CN101928244A - Structural analogue and derivative of isochromanone-4 compound with cardiovascular activity, preparation method and application thereof - Google Patents
Structural analogue and derivative of isochromanone-4 compound with cardiovascular activity, preparation method and application thereof Download PDFInfo
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- CN101928244A CN101928244A CN 201010224458 CN201010224458A CN101928244A CN 101928244 A CN101928244 A CN 101928244A CN 201010224458 CN201010224458 CN 201010224458 CN 201010224458 A CN201010224458 A CN 201010224458A CN 101928244 A CN101928244 A CN 101928244A
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Abstract
The invention relates to the field of medicinal chemistry, in particular to a structural analogue and a derivative of an isochromanone-4 compound, and also discloses a preparation method for the structural analogue and the derivative of the isochromanone-4 compound and application of a medicinal composition which contains the compound and the compound to treating cardiovascular disease or disease symptom.
Description
Technical field
The present invention relates to natural drug and pharmaceutical chemistry field, be specifically related to the analog of isochromanone 4 compounds and its derivative, the invention also discloses the preparation method of the analog of these isochromanone-4 compounds and its derivative and contain the pharmaceutical composition of described compound and described compound to treating application in other disease or the illness in treatment hypertension, atherosclerosis, heart failure and by inhibition hypertensinase (ACE).
Background technology
Hypertension is the disease of 21 century common but severe harm humans health, also is the inducement of many other cardiovascular and cerebrovascular diseases.The state of an illness did not significantly improve after hyperpietic's medication of 1/3rd was arranged at present, and the development of antihypertensive drug still will be the focus that people pay close attention to.
Banana is common fruit, and its micromicro is as medicinal.The water-soluble portion of the dry fruit leather armour ethanol-extracted of the sophisticated banana of record has the effect that suppresses fungi, bacterium in " Chinese materia medica voluminous dictionary ", can cure by fungi and the caused skin pruritus of infectation of bacteria.Antimycotic material may be a burnt skin element (Musarin).Pericarpium Musae also has the effect of ending polydipsia, moistening lung intestines, promoting blood circulation, increasing marrow.Pericarpium Musae mashed add that ginger juice can anti-inflammatory analgetic.With the Pericarpium Musae foot of rubbing hands, can prevent treating chilblain.In addition, it also can treat hypertension, and can prevent and treat Intracerebral hemorrhage disease.Any of several broadleaf plants skin dries wears into the cosmetic good merchantable brand that powder is still protected skin.Record Pericarpium Musae or carpopodium 30-60g in " modern Chinese herbal medicine voluminous dictionary " fry in shallow oil the soup clothes, can treat hypertension (" food Chinese medicine is with just square ").
(Angiotensin Converting Enzyme Inhibitor is the good medicine that can bring high blood pressure down effectively in the discovery of eighties of last century the seventies ACEI), for the wound of depressor is ground the new approach of having opened up to angiotensin-convertion enzyme inhibitor at first.First ACE inhibitor captopril in 1981 listing, after this, the development of this class medicine is very fast, has developed into the third generation till now, have 20 at present surplus the kind listing.Recently discover that ACE inhibitor not only can effectively bring high blood pressure down, but also to congestive heart failure, myocardial infarction, diabetic nephropathy, proteinuria etc. have significant curative effect.
The inventor found in the research to Pericarpium Musae in early stage, its effective part extract has antihypertensive activity (seeing patent CN1857530A), and extraction obtains a new effective constituent isochromanome-4 (XJP) from efficient part, and it has been carried out complete synthesis research (seeing patent CN101016291A).Compound (XJP) is further being found that its mechanism of action is an ACE inhibitor in the pharmacological testing, and it suppresses active suitable with captopril.
Summary of the invention
For searching has the more vasoactive ACE inhibitor kind new medicine of cardiac stimulant, the present invention carries out chemical structure to compound (XJP) and modifies and transform, thereby a series of derivatives with general formula (I) structural performance are provided.
The technical problem to be solved in the present invention is that the ACE that has of research general formula (I) suppresses active compound, and a kind of pharmaceutical composition for the treatment of hypertension, congestive heart failure and other disease or illness further is provided, and its curative effect is better than compound (XJP).Another object of the present invention provides above-mentioned medicinal compositions in the purposes of preparation aspect the medicine that suppresses ACE and treat other disease or illness.
For solving the problems of the technologies described above, the invention provides following technical scheme:
The compound or pharmaceutically acceptable salt thereof of general formula (I):
R wherein
1Expression: the alkyl of hydrogen, C1-C8 ,=CHAr;
The alkyl of above-mentioned C1-C8 is meant the alkyl of the straight or branched of C1-C8, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, heptyl or octyl group etc.
Ar represents
R wherein
4Expression hydrogen, hydroxyl, alkoxyl group, aldehyde radical, carboxyl, ester group, amido, amide group, halogen.
R
2, R
3Expression hydrogen, hydroxyl, OR
5, OCOR
5, OCH
2CH (OH) NR
6R
7
X representative: O, S, NH, (CH
2) n; N=1-3
Y representative :=O ,=S ,=NOH ,=NOOR
5,=CH
2,-OR
5,-R
8
R
5Alkane, alkene, alkynes, naphthenic hydrocarbon, phenyl, benzyl, the naphthyl of representing the C1-C8 straight or branched that non-replacement or Z replace;
R
6, R
7Identical or different, representative: the phenyl that the alkane of hydrogen, C1-C8 straight or branched, alkene, alkynes, naphthenic hydrocarbon, heterocyclic radical, benzyl, Z replace;
R
8Representative: alkane, alkene, alkynes, naphthenic hydrocarbon, amino, phenyl, benzyl, the naphthyl of the C1-C8 straight or branched that hydrogen, halogen, hydroxyl, non-replacement or Z replace.
Z representative: hydrogen, halogen, CN, NH
2, NO
2, CF
3, OH, OCH
3, COOH, COOCH
3
The compound or pharmaceutically acceptable salt thereof of general formula (I), wherein R
1Represent hydrogen, methyl ,=CHAr;
Ar represents
R wherein
4Expression hydrogen, hydroxyl, alkoxyl group, aldehyde radical, halogen.
R
2, R
3Expression hydrogen, hydroxyl, OR
5, OCOR
5, OCH
2CH (OH) NR
6R
7
X representative: O, NH, CH
2
Y representative :=O ,=NOH ,=NOOR
5,=CH
2,-OR
5,-R
8
R
5The phenyl that alkane, alkene, alkynes, naphthenic hydrocarbon, heterocyclic radical, benzyl, the Z of expression C1-C8 straight or branched replaces;
R
6, R
7Identical or different, representative: the phenyl that the alkane of hydrogen, C1-C8 straight or branched, alkene, heterocyclic radical, benzyl, Z replace;
R
8Representative: hydrogen, the alkane phenyl of C1-C4 straight or branched, benzyl.
Z representative: hydrogen, halogen, CN, NH
2, NO
2, OH, OCH
3
The present invention includes a kind of Mammals that is used for the treatment of, be preferable over the pharmaceutical composition of treatment human diseases or illness, it comprises treatment hypertension, atherosclerosis and the compound or its salt and the pharmaceutically acceptable carrier for the treatment of the general formula (I) of significant quantity in other disease or the illness by inhibition hypertensinase (ACE).
In embodiment preferred of the present invention, R
1Be hydrogen or methyl;
R
2, R
3Be hydrogen, hydroxyl, OCH
3
X representative: O, NH;
-Y representative :=O;
At one more in the embodiment preferred, R
1It is methyl; R
2, R
3Be OCH
3X is O, NH;-Y is=O.
In another embodiment preferred of the present invention, R
1Be hydrogen or methyl;
R
2, R
3Be hydroxyl, OCH
3, OCOR
5
X is O;
Y representative :=O;
R
5It is the phenyl that the alkane, alkene, alkynes, naphthenic hydrocarbon, Z of C1-C8 straight or branched replaces;
Z representative: hydrogen, halogen, NO
2, OH, OCH
3, CH
3
At one more in the embodiment preferred, R
1It is methyl; R
2Be OCH
3R
3Be OCOCH
3X is O; Y is=O.
At another more in the embodiment preferred, R
1It is methyl; R
2Be OCOR
5R
3Be OCOR
5X is O;-Y is=O.
R
5It is the phenyl of the alkane Z replacement of C1-C8 straight or branched;
Z representative: hydrogen, halogen, NO
2, OH, OCH
3, CH
3
In a highly preferred embodiment, R
1It is methyl; R
2Be OCOR
5R
3Be OCOR
5X is O;-Y is=O.
R
5It is Chloro-O-Phenyl;
Part of compounds of the present invention is:
3-methyl-7,8-dimethoxy-isoquinoline ketone-4
3-methyl-7-methoxyl group-8-hydroxyl isoquinolines-4
3-methyl-7,8-hydroxyl isoquinolines-4
(Z)-and 3-benzene methene base-7,8-dimethoxy isochromanome-4
(Z)-and 3-(4-fluorobenzene methene base)-7,8-dimethoxy isochromanome-4
(Z)-and 3-(4-hydroxybenzene methene base)-7,8-dimethoxy isochromanome-4
(Z)-and 3-(2,3-dimethoxy benzene methene base)-7,8-dimethoxy isochromanome-4
(Z)-and 3-(3-oil of mirbane methene base)-7,8-dimethoxy isochromanome-4
(Z)-and 3-(4-chlorobenzene methene base)-7,8-dimethoxy isochromanome-4
(Z)-and 3-(2,6-dichlorobenzene methene base)-7,8-dimethoxy isochromanome-4
(Z)-and 3-(2-fural)-7,8-dimethoxy isochromanome-4
(Z)-3-(2-benzene methene base)-7-methoxyl group-8-hydroxyl isochromanome-4
(Z)-3-(4-fluorobenzene methene base)-7-methoxyl group-8-hydroxyl isochromanome-4
(Z)-3-(2,3-dimethoxy benzene methene base)-7-methoxyl group-8-hydroxyl isochromanome-4
(Z)-3-(4-chlorobenzene methene base)-7-methoxyl group-8-hydroxyl isochromanome-4
(Z)-3-(2,6-dichlorobenzene methene base)-7-methoxyl group-8-hydroxyl isochromanome-4
(Z)-3-(2-fural)-7-methoxyl group-8-hydroxyl isochromanome-4
3-methyl-7,8-dihydroxyl isochromanome-4 oxime
(E)-and O-benzoyl-3-methyl-7,8-dimethoxy isochromanome-4 oxime
(E)-and O-(4-anisoyl)-3-methyl-7,8-dimethoxy isochromanome-4 oxime
(E)-and O-(2-chlorobenzene formacyl)-3-methyl-7,8-dimethoxy isochromanome-4 oxime
(E)-and O-(4-nitro benzoyl)-3-methyl-7,8-dimethoxy isochromanome-4 oxime
(E)-and O-(4-chlorobenzene formacyl)-3-methyl-7,8-dimethoxy isochromanome-4 oxime
(E)-and O-ethanoyl-3-methyl-7,8-dimethoxy isochromanome-4 oxime
(E)-and O-propionyl-3-methyl-7,8-dimethoxy isochromanome-4 oxime
(E)-and O-pentanoyl-3-methyl-7,8-dimethoxy isochromanome-4 oxime
(E)-and O-(3-carboxyl butyryl radicals)-3-methyl-7,8-dimethoxy isochromanome-4 oxime
3-methyl-4-hydroxyl-7, the 8-dimethoxy is heterochromatic full
3-methyl-7-methoxyl group-4, the 8-dihydroxyl is heterochromatic full
3-methyl-4-oxyethyl group-7, the 8-dimethoxy is heterochromatic full
3-methyl-7,8-two (2-chlorobenzoyl oxygen base) isochromanome-4
3-methyl-7-methoxyl group-8-(2, the 3-epoxypropyl)-isochromanome-4
3-methyl-7-(2, the 3-epoxypropyl)-8-hydroxyl isochromanome-4
2-(3-methyl-7-methoxyl group-4-oxo heterochromatic full-8-oxygen base) ethyl propionate
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(ethamine amino) propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(uncle's fourth amino) propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(diethylin) propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(third amino) propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(fourth amino) propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(phenylamino) propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(2-hydroxyl ethylamino) propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-morpholine propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(piperidyl) propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(six hydrogen indyls) propoxy-) isochromanome-4
The present invention includes a kind of Mammals that is used for the treatment of, be preferable over the pharmaceutical composition of treatment human diseases or illness, compound or its salt and pharmaceutically acceptable carrier that it comprises treatment hypertension, congestive heart failure, myocardial infarction, diabetic nephropathy, proteinuria and treats the general formula (I) of the significant quantity of other disease or illness by inhibition ACE.
The present invention also comprises the application of compound or its salt in preparing the medicine for the treatment of hypertension, congestive heart failure, myocardial infarction, diabetic nephropathy, proteinuria and treating other disease or illness by inhibition ACE of general formula (I).
General formula (I) compound can and be described preparation according to following reaction scheme.Unless otherwise indicated, hereinafter diagram and describe in Ar, X, Y, R
1, R
2And the structure of formula (I) is same as above.Wherein compound (I) prepares according to patent CN101016291A method.
Reaction 1
Reaction 2
Reaction 3
Reaction 4
Reaction 5
With reference to reaction 1, under alkaline condition, 2,3-dimethoxy-6-bromobenzyl bromine (1) carries out substitution reaction with compound 2, forms compound 3.Usually in such as alkaline mediums such as sodium hydroxide, Anhydrous potassium carbonate, sodium hydrides, DMF, methyl-sulphoxide (DMSO), N,N-dimethylacetamide (DMA), N-N-methyl-2-2-pyrrolidone N-(NMP), acetonitrile isopolarity solvent carry out above-mentioned reaction 6～48h under-20～120 ℃.Preferred Anhydrous potassium carbonate is a medium, and dry DMF is a solvent, under refluxad reacts 5h.
Compound 4 is with compound 3 the nucleophilic addition cyclization to take place under the organolithium effect to make.Organolithium reagent can be n-Butyl Lithium, s-butyl lithium or tert-butyl lithium, and the organolithium reagent consumption can be 1～3 times of equivalent of compound 3.Reaction solvent can be THF, ether, CH
2Cl
2, temperature of reaction can-110 ℃ to selecting suitable temperature between the room temperature, the reaction times is 1～12 hour.Preferred organolithium reagent is a n-Butyl Lithium, and consumption is 3 times of equivalents of compound 3, and solvent is anhydrous THF, and temperature of reaction is-50 ℃, reaction times 2h.
Compound 4 is removed 8 methyl or 7,8 methyl to be removed simultaneously and obtains compound 5 and 6.At mineral acid such as Hydrogen bromide, hydrochloric acid, phosphoric acid or polyphosphoric acid, perhaps with reacting under the acidic medium conditions such as Lewis acid such as aluminum chloride, boron tribromide or boron trifluoride, solvent can be oil of mirbane, dithiocarbonic anhydride, benzene, methylene dichloride, chloroform, ether, tetrahydrofuran (THF), or directly be solvent with the mineral acid, temperature of reaction can be selected suitable temp between the boiling temperature of 0 ℃ and solvent for use, the reaction times is 1～12h.The preferred acidic medium is an aluminum chloride, and solvent is a chloroform, and temperature of reaction is the chloroform reflux temperature, reaction times 8h.
With reference to reaction 2, compound 7 and substituted aroma aldehyde compound are carried out condensation reaction, obtain compound 8.Under the catalysis of diluted alkaline bar, as sodium hydroxide, potassium hydroxide, hydrated barta, trimethyl carbinol aluminium, sodium methylate etc., solvent is water, methyl alcohol, ethanol, ethylene glycol, acetone, THF etc., and normal temperature is to solvent refluxing thermotonus 0.5～8h.Preferred 10% aqueous sodium hydroxide solution is a basic catalyst, and solvent is a methyl alcohol, normal-temperature reaction 2h.
With reference to reaction 3, with compound 9 in methyl alcohol, ethanol and/or dioxane, be reacted into oxime with the oxammonium hydrochloride of crossing through alkaline matter for processing and get compound 10, above-mentioned alkaline matter is sodium hydroxide, sodium ethylate, sodium bicarbonate, saleratus or yellow soda ash, even more preferably sodium ethylate.Temperature of reaction is 0～100 ℃, and 1 day reaction times more preferably was room temperature, reaction times 2h.Subsequently, compound 10 becomes ester to obtain compound 11 with corresponding acyl chloride reaction according to chemical ordinary method acidylate.Reaction is a solvent with methylene dichloride, chloroform, tetracol phenixin or pyridine, with alkaline matter catalysis, and as sodium hydroxide, pyridine, N, accelerine, triethylamine etc., 0～100 ℃, reaction times 1-12h.Preferably be the solvent catalyzer of holding concurrently with the pyridine, 0 ℃ of reaction 2h.
With reference to reaction 4, compound 12 becomes ester to obtain compound 11 with corresponding acyl chloride reaction according to chemical ordinary method acidylate.Reaction is a solvent with methylene dichloride, chloroform, tetracol phenixin or pyridine, with alkaline matter catalysis, and as sodium hydroxide, pyridine, N, accelerine, triethylamine etc., 0～100 ℃, reaction times 4-48h.Preferably be the solvent catalyzer of holding concurrently with the pyridine, normal-temperature reaction 12h.
With reference to reaction 5, compound 14 and halogenated epoxy propane carry out substitution reaction, the 3-methyl-7-methoxyl group-8-of etherificate system (2, the 3-epoxypropyl)-isochromanome-4 (compound 15).Reaction is finished by the conventional etherification method in compound field, usually in such as alkaline mediums such as sodium hydroxide, sodium methylate, yellow soda ash, sodium bicarbonate, saleratus, with acetone, chloroform, methyl-sulphoxide, DMF, tetrahydrofuran (THF) etc. is solvent, and room temperature is reacted 2-12h to the solvent refluxing temperature.Preferred halogenated epoxy propane is epoxy chloropropane, is base catalysis with Carbon Dioxide hydrogen potassium, acetone back flow reaction 3h.Subsequently, compound 15 and corresponding aminated compounds reaction aminolysis reaction obtain compound 16.Reacting amines is one-level or secondary amine, and the amine that reacts with methyl alcohol, ethanol, ethylene glycol or direct employing is solvent, and room temperature to reflux temperature reacts 1-8h.Preferred alcohol is a solvent, alcohol reflux thermotonus 2h.
In formula (I), work as R
2, R
3During for OH, adopt ordinary method, with the solution or the suspension of the corresponding free phenol of two stoichiometric pharmaceutically acceptable alkaline purifications, can make the pharmacologically acceptable salt of formula (I) compound, the alkali that can enumerate is: sodium, potassium and calcium.When X is NH, adopt ordinary method, handle corresponding alkali solution or suspension with a stoichiometric pharmaceutically acceptable acid, can make the pharmacologically acceptable salt of formula (I) compound, the alkali that can enumerate is: hydrochloric acid, succsinic acid and Phenylsulfonic acid.In the compound 16, adopt ordinary method, handle corresponding alkali solution or suspension with a stoichiometric pharmaceutically acceptable acid, can make the pharmacologically acceptable salt of formula (I) compound, the alkali that can enumerate is: hydrochloric acid, tartrate, succsinic acid, toxilic acid.
Be the experiment of compound of the present invention below to the active influence of tonin (ACE).
ACE enzyme liquid and preparation method thereof:
With reference to methods such as Cushman (Cushman DW, et al, Biochem Plamacol, 1971,20:1637-1648), get the pig lung tissue, clean with the 0.1mol/L borate buffer, remove lung pipe and fatty tissue, back homogenate is cut into small pieces.At 4 ℃, the centrifugal 10min of 5000r/min, abandon precipitation, supernatant spends the night with the borate buffer low temperature dialysis, changes liquid 4 times, each 1L; Under 4 ℃ of conditions, the centrifugal 40min of 4000r/min collects supernatant and gets the ACE enzyme extract, measures the activity of ACE enzyme extract, packing be stored in 4 ℃ standby.
Formula (I) compound is tested the restraining effect of ACE:
(Clin Chem 1993,39 (2): 312-316 for Buttery JE, et al for the reference literature method; Bramucci M, et al, Am J Physiol, 1997,273:R2089-R2096; Gorski TP, et al, Clin Chem, 1991,37 (8): 1390-1393), the captopril of different concns, formula of the present invention (I) compound and each 50ul of solvent DMSO join respectively in the 800ul borate buffer, add enzyme extract 50ul again in this system respectively, 37 ℃ of reaction 30min.Establishing blank simultaneously is the 900ul borate buffer, and negative control is that 50ul damping fluid and 50ul enzyme crude extract join in the 800ul borate buffer.Each group adds 100ulFAPGG subsequently, and fully mixing is counted 0min this moment.Reaction solution is hatched 60min, the absorption value A0 when the 342nm place measures 0min and 60min respectively, At in 37 ℃.
The result calculates:
Ultraviolet is calculated: Δ A=A
t-A
0
Inhibiting rate=(negative control-testing sample)/(negative degree contrast-blank) * 100%
Preliminary biological activity test result shows: formula (I) compound is 10 in concentration
-12～10
-8In the time of between the mol/L, its ACE restraining effect increases gradually along with the increase of concentration.Wherein, under identical concentration, there is the enzyme inhibition of part kind compound to be equal to or higher than captopril.
Formula (I) part is to the experiment of the active influence of tonin (ACE)
Embodiment
The preparation of following embodiment formula (I) compound, all temperature all are ℃.
Embodiment 1
2-(2,3-dimethoxy-6-bromobenzyl amido) methyl propionate
With 2, (6.16g, 0.02mol) (2.68g 0.026mol) is dissolved in the 250mlDMF solution 3-dimethoxy-6-bromobenzyl bromine, adds 2.76g (0.02mol) K with the L-alanine methyl ester
2CO
3, reflux and stir 5h, be cooled to room temperature, to filter, filtrate decompression concentrates, and gets colorless oil title compound 5.96g, productive rate 89%.
IR(KBr)，cm
-1：3450，3007，2979，2940，2835，2377，2310，1660，1573，1473，1297，1074，1000，810；
1H-NMR(CDCl
3，300MHz)：δ1.33(d，3H，J＝8.19，-CH
3)，3.46(q，1H，-CH-)，3.71(s，3H，-CH
3)，3.87(s，3H，-OCH
3)，3.89(s，3H，-OCH
3)，4.01(q，2H，J＝14.1，-CH
2-)，6.75(d，1H，J＝8.7，Ar-H)，7.28(d，1H，J＝8.7，Ar-H)；MS(ESI，m/z)：[M+H]
+332
Embodiment 2
3-methyl-7,8-dimethoxy-isoquinoline ketone-4
(6.62g 0.02mol) adds among the 50mL THF with 2-(2,3-dimethoxy-6-bromobenzyl amido) methyl propionate, be cooled to-50 ℃, the n-BuLi hexane solution that adds 16mL 2.5mol/L finishes reaction, in reaction solution impouring 50ml saturated aqueous ammonium chloride behind the 1h, use extracted with diethyl ether, each 100mL extracts 2 times, merges ether solution, wash anhydrous sodium sulfate drying with saturated sodium bicarbonate solution, saturated aqueous common salt collection successively.Extraction liquid concentrates, the crude product silica gel column chromatography, [sherwood oil (60 ℃～90 ℃): acetone=4: 1 (v: v)], get white solid title compound 2.65g, mp:232-235 ℃, yield 60%.IR(KBr)，cm
-1：3452，3008，2980，2940，2836，1990，1662，1455，1297，1074，1001，810；
1H-NMR(CDCl
3，300MHz)：δ1.56(d，3H，J＝7.1，-CH
3)，3.76(s，3H，-OCH
3)，3.77(m，1H，-CH-)，3.85(s，3H，-OCH
3)，4.29(d，1H，J＝14.1，-CH
2-)，5.37(d，1H，J＝14.1，-CH
2-)，6.78(d，1H，J＝8.8，Ar-H)，7.24(d，1H，J＝8.8，Ar-H)；MS(ESI，m/z)：[M+H]
+222
Embodiment 3
(Z)-and 3-benzene methene base-7,8-dimethoxy isochromanome-4
With 7, (0.22g 0.001mol) is dissolved in the ethanol of 5ml 95% to 8-dimethoxy isochromanome-4, adds 10%NaOH solution 5ml, add phenyl aldehyde (0.001mol) immediately, at room temperature stirred 2 hours, and had a large amount of precipitations to produce, filter, to be washed to neutrality, recrystallization gets glassy yellow crystalline solid title compound 0.24g, mp:222-224 ℃, productive rate 82% in the ethanol.IR(KBr)，cm-1：3450，2919，2844，1894，1672，1592，1494，1284，1089，1046，970，688；1H-NMR(CDCl
3，300MHz)：δ3.80(s，3H，-OCH
3)，3.89(s，3H，-OCH
3)，5.21(s，2H，-CH
2-)，6.94(d，1H，J＝8.6，Ar-H)，6.96(s，1H，＝CH-)，7.24(d，1H，J＝7.2，Ar-H)，7.31(t，2H，J＝7.2，Ar-H)，7.79(d，2H，J＝7.2，Ar-H)，7.85(d，1H，J＝8.6，Ar-H)MS(ESI，m/z)：[M+Na]+319.0，[M+K]+335.1
Embodiment 4
3-methyl-7,8-dimethoxy isochromanome-4 oxime
With 3-methyl-7, (0.22g 0.001mol) adds in the reaction flask 8-dimethoxy isochromanome-4, after stirring and dissolving in the 10ml methyl alcohol, slowly add the oxammonium hydrochloride be dissolved in the 10ml water (0.07g, 0.001mol), add again sodium ethylate (0.068g, 0.001mol).Normal temperature adds about 60ml water after reacting 2h down, filters, and precipitation water washing 2 times, ethyl alcohol recrystallization obtains colorless solid title compound 0.18g, productive rate 76.0%, mp135-136 ℃.MS(ESI，m/z)：[M+H]
+328
Embodiment 5
(E)-and O-benzoyl-3-methyl-7,8-dimethoxy isochromanome-4 oxime (IVe)
(0.004mol) joins 2mlSOCl with phenylformic acid
2In be heated to 80 ℃ of backflow 2h, step-down steams the SOCl in the system then
2, promptly obtaining substituted benzoyl chloride, yellow oil is directly used in the next step.
Add the 10ml anhydrous pyridine in Benzoyl chloride, stirring and dissolving adds compound 3-methyl-7, and (0.47g 0.002mol), reacts 2h to 8-dimethoxy isochromanome-4 oxime under condition of ice bath.In reaction solution impouring frozen water, treat ice-out after, consider the collection precipitation, drying obtains white solid title compound 0.38g, mp:115-118 ℃, productive rate 55%.
IR(KBr)，cm-1：3445，2979，2935，2847，1747，1613，1497，1281，1062；
1H-NMR(CDCl
3，300MHz)：δ1.58(d，3H，J＝6.9Hz，-CH
3)，2.44(s，3H，-CH
3)，3.85(s，3H，-OCH
3)，3.92(s，3H，-OCH
3)，4.86(dd，2H，-CH
2-)，5.44(q，lH，J＝6.9，-CH-)，6.91(d，1H，J＝8.8Hz，Ar-H)，7.28(t，2H，J＝8.8Hz，Ar-H)；8.01(m，3H，Ar-H)；MS(ESI，m/z)：[M+H]
+357
Embodiment 6
3-methyl-7-methoxyl group-8-acetoxyl group isochromanome-4
With compound 3-methyl-7-methoxyl group-8-methoxyl group isochromanome-4 (0.21g, 0.001mol) be dissolved among the pyridine 10ml, dripping acetyl chloride 0.15ml under the ice bath, stirring at room reaction 4h, steam solvent to the greatest extent, add water 10ml, ethyl acetate extraction 3 times, each 10ml, ethyl acetate layer is used 10% dilute hydrochloric acid more successively, saturated sodium bicarbonate solution, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, after concentrating, crude product column chromatography [sherwood oil (60 ℃～90 ℃): ethyl acetate=10: 1 (v: v)], obtain colorless oil title compound 0.21g, mp 113-115 ℃, productive rate 84%.
IR(KBr)，cm
-1：3458，2842，1750，1689，1606，1293，1211，1078；
1H-NMR(CDCl
3，300MHz)：δ1.49(d，3H，J＝6.7，-CH
3)，2.38(s，3H，-COCH
3)，3.90(s，3H，-OCH
3)，4.20(q，1H，J＝6.7，-CH-)，4.70(d，lH，J＝15.6，-CH
2-)，4.91(d，lH，J＝15.6，-CH
2-)，6.99(d，1H，J＝8.7，Ar-H)，7.89(d，1H，J＝8.7，Ar-H)；MS(ESI，m/z)：[M+H]
+253
Embodiment 7
3-methyl-7,8-two propionyloxy isochromanomes-4
With compound 3-methyl-7,8-dihydroxyl isochromanome-4 (XJP) (0.19g, 0.001mol) be dissolved among the pyridine 10ml, ice bath drips an amount of propionyl chloride (3equiv mol) down, stirring at room reaction 3h, steam solvent to the greatest extent, add water 10ml, ethyl acetate extraction 3 times, each 10ml, ethyl acetate layer is used 10% dilute hydrochloric acid more successively, saturated sodium bicarbonate solution, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, after concentrating, crude product column chromatography [sherwood oil (60 ℃～90 ℃): ethyl acetate=10: 1 (v: v)], get yellow oily title compound 0.21g, productive rate 68%.
IR(KBr)，cm
-1：2973，2918，2832，1769，1697，1592，1343，1276，1113；
1H-NMR(CDCl
3，300MHz)：δ1.18(m，6H，-CH
3)，1.50(d，3H，-CH
3)，2.60(m，4H，-CH
2-)，4.24(m，1H，-CH-)，4.80(dd，2H，-CH
2-)，7.26(d，1H，J＝8.4Hz，Ar-H)，8.00(d，lH，J＝8.4Hz，Ar-H)；MS(ESI，m/z)：[M+NH
4]
+324
Embodiment 8
3-methyl-7,8-diamyl acyloxy isochromanome-4
With compound 3-methyl-7,8-dihydroxyl isochromanome-4 (XJP) (0.19g, 0.00lmol) be dissolved among the pyridine 10ml, ice bath drips an amount of valeryl chloride (3equiv mol) down, stirring at room reaction 3h, steam solvent to the greatest extent, add water 10ml, ethyl acetate extraction 3 times, each 10ml, ethyl acetate layer is used 10% dilute hydrochloric acid more successively, saturated sodium bicarbonate solution, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, after concentrating, crude product column chromatography [sherwood oil (60 ℃～90 ℃): ethyl acetate=10: 1 (v: v)], get yellow oily title compound 0.25g, productive rate 68%.
IR(KBr)，cm
-1：2960，2927，2865，1764，1696，1668，1266，1216，1127，1077，923；
1H-NMR(CDCl
3，300MHz)：δ0.97(m，6H，-CH
3)，1.41(m，4H，-CH
2-)，2.56(m，4H，-CH
2-)，4.23(q，1H，J＝6.6，-CH-)，4.72(d，1H，J＝15.6，-CH2-)，4.85(d，1H，J＝15.6，-CH2-)，7.24(d，1H，J＝8.6，Ar-H)，7.98(d，1H，J＝8.6，Ar-H)；MS(ESI，m/z)：[M+NH
4]
+380
Embodiment 9
3-methyl-7,8-two (2-chlorobenzoyl oxygen base) isochromanome-4
The o-chlorobenzoyl chloride preparation: (0.63g 0.004mol) joins 2mlSOCl with 0-chloro-benzoic acid
2In be heated to 80 ℃ of backflow 2h, step-down steams the SOCl in the system then
2, promptly obtaining substituted benzoyl chloride, yellow oil is directly used in the next step.
With compound 3-methyl-7,8-dihydroxyl isochromanome-4 (XJP) (0.19g, 0.001mol) be dissolved among the pyridine 10ml, ice bath drips the o-chlorobenzoyl chloride that makes down, stirring at room reaction 3h, steam solvent to the greatest extent, add water 10ml, ethyl acetate extraction 3 times, each 10ml, ethyl acetate layer is used 10% dilute hydrochloric acid more successively, saturated sodium bicarbonate solution, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying concentrates back crude product column chromatography [sherwood oil (60 ℃～90 ℃): ethyl acetate=10: 1 (v: v)], get white solid title compound 0.37g, mp:132-135 ℃, productive rate 79%.
IR(KBr)，cm
-1：3453，1751，1706，1641，1590，1271，1032，738；
1H-NMR(CDCl
3，300MHz)：δ1.54(d，3H，J＝6.8，-CH
3)，4.30(q，1H，J＝6.8，-CH-)，4.90(d，1H，J＝15.6，-CH
2-)，5.05(d，1H，J＝15.6，-CH
2-)，7.30(m，2H，Ar-H)，7.47(m，5H，Ar-H)，7.94(t，2H，J＝7.8，Ar-H)，8.11(d，1H，J＝8.6，Ar-H)；MS(ESI，m/z)：[M+NH
4]
+488
Embodiment 10
3-methyl-7-methoxyl group-8-(2, the 3-epoxypropyl)-isochromanome-4
(0.21g 0.001mol) adds among the acetone 20ml, adds K with 3-methyl-7-methoxyl group-8 hydroxyl isochromanome-4
2CO
30.5g, epoxy chloropropane 2ml, back flow reaction 3h, stopped reaction filters, and filtrate concentrates, the crude product column chromatography [sherwood oil (60 ℃～90 ℃): acetone=6: 1 (v: v)], get white solid 0.23g, mp:104-106 ℃, productive rate 86%.IR(KBr)，cm
-1：3450，2978，2841，1689，1594，1284，1074，863；
1H-NMR(CDCl
3，300MHz)：δ1.49(d，3H，J＝6.7，-CH
3)，2.67(m，1H，-CH-C
H 2-O-)，2.86(m，1H，-CH-C
H 2-O-)，3.30(m，1H，-C
H-CH
2-O-)，3.92(m，1H，Ar-O-C
H 2-)，3.94(s，3H，-OCH
3)，4.19(q，1H，J＝6.7，-CH-)，4.30(m，1H，Ar-O-C
H 2-)，4.82(d，1H，-CH
2-)，5.19(q，1H，-CH
2-)，6.94(d，1H，J＝8.7，Ar-H)，7.84(d，1H，J＝8.7，Ar-H)；MS(ESI，m/z)：[M+H]
+265
Embodiment 11
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(isopropylamino) propoxy-) isochromanome-4
With compound 3-methyl-7-methoxyl group-8-(2, the 3-epoxypropyl)-isochromanome-4 (0.26g, 0.001mol) join in the 10ml95% ethanol, evenly be stirred to dissolving, add Isopropylamine 2ml, reflux 3h-6h, stopped reaction removes ethanol and remaining amine under reduced pressure, residuum is dissolved in the 10ml chloroform, saturated common salt washing (10ml * 2 time), anhydrous sodium sulfate drying filters, filtrate concentrates, crude product column chromatography [methylene dichloride: methyl alcohol=20: 1 (v: v)] obtain white solid target compound 0.23g, mp:115-118 ℃, productive rate 70%.
IR(KBr)，cm
-1：3441，3272，1696，1595，1288，1076，788；
1H-NMR(CDCl
3，300MHz)：δ1.09(s，3H，J＝6.24，-CH
2C
H 3)，1.49(d，3H，J＝6.7，-CH
3)，2.71(m，1H，-NH-C
H(CH
3)
2)，2.82(m，2H，-CH-C
H 2-NH-)，3.93(s，3H，-OCH
3)，3.94(m，2H，-OCH
2-)，4.02(m，1H，-C
H-)，4.19(q，1H，J＝6.7，-CH-)，4.82(dd，1H，-CH
2-)，5.17(dd，1H，-CH
2-)，6.94(d，1H，J＝8.7，Ar-H)，7.84(d，1H，J＝8.7，Ar-H)；MS(ESI，m/z)：[M+H]
+310
Embodiment 12
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(third amino) propoxy-) isochromanome-4
With compound 3-methyl-7-methoxyl group-8-(2, the 3-epoxypropyl)-isochromanome-4 (0.26g, 0.001mol) join in the 10ml95% ethanol, evenly be stirred to dissolving, add propylamine 2ml, reflux 3h-6h, stopped reaction removes ethanol and remaining amine under reduced pressure, residuum is dissolved in the 10ml chloroform, saturated common salt washing (10ml * 2 time), anhydrous sodium sulfate drying filters, filtrate concentrates, crude product column chromatography [methylene dichloride: methyl alcohol=20: 1 (v: v)] obtain white solid target compound 0.23g, mp:123-125 ℃, productive rate 70%.
IR(KBr)，cm
-1：3443，1641，1288，1078，987，620；
1H-NMR(CDCl
3，300MHz)：δ0.93(t，3H，J＝7.4，-CH
2C
H 3)，1.49(d，3H，J＝6.7，-CHC
H 3)，1.54(m，2H，-C
H 2CH
3)，2.64(m，2H，-NHC
H 2CH
2CH
3)，2.79(m，2H，-CH(OH)C
H 2NH-)，3.92(s，3H，-OCH
3)，4.01(m，1H，-CH-)，4.04(m，2H，-OCH
2-)，4.19(q，1H，J＝6.7，-CH-)，4.82(d，1H，J＝15.6，-CH
2-)，5.19(d，1H，J＝15.6，-CH
2-)，6.94(d，1H，J＝8.7，Ar-H)，7.84(d，1H，J＝8.7，Ar-H)；MS(ESI，m/z)：[M+H]
+324
Embodiment 13
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(2-hydroxyl ethylamino) propoxy-) isochromanome-4
With compound 3-methyl-7-methoxyl group-8-(2, the 3-epoxypropyl)-isochromanome-4 (0.26g, 0.001mol) join in the 10ml95% ethanol, evenly be stirred to dissolving, add thanomin 2ml, reflux 3h-6h, stopped reaction removes ethanol and remaining amine under reduced pressure, residuum is dissolved in the 10ml chloroform, saturated common salt washing (10ml * 2 time), anhydrous sodium sulfate drying filters, filtrate concentrates, the crude product column chromatography [methylene dichloride: methyl alcohol=15: 1 (v: v)] obtain white solid 0.23g, mp:81-83 ℃, productive rate 70%.
IR(KBr)，cm
-1：3421，2843，1689，1594，1288，1077，1029，836；
1H-NMR(CDCl
3，300MHz)：δ1.49(d，3H，J＝6.7，-CH
3)，2.84(m，4H，-C
H 2NHC
H 2-)，3.71(t，2H，J＝5.1，-CH
2C
H 2OH)，3.95(1H，-C
HOH-)，3.99(s，3H，-OCH
3)，4.05(m，2H，-OCH
2-)，4.17(q，1H，J＝6.7，-CH-)，4.81(d，1H，J＝15.7，-CH
2-)，5.17(d，1H，J＝15.7，-CH
2-)，6.95(d，1H，J＝8.7，Ar-H)，7.85(d，1H，J＝8.7，Ar-H)；MS(ESI，m/z)：[M+H]
+326
Embodiment 14
Tablet
Embodiment 11 50g
HPMC E5 15g
Microcrystalline Cellulose MCC102 18g
8% 30 POVIDONE K 30 BP/USP 30 is an amount of
Magnesium stearate 2g
1000
Get above-mentioned prescription, be prepared into tablet with ordinary method.
Claims (5)
1. the compound or pharmaceutically acceptable salt thereof of general formula (I):
R wherein
1Expression: the alkyl of hydrogen, C1-C8 ,=CHAr;
The alkyl of above-mentioned C1-C8 is meant the alkyl of the straight or branched of C1-C8, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, heptyl or octyl group etc.;
Ar represents
R wherein
4Expression hydrogen, hydroxyl, alkoxyl group, aldehyde radical, carboxyl, ester group, amido, amide group, halogen;
R
2, R
3Expression hydrogen, hydroxyl, OR
5, OCOR
5, OCH
2CH (OH) NR
6R
7
X representative: O, S, NH, (CH
2)
nN=1-3;
Y representative :=O ,=S ,=NOH ,=NOOCR
5,=CH
2,-OR
5,-R
8
R
5Alkane, alkene, alkynes, naphthenic hydrocarbon, phenyl, benzyl, the naphthyl of representing the C1-C8 straight or branched that non-replacement or Z replace;
R
6, R
7Identical or different, representative: the phenyl that the alkane of hydrogen, C1-C8 straight or branched, alkene, alkynes, naphthenic hydrocarbon, heterocyclic radical, benzyl, Z replace;
R
8Representative: alkane, alkene, alkynes, naphthenic hydrocarbon, amino, phenyl, benzyl, the naphthyl of the C1-C8 straight or branched that hydrogen, halogen, hydroxyl, non-replacement or Z replace;
Z representative: hydrogen, halogen, CN, NH
2, NO
2, CF
3, OH, OCH
3, COOH, COOCH
3
2. the compound or pharmaceutically acceptable salt thereof of the general formula of claim 1 (I):
R wherein
1Represent hydrogen, methyl ,=CHAr;
Ar represents
R wherein
4Expression hydrogen, hydroxyl, alkoxyl group, aldehyde radical, halogen;
R
2, R
3Expression hydrogen, hydroxyl, OR
5, OCOR
5, OCH
2CH (OH) NR
6R
7
X representative: O, NH, CH
2
Y representative :=O ,=NOH ,=NOOR
5,=CH
2,-OR
5,-R
8
R
5The phenyl that alkane, alkene, alkynes, naphthenic hydrocarbon, heterocyclic radical, benzyl, the Z of expression C1-C8 straight or branched replaces;
R
6, R
7Identical or different, representative: the phenyl that the alkane of hydrogen, C1-C8 straight or branched, alkene, heterocyclic radical, benzyl, Z replace;
R
8Representative: hydrogen, the alkane phenyl of C1-C4 straight or branched, benzyl;
Z representative: hydrogen, halogen, CN, NH
2, NO
2, OH, OCH
3
3. the compound of the general formula of claim 2 (I) is following arbitrary structural compounds:
3-methyl-7,8-dimethoxy-isoquinoline ketone-4
3-methyl-7-methoxyl group-8-hydroxyl isoquinolines-4
3-methyl-7,8-hydroxyl isoquinolines-4
(Z)-and 3-benzene methene base-7,8-dimethoxy isochromanome-4
(Z)-and 3-(4-fluorobenzene methene base)-7,8-dimethoxy isochromanome-4
(Z)-and 3-(4-hydroxybenzene first is base again)-7,8-dimethoxy isochromanome-4
(Z)-and 3-(2,3-dimethoxy benzene methene base)-7,8-dimethoxy isochromanome-4
(Z)-and 3-(3-oil of mirbane methene base)-7,8-dimethoxy isochromanome-4
(Z)-and 3-(4-chlorobenzene methene base)-7,8-dimethoxy isochromanome-4
(Z)-and 3-(2,6-dichlorobenzene methene base)-7,8-dimethoxy isochromanome-4
(Z)-and 3-(2-fural)-7,8-dimethoxy isochromanome-4
(Z)-3-(2-benzene methene base)-7-methoxyl group-8-hydroxyl isochromanome-4
(Z)-3-(4-fluorobenzene methene base)-7-methoxyl group-8-hydroxyl isochromanome-4
(Z)-3-(2,3-dimethoxy benzene methene base)-7-methoxyl group-8-hydroxyl isochromanome-4
(Z)-3-(4-chlorobenzene methene base)-7-methoxyl group-8-hydroxyl isochromanome-4
(Z)-3-(2,6-dichlorobenzene methene base)-7-methoxyl group-8-hydroxyl isochromanome-4
(Z)-3-(2-fural)-7-methoxyl group-8-hydroxyl isochromanome-4
3-methyl-7,8-dihydroxyl isochromanome-4 oxime
(E)-and O-benzoyl-3-methyl-7,8-dimethoxy isochromanome-4 oxime
(E)-and O-(4-anisoyl)-3-methyl-7,8-dimethoxy isochromanome-4 oxime
(E)-and O-(2-chlorobenzene formacyl)-3-methyl-7,8-dimethoxy isochromanome-4 oxime
(E)-and O-(4-nitro benzoyl)-3-methyl-7,8-dimethoxy isochromanome-4 oxime
(E)-and O-(4-chlorobenzene formacyl)-3-methyl-7,8-dimethoxy isochromanome-4 oxime
(E)-and O-ethanoyl-3-methyl-7,8-dimethoxy isochromanome-4 oxime
(E)-and O-propionyl-3-methyl-7,8-dimethoxy isochromanome-4 oxime
(E)-and O-pentanoyl-3-methyl-7,8-dimethoxy isochromanome-4 oxime
(E)-and O-(3-carboxyl butyryl radicals)-3-methyl-7,8-dimethoxy isochromanome-4 oxime
3-methyl-4-hydroxyl-7, the 8-dimethoxy is heterochromatic full
3-methyl-7-methoxyl group-4, the 8-dihydroxyl is heterochromatic full
3-methyl-4-oxyethyl group-7, the 8-dimethoxy is heterochromatic full
3-methyl-7,8-two (2-chlorobenzoyl oxygen base) isochromanome-4
3-methyl-7-methoxyl group-8-(2, the 3-epoxypropyl)-isochromanome-4
3-methyl-7-(2, the 3-epoxypropyl)-8-hydroxyl isochromanome-4
2-(3-methyl-7-methoxyl group-4-oxo heterochromatic full-8-oxygen base) ethyl propionate
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(ethamine amino) propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(uncle's fourth amino) propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(diethylin) propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(third amino) propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(fourth amino) propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(phenylamino) propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(2-hydroxyl ethylamino) propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-morpholine propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(piperidyl) propoxy-) isochromanome-4
3-methyl-7-methoxyl group-8-(2-hydroxyl-3-(six hydrogen indyls) propoxy-) isochromanome-4.
4. one kind is used for the treatment of Mammals, be preferable over the pharmaceutical composition of treatment human diseases or illness, it comprises compound or its salt and pharmaceutically acceptable carrier of the claim 1 of the significant quantity for the treatment of hypertension, congestive heart failure, myocardial infarction, diabetic nephropathy, proteinuria and treating other disease or illness by inhibition ACE.
5. the application of the compound or its salt of claim 1 in preparing the medicine for the treatment of hypertension, congestive heart failure, myocardial infarction, diabetic nephropathy, proteinuria and treating other disease or illness by inhibition ACE.
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| CN115286605A (en) * | 2022-08-19 | 2022-11-04 | 武汉大学 | Method for synthesizing isochromanone compounds based on carbon monoxide gas or carbon monoxide substitute source |
| CN115286605B (en) * | 2022-08-19 | 2024-04-09 | 武汉大学 | Method for synthesizing isochromanone compounds based on carbon monoxide gas or carbon monoxide alternative source |
| WO2024193313A1 (en) * | 2023-03-20 | 2024-09-26 | 江苏联环药业股份有限公司 | Isochromane compounds as well as pharmaceutical composition thereof and use thereof |
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