS(ESI,pos,ion)m/z:256[M+H].
The synthesis of 1-2, (7- methoxyl group -2- oxo -2H- chromene -3- bases) Methanesulfomide
At room temperature, in the presence of Anhydrous potassium carbonate (6.3g, 45.58mmol), with being dissolved in acetone (50.0mL) Methyl iodide (4.0mL) solution and compound 3 (21.2g, 83.06mmol) are reacted one hour, and concentrated solvent is beaten with water, filtering, Obtain (7- methoxyl group -2- oxo -2H- chromene -3- bases) Methanesulfomide (compound 4), 12.0g, yield 98%.1H-NMR (400MHz,CDCl3)δ:3.84(s,3H),4.08(s,2H),5.87(s,2H),7.01(dd,1H),7.04(s,1H),7.58 (s,1H),7.68(dd,1H).13C-NMR(125MHz,CDCl3)δ:56.08,63.62,101.23,112.76,113.78, 119.70,128.73,140.10,156.59,157.32,162.49.LC-MS(ESI,pos,ion)m/z:270[M+H].
The synthesis of 1-3, (7- methoxyl group -2,2- dimethyl -2H- chromene -3- bases) Methanesulfomide
Using THF as solvent, compound 4 (12.0g, 44.56mmol) is made to occur with iodide (13g, 78.20mmol) Reaction flows back 4 hours, and after the completion of reaction, reaction, concentrated solvent, flash column chromatography separation, you can obtain yellow is quenched in acid adding Solid (7- methoxyl group -2,2- dimethyl -2H- chromene -3- bases) Methanesulfomide (compound 5), 10.5g, yield 83%.1H-NMR(400MHz,CDCl3)δ:1.45(s,6H),3.84(s,3H),4.08(s,2H),4.29(s,2H),6.43(s,1H), 6.65(dd,1H),7.18(s,1H),7.91(dd,2H).13C-NMR(125MHz,CDCl3)δ:27.07,56.08,62.25, 74.02,103.68,105.06,113.29,119.81,124.15,128.02,155.91,161.96.LC-MS(ESI,pos, ion)m/z:284[M+H].
The conjunction of 1-4, (4- (hexichol [b, d] thiene-3-yl) -7- methoxyl group -2,2- lutidines -3- bases) Methanesulfomide At
Compound 5 (10.5g, 37.06mmol) is dissolved in anhydrous dichloroethylene (10mL), and is stirred continuously, at 5 DEG C Under, anhydrous Aluminum chloride (15.0g, 112.5mmol) is added into the solution of above-mentioned stirring, after stirring 0.5 hour, hexichol is added [b, d] thiophene (182.3mmol) simultaneously stirs mixture 12 hours at 50-60 DEG C.It is then added into ice and concentrated hydrochloric acid In the mixture of (13mL) to quench the reaction.It is extracted again by organic layer separation and by water layer with dichloromethane (2*25mL).It will close And extract washed with sodium bicarbonate (50mL), dried with anhydrous sodium sulfate, filter and evaporate.Obtained crude on silica gel Chromatography obtains thick liquid (4- (hexichol [b, d] thiene-3-yl) -7- methoxyl group -2,2- lutidines -3- bases) Methanesulfomide (compound 6), 14.21g, yield 82%.1H-NMR(400MHz,CDCl3)δ:1.36(s,6H),3.21(dd,1H),3.46 (dd,1H),3.59(dt,1H),3.84(s,5H),4.51(d,1H),6.53-6.57(m,2H),7.24-7.31(m,3H), 7.56(td,1H),7.77(d,1H),7.86(dd,1H),8.03(d,1H),8.45(dd,1H).13C-NMR(125MHz, CDCl3)δ:25.75,47.5,50.49,53.73,56.08,77.15,103.64,105.65,117.38,119.13, 123.45,124.32,124.34,124.54,127.02,127.42,128.3,133.41,134.51,138.41,139.2, 140.4,154.65,161.83.LC-MS(ESI,pos,ion)m/z:468[M+H].
1-5, N- (((4- (hexichol [b, d] thiene-3-yl) -7- methoxyl group -2,2- lutidines -3- bases) methyl) sulphur Acyl group) isoxazole -5- formamides synthesis
Compound 6 (14.21g, 30.39mmol) is added in absolute ethyl alcohol (150mL), different evil is then gradually added into Azoles -5- formyl chlorides (35mmol), stirring are warming up to reaction reflux.It reacts and finishes after about 8 hours, TLC monitors reaction end.It will be anti- Answer liquid stand it is cooling after, filter, a small amount of absolute ethyl alcohol be used in combination to wash filter cake, obtain white solid product N- (((4- (hexichol [b, D] thiene-3-yl) -7- methoxyl group -2,2- lutidines -3- bases) methyl) sulfonyl) isoxazole -5- formamides, 15.73g, Yield 92%.1H-NMR(400MHz,CDCl3)δ:1.36(s,6H),3.21(m,1H),3.46-3.52(m,2H),3.84(s, 3H),4.51(d,1H),6.00(d,1H),6.53-6.57(m,3H),7.24-7.31(m,3H),7.56(td,1H),7.77(d, 1H),7.86(dd,1H),8.16(d,1H),8.29(d,1H),8.45(dd,1H).13C-NMR(125MHz,CDCl3)δ: 25.75,47.5,52.81,54.09,56.08,77.15,103.64,105.65,108.06,117.38,119.13,123.45, 124.32,124.34,124.54,127.02,127.42,128.3,133.41,134.51,138.41,139.2,140.4, 141.68,153.55,154.65,161.79,161.83.LC-MS(ESI,pos,ion)m/z:563[M+H]。
Embodiment 2：N- (((4- (hexichol [b, d] thiene-3-yl) -7- methoxyl group -2,2- lutidines -3- bases) first Base) sulfonyl)-(the fluoro- isoxazoles of 3-) -5- formamides synthesis
Compound 6 (14.21g, 30.39mmol) is added in absolute ethyl alcohol (150mL), is then gradually added into that (3- is fluoro- Isoxazole) -5- formyl chlorides (35mmol), stirring, which is warming up to, reacts reflux.It reacts and finishes after about 8 hours, TLC monitorings reaction is eventually Point.It after reaction solution is stood cooling, filters, a small amount of absolute ethyl alcohol washing filter cake is used in combination, obtains white solid product N- (((4- (hexichol [b, d] thiene-3-yl) -7- methoxyl group -2,2- lutidines -3- bases) methyl) sulfonyl)-(the fluoro- isoxazoles of 3-) - 5- formamides, 16.59, yield 94%.LC-MS(ESI,pos,ion)m/z:581[M+H].
Embodiment 3：N- (((4- (hexichol [b, d] thiene-3-yl) -7- methoxyl group -2,2- lutidines -3- bases) first Base) sulfonyl)-(3- hydroxyls-isoxazole) -5- formamides synthesis
Compound 6 (14.21g, 30.39mmol) is added in absolute ethyl alcohol (150mL), (3- hydroxyls are then gradually added into Base-isoxazole) -5- formyl chlorides (35mmol), stirring, which is warming up to, reacts reflux.It reacts and finishes after about 8 hours, TLC monitoring reactions Terminal.It after reaction solution is stood cooling, filters, a small amount of absolute ethyl alcohol washing filter cake is used in combination, obtains white solid product N- (((4- (hexichol [b, d] thiene-3-yl) -7- methoxyl group -2,2- lutidines -3- bases) methyl) sulfonyl)-(3- hydroxyls-different evil Azoles) -5- formamides, 16.00g, yield 91%.LC-MS(ESI,pos,ion)m/z:579[M+H].
Embodiment 4：N- (((4- (hexichol [b, d] thiene-3-yl) -7- methoxyl group -2,2- lutidines -3- bases) first Base) sulfonyl)-(3- methyl-isoxazole) -5- formamides synthesis
Compound 6 (14.21g, 30.39mmol) is added in absolute ethyl alcohol (150mL), (3- first is then gradually added into Base-isoxazole) -5- formyl chloride 35mmol), stirring is warming up to reaction reflux.It reacts and finishes after about 8 hours, TLC monitorings reaction is eventually Point.It after reaction solution is stood cooling, filters, a small amount of absolute ethyl alcohol washing filter cake is used in combination, obtains white solid product N- (((4- (hexichol [b, d] thiene-3-yl) -7- methoxyl group -2,2- lutidines -3- bases) methyl) sulfonyl)-(3- methyl-different evil Azoles) -5- formamides, 14.89g, yield 85%.LC-MS(ESI,pos,ion)m/z:577[M+H].Test example 1：Inhibit endothelium The contraction of element induction isolated rabbit aortic annulus
Normal rabbits auricular vein pneumatic needl opens chest after putting to death, take out aorta pectoralis, separation.It is placed in 4 containing saturated oxygen Connective tissue is removed in DEG C cold K-H liquid.Gently rubbed removal endarterium epithelial cell with cotton thread.It is cut into the vascular circle of 4-6mm, It hangs in the 8mL baths containing K-H buffer salt solutions, leads to pure O2, pH7.4,37 DEG C of constant temperature.Adjusting rest tension is 2g, balance 60min。
ET-1 (10 is added-8Mol/L final concentrations), 40min is incubated when vessel retraction reaches maximum tension, administration group difference Test-compound (10 is added-6Mol/L final concentrations), if solvent group is control.Observe its vessel retraction to Endothelin in 40min The antagonism of reaction.The calculating of endothelin antagonist inhibiting rate：ET-1 to vessel retraction 40min when tension be A (g), Test-compound (10-6Mol/L final concentrations) be incubated 40min after vessel retraction tension be B (g), then its inhibit percentage be (A- B)/A × 100%.(N=6)
Table 1ERA induces rabbit myocardium vessel tension variation to ET-1
Amide derivatives formula I of the present invention has preferable endothelin receptor antagonizing activity, can be used as Endothelin Receptor antagonist be used to prepare treatment cardiovascular and cerebrovascular, hypertension, pulmonary hypertension, myocardial infarction, tumour, diabetic complication, Nephrosis, asthma and thyroid gland are hyperfunction etc..

Claims (5)

1. a kind of general formula structure is the amide derivatives and its pharmaceutically acceptable salt or solvate of formula I
Wherein：R1、R2It is independently selected from H, F, OH or CH3。
2. amide derivatives formula I as described in claim 1, characterized in that be selected from following compound：
3. application of the amide derivatives formula I as claimed in claim 1 or 2 as endothelin-receptor antagonists.
4. application of the amide derivatives formula I as claimed in claim 1 or 2 in the drug for preparing cardiovascular and cerebrovascular disease.
5. amide derivatives formula I as claimed in claim 1 or 2 is preparing cardiovascular and cerebrovascular, hypertension, pulmonary hypertension, the heart Application in the hyperfunction drug of flesh infarct, tumour, diabetic complication, nephrosis, asthma, thyroid gland.
CN201810560186.4A 2018-06-03 2018-06-03 Amide derivatives and its application as endothelin-receptor antagonists in the diseases such as cardiovascular and cerebrovascular, pulmonary hypertension Withdrawn CN108586445A (en)

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