CN105601532A - Hypotensively active compound and preparation method thereof - Google Patents
Hypotensively active compound and preparation method thereof Download PDFInfo
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- CN105601532A CN105601532A CN201610024753.5A CN201610024753A CN105601532A CN 105601532 A CN105601532 A CN 105601532A CN 201610024753 A CN201610024753 A CN 201610024753A CN 105601532 A CN105601532 A CN 105601532A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/287—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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Abstract
The invention discloses a hypotensively active compound as well as a preparation method and application thereof. Pharmacological experiments show that the compound according to formula I has hypotensive activity, is useful in treating cardiovascular diseases and is basically free of effects upon various human organics. Therefore, the compound of the invention is useful in the preparation of hypotensive drugs, has a promising development and application prospect and is widely applicable to clinical and medical researches.
Description
Technical field
The present invention relates to the drug world relevant to hypertension. Particularly, the present invention relates to have antihypertensive activityCompound and preparation method thereof.
Background technology
Hypertension is a kind of chronic disease taking the lasting rising of arterial pressure as main manifestations, often causes that the heart, brain, kidney etc. are heavyWant the pathology of organ and occur corresponding consequence. Normal person's blood pressure changes fluctuation within the specific limits with internal and external environment. WholeBody crowd, blood pressure level raise gradually with the age, more obvious with systolic pressure, but after 50 years old, diastolic pressure presents downward trend, arteries and veinsPress also and strengthen thereupon. In recent years, people's recognizing the effect of cardiovascular disease multiple risk factors and the heart, brain, kidney target-organ protectionKnowledge deepens continuously, and hypertensive diagnostic criteria, also in continuous adjustment, thinks that the patient of same blood pressure level occurs cardiovascular at presentSick danger difference, has therefore had the concept of blood pressure layering, the patient that cardiovascular disease risk factor is different occurs, suitable blood pressure waterFlat should have difference. When facing patient, doctor on the basis of normative reference, judges that according to its concrete condition this patient is most suitableBlood pressure range, adopts the measure for the treatment of targetedly.
Hypertensive symptom varies with each individual. Early stage possibility is asymptomatic or symptom is not obvious, only can be tired, spiritual tight, there is blood pressure after anxious state of mind and raise, and after rest, recover normal. Along with the course of disease extends, blood pressure significantly continues to raise,There will be gradually various symptoms. Now be called as benign hypertension. The common clinical symptoms of benign hypertension have headBitterly, dizzy, absent minded, failure of memory, extremity numbness, enuresis nocturna increase, palpitaition, uncomfortable in chest, weak etc. When blood pressure unexpectedWhile being elevated to a certain degree, even there will be severe headache, vomiting, palpitaition, the symptom such as dizzy, when serious, can occur obnubilation,Twitch. This just belongs to accelerated hypertension and hypertension critical illness, how the organs such as the serious heart, brain, kidney can occur in a short timeInfringement and pathology, as apoplexy, heart stalk, renal failure etc. Symptom there is no consistent relation with the level that blood pressure raises. Treatment of HypertensionFinal purpose is to reduce incidence and the death rate of hyperpietic's heart, cerebrovascular disease. Treatment of Hypertension should be established controlling of blood pressureDesired value. On the other hand, hypertension usually merges and exists with the hazards of other hearts, cerebrovascular disease, for example hypercholesteremiaDisease, obesity, diabetes etc., work in coordination with and increase the weight of angiocardiopathy danger, and treatment measure should be comprehensive.
Most ofly can separately or combine and use thiazide diuretic, beta receptor retardance without complication or complication patientAgent etc. Treatment should be from low dose, progressively ascending-dose. When clinical practice uses, patient's Analysis on Cardiovascular Risk Factors situation, targetOrgan injury, Complication, efficacy of antihypertensive treatment, bad reaction etc., all can affect the selection of depressor. 2 grades of hyperpieticsIn the time starting, just can adopt two kinds of antihypertensive drugs therapeutic alliances.
The invention discloses a kind of compound with antihypertensive activity, can be used for preparing antihypertensive medicine.
Summary of the invention
An object of the present invention is to overcome the shortcoming and defect of prior art, a kind of antihypertensive activity of having is providedFormula I compound.
Another object of the present invention is to provide the method for the compound of preparation formula I.
A further object of the present invention is to provide the compound that contains formula I as active ingredient and one or more pharmaceuticallyThe Pharmaceutical composition of acceptable carrier, excipient or diluent is used for the treatment of hypertension jointly.
The compound that the present invention has formula I structure has following structural formula:
Formula I compound of the present invention synthesizes by following steps:
。
Suc as formula the compound of I structure in the purposes aspect preparation treatment antihypertensive medicine.
Further, described formula I compound can be with pharmaceutically acceptable carrier or mixed with excipients be prepared clinicalUpper acceptable pharmaceutical preparation.
Further, described pharmaceutical preparation is oral Preparation; Muscle or intravenous administration formulation.
Further, described oral Preparation is tablet, capsule, granule, sustained release preparation, dripping pill.
Compd A reacts with chlorobenzoyl chloride, obtains compd B, then with SOCl2Obtain Compound C through acyl chloride reaction,Compound C and ethylaminoethanol nitrate make suc as formula compound shown in I through amidation process.
The present invention finds to have antihypertensive activity suc as formula I compound by pharmacological evaluation, can be used for treating cardiovascular diseaseDisease, has no significant effect substantially to the each organ of human body. Therefore, compound of the present invention can be for the preparation of antihypertensive medicine, and it is openedSend out application prospect good, can be widely used in clinical and medical research.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not subject to concrete realityExecute any restriction of example, but be limited by claim.
Brief description of the drawings
Fig. 1 is the formula I compound for preparing of the present invention1HNMR figure.
Fig. 2 is the structural formula of the formula I compound for preparing of the present invention.
Fig. 3 is the syntheti c route of the formula I compound for preparing of the present invention.
Detailed description of the invention
Embodiment 1:
4.47g (15mmol) compd A is dissolved in 100mL round-bottomed flask with 50mL toluene, then adds 2mmolDMF, 20mmol chlorobenzoyl chloride, then stir 40 DEG C of following border rings, reacts 2 hours. Add again 100mL toluene, with distillationTime washing of water 100mL × 3, anhydrous sodium sulfate drying, reduced pressure concentration organic phase, finally adopts silica gel column chromatography separate mode to carry outPurify, eluant, eluent is petrol ether/ethyl acetate=2:1, obtains oily compound B, ESI-MS, m/e=402.11 ([M+NH4]+)。
15mmol compd B is dissolved with 50mL toluene, then add 20mmol triethylamine, then under nitrogen protection, 10At DEG C, drip thionyl chloride 20mmol, stir on dropping limit, limit, after 20 minutes, naturally rises to room temperature, continues to stir 0.5 hour. With fullWith saline solution 100mL × 3 time washing reaction liquid, anhydrous sodium sulfate drying, reduced pressure concentration organic phase, finally adopts silica gel column chromatographySeparate mode is purified, and eluant, eluent is petrol ether/ethyl acetate=2:1, obtains Compound C, ESI-MS, m/e=420.08 ([M+NH4]+)。
Get 10mmol Compound C and be dissolved in 20mL toluene, after add 3mmolTEA, 10mmol ethylaminoethanol nitrate alsoAt room temperature stirring reaction 2 hours. In reactant mixture impouring 100mL frozen water, stir, with the dichloroethanes extraction of 50mL × 3,Merge extraction phase, once, anhydrous sodium sulfate drying, boils off solvent at Rotary Evaporators and obtains residue in salt water washing, and rear pillarChromatographic purifying, obtains the sterling of I, ESI-MS, m/z=490.14 ([M-H]-)。
Its physical property:
1H-NMR:δH(DMSO):3.15(t,2H),3.79(t,2H),5.0(s,1H),5.0(s,1H),6.16(s,1H),6.51(s,1H),6.51(s,1H),6.67(t,1H),6.69(t,1H),7.31(t,1H),7.31(t,1H),7.47(s,1H),7.47(t,1H),7.47(t,1H),7.60(t,1H),7.71(d,1H),7.82(d,1H)，8.0(d,1H)，8.13(d,1H)，8.13(d,1H)。
Elementary analysis: theoretical value: C:63.67, H:4.52, N:5.71, O:26.10.
Measured value: C:63.65, H:4.51, N:5.72, O:26.12.
Embodiment 2:
The maximum tolerance experiment of formula I compound of the present invention:
40 of the mouse of getting body weight 20 ± 2g, male and female half and half, by 0.8mg/20g gavage suc as formula the concentration of I compound areThe suspension of 100mg/ml, the death condition of animal in Continuous Observation 30 days, result, in 30 days, all animal feed activities are justOften, there is no death, LD do not detected50, think that it is nontoxic.
Embodiment 3:
The test of the pharmacologically active of compound described in formula I of the present invention:
1, the radiommunoassay of cGMP:
40 of the Wistar big white mouse of getting body weight and be 180-220g health, male and female half and half, divide two groups at random, and control group givesPhysiological saline, experimental group is by body weight 500 μ g/kg administrations, and inject seven days continuously in abdominal cavity, after seven days, gets blood for two groups, detects ratThe normal value of cGMP and the cGMP of cardiac muscular tissue, its result is as follows: in table 1.
Table 1 is the impact on blood plasma and myocardium cGMP suc as formula I compound
With control group comparison, P < 0.001.
2, Acute Hypotensive Effect
Get 45 of healthy Wistar rats, male and female dual-purpose, body weight 180-220g, divides three groups (15/group) at random. FirstGroup: intraperitoneal injection of saline; Second group: lumbar injection formula I compound; The 3rd group: lumbar injection monobel is done positive rightAccording to. Each group all adopts 500 μ g/kg, and investigational agent is all made into the liquid of 1mg/ml. Pack three groups of rats into mouse arteria caudalis blood respectivelyPress instrument, after its blood pressure stabilization, by above-mentioned dosed administration, 60 minutes blood pressures and heart rate after mensuration administration. The results are shown in Table 2.
The acute step-down result of table 2 waking state following formula I compound (500 μ g/kg)
| Project | Mediodespidine average mmHg | Heart rate mean value beat/min |
| Normal value | 131.58±8.94 | 398±48 |
| Formula I compound | 114.78±7.13 | 385±52 |
| Monobel | 119.47±8.90 | 388±45 |
Experimental result shows, after injecting type I compound 60 minutes, there is certain hypotensive effect, and heart rate also slightly declines, largeMouse is waking state, and therefore this point has Special Significance to disease of cardiovascular system. And blood pressure drops after injection monobelDegree is also larger, but the relatively short and heart rate of holding time is like on the rise.
Shown by above-described embodiment, formula I compound of the present invention is a kind of new compound, safer, can make for a long timeWith, toxicity is lower, and side effect is less, and can not cause heart rate quickening, suppresses the conduction of heart excitement, is applicable to low dosage long-termUse.
Claims (6)
1. the compound of a formula I structure:
2. the method for the compound of the synthetic defined formula I structure of claim 1, comprises the following steps:
3. the purposes of the compound of formula I structure as defined in claim 1 aspect preparation treatment antihypertensive medicine.
4. application according to claim 3, is characterized in that: described formula I compound can with acceptable pharmaceuticallyCarrier or mixed with excipients preparation acceptable pharmaceutical preparation clinically.
5. application according to claim 4, is characterized in that: described pharmaceutical preparation is oral Preparation; Muscle orIntravenous administration formulation.
6. application according to claim 5, is characterized in that: described oral Preparation is tablet, capsule, particleAgent, sustained release preparation, dripping pill.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610024753.5A CN105601532A (en) | 2016-01-14 | 2016-01-14 | Hypotensively active compound and preparation method thereof |
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| CN201610024753.5A CN105601532A (en) | 2016-01-14 | 2016-01-14 | Hypotensively active compound and preparation method thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015010655A1 (en) * | 2013-07-26 | 2015-01-29 | 四川海思科制药有限公司 | Triadic fused cyclic carboxylic acids derivatives, preparation method therefor and pharmaceutical use thereof |
| CN105418508A (en) * | 2015-12-28 | 2016-03-23 | 青岛友诚高新技术有限公司 | Compound with breast cancer prevention activity, and preparation method and use thereof |
-
2016
- 2016-01-14 CN CN201610024753.5A patent/CN105601532A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015010655A1 (en) * | 2013-07-26 | 2015-01-29 | 四川海思科制药有限公司 | Triadic fused cyclic carboxylic acids derivatives, preparation method therefor and pharmaceutical use thereof |
| CN105418508A (en) * | 2015-12-28 | 2016-03-23 | 青岛友诚高新技术有限公司 | Compound with breast cancer prevention activity, and preparation method and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| 赵建庄 等: "《有机化学 2014年1月第1版第1印》", 31 January 2014 * |
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Application publication date: 20160525 |