CN108774242B - Medicine for preventing and treating coronary heart disease and preparation method thereof - Google Patents
Medicine for preventing and treating coronary heart disease and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The invention relates to indolinone derivatives or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates and prodrugs thereof. The compound of the present invention has an excellent LCAT-activating effect and can significantly increase HDL levels, and therefore, is useful as an active ingredient in a therapeutic or prophylactic agent for coronary heart disease (including heart failure, myocardial infarction, angina pectoris, myocardial ischemia, cardiovascular disorders and angiogenic restenosis), arteriosclerosis, arteriosclerotic heart disease, cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complications), dyslipidemia, low HDL cholesterolemia, high LDL cholesterolemia or nephropathy, in particular, as an active ingredient in a therapeutic or prophylactic agent for coronary heart disease.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a medicament capable of effectively activating lecithin-cholesterol acetyltransferase (LCAT) and a preparation method thereof.
Background
Coronary atherosclerotic heart disease is a heart disease caused by myocardial ischemia, hypoxia or necrosis due to stenosis or obstruction of a blood vessel cavity caused by atherosclerotic lesions generated in coronary vessels, and is often referred to as "coronary heart disease". Coronary heart disease may be more widespread, but also includes inflammation, embolism and the like resulting in stenosis or occlusion of the lumen. The world health organization classifies coronary heart disease into 5 major categories: asymptomatic myocardial ischemia (occult coronary heart disease), angina pectoris, myocardial infarction, ischemic heart failure (ischemic heart disease) and sudden death 5 clinical types.
Risk factors for coronary heart disease include modifiable risk factors and non-modifiable risk factors. Understanding and intervening risk factors can help prevent and treat coronary heart disease. The risk factors that can be varied are: hypertension, dyslipidemia (total or low density lipoprotein cholesterol, triglycerides, high density lipoprotein cholesterol too low), overweight/obesity, hyperglycemia/diabetes, poor lifestyle including smoking, improper diet (high fat, high cholesterol, high calorie, etc.), lack of physical activity, excessive drinking, and psychosocial factors. The immutable risk factors are: gender, age, family history. Furthermore, infections such as cytomegalovirus, Chlamydia pneumoniae, helicobacter pylori, etc. are involved.
Currently, there are many drugs for treating hypertension, dyslipidemia and diabetes, for example, a-II antagonists, ACE inhibitors, calcium antagonists are used for treating hypertension, clofibrate drugs, HMG-CoA reductase inhibitors are used for treating dyslipidemia, and insulin, metformin, glitazone, etc. are used for treating diabetes. These drugs help to ameliorate some of the risk factors that lead to coronary heart disease, such as regulating blood pressure or lowering blood lipid or glucose levels, but are still ineffective in treating coronary heart disease.
Studies have shown that lecithin-cholesterol acetyltransferase (LCAT) has a major impact in the development of coronary heart disease, which leads to esterification of cholesterol on High Density Lipoprotein (HDL) and the production of cholesteryl esters, thereby allowing cholesterol to flow out of macrophages, while increased LCAT activity can facilitate this process (Matsuura, f., j.clin.invest.2006, vol.116, p.1435-1442). This ultimately leads to a decrease in the concentration of low-density lipoprotein (LDL) and an increase in high-density lipoprotein (HDL), thereby preventing and treating coronary heart disease and other cardiovascular and cerebrovascular diseases.
Therefore, there is a need to develop a drug that can effectively activate LCAT, thereby preventing and treating cardiovascular and cerebrovascular diseases such as coronary heart disease.
Disclosure of Invention
The invention provides a medicament capable of effectively activating LCAT, which has good prevention and treatment effects on cardiovascular and cerebrovascular diseases such as coronary heart disease and the like.
Specifically, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, prodrug thereof:
wherein:
R1、R2、R3、R4each independently hydrogen, deuterium, halogen, CN, C1-12 alkyl, halo C1-12 alkyl, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl or 3-12 membered heterocycloalkyl;
R5、R6each independently is hydrogen, deuterium, halogen, CN, nitro, C1-12 alkyl or C1-12 alkoxy;
R7selected from hydrogen, deuterium, C1-12 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heterocycloalkyl, -SO2NRaRb、-NRaRb、-C(O)Ra、-NRaC(O)Rbor-C (O) NRaRb；
RaAnd RbEach independently hydrogen or C1-6 alkyl.
In one embodiment of the present invention, the C1-12 alkyl group is preferably a C1-6 alkyl group, more preferably a C1-3 alkyl group.
In one embodiment of the invention, R1、R2、R3、R4Each independently hydrogen, methyl, methoxy, chloro, piperidinyl or cyclopropyl.
In one embodiment of the invention, R5、R6Each independently hydrogen or fluorine.
In one embodiment of the invention, R7Is hydrogen, tert-butyloxycarbonyl, methylcarbonyl or ethyl.
In one embodiment of the invention, the compound is selected from:
SP-1：
SP-2：
SP-3：
SP-4：
SP-5：
in another aspect, the present invention relates to a pharmaceutical composition comprising at least one of said compounds or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, prodrug thereof as active ingredient. The pharmaceutical composition may comprise a pharmaceutically acceptable carrier or excipient.
In another aspect, the invention relates to an application of the compound or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates and prodrugs thereof in preparing a medicament for treating cardiovascular and cerebrovascular diseases, preferably the cardiovascular and cerebrovascular diseases comprise coronary heart disease and the like.
Advantageous effects
The test results show that the compound of the present invention has excellent LCAT activation effect and can significantly increase HDL level. The compound of the present invention is useful as an active ingredient in a therapeutic or prophylactic agent for coronary heart disease (including heart failure, myocardial infarction, angina pectoris, myocardial ischemia, cardiovascular disorders and angioplastic restenosis), arteriosclerosis, arteriosclerotic heart disease, cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complications), dyslipidemia, low HDL cholesterolemia, high LDL cholesterolemia or nephropathy, and particularly, as an active ingredient in a therapeutic or prophylactic agent for coronary heart disease, because it has excellent LCAT-activating effect and an action of increasing HDL level.
Detailed Description
Hereinafter, the present invention will be described in detail.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned in this application are herein incorporated by reference.
In the present invention, the term "halogen" denotes fluorine, chlorine, bromine or iodine.
In the present invention, the term "alkyl" (including when used alone and included among other groups) means a branched and straight chain saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 4-dimethylpentyl, 2, 4-trimethylpentyl, undecyl, dodecyl, and their various isomers, and the like; and the above alkyl group containing any of 1 to 4 substituents as follows: deuterium, halogen (preferably F, Br, Cl or I), alkyl, alkoxy, aryl, aryloxy, aryl-substituted aryl or diaryl, aralkyl, aralkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkoxy, amino, optionally substituted amino (such as 1-2C 1-C3 alkyl-substituted amino), hydroxyl, hydroxyalkyl, acyl, aldehyde, heteroaryl, heteroaryloxy, heterocycloalkyl, heterocycloalkoxy, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamino, acylamino, arylcarbonylamino, nitro, nitrile, mercapto, haloalkyl, trihaloalkyl (such as trifluoromethyl) and/or alkylthio. As used herein, "Cx 1-y 1" alkyl groups (x1 and y1 are integers) defining a carbon number range, such as "C1-12 alkyl groups," are defined identically except that the carbon number range is different from the carbon number range defined for "alkyl" in this paragraph.
In the present invention, the term "cycloalkyl" (including when used alone and when included among other groups) comprises saturated cyclic hydrocarbon groups containing 1 to 3 rings, including monocycloalkyl, bicycloalkyl and tricycloalkyl groups containing 3 to 20 carbons from which a ring may be formed, preferably 3 to 12 carbons, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecane and cyclododecyl, cyclohexenyl; the cycloalkyl group may be substituted with any of 1 to 4 substituents as follows: deuterium, halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, aralkyl, cycloalkyl, alkylamino, acylamino, oxygen, acyl, arylcarbonylamino, amino, nitro, nitrile, mercapto and/or alkylthio and/or any alkyl substituents.
In the present invention, the term "alkoxy" denotes a cyclic or acyclic alkyl group having the indicated number of carbon atoms, linked via an oxygen bridge. Thus, "alkoxy" encompasses the above definitions of alkyl and cycloalkyl.
In the present invention, the term "alkenyl group" means a straight-chain, branched-chain or cyclic non-aromatic hydrocarbon group containing the specified number of carbon atoms and at least one carbon-carbon double bond. Preferably, there is one carbon-carbon double bond, and up to four non-aromatic carbon-carbon double bonds may be present. Thus, "C2-12 alkenyl" refers to alkenyl groups having 2-12 carbon atoms. "C2-6 alkenyl" refers to alkenyl groups having 2-6 carbon atoms and includes ethenyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. The linear, branched, or cyclic portion of the alkenyl group may contain a double bond, and may be substituted if indicated as a substituted alkenyl group.
In the present invention, the term "alkynyl" refers to a straight, branched or cyclic hydrocarbon group containing the specified number of carbon atoms and at least one carbon-carbon triple bond. Where up to three carbon-carbon triple bonds may be present. Thus, "C2-12 alkynyl" refers to alkynyl groups having 2-12 carbon atoms. "C2-6 alkynyl" means alkynyl having 2-6 carbon atoms and includes ethynyl, propynyl, butynyl, 3-methylbutynyl and the like.
In the present invention, the term "haloalkyl" denotes an alkyl group substituted at any position by halogen. Thus, "haloalkyl" encompasses the above definitions of halogen and alkyl.
In the present invention, the term "aryl" refers to any stable monocyclic or bicyclic carbocyclic ring of 6 to 20 carbon atoms, preferably 6 to 14 carbon atoms, more preferably 6 to 10 carbon atoms, up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of the above aryl unit include phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, phenanthryl, anthryl or acenaphthenyl. It will be understood that where the aryl substituent is a bicyclic substituent and one of the rings is non-aromatic, the attachment is through an aromatic ring. And the above aryl group containing any of 1 to 4 substituents as follows: deuterium, halogen (F, Br, Cl or I), alkyl, alkoxy, aryl, aryloxy, aryl-substituted aryl or diaryl, aralkyl, aralkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkoxy, optionally substituted amino, hydroxyl, hydroxyalkyl, acyl, aldehyde, heteroaryl, heteroaryloxy, heterocycloalkyl, heterocycloalkoxy, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamino, acylamino, arylcarbonylamino, nitro, nitrile, mercapto, haloalkyl, trihaloalkyl and/or alkylthio.
In the present invention, the term "heterocycloalkyl" denotes a 5-to 10-membered saturated heterocyclic ring containing 1 to 4 heteroatoms selected from O, N and S, and may include bicyclic groups. Examples of "heterocyclyl" include, but are not limited to, the following: azetidinyl, 1, 4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, and tetrahydrothienyl. The heterocycloalkyl group may be attached to other groups via a carbon atom or a heteroatom therein.
In the present invention, "pharmaceutically acceptable salts" refer to addition salts of the active compounds with pharmaceutically acceptable acids, which are relatively non-toxic to the patient and have harmless activity, without side effects that reduce the beneficial effects of the active compounds. The acid comprises: inorganic acids such as hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, and phosphoric acid; or organic acids such as citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, methanesulfonic acid, succinic acid, tartaric acid, galacturonic acid, pamoic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, methanesulfonic acid, ethanesulfonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, and malonic acid.
In the present invention, "stereoisomers" include: enantiomers and diastereomers, wherein a cis-trans isomer is one of the diastereomers. Thus, the compounds of formula I of the present invention may be enantiomers, diastereomers and any mixtures thereof, all of which stereoisomers are encompassed by the present invention. In the present invention, when the compounds of formula I are present in stereoisomeric forms, the individual stereoisomers as well as mixtures thereof are included within the scope of the present invention.
In the present invention, "tautomers" refer to structural isomers that have different energies and can be transformed into each other by a low energy barrier. If tautomerism is possible, the chemical equilibrium of the tautomer can be reached. For example, proton tautomers, also referred to as proton transfer tautomers, include interconversions by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons.
In the present invention, the term "solvate" refers to a form of a compound that forms a complex in a solid or liquid state by coordinating with a solvent molecule.
In the present invention, the term "prodrug" refers to a compound that is converted into an active compound as a result of reaction with an enzyme, gastric acid, or the like in vivo. As prodrugs, many types of prodrugs are known, and suitable prodrugs can be selected from known literature and synthesized by known methods.
The invention also provides a preparation method of the compound shown in the formula I, which comprises the following steps:
reacting a compound of formula II with a compound of formula III in the presence of a base to produce a compound of formula I
Wherein R is1-R7As defined hereinDefining;
the base is selected from organic bases such as triethylamine or pyridine; or an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
The invention also relates to a pharmaceutical composition comprising at least one of said compounds or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, prodrug thereof as active ingredient. The pharmaceutical composition may comprise a pharmaceutically acceptable carrier or excipient.
The pharmaceutical compositions may be prepared according to methods well known in the art. The active compounds can be formulated into any dosage form suitable for human or animal use by combining them with a pharmaceutically acceptable carrier or excipient. The compounds of the invention are generally present in the pharmaceutical composition in an amount of 0.1 to 95% by weight.
The compounds of the present invention in dosage unit form may be administered one or more times per day at appropriate intervals. Conveniently, the dosage unit formulation contains from 0.1mg to 1000mg, preferably from 1mg to 100mg, such as 5-50mg, of a compound of formula I. Suitable dosages of the compounds of the invention will depend, inter alia, on the age and condition of the patient, the severity of the disease being treated and other factors well known to the practitioner.
Such formulations include, for example, those suitable for oral (including sustained or timed release), rectal, parenteral (including subcutaneous, intraperitoneal, intramuscular, intraarticular and intravenous), transdermal, ocular, topical, dermal, nasal, buccal or intradermal administration.
Examples of formulations for oral administration are tablets, pills, hard/soft capsules, solutions, suspensions, emulsions, syrups, granules and the like. These formulations may contain, in addition to the active ingredient, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine) and lubricants (e.g., silica, talc, stearates and their magnesium or calcium salts, and/or polyethylene glycol). Tablets may contain binders such as magnesium aluminium silicate, starch paste, gelatin, methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, if necessary disintegrating agents such as starch, agarose, alginic acid or a sodium salt thereof or azeotropic mixtures, and/or adsorbents, colorants, flavors and sweeteners may also be contained therein.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol, spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
As examples of pharmaceutically acceptable excipients and adjuvants which can be contained in the pharmaceutical composition, mention may be made of diluents, binders, lubricants, preservatives, thickeners, stabilizers, disintegrants, wetting agents, emulsifiers, buffer substances, colorants, flavors and fragrances, examples of which are water, physiological solutions of sodium chloride, vegetable oils, waxes, alcohols, triacetin, polyvinylpyrrolidone, gelatin, cellulose, carbohydrates, talc, lanolin, vaseline or mixtures thereof and the like.
The pharmaceutical composition of the present invention containing the compound of the present invention as an active ingredient can be administered orally or parenterally, and used in the general form of pharmaceutical preparations, but is not limited thereto.
The effective dose of the compound of the present invention can be determined according to age, body weight, sex, administration method, health condition and severity of the condition. For example, the dose for an adult human of 70kg body weight is 0.1 to 1,000 mg/day, preferably 1 to 500 mg/day. Such administration may be performed once to many times a day, at the discretion of a physician or pharmacist.
The compounds of the present invention may be combined or used in combination with other agents that are useful in the treatment, prevention, inhibition, or amelioration of the diseases or conditions for which the compounds of the present invention are useful. The additional agent may be selected from: antihypertensives such as A-II antagonists, ACE inhibitors, calcium antagonists and the like, hypolipidemic agents such as clofibrate drugs, HMG-CoA reductase inhibitors and the like, and diabetes therapeutic agents such as insulin, metformin, glitazone and the like.
Examples
Preparation examples
Example 1: (Z) -6- ((6-methyl-2-oxoindole-3-methylene) methyl) -4-oxospiro [ chroman-2, 4 '-piperidine ] -1' -carboxylic acid tert-butyl ester (Compound SP-1)
6-formyl-4-oxospiro [ chroman-2, 4 '-piperidine ] -1' -tert-butyl formate (10.0mmol) is placed in a flask, 100m of absolute ethanol is added to dissolve the tert-butyl formate, then 6-methylindoline-2-one (10.0mmol) and 2ml of triethylamine are added, and the mixture is stirred and reacted for 3 hours at room temperature, so that a large amount of precipitate is generated. Vacuum filtration was carried out, and the filter cake was washed with a small amount of anhydrous ethanol and dried under vacuum to obtain 4.34g of the title product as a white solid with a yield of 91.5%.
ESI-MS：475.22[M+H]+
Elemental analysis: theoretical value C, 70.87; h, 6.37; n, 5.90; o,16.86
Found C, 70.58; h, 6.55; n, 5.79; o,17.08
1H NMR(400MHz,CDCl3)11.08(s,1H),7.85(d,1H),7.70(s,1H),7.51(d,1H),7.39(d,1H),7.13(s,1H),7.02(d,1H),6.88(d,1H),3.31(t,4H),2.56(s,2H),2.36(s,3H),1.96(t,4H),1.61(s,9H)。
Example 2: (Z) -6- ((5, 6-dimethoxy-2-oxoindolin-3-methylene) methyl) spiro [ chroman-2, 4' -piperidin ] -4-one (SP-2)
The title compound was obtained as a gray solid in 87.9% yield by the method of example 1 substituting 4-oxospiro [ chroman-2, 4' -piperidine ] -6-carbaldehyde for tert-butyl 6-aldehyde-4-oxospiro [ chroman-2, 4' -piperidine ] -1' -carboxylate and 5, 6-dimethoxyindolin-2-one for 6-methylindolin-2-one.
ESI-MS：423.18[M+H]+
Elemental analysis: theoretical value C, 68.23; h, 6.20; n, 6.63; o,18.94
Found C, 68.35; h, 6.02; n, 6.97; o,18.66
1H NMR(400MHz,CDCl3)11.10(s,1H),7.88(d,1H),7.53(s,1H),7.29(s,1H),7.22(s,1H),7.10(d,1H),6.89(d,1H),3.85(s,6H),2.85(t,4H),2.66(s,2H),2.02(s,1H),1.91(t,4H)。
The following compounds were synthesized according to a similar method to example 1:
examples of the drug action
Example 1: in vitro LCAT activation activity assay
Fraction consisting of HDL3 (1.125) was obtained from healthy human plasma by density gradient centrifugation<Specific gravity of<1.210/mL). The obtained fractions were dialyzed against phosphate-buffered saline (pH 7.4) and used as enzyme source and acceptor for LCAT. Samples containing different concentrations of the compounds SP-1 to SP-5, respectively, were prepared by dissolving in dimethyl sulfoxide. The solution was prepared by mixing DTNB (Ellman's reagent, final concentration: 0.5mM), mercaptoethanol (final concentration: 12.5mM) and 0.6% bovine serum albumin14C]Cholesterol was added to phosphate-buffered saline (pH 7.4) containing 1mg/mL HDL3, and further different concentrations of test drug were added thereto to adjust the total amount to 80 μ L. The mixture was incubated at 37 ℃ for about 16 hours. Then, a mixed solution of hexane and isopropyl alcohol (mixing ratio ═ 3:2) was added thereto to stop the reaction. After stirring, the hexane layer was collected and evaporated to dryness. A chloroform solution (concentration: 10mg/mL) was added thereto, and the mixture was spotted on a thin layer silica gel plate and developed using a mixed solution of hexane, diethyl ether and ethyl acetate (mixing ratio: 85:15: 2). The radioactivity of the fraction corresponding to cholesterol oleate was measured using an image analyzer BAS-2500. Unsupplemented test drugs were similarly processed and analyzedThe sample of (1). Calculating the EC for LCAT activation relative to the LCAT activity of the sample not supplemented with the test drug according to equation 150The value is obtained.
[ equation 1]
Wherein X represents the logarithm of the concentration of the test drug; y represents the responsiveness (i.e., LCAT activity) of the test drug; the top represents the maximum; the bottom represents the minimum; EC (EC)50Representing 50% effective concentration. The results are shown in table 1 below:
TABLE 1
The test results show that the compounds of the invention, in particular the compounds SP-1 to SP-5, have excellent LCAT activating effect.
Example 2: kiwi efficacy testing
The compounds SP-1 to SP-5 were dissolved in propylene glycol-Tween 80 mixed solution [4/1(v/v) ] or 0.5% (w/v) methyl cellulose aqueous solution, respectively, and the solutions were orally administered to the macaques for 1 day or 7 days. On day 1 or 7 of the dosing period, blood was collected before and after dosing, and plasma was obtained. The cholesterol content in plasma was measured using a commercially available assay kit. The distribution of the lipoproteins was analyzed by HPLC. HDL cholesterol and non-HDL cholesterol levels are calculated according to the following calculation formulas 2 and 3:
[ formula 2]
HDL cholesterol level (cholesterol level in plasma) x (HDL cholesterol peak area/sum of peaks) [ formula 3]
non-HDL cholesterol content ═ cholesterol content in plasma × (peak area/sum of peaks for non-HDL cholesterol)
The increase rate (%) of HDL levels after administration of 10mg/kg single dose compared to before administration was determined from AUC before administration and 24 hours after administration. The results are shown in table 2 below:
TABLE 2
The test results show that the compounds of the present invention, particularly compounds SP-1 to SP-5, are capable of significantly increasing HDL levels.
In general, the compounds of the present invention, particularly the compounds SP-1 to SP-5, have excellent LCAT activating effects and can significantly increase HDL levels, and thus, can be used for the prevention and treatment of cardiovascular and cerebrovascular diseases, particularly coronary heart disease.
The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations of the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.
Claims (10)
1. A compound of formula I:
formula I
Wherein:
R1、R2、R3、R4each independently hydrogen, deuterium, halogen, C1-6 alkyl or haloC 1-6 alkyl;
R5、R6each independently hydrogen, deuterium, halogen or C1-6 alkyl;
R7selected from tert-butyloxycarbonyl.
2. A compound of claim 1, wherein R is1、R2、R3、R4Each independently hydrogen, methyl or chlorine.
3. A compound of claim 1, wherein R is5、R6Each independently hydrogen or fluorine.
4. The compound according to claim 1, selected from:
SP-1：
。
5. a pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier or excipient.
7. The use of a compound of formula I according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 5 or 6 for the manufacture of a medicament for the treatment of cardiovascular and cerebrovascular diseases.
8. The use of claim 7, wherein the cardiovascular disease comprises coronary heart disease.
9. A process for the preparation of a compound of formula I according to claim 1, comprising the steps of:
reacting a compound of formula II with a compound of formula III in the presence of a base to produce a compound of formula I
Wherein R is1-R7As defined in claim 1;
the base is selected from an organic base or an inorganic base.
10. The process according to claim 9, wherein the organic base is triethylamine or pyridine and the inorganic base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
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| CN105873928A (en) * | 2013-12-13 | 2016-08-17 | 第三共株式会社 | 5-hydroxy-4-(trifluoromethyl)pyrazolopyridine derivative |
| CN106916143A (en) * | 2017-03-14 | 2017-07-04 | 哈尔滨医科大学 | A kind of medicine for preventing and treating coronary heart disease and its application |
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| WO2008102749A1 (en) * | 2007-02-20 | 2008-08-28 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
| WO2011020193A1 (en) * | 2009-08-18 | 2011-02-24 | Merck Frosst Canada Ltd. | Renin inhibitors |
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| CN105873928A (en) * | 2013-12-13 | 2016-08-17 | 第三共株式会社 | 5-hydroxy-4-(trifluoromethyl)pyrazolopyridine derivative |
| CN106916143A (en) * | 2017-03-14 | 2017-07-04 | 哈尔滨医科大学 | A kind of medicine for preventing and treating coronary heart disease and its application |
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Inventor after: Kong Juan Inventor after: Tang Yuli Inventor after: Hou Liyuan Inventor after: Yang Chao Inventor after: Ma Xiaosheng Inventor after: Jin Tao Inventor before: Kong Juan Inventor before: Tang Yuli Inventor before: Hou Liyuan Inventor before: Yang Chao Inventor before: Ma Xiaosheng Inventor before: Jin Tao |