CN101684099A - Propionic acid derivative of substituted aromatic ring and aromatic heterocycle and preparation method and application thereof - Google Patents
Propionic acid derivative of substituted aromatic ring and aromatic heterocycle and preparation method and application thereof Download PDFInfo
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- CN101684099A CN101684099A CN200810151499A CN200810151499A CN101684099A CN 101684099 A CN101684099 A CN 101684099A CN 200810151499 A CN200810151499 A CN 200810151499A CN 200810151499 A CN200810151499 A CN 200810151499A CN 101684099 A CN101684099 A CN 101684099A
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- Prior art keywords
- phenyl
- pyrimidinyl
- dimethoxy
- methoxy
- acid
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The invention relates to a propionic acid compound of an aromatic ring and an aromatic heterocycle, a derivative thereof, a preparation method thereof, a medical composition and an application as an endothelin receptor antagonist in preparing medicaments for treating diseases including hypertension, pulmonary hypertension, local anemia, vasospasm, heart failure, tumor and the like, wherein the definition of a group is described in a specification.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to aromatic ring and aromatic heterocyclic propionic acid compounds, derivatives thereof, a preparation method thereof, a pharmaceutical composition thereof, and application of the compounds as endothelin receptor antagonists in treating diseases such as hypertension, pulmonary hypertension, ischemia, vasospasm, heart failure, tumor and the like.
Background
Cardiovascular diseases such as hypertension, pulmonary hypertension, etc. and tumors are diseases that seriously harm human health. The search for safe and effective therapeutic drugs for these diseases is always an urgent desire.
Endothelin (ET) is a polypeptide found by Yanagisawa ET al, a japanese scholarian, with a strong vasoconstrictive action, consisting of 21 amino acids. Endothelin acts in a paracrine, autocrine manner on specific endothelin receptors on target cells, producing biological effects through the interaction of its receptors with guanylate binding proteins (G proteins). The endothelin receptor has now been identified as type A (ET)AR) and B forms (ETBR), these 2 receptors mediate multiple physiological functions of endothelin. In pathological conditions, excessive activation of the signaling system consisting of endothelin and its receptors is also involved in mediating the development of a variety of diseases. Therefore, endothelin receptor antagonists have the potential to treat a variety of diseases associated with excessive activation of the endothelin signaling system.
Endothelin has strong blood vessel effect, and can contract blood vessel, increase blood pressure, enhance central and peripheral sympathetic nerve activity, and stimulate secretion of renin and aldosterone. Research shows that the ET content of patients with hypertension complicated with cardiac and renal insufficiency or cerebral apoplexy is 4-10 times higher than that of normal people, and the ET content in blood plasma of patients with cardiac hypertrophy and cardiac insufficiency is also obviously increased. Compared with normal people, the level of ET-1 in plasma and lung tissues of patients with pulmonary hypertension is abnormally increased, and ET-1 plays an important role in the pathological mechanism of the pulmonary hypertension due to strong vasoconstriction effect and smooth muscle cell proliferation promotion effect. Reports show that after a successful surgical operation is carried out on children suffering from pulmonary hypertension secondary to congenital heart disease, the original high ET-1 level in blood plasma of the children is obviously reduced. The existing endothelin receptor antagonists also have good therapeutic effects in pulmonary hypertension.
Endothelin can cause hemodynamic changes and increased circulatory resistance in living animals or isolated heart and myocardium, and has direct promoting effect on the pathogenesis process of Chronic Heart Failure (CHF). The ET level in the blood of CHF animal models and patients is obviously increased, and the ET-1 level is reduced after effective treatment. This suggests a role for endothelin receptor antagonists in the treatment of heart failure.
ET-1 has strong vasoconstrictor action and strong cell growth promoting action. The expression of ET-1 and its receptor in tumor tissue, and research has proved that ET-1 can promote the proliferation of prostate cancer, colorectal cancer, Kaposi sarcoma, liver cancer, ovarian cancer and melanoma. This suggests a role for endothelin receptor antagonists in the treatment of certain tumors.
Disclosure of Invention
The invention aims to provide a compound with a general formula I or a pharmaceutically acceptable salt thereof aiming at clinical treatment of drug deficiency and searching for a blood pressure lowering drug with better activity from a new mechanism.
The invention also aims to provide a preparation method of the compound with the structure of the general formula I or the pharmaceutically acceptable salt thereof.
It is a further object of the present invention to provide a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient, together with one or more pharmaceutically acceptable carriers, excipients or diluents, and the use thereof in the treatment of hypertension or pulmonary hypertension.
The invention will now be described, one by one, with reference to the objects of the invention:
the compounds of formula I of the present invention have the following structural formula:
wherein,
R1is H, contains C1-C5Linear or branched alkyl, aromatic hydrocarbons;
R2、R3is H or C1-C5Linear or branched alkyl, -SR ', -COOR ', CONR ' and other substituents; r2And R3The same or different substituents may be used;
R4is composed of
Or
Wherein X ═ F, Cl, Br; Y-N, CH and Z-N, CH.
The compound of the general formula I contains two chiral centers, can generate four optical isomers, and comprises any optical isomer and a diastereoisomer mixture thereof.
Preference is given to compounds of the general formula I or pharmaceutically acceptable salts thereof, in which,
R1comprises the following steps: H. isopropyl, methyl, ethyl, n-propyl, n-butyl, isobutyl, tert-butyl, aromatic ring, substituted aromatic ring
R2And R3Comprises the following steps: H. methyl, ethyl, n-propyl, isopropyl, methylmercapto, ethylmercapto; r2And R3The same or different substituents may be used.
R4Is composed of
Or
Wherein X ═ F, Cl, Br; Y-N, CH and Z-N, CH.
The compound of the general formula I contains two chiral centers, can generate four optical isomers, and comprises any optical isomer and a diastereoisomer mixture thereof.
More preferred compounds of formula I according to the invention are selected from:
3-methoxy-3-phenyl-3- (3-fluoro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (2-fluoro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-ethoxy-3-phenyl-3- (3-fluoro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-ethoxy-3-phenyl-3- (2-fluoro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (4-fluoro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (3-chloro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (3-bromo) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (2-chloro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (2-bromo) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (4-chloro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (4-bromo) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (3-pyridyl) -2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
3-methoxy-3-phenyl-3- (2-pyridyl) -2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
3-methoxy-3-phenyl-3- (4-pyridyl) -2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
3-ethoxy-3-phenyl-3- (4-pyridyl) -2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
3-methoxy-3-phenyl-3- (5-pyrimidinyl) -2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
3-methoxy-3-phenyl-3- (4-pyridyl) -2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
The compound of the general formula I is synthesized by the following general formula steps:
mixing VII with SOCl2Stirring and refluxing at 80 ℃ to prepare acyl chloride, and then reacting with benzene under the catalysis of anhydrous aluminum trichloride to obtain a compound VI. And reacting the compound VI with methyl chloroacetate under the catalysis of sodium methoxide to obtain a compound V. And (3) carrying out a ring-opening reaction on the compound V under the action of p-toluenesulfonic acid to obtain a compound IV, then hydrolyzing to remove methyl to obtain free acid III, and reacting the compound III with 2-sulfonyl-4, 6-dimethoxypyrimidine (II) to obtain a product I.
Wherein: r1、R2、R3、R4As defined above.
The pharmaceutically acceptable salts of the compounds of formula I of the present invention are reacted with basic materials such as hydroxides, carbonates and bicarbonates of alkali or alkaline earth metals, including, but not limited to: sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, and the like form pharmaceutically acceptable salts, such as the corresponding sodium, potassium, or calcium salts, and the like. Common organic bases such as methylamine, triethylamine, meglumine and the like can also be adopted to generate salts.
The compound of formula I or the pharmaceutically acceptable salt thereof can be prepared into a pharmaceutical composition together with one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutical composition can be made into solid oral preparation, liquid oral preparation, injection, etc. Such solid and liquid oral formulations include, but are not limited to: tablet, dispersible tablet, sugar-coated preparation, granule, dry powder, capsule and solution. The injection comprises: small needle, large infusion solution, lyophilized powder for injection, etc.
The composition of the invention, the pharmaceutically or dietetically acceptable auxiliary materials are selected from: fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, coating materials, or other excipients.
The composition of the invention, and the pharmaceutically or dietetically acceptable auxiliary materials. The filler is one or more of lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, and microcrystalline cellulose; the adhesive comprises one or a combination of more of sucrose, starch, polyvidone, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyethylene glycol, medicinal ethanol and water; the disintegrating agent comprises one or more of starch, cross-linked polyvidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and effervescent disintegrating agent.
The compound of the general formula I or the salt thereof has the effect of resisting endothelin, and can be used as an effective component for preparing medicaments for treating diseases related to endothelin disorder, such as hypertension, pulmonary hypertension, ischemia, vasospasm, heart failure, tumor and the like. The activity of the compound of the general formula I is verified by an in vivo pressure reduction model.
The compounds of formula I of the present invention are effective over a relatively wide dosage range. For example, the daily dosage may be in the range of about 0.1mg to about 1000mg per person, divided into one or more administrations. The actual dosage of the compounds of formula I to be administered according to the invention may be determined by the physician in the light of the specific circumstances. These include: the physical state of the subject, the route of administration, the age, body weight, individual response to the drug, severity of the symptoms, and the like.
Detailed Description
The present invention will be further described with reference to the following examples. It should be noted that the following examples are only for illustration and are not intended to limit the present invention. Variations of the teachings of the present invention may be made by those skilled in the art without departing from the scope of the claims of the present application.
Example 1
Synthesis of 3-methoxy-3-phenyl-3- (3-fluoro) -phenyl 2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
(1) Synthesis of 3-fluoro-benzophenone
In a dry 500mL one-neck flask were added m-fluorobenzoic acid (one of VII) (30g, 0.2142mmol), thionyl chloride (20.25mL, 0.2784mmol) and a small amount of anhydrous benzene in that order, and stirred at 80 ℃ under reflux for 2 h. Distilling the liquid under reduced pressure, transferring the concentrated solution and benzene (20ml, 0.2142mmol) into a 250ml three-neck flask, stirring and cooling to below 5 ℃ under ice salt bath, adding 45g of anhydrous aluminum trichloride several times, controlling the temperature below 10 ℃ all the time, and finishing the addition within 1 h. The mixture was refluxed with stirring at 45 to 60 ℃ for 5 hours, cooled to room temperature, and poured into a mixture of 375g of ice and 150ml of concentrated hydrochloric acid. After extraction with ethyl acetate (50 ml. times.2), the extract was washed with 150ml of a saturated sodium bicarbonate solution and water (100 ml. times.2) to neutrality, filtered off the floc by suction filtration, dried over anhydrous magnesium sulfate to obtain 30.76g (one of VI) of colorless rod-like crystals, and then recrystallized under reduced pressure to obtain 72% yield. mp: 62.6-63.4 ℃. ESI-MS: m/z 201[ M +1], 223[ M +23 ].
(2) Synthesis of ethyl 3- (1-phenyl-3-fluorophenyl) -2, 3-epoxypropionate
3-fluoro-benzophenone (29.646g, 0.148mmol) and methyl chloroacetate 42ml were dissolved in 40ml THF and placed in a constant pressure funnel for further use. 200ml of THF was placed in a 250ml three-necked flask, sodium methoxide (24g, 0.444mmol) was added with stirring, and the reaction mixture was cooled to 0 ℃ in an ice-salt bath and then added dropwise while controlling the temperature to 10 ℃ or lower. Cooled to room temperature, added with 150ml of water, extracted with ethyl acetate (70 ml. times.3), washed with brine 2 times, dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure, and the concentrate was 41.9g of an oil (one of V), yield 75%, ESI-MS: m/z 273[ M +1] is used directly in the next reaction.
(3) Synthesis of 2-hydroxy-3-methoxy-3-phenyl-3- (3-fluoro) -phenylpropionic acid
The solution from the previous step was diluted with 200ml of methanol, p-toluenesulphonic acid (0.65g, 3.42mmol) was added at room temperature, the reaction exothermed and heated at 66 ℃ under reflux for 1 h.
And (3) cooling the reaction liquid to room temperature, adding 200ml of 10% KOH solution into the solution, heating and refluxing at 60 ℃, and finishing the reaction after half an hour. After cooling to room temperature, 100ml of water and dichloromethane (50ml × 3) were added and the aqueous layer was acidified with concentrated hydrochloric acid to PH 3. At this time, the product was dissolved in an organic layer with hydrochloric acid, extracted with dichloromethane (100 ml. times.3), and the organic layer was taken out, dried over anhydrous sodium sulfate, filtered, and dichloromethane was distilled off under reduced pressure. The pale yellow product 38.052g (one of III) was obtained in 87.3% yield. Recrystallization from diethyl ether gave transparent, blocky crystals, mp: 106.5-107 deg.C, ESI-MS M/z 313[ M +1], 335[ M +23 ].
(4) Synthesis of 3-methoxy-3-phenyl-3- (3-fluoro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
2-hydroxy-3-methoxy-3-phenyl-3- (3-fluoro) -phenylpropionic acid (1g, 3.57mmol) was placed in a 100ml three-necked flask, DMF25ml was added to dilute and dissolve, and sodium hydride (0.258g, 10.71mmol) was added under stirring for reaction for 4 h. Adding water 100ml and ethyl acetate (20ml × 3) for extraction, acidifying organic layer and water layer with hydrochloric acid, extracting with ethyl acetate (20ml × 3) to obtain organic layer, mixing, washing with water, drying, distilling under reduced pressure to obtain golden yellow product 1.987g, recrystallizing with diethyl ether, and purifying to obtain white powder (I-1). mp: 171-171.5 deg.C, ESI-MS M/z 429[ M +1], 451[ M +23 ].
Example 2
Synthesis of 3-methoxy-3-phenyl-3- (3-pyridyl) -2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
Referring to the procedure of example 1, nicotinic acid was used as reactant VII instead of m-fluorobenzoic acid to give a white solid in 60% yield, mp: ESI at 181-182.5 deg.C-MS m/z：412[M+1]+，434[M+23]+。
Example 3
Synthesis of 3-methoxy-3-phenyl-3- (4-fluoro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
Referring to the procedure of example 1, 4-fluorobenzoic acid was used as reactant VII instead of m-fluorobenzoic acid to give a white solid in yield: 70%, mp: 185-186.5 deg.C, ESI-MS M/z 429[ M +1], 451[ M +23 ].
Example 4
Synthesis of 3-methoxy-3-phenyl-3- (2-fluoro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
Referring to the procedure of example 1, 2-fluorobenzoic acid was used as reactant VII instead of m-fluorobenzoic acid to give a white solid in yield: 70%, mp: 181 ℃ and 182 ℃, ESI-MS M/z 429[ M +1], 451[ M +23 ].
Example 5
Synthesis of 3-methoxy-3-phenyl-3- (3-chloro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
Referring to the procedure of example 1, 3-chlorobenzoic acid was used as reactant VII instead of m-fluorobenzoic acid to give a white solid in yield: 60%, mp: 176 ℃ and 177 ℃, ESI-MS M/z 445[ M +1 ].
Example 6
Synthesis of 3-methoxy-3-phenyl-3- (3-bromo) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
Referring to the procedure of example 1, 3-bromobenzoic acid was used as reactant VII instead of m-fluorobenzoic acid to give a white solid in yield: 50%, mp: 191-192.5 deg.C, ESI-MS M/z 489[ M +1 ].
Example 7
Synthesis of 3-ethoxy-3-phenyl-3- (3-fluoro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
Referring to the procedure of example 1, ethanol was used as a reactant instead of methanol in the third step to obtain a white solid in yield: 50%, mp: 173-174.5 ℃ and ESI-MS M/z 443[ M +1 ]. .
Example 8
Synthesis of 3-methoxy-3-phenyl-3- (2-pyridyl) -2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
Referring to the procedure of example 1, 2-picolinic acid was used as reactant VII instead of m-fluorobenzoic acid to give a white solid in yield: 60%, mp: 178-179.5 deg.C, ESI-MS M/z 412[ M +1]]+，434[M+23]+。
Example 9
Synthesis of 3-methoxy-3-phenyl-3- (2-pyridyl) -2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
Referring to the procedure of example 1, 2-picolinic acid was used as reactant VII instead of m-fluorobenzoic acid to give a white solid in yield: 60%, mp: 183 ℃ 185 ℃, ESI-MS M/z 412[ M +1]]+，434[M+23]+。
Example 10
0.2 g of the product obtained in the example 1 is taken, a proper amount of NaOH (1mol/L) solution is added, the mixture is slightly heated to be dissolved, absolute ethyl alcohol with the same volume is added, the mixture is placed, full crystallization is carried out, and sodium salt is obtained.
Example 11
0.2 g of the product of the example 1 is taken, an appropriate amount of meglumine solution is added, the mixture is slightly heated to be dissolved, absolute ethyl alcohol with the same volume is added, the mixture is placed and fully crystallized, and meglumine salt is collected.
Example 12
Dosage/tablet
EXAMPLE 1 sample 20mg
Microcrystalline cellulose 60mg
Pregelatinized starch 40mg
Polyvinylpyrrolidone 3mg
Carboxymethyl starch sodium salt 5mg
Magnesium stearate 1mg
Talcum powder 1mg
Sieving active ingredients, pregelatinized starch and microcrystalline cellulose, mixing, adding polyvinylpyrrolidone solution, mixing, making soft mass, sieving, making wet granule, drying at 50-60 deg.C, sieving carboxymethyl starch sodium salt, magnesium stearate and pulvis Talci, adding into the above granule, and tabletting.
Example 13
Dosage/granule
EXAMPLE 8 sample 10mg
Microcrystalline cellulose 45mg
Pregelatinized starch 40mg
Polyvinylpyrrolidone 3mg
Magnesium stearate 2mg
Talcum powder 1mg
Sieving active ingredients, pregelatinized starch and microcrystalline cellulose, mixing, adding polyvinylpyrrolidone solution, mixing, making soft material, sieving, making wet granule, drying at 50-60 deg.C, sieving magnesium stearate and pulvis Talci, adding into the above granule, and making into capsule.
Example 14
Dosage per 100ml
Example 10 sample 100mg
Sodium citrate 200mg
Appropriate amount of NaOH (adjusting pH to about 7.0)
Distilled water 100ml
Adding distilled water and citric acid into distilled water, stirring for dissolving, adding sample, slightly heating for dissolving, adjusting pH to 7.0, adding 0.1 g of activated carbon, stirring at room temperature for 20 min, filtering, measuring solution concentration by central control, packaging in ampoule at 2ml, and sterilizing at high temperature for 30 min to obtain injection.
Example 15
Taking a Wistar rat with the weight of 180-. Grouping according to Latin prescription according to basic blood pressure value, and setting blank group, positive drug control group and experimental group, each group has 5-6. The positive control drug was telmisartan. The results show that the sample of the general formula I has the function of reducing blood pressure.
Effect of different Compounds on blood pressure in rats (n ═ 6)
P < 0.05 in comparison with blank
Claims (7)
1. A compound having the general formula I:
wherein,
R1is H, contains C1-C5Linear or branched alkyl, aromatic hydrocarbons;
R2、R3is H or C1-C5Straight chain orBranched alkyl, -SR ', -COOR ', CONR ' and other substituents; r2And R3The same or different substituents may be used;
R4is composed of
Wherein X ═ F, Cl, Br; Y-N, CH and Z-N, CH.
The compound of the general formula I contains two chiral centers, can generate four optical isomers, and comprises any optical isomer and a diastereoisomer mixture thereof.
2. A compound of the general formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, wherein,
R1comprises the following steps: H. isopropyl, methyl, ethyl, n-propyl, n-butyl, isobutyl, tert-butyl, aromatic ring, substituted aromatic ring
R2And R3Comprises the following steps: H. methyl, ethyl, n-propyl, isopropyl, methylmercapto, ethylmercapto; r2And R3The same or different substituents may be used.
R4Is composed of
Wherein X ═ F, Cl, Br; Y-N, CH and Z-N, CH.
The compound of the general formula I contains two chiral centers, can generate four optical isomers, and comprises any optical isomer and a diastereoisomer mixture thereof.
3. A compound of general formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, selected from:
3-methoxy-3-phenyl-3- (3-fluoro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (2-fluoro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-ethoxy-3-phenyl-3- (3-fluoro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-ethoxy-3-phenyl-3- (2-fluoro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (4-fluoro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (3-chloro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (3-bromo) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (2-chloro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (2-bromo) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (4-chloro) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (4-bromo) -phenyl-2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxopropanoic acid
3-methoxy-3-phenyl-3- (3-pyridyl) -2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
3-methoxy-3-phenyl-3- (2-pyridyl) -2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
3-methoxy-3-phenyl-3- (4-pyridyl) -2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
3-ethoxy-3-phenyl-3- (4-pyridyl) -2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
3-methoxy-3-phenyl-3- (5-pyrimidinyl) -2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
3-methoxy-3-phenyl-3- (4-pyridyl) -2- [2- (4, 6-dimethoxy-1, 3-pyrimidinyl) ] oxypropionic acid
4. A process for the synthesis of a compound of general formula I according to any one of claims 1 to 3, comprising the steps of:
mixing VII with SOCl2At 80 deg.CStirring and refluxing to prepare acyl chloride, and then reacting with benzene under the catalysis of anhydrous aluminum trichloride to obtain a compound VI. And reacting the compound VI with methyl chloroacetate under the catalysis of sodium methoxide to obtain a compound V. And (3) carrying out a ring-opening reaction on the compound V under the action of p-toluenesulfonic acid to obtain a compound IV, then hydrolyzing to remove methyl to obtain free acid III, and reacting the compound III with 2-sulfonyl-4, 6-dimethoxypyrimidine (II) to obtain a product I.
Wherein: r1、R2、R3、R4As defined above.
5. Use of a compound of general formula I as defined in claims 1-3 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease associated with endothelin disorders, in particular for the treatment of diseases such as hypertension, pulmonary hypertension, ischemia, vasospasm, heart failure and tumors.
6. A pharmaceutical composition comprising a compound of general formula I according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, together with a suitable carrier or excipient.
7. The pharmaceutical composition of claim 6, wherein the composition is a solid oral preparation, a liquid oral preparation or an injection.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104693027A (en) * | 2013-12-06 | 2015-06-10 | 天津药物研究院 | Method for synthesizing 2-hydroxy-3-alkoxy propionate compounds |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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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