CN101768108A - Pyridine ring-substituted alpha-hydroxycarboxylic acid derivatives, preparation method thereof and use thereof - Google Patents
Pyridine ring-substituted alpha-hydroxycarboxylic acid derivatives, preparation method thereof and use thereof Download PDFInfo
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- CN101768108A CN101768108A CN200810154645A CN200810154645A CN101768108A CN 101768108 A CN101768108 A CN 101768108A CN 200810154645 A CN200810154645 A CN 200810154645A CN 200810154645 A CN200810154645 A CN 200810154645A CN 101768108 A CN101768108 A CN 101768108A
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Abstract
The invention relates to the fields of medicaments for treating blood pressure diseases and particularly relates to pyridine ring-substituted alpha-hydroxycarboxylic acid derivatives of a general formula I, preparation method thereof, medicinal compositions having the same and use thereof as an endothelin antagonist in the preparation of medicaments for treating hypertension and pulmonary hypertension, wherein groups are defined in the description.
Description
Technical field
The present invention relates to the relevant pharmaceutical field of hypertension, particularly, the present invention relates to have the plain selectivity endothelin-receptor antagonists of the cyclosubstituted alpha-hydroxy carboxylic acid compounds derivatives class of pyridine skin of hypotensive activity, and preparation method thereof and pharmaceutical composition, and in the application of preparation aspect the Altace Ramipril.
Background technology
Blood pressure such as hypertension, pulmonary hypertension disease is to endanger bigger disease.Hypertension is the high common disease of sickness rate, need take medicine for a long time usually, seeks the eager desire that safe and effective medicine is people always.Pulmonary hypertension is a kind of disease that still perplexs medical circle so far, the ill untimely treatment in back, and survival time only two to three years, pulmonary hypertension still lacks effective medicine at present.
(endothelin is a kind of polypeptide with strong vasoconstriction effect of discoveries such as Japanese scholar Yanagisawa ET) to endothelin, is made up of 21 amino acid.Endothelin is quite low at normal body intensive amount, the body ischemic, stress, various inflammatory mediator (IL-1, IL-2, IL-8, TNF etc.) act on down, the secretion of ET increases severely, have the very strong vascular effect that contracts, its intensity is 10 times of Angiotensin II, is adrenergic 1000 times.It is the only vaso-excitor material of knowing at present that can act on diameter less than the 50nm capillary vessel, is playing important effect aspect the perfusion of adjusting microcirculation blood flow.Mammals has mainly contained two kinds of endothelin receptors: i.e. ETA and ETB.ETB mainly is distributed in pulmonary vascular endothelial cell, and ETA mainly is distributed in pulmonary vascular smooth muscle.Therefore, endothelin antagonist has the good potential of treatment hypertension and pulmonary hypertension.
Summary of the invention
An object of the present invention is to lack, seek active better Altace Ramipril, compound or its pharmacy acceptable salt with general formula I structure are provided from new mechanism at medicine clinically.
Another object of the present invention provides the compound with general formula I structure or the preparation method of its pharmacy acceptable salt.
A further object of the present invention provides the compound that contains the general formula I structure or its pharmacy acceptable salt as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application in the treatment of hypertension or pulmonary hypertension.
Now the present invention is described one by one in conjunction with purpose of the present invention:
The compound of general formula I of the present invention has following structural formula:
R
1For: OH, contain OR
6Straight or branched alkyl, SH, SR
6, NH
2, NHR
6, N (R
6)
2
R
2, R
3For: H, F, Cl, Br, NO
2, CH
3, OH, OR
6, R
2And R
3Can adopt identical or different substituting group, can replace, can replace or two replacement for single in different positions.
R
4For: H, C
1-C
5The straight or branched alkyl;
R
5For:
R in the above-mentioned substituting group
6Be C
1-C
5The straight or branched alkyl; R
7And R
8For: H, nitro, hydroxyl, amino, NH (C
1-C
4Alkyl), N (C
1-C
4Alkyl)
2, halogen, C
1-C
4Alkyl, C
3-C
8Cycloalkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio; R
7And R
8Can adopt identical or different substituting group, can replace in different positions.
Contain one or two chiral centre in the compound of general formula I, can produce two or four optical isomers, the present invention has comprised arbitrary optical isomer and non-enantiomer mixture thereof.
Preferential following compound of Formula I or its pharmacy acceptable salt, wherein,
R
1For: OH, contain OR
6Straight or branched alkyl, SH, SR
6, NH
2, NHR
6, N (R
6)
2
R
2, R
3For: H, F, Cl, Br, NO
2, CH
3, OH, OR
6, R
2And R
3Can adopt identical or different substituting group, can replace, can replace or two replacement for single in different positions.
R
4For: H, sec.-propyl, methyl, ethyl, n-propyl, normal-butyl, isobutyl-, the tertiary butyl;
R
5For:
R in the above-mentioned substituting group
6Be sec.-propyl, methyl, ethyl, n-propyl, normal-butyl, isobutyl-, the tertiary butyl; R
7And R
8For: H, nitro, hydroxyl, amino, NH (C
1-C
4Alkyl), N (C
1-C
4Alkyl)
2, halogen, C
1-C
4Alkyl, C
3-C
8Cycloalkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio; R
7And R
8Can adopt identical or different substituting group, can replace in different positions.
Contain one or two chiral centre in the compound of general formula I, can produce two or four optical isomers, the present invention has comprised arbitrary optical isomer and non-enantiomer mixture thereof.
Preferred compound of Formula I of the present invention is selected from:
3,3-phenylbenzene-3-methoxyl group-2-(2-chloropyridine-4-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(3-nitropyridine-4-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(2,6-methoxypyridine-4-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(2,6-lutidine-4-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(2-chloro-6-picoline-4-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(2-chloro-6-methoxypyridine-4-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(3-nitropyridine-2-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(5-methyl-3-nitro-pyridine-2-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(6-methyl-3-nitro-pyridine-2-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(4,6-lutidine-3-yl) oxygen base methyl propionate
3,3-two p-methylphenyls-3-methoxyl group-2-(3-nitropyridine-2-yl) oxygen base ethyl propionate
3,3-two m-nitros base-3-methoxyl group-2-(5-methyl--nitro-pyridine-2-yl) oxygen base ethyl propionate
3, two fluorine-based phenyl-3-methoxyl group-2-of 3-(3-nitropyridine-2-yl) oxygen base methyl propionate
3-phenyl-3-(2-aminomethyl phenyl)-3-methoxyl group-2-(3-nitropyridine-2-yl) oxygen base methyl propionate
3-phenyl-3-(4-cyano-phenyl)-3-methoxyl group-2-(4,6-dimethyl-3-nitropyridine-2-yl) oxygen base methyl propionate
3-phenyl-3-(3, the 4-difluorophenyl)-3-methoxyl group-2-(4,6-dimethyl-3-nitropyridine-2-yl) oxygen base methyl propionate
3-phenyl-3-(4-p-methoxy-phenyl)-3-methoxyl group-2-(4,6-dimethyl-3-nitropyridine-2-yl) oxygen base methyl propionate
3-phenyl-3-(5-methyl-2-hydroxy phenyl)-3-methoxyl group-2-(4,6-dimethyl-3-nitropyridine-2-yl) oxygen base methyl propionate
3-phenyl-3-(4-chloro-phenyl-)-3-methoxyl group-2-(5-methyl-3-nitro pyridine-2-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-oxyethyl group-2-(3-nitro-5-picoline-2-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-dimethylamino-2-(3-nitro-5-picoline-2-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-ethylmercapto group-2-(3-nitro-5-picoline-2-yl) oxygen base methyl propionate
3, two pairs of fluorophenyls of 3--3-methoxyl group-2-(3-nitro-5-picoline-2-yl) oxygen base methyl propionate
3,3-two adjacent fluorophenyl-3-methoxyl group-2-(3-nitro-5-picoline-2-yl) oxygen base methyl propionate
3,3-two-(3-trifluoromethyl) phenyl-3-methoxyl group-2-(3-nitro-5-picoline-2-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(3-pyridyl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(3-amino-5-picoline-2-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(3-methylamino--5-picoline-2-yl) oxygen base methyl propionate
3,3-phenylbenzene 3-methoxy-Ji-2-(5-methyl-3-nitro pyridine-2-yl) oxygen base propionic acid
3,3-phenylbenzene-3-methoxyl group-2-(5-methyl-3-methylamino pyridine-2-yl) oxygen base propionic acid
3,3-phenylbenzene-3-methoxyl group-2-(2,6-lutidine-4-yl) oxygen base propionic acid
3,3-phenylbenzene-3-methoxyl group-2-(5-methyl-3-nitro pyridine-2-yl) oxygen base propionic acid sylvite
3,3-phenylbenzene-3-methoxyl group-2-(5-methyl-3-nitro pyridine-2-yl) oxygen base propionic acid meglumine salt
3,3-phenylbenzene-3-methoxyl group-2-(3-methylamino--5-picoline-2-yl) oxygen base methyl propionate hydrochloride
3,3-phenylbenzene-3-methoxyl group-2-(3-methylamino--5-picoline-2-yl) oxygen base methyl propionate oxalate
Compound of Formula I of the present invention is synthetic by following general formula step:
Commercial compound VII obtains compound V with chloracetate class (VI) reaction under sodium methylate catalysis.The open loop that reacts of compound V and alcohols, Ammonia or thio-alcohol material (IV) obtains compound III, and III obtains product I with compound (II) reaction again.
In the above-mentioned route, Z is halogen, nitro or sulphonate in the structure of II.
The pharmacy acceptable salt of the compound of formula I of the present invention, be to react with alkaline matter (as oxyhydroxide, carbonate and the supercarbonate of basic metal or alkaline-earth metal), they comprise, but be not limited to: sodium hydroxide, potassium hydroxide, calcium hydroxide, yellow soda ash etc. form pharmacy acceptable salt, as corresponding sodium salts, sylvite or calcium salt or the like.Also can adopt common organic bases such as methylamine, triethylamine, meglumine etc. to generate salt.Basic group can with various mineral acids (as, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., but be not limited only to this) or organic acid (formic acid, acetate, citric acid, oxalic acid, fumaric acid, toxilic acid, amino acid or the like, but be not limited only to this) generate salt.
The compound of formula I of the present invention or its pharmacy acceptable salt can be made pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be made formulations such as solid orally ingestible, liquid oral medicine, injection.Described solid and liquid oral medicine comprise: tablet, dispersible tablet, sugar-coat agent, granule, dry powder doses, capsule and solution.Described injection comprises: little pin, infusion solutions, freeze-dried powder etc.
Composition of the present invention can be accepted auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle on described pharmacy or the bromatology.
Composition of the present invention can be accepted auxiliary material on described pharmacy or the bromatology.Weighting agent is one or more the composition that weighting agent comprises lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, lime carbonate, Microcrystalline Cellulose; Described tackiness agent comprises one or more composition of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises one or more composition of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
The compound or its salt of general formula I of the present invention has the effect to anti-endothelin, can be used as the medicine that effective constituent is used to prepare hypertension or pulmonary hypertension aspect.The activity of compound of Formula I of the present invention is by step-down modelling verification in the body.
Compound of Formula I of the present invention is effective in quite wide dosage range.For example the dosage of taking every day is divided into once or administration for several times in 0.1mg-1000mg/ people's scope.The actual dosage of taking compound of Formula I of the present invention can be decided according to relevant situation by the doctor.These situations comprise: by curer's physical state, route of administration, age, body weight, to the individual reaction of medicine, the severity of symptom etc.
Embodiment
The present invention is further illustrated below in conjunction with embodiment.Need to prove that following embodiment is used for explanation, and is not to be used to limit the present invention.The various variations that those skilled in the art make according to derivation of the present invention all should be within the desired protection domain of the application's claim.
Embodiment 13-phenyl-3-(3-fluorophenyl)-2, epihydric acid 2 methyl esters synthetic
Be dissolved among the 40ml THF in 3-fluoro-benzophenone (VII's is a kind of for 29.646g, 0.148mmol) and methyl chloroacetate (VI's is a kind of) 42ml, the constant pressure funnel of packing into is standby.Add 200mlTHF in the 250ml there-necked flask, (24g 0.444mmol), drips above-mentioned mixing solutions after the cryosel bath is cooled to 0 ℃, and controlled temperature is no more than 10 ℃ to add sodium methylate under stirring.Finish, room temperature reaction 0.5 hour adds water 150ml, ethyl acetate (100ml * 3) extraction merges organic phase, with saturated common salt water washing 2 times, the anhydrous sodium sulfate drying after-filtration, underpressure distillation, enriched material 41.9g oily matter (V's is a kind of), yield 75%, ESI-MS:m/z213[M-59], 241[M-31], 273[M+1], 295[M+23] and be directly used in the next step.
Embodiment 2-12
The synthetic operation of reference example 1 replaces 3-fluoro-benzophenone (VII) among the embodiment 1 with different benzophenone derivates, obtains differently 3, and the 3-diaryl replaces-2, the derivative of epihydric acid 2 methyl esters (V).
| ??VII | ??VI | ??V | |
| Implement 2 | Benzophenone | Methyl chloroacetate | 3,3-phenylbenzene-2, epihydric acid 2 methyl esters |
| Implement 3 | The di-p-tolyl ketone | Ethyl chloroacetate | 3,3-two p-methylphenyls-2, epihydric acid 2 ethyl ester |
| ??VII | ??VI | ??V | |
| Implement 4 | Two m-nitro ketones | Methyl chloroacetate | 3,3-two m-nitro bases-2, epihydric acid 2 methyl esters |
| Implement 5 | Two fluorophenyl ketones | Methyl chloroacetate | 3, two fluorophenyls-2 of 3-, epihydric acid 2 methyl esters |
| Implement 6 | 2 methyl benzophenone | Methyl chloroacetate | 3-(2-aminomethyl phenyl)-3-phenyl-2,3-glycidic acid methyl esters |
| Implement 7 | 4-Benzoylbenzene nitrile | Methyl chloroacetate | 3-phenyl-3-(4-cyano-phenyl)-2, the epihydric acid 2 methyl esters |
| Implement 8 | 3, the 4-difluoro benzophenone | Methyl chloroacetate | 3-phenyl-3-(3, the 4-difluorophenyl)-2,3-glycidic acid methyl esters |
| Implement 9 | The 4-methoxy benzophenone | Methyl chloroacetate | 3-phenyl-3-(4-p-methoxy-phenyl)-2, the epihydric acid 2 methyl esters |
| Implement 10 | 5-methyl-2-dihydroxy benaophenonel | Methyl chloroacetate | 3-phenyl-3-(5-methyl-2-hydroxy phenyl)-2, the epihydric acid 2 methyl esters |
| Implement 11 | The 4-chlorobenzophenone | Methyl chloroacetate | 3-phenyl-3-(4-chloro-phenyl-)-2, the epihydric acid 2 methyl esters |
| Implement 12 | 4-dimethylamino benzophenone | Methyl chloroacetate | 3-phenyl-3-(4-dimethylamino phenyl)-2, the epihydric acid 2 methyl esters |
| Implement 13 | Two pairs of fluorophenyl ketones | Methyl chloroacetate | 3, two pairs of fluorophenyls-2 of 3-, epihydric acid 2 methyl esters |
| Implement 14 | Two adjacent fluorophenyl ketones | Methyl chloroacetate | 3,3-two adjacent fluorophenyls-2, epihydric acid 2 methyl esters |
| Implement 15 | Two-(3-trifluoromethyl) phenyl ketones | Methyl chloroacetate | 3,3-two-(3-trifluoromethyl) phenyl-2, epihydric acid 2 methyl esters |
Synthesizing of embodiment 163-phenyl-3-(3-fluoro-phenyl)-2-hydroxyl-3-methoxypropionic acid methyl esters
Product (V's is a kind of) with 200ml methyl alcohol (IV's is a kind of) dilution embodiment 1, at room temperature add benzene methanesulfonic acid (0.65g, 3.42mmol), reflux 1h, concentrating under reduced pressure, resistates is dissolved in methylene dichloride, with the dilute sodium carbonate solution washing, the organic phase drying concentrates and obtains light yellow thick liquid, be 3-phenyl-3-(3-fluoro-phenyl)-2-hydroxyl-3-methoxypropionic acid methyl esters (compound III a kind of), yield 80%, ESI-MS:m/z 245[M-59], 273[M-31], 305[M+1], 327[M+23].
Embodiment 17-32
The synthetic operation of reference example 16 replaces corresponding reactant with different V and IV, obtains different product (III).
| ??V | ??IV | ??III | |
| Implement 17 | 3,3-phenylbenzene-2, epihydric acid 2 methyl esters | Methyl alcohol | 3,3-phenylbenzene-2-hydroxyl-3-methoxypropionic acid methyl esters |
| Implement 18 | 3,3-two p-methylphenyls-2, epihydric acid 2 ethyl ester | Methyl alcohol | 3,3-two p-methylphenyls-2-hydroxyl-3-methoxy propyl acetoacetic ester |
| Implement 19 | 3,3-two m-nitro bases-2, epihydric acid 2 ethyl ester | Methyl alcohol | 3,3-two m-nitros base-2-hydroxyl-3-methoxy propyl acetoacetic ester |
| Implement 20 | 3, two fluorophenyls-2 of 3-, epihydric acid 2 methyl esters | Methyl alcohol | 3, two fluorophenyls of 3--2-hydroxyl-3-methoxypropionic acid methyl esters |
| Implement 21 | 3-(2-aminomethyl phenyl)-3-phenyl-2, the epihydric acid 2 methyl esters | Methyl alcohol | 3-phenyl-3-(2-aminomethyl phenyl)-2-hydroxyl-3-methoxypropionic acid methyl esters |
| Implement 22 | 3-phenyl-3-(4-cyano-phenyl)-2,3-glycidic acid methyl esters | Methyl alcohol | 3-phenyl-3-(4-cyano-phenyl)-2-hydroxyl-3-methoxypropionic acid methyl esters |
| Implement 23 | 3-phenyl-3-(3, the 4-difluorophenyl)-2, the epihydric acid 2 methyl esters | Methyl alcohol | 3-phenyl-3-(3, the 4-difluorophenyl)-2-hydroxyl-3-methoxypropionic acid methyl esters |
| Implement 24 | 3-phenyl-3-(4-p-methoxy-phenyl)-2,3-glycidic acid methyl esters | Methyl alcohol | 3-phenyl-3-(4-p-methoxy-phenyl)-2-hydroxyl-3-methoxypropionic acid methyl esters |
| ??V | ??IV | ??III | |
| Implement 25 | 3-phenyl-3-(5-methyl-2-hydroxy phenyl)-2, the epihydric acid 2 methyl esters | Methyl alcohol | 3-phenyl-3-(5-methyl-2-hydroxy phenyl)-2-hydroxyl-3-methoxypropionic acid methyl esters |
| Implement 26 | 3-phenyl-3-(4-chloro-phenyl-)-2, the epihydric acid 2 methyl esters | Methyl alcohol | 3-phenyl-3-(4-chloro-phenyl-)-2-hydroxyl-3-methoxypropionic acid methyl esters |
| Implement 27 | 3,3-phenylbenzene-2, epihydric acid 2 methyl esters | Ethanol | 3,3-phenylbenzene-2-hydroxyl-3-ethoxy-propionic acid methyl esters |
| Implement 28 | 3,3-phenylbenzene-2, epihydric acid 2 methyl esters | Dimethylamine | 3,3-phenylbenzene-3-dimethylamino-2 hydroxy propanoic acid methyl esters |
| Implement 29 | 3,3-phenylbenzene-2, epihydric acid 2 methyl esters | Sulfur alcohol | 3,3-phenylbenzene-2-hydroxyl-3-ethylmercapto group methyl propionate |
| Implement 30 | 3, two pairs of fluorophenyls-2 of 3-, epihydric acid 2 methyl esters | Methyl alcohol | 3, two pairs of fluorophenyls of 3--2-hydroxyl-3-methoxypropionic acid methyl esters |
| Implement 31 | 3,3-two adjacent fluorophenyls-2, epihydric acid 2 methyl esters | Methyl alcohol | 3,3-two adjacent fluorophenyls-2-hydroxyl-3-methoxypropionic acid methyl esters |
| Implement 32 | 3,3-two-(3-trifluoromethyl) phenyl-2,3-glycidic acid methyl esters | Methyl alcohol | 3,3-two-(3-trifluoromethyl) phenyl-2-hydroxyl-3-methoxypropionic acid methyl esters |
Embodiment 333,3-phenylbenzene-3-methoxyl group-2-(2-chloropyridine-4-yl) oxygen base methyl propionate synthetic
With 3,3-phenylbenzene-2-hydroxyl-3-methoxypropionic acid methyl esters (III's is a kind of for 2.86g, 0.01mol) is dissolved in N, dinethylformamide (10mL), add NaH (60%, 0.48g), 15 minutes postcooling to 0 of stirring at room ℃, in this reaction solution, add 2-chloro-4-nitropyridine (1.74g in batches, 0.011mol II's is a kind of), temperature of reaction is controlled at 0～5 ℃ in the adition process.Finish, continue stirring reaction 0.5h.Slowly add entry 100mL in reaction solution, temperature is controlled at 0～5 ℃.After adding, water layer is transferred PH to 8-9 with dilute hydrochloric acid, methylene dichloride (50ml * 3) extraction, merge organic phase, the anhydrous sodium sulfate drying after-filtration removes methylene dichloride under reduced pressure, resistates gets white foam shape solid 2g (I) through silica gel column chromatography (the eluent sherwood oil: ethyl acetate=10: 1 is to 6-1) purifying, yield 87.3%, mp:110-114 ℃, ESI-MS m/z 366[M-CH
3OH], 398[M+1], 420[M+23].
Embodiment 34-37
The synthetic operation of reference example 33 replaces corresponding reactant with different III and II, obtains different product (I).
Embodiment 383,3-phenylbenzene-3-methoxyl group-2-(3-nitropyridine-2-yl) oxygen base methyl propionate synthetic
With 3,3-phenylbenzene-2-hydroxyl-3-methoxypropionic acid methyl esters (III's is a kind of for 2.86g, 0.01mol) is dissolved in N, dinethylformamide (10mL), add NaH (60%, 0.48g), 15 minutes postcooling to 0 of stirring at room ℃, in this reaction solution, add 2-chloro-3-nitropyridine (1.74g in batches, 0.011mol II's is a kind of), temperature of reaction is controlled at 0～5 ℃ in the adition process.Finish, continue stirring reaction 0.5h.Slowly add entry 100mL in reaction solution, temperature is controlled at 0～5 ℃.After adding, water layer is transferred PH to 8-9 with dilute hydrochloric acid, methylene dichloride (50ml * 3) extraction, merge organic phase, the anhydrous sodium sulfate drying after-filtration removes methylene dichloride under reduced pressure, resistates gets yellow spumescence solid through silica gel column chromatography (the eluent sherwood oil: ethyl acetate=10: 1 is to 6-1) purifying, yield: 80%, mp:106.5-112.9 ℃, ESI-MS m/z377[M-CH
3O], 409[M+1], 431[M+23].
Embodiment 39-47
The synthetic operation of reference example 38 replaces corresponding reactant with different III and II, obtains different product (I).
Embodiment 573,3-phenylbenzene-3-methoxyl group-2-(3-pyridyl) oxygen base methyl propionate synthetic
With 2-hydroxyl-3-methoxyl group-3, and 3-diphenyl-propionic acid methyl esters (2.86g, 0.01mol), CuI (190mg, 1mmol), 1, the 10-phenanthroline (360mg, 2mmol), Cs
2CO
3(6.52g, 0.02mol), (2.05g 0.01mol) puts into sealed tube with toluene 30mL to the 3-iodine pyridine, 110 ℃ of reaction 40h.Reaction mixture is put cold, and silicagel pad is filtered, the ethyl acetate washing, and filtrate concentrates, and (the eluent sherwood oil: ethyl acetate=6: 1) purifying gets yellow thick liquid 2.18g to resistates through silica gel column chromatography.Yield: 60%, ESI-MS m/z 272[M-2CH
3OH-CO], 332[M-CH
3OH], 364[M+1]
+, 386[M+23]
+
Embodiment 583,3-phenylbenzene-3-methoxyl group-2-(3-amino-5-picoline-2-yl) oxygen base methyl propionate synthetic
With 3,3-phenylbenzene-3-methoxyl group-2-(5-methyl-3-nitro pyridine-2-yl) oxygen base methyl propionate (8.44g, 0.02mol) add in the reactor, add 100mL ethanol and 50mL chloroform, add 10% Pd/C 800mg again, behind the hydrogen exchange, be pressurized to 0.3MPa, be warming up to 60 ℃, reaction 5h.Cooling, behind the nitrogen replacement, reacting liquid filtering is removed Pd/C, concentrating under reduced pressure, resistates gets yellow liquid 5.5g through silica gel column chromatography (the eluent sherwood oil: ethyl acetate=1: 3 adds 4 methyl alcohol) purifying.Yield: 75%, ESI-MS m/z 361[M-CH
3OH], 393[M+1], 415[M+23].
Embodiment 593,3-phenylbenzene-3-methoxyl group-2-(3-methylamino--5-picoline-2-yl) oxygen base methyl propionate synthetic
3, and 3-phenylbenzene-3-methoxyl group-2-(2-methylamino--5-picoline-2-yl) oxygen base methyl propionate (3.92g, 0.01mol), be dissolved in the 20mL chloroform, add triethylamine 1.2g, 0 ℃ of stirring slowly drips methyl iodide (1.42 down, 0.01mol), drip and finish, 0 ℃ is continued reaction 0.5h.The reaction solution concentrating under reduced pressure, (the eluent sherwood oil: ethyl acetate=1: 3) purifying gets yellow thick liquid 1.2g to resistates through silica gel column chromatography.Yield: 30%, ESI-MS m/z 375[M-CH
3OH], 407[M+1].
Embodiment 603-methoxyl group-3,3-phenylbenzene-2-(5-methyl-3-nitro pyridine-2-yl) oxygen base propionic acid synthetic
With 3, and 3-phenylbenzene-3-methoxyl group-2-(5-methyl-3-nitro pyridine-2-yl) oxygen base methyl propionate (2.11g, 0.005mol), be dissolved in the ethanol of 5mL, stir the potassium hydroxide solution 7.5mL of dropping 10% down, behind the backflow 3h, add 10% potassium hydroxide solution 4mL, 3h again refluxes.Cooling, add the dilution of 30mL water, ethyl acetate extraction, water layer is acidified to PH=5 with dilute hydrochloric acid, methylene dichloride (20ml * 3) extraction, organic layer anhydrous sodium sulfate drying after-filtration, concentrating under reduced pressure, resistates gets yellow solid 1g through silica gel column chromatography (the eluent sherwood oil: ethyl acetate=4: 1 adds an acetic acid) purifying.Yield: 50%, mp:113.2-113.4 ℃, ESI-MS m/z 377[M-CH
3O], 409[M+1], 431[M+23].
Embodiment 613-methoxyl group-3,3-phenylbenzene-2-(5-methyl-3-methylamino pyridine-2-yl) oxygen base propionic acid synthetic
Method with reference to embodiment 60 obtains yellow solid, yield: 70%, and mp:125-128 ℃, ESI-MS m/z 361[M-CH
3O], 393[M+1]
+, 415[M+23]
+
Embodiment 623,3-phenylbenzene-3-methoxyl group-2-(2,6-lutidine-4-yl) oxygen base propionic acid synthetic
Method with reference to embodiment 60 obtains light yellow solid, yield: 70%, and mp:115-118 ℃, ESI-MS m/z346[M-CH
3O], 378[M+1]
+, 400[M+23]
+
Embodiment 633,3-phenylbenzene-3-methoxyl group-2-(5-methyl-3-nitro pyridine-2-yl) oxygen base propionic acid sylvite synthetic
With 3, and 3-phenylbenzene-3-methoxyl group-2-(5-methyl-3-nitro pyridine-2-yl) oxygen base methyl propionate (2.11g, 0.005mol), be dissolved in the ethanol of 5mL, stir the potassium hydroxide solution 7.5mL of dropping 10% down, behind the backflow 3h, add 10% potassium hydroxide solution 4mL, 3h again refluxes.Cooling, add the dilution of 30mL water, ethyl acetate extraction, water layer is acidified to PH=5 with dilute hydrochloric acid, methylene dichloride (20ml * 3) extraction, organic layer anhydrous sodium sulfate drying after-filtration, concentrating under reduced pressure, resistates gets yellow solid 1g through silica gel column chromatography (the eluent sherwood oil: ethyl acetate=4: 1 adds an acetic acid) purifying.Gained acid is dissolved in the equivalent potassium hydroxide aqueous solution, and evaporated under reduced pressure gets white powder, is 3,3-phenylbenzene-3-methoxyl group-2-(5-methyl-3-nitro pyridine-2-yl) oxygen base propionic acid sylvite.
Embodiment 64
Get product 0.2 gram of embodiment 60, it is an amount of to add meglumine solution, and low-grade fever makes dissolving, adds isopyknic dehydrated alcohol, place, sufficient crystallising, collect 3-methoxyl group-3,3-phenylbenzene-2-(5-methyl-3-nitro pyridine-2-yl) oxygen base propionic acid meglumine salt.
Embodiment 65
Get product 0.2 gram of embodiment 59, it is an amount of to add hydrochloric acid soln, and low-grade fever makes dissolving, adds isopyknic dehydrated alcohol, place, sufficient crystallising, collect 3,3-phenylbenzene-3-methoxyl group-2-(3-methylamino--5-picoline-2-yl) oxygen base methyl propionate hydrochloride.
Embodiment 66
Get product 0.2 gram of embodiment 59, it is an amount of to add oxalic acid solution, and low-grade fever makes dissolving, adds isopyknic dehydrated alcohol, place, sufficient crystallising, collect 3,3-phenylbenzene-3-methoxyl group-2-(3-methylamino--5-picoline-2-yl) oxygen base methyl propionate oxalate.
Embodiment 67
Consumption/sheet
Embodiment 33 sample 20mg
Microcrystalline Cellulose 50mg
Pregelatinized Starch 30mg
Polyvinylpyrrolidone 3mg
Carboxymethyl starch sodium salt 5mg
Magnesium Stearate 1mg
Talcum powder 1mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds polyvinylpyrrolidonesolution solution, mixes, the system softwood sieves, system wet granular, 50-60 ℃ of drying, with the carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.
Embodiment 68
Consumption/grain
Embodiment 36 sample 50mg
Microcrystalline Cellulose 20mg
Pregelatinized Starch 30mg
Polyvinylpyrrolidone 3mg
Magnesium Stearate 2mg
Talcum powder 1mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds polyvinylpyrrolidonesolution solution, mixes, the system softwood sieves, and the system wet granular is in 50-60 ℃ of drying, Magnesium Stearate and talcum powder are sieved in advance, join then in the above-mentioned particle, encapsulated, promptly.
Embodiment 69
Consumption/100ml
Embodiment 63 sample 100mg
Trisodium Citrate 100mg
NaOH or HCl an amount of (transferring pH about 4.5)
Distilled water 100ml
In distilled water, add earlier distilled water and citric acid, stirring and dissolving and after, add sample again, low-grade fever makes dissolving, and adjust pH is 7.0, add 0.1 gram activated carbon, stirred 20 minutes under the room temperature, filter filtrate, strength of solution is decided in middle detection, by 2 milliliters of packing of every peace bottle, high-temperature sterilization 30 minutes promptly gets injection liquid.
Embodiment 70
Get the Wistar mouse, body weight 180-280g, male and female dual-purpose, after vetanarcol (45mg/kg) anesthesia, separate arteria carotis communis, do arterial cannulation, by the pressure transducer recording blood pressure, treat that the blood pressure balance is about 30 minutes, abdominal injection drug administration by injection (medicine suspendible or dissolving are made into the proper concn administration, and the administration volume is generally 0.2ml/100g), the continuous recording animal blood pressure changes, and the positive control medicine is a nicardipine.Result such as following table:
Different compounds are to the influence (n=5-6) of anesthetized rat blood pressure
The result shows that the compound of general formula I of the present invention has hypotensive activity preferably, and is suitable with positive drug calcium antagonist effect degree, and sample segment is longer action time, is the hypotensive compound of a class new texture.
Claims (10)
1. the compound or its pharmacy acceptable salt that have general formula I:
R
1For: OH, contain OR
6Straight or branched alkyl, SH, SR
6, NH
2, NHR
6, N (R
6)
2R
2, R
3For: H, F, Cl, Br, NO
2, CH
3, OH, OR
6, R
2And R
3Can adopt identical or different substituting group, can replace, can replace or two replacement for single in different positions;
R
4For: H, C
1-C
5The straight or branched alkyl;
R
5For:
R in the above-mentioned substituting group
6Be C
1-C
5The straight or branched alkyl; R
7And R
8For: H, nitro, hydroxyl, amino, NH (C
1-C
4Alkyl), N (C
1-C
4Alkyl)
2, halogen, C
1-C
4Alkyl, C
3-C
8Cycloalkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio; R
7And R
8Can adopt identical or different substituting group, can replace in different positions.
2. the defined compound of Formula I of claim 1 or its pharmacy acceptable salt are wherein preferred,
R
1For: OH, contain OR
6Straight or branched alkyl, SH, SR
6, NH
2, NHR
6, N (R
6)
2
R
2, R
3For: H, F, Cl, Br, NO
2, CH
3, OH, OR
6, R
2And R
3Can adopt identical or different substituting group, can replace, can replace or two replacement for single in different positions.
R
4For: H, sec.-propyl, methyl, ethyl, n-propyl, normal-butyl, isobutyl-, the tertiary butyl; R
5For:
R in the above-mentioned substituting group
6Be sec.-propyl, methyl, ethyl, n-propyl, normal-butyl, isobutyl-, the tertiary butyl; R
7And R
8For: H, nitro, hydroxyl, amino, NH (C
1-C
4Alkyl), N (C
1-C
4Alkyl)
2, halogen, C
1-C
4Alkyl, C
3-C
8Cycloalkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio; R
7And R
8Can adopt identical or different substituting group, can replace in different positions.
3. the defined compound of Formula I of claim 2 or its pharmacy acceptable salt are selected from:
3,3-phenylbenzene-3-methoxyl group-2-(2-chloropyridine-4-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(3-nitropyridine-4-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(2,6-methoxypyridine-4-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(2,6-lutidine-4-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(2-chloro-6-picoline-4-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(2-chloro-6-methoxypyridine-4-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(3-nitropyridine-2-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(5-methyl-3-nitro-pyridine-2-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(6-methyl-3-nitro-pyridine-2-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(4,6-lutidine-3-yl) oxygen base methyl propionate
3,3-two p-methylphenyls-3-methoxyl group-2-(3-nitropyridine-2-yl) oxygen base ethyl propionate
3,3-two m-nitros base-3-methoxyl group-2-(5-methyl--nitro-pyridine-2-yl) oxygen base ethyl propionate
3, two fluorine-based phenyl-3-methoxyl group-2-of 3-(3-nitropyridine-2-yl) oxygen base methyl propionate
3-phenyl-3-(2-aminomethyl phenyl)-3-methoxyl group-2-(3-nitropyridine-2-yl) oxygen base methyl propionate
3-phenyl-3-(4-cyano-phenyl)-3-methoxyl group-2-(4,6-dimethyl-3-nitropyridine-2-yl) oxygen base methyl propionate
3-phenyl-3-(3, the 4-difluorophenyl)-3-methoxyl group-2-(4,6-dimethyl-3-nitropyridine-2-yl) oxygen base methyl propionate
3-phenyl-3-(4-p-methoxy-phenyl)-3-methoxyl group-2-(4,6-dimethyl-3-nitropyridine-2-yl) oxygen base methyl propionate
3-phenyl-3-(5-methyl-2-hydroxy phenyl)-3-methoxyl group-2-(4,6-dimethyl-3-nitropyridine-2-yl) oxygen base methyl propionate
3-phenyl-3-(4-chloro-phenyl-)-3-methoxyl group-2-(5-methyl-3-nitro pyridine-2-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-oxyethyl group-2-(3-nitro-5-picoline-2-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-dimethylamino-2-(3-nitro-5-picoline-2-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-ethylmercapto group-2-(3-nitro-5-picoline-2-yl) oxygen base methyl propionate
3, two pairs of fluorophenyls of 3--3-methoxyl group-2-(3-nitro-5-picoline-2-yl) oxygen base methyl propionate
3,3-two adjacent fluorophenyl-3-methoxyl group-2-(3-nitro-5-picoline-2-yl) oxygen base methyl propionate
3,3-two-(3-trifluoromethyl) phenyl-3-methoxyl group-2-(3-nitro-5-picoline-2-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(3-pyridyl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(3-amino-5-picoline-2-yl) oxygen base methyl propionate
3,3-phenylbenzene-3-methoxyl group-2-(3-methylamino--5-picoline-2-yl) oxygen base methyl propionate
3,3-phenylbenzene 3-methoxy-Ji-2-(5-methyl-3-nitro pyridine-2-yl) oxygen base propionic acid
3,3-phenylbenzene-3-methoxyl group-2-(5-methyl-3-methylamino pyridine-2-yl) oxygen base propionic acid
3,3-phenylbenzene-3-methoxyl group-2-(2,6-lutidine-4-yl) oxygen base propionic acid
3,3-phenylbenzene-3-methoxyl group-2-(5-methyl-3-nitro pyridine-2-yl) oxygen base propionic acid sylvite
3,3-phenylbenzene-3-methoxyl group-2-(5-methyl-3-nitro pyridine-2-yl) oxygen base propionic acid meglumine salt
3,3-phenylbenzene-3-methoxyl group-2-(3-methylamino--5-picoline-2-yl) oxygen base methyl propionate hydrochloride
3,3-phenylbenzene-3-methoxyl group-2-(3-methylamino--5-picoline-2-yl) oxygen base methyl propionate oxalate.
4. the described defined compound of Formula I of claim 1-3 or its pharmacy acceptable salt can be selected from its arbitrary optical isomer, non-enantiomer mixture.
5. synthesize the method for the compound of Formula I of one of claim 1-3, may further comprise the steps:
Commercial compound VII obtains compound V with chloracetate class (VI) reaction under sodium methylate catalysis.The open loop that reacts of compound V and alcohols, Ammonia or thio-alcohol material (IV) obtains compound III, and III obtains product I with compound (II) reaction again.
In the above-mentioned route, Z is halogen, nitro or sulphonate in the structure of II.
6. the defined compound of Formula I of claim 1-3 or its pharmacy acceptable salt application aspect preparation endothelin antagonist medicine.
7. the defined compound of Formula I of claim 6 or its pharmacy acceptable salt application aspect the hypotensive or pulmonary hypertension medicine of preparation.
8. pharmaceutical composition contains compound of Formula I or its pharmacy acceptable salt of one of claim 1-3 and appropriate carriers or vehicle.
9. the described pharmaceutical composition of claim 8, wherein, described composition is solid orally ingestible, liquid oral medicine or injection.
10. comprise according to described solid of claim 9 and liquid oral medicine: tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, granule, oral solution, described injection preparation comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions, primary infusion.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104693027A (en) * | 2013-12-06 | 2015-06-10 | 天津药物研究院 | Method for synthesizing 2-hydroxy-3-alkoxy propionate compounds |
-
2008
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104693027A (en) * | 2013-12-06 | 2015-06-10 | 天津药物研究院 | Method for synthesizing 2-hydroxy-3-alkoxy propionate compounds |
| CN104693027B (en) * | 2013-12-06 | 2016-06-22 | 天津药物研究院 | A kind of method synthesizing 2-hydroxyl-3-alkoxyl propionic ester compounds |
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