CN106946879B - A kind of drug and preparation method thereof for reducing blood lipid - Google Patents
A kind of drug and preparation method thereof for reducing blood lipid Download PDFInfo
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- CN106946879B CN106946879B CN201710149506.2A CN201710149506A CN106946879B CN 106946879 B CN106946879 B CN 106946879B CN 201710149506 A CN201710149506 A CN 201710149506A CN 106946879 B CN106946879 B CN 106946879B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The drug and preparation method thereof that the present invention relates to a kind of for reducing blood lipid.The invention discloses a kind of drugs for treating hyperlipidemia and/or treating atherosclerosis.Compound of the present invention can increase liver cell to the uptake ratio of low-density lipoprotein, the serum total cholesterol, serum triglyceride, serum LDL cholesterol of rat can be significantly reduced, function and effect are suitable with Simvastatin, show the compounds of this invention with excellent hypolipidemic activity, in the treatment that can be applied to hyperlipemia and atherosclerosis.
Description
Technical field
The invention belongs to field of medicinal chemistry, more specifically, are related to a new class of jeterocyclic chemistry with hypolipidemic activity
Close object, preparation method and its purposes being used to prepare in the drug of reducing blood lipid and/or treatment atherosclerosis.
Background technique
Hyperlipidemia (hyperlipidemia, HLP) is that people's HypercholesterolemicRats are not normal, one or more lipids in blood plasma
A kind of illness that composition increases extremely.Hyperlipidemia can cause the exception of antioxidant ability of organism and hemorheology, these
Abnormal factors can be used as a kind of intermediate link or promotive factor of hyperlipidemia again, and Artery Endothelial function is caused to damage, cause in
The damage of chrotoplast dysfunction or vascular wall function and structure influences vascular function, aggravates and promotes caused by hyperlipidemia
Pathological change and clinical symptoms.Studies have shown that hyperlipidemia is the primary risk factor of atherosclerosis, it can cause sternly
The cardiovascular and cerebrovascular disease of weight, such as hypertension, coronary heart disease, cerebrovascular disease, senile dementia.Therefore, how effectively to prevent and
Treat one of the hot spot that hyperlipidemia has become Medical research.
Clinical mainstream medicine mainly has HMG-CoA reductase inhibitor, niacin and its derivative, fibrates currently on the market
Drug.HMG-CoA reductase inhibitor class drug includes Lovastatin, Simvastatin, Atorvastatin, Fluvastatin, general cuts down
Statin etc., niacin and its derivative have niacin, Acipimox, hexanicit, and fibrate includes fenofibrate, chlorine shellfish fourth
Ester, ciprofibrate etc..These drugs itself all have the defects that certain, and such as fenofibrate is only made due to being practically insoluble in water
At special pharmaceutical preparation, to guarantee good bioavilability, but insoluble, the preparation release due to fenofibrate in water
There is the trend of recrystallization in the process, affects bioavilability.
In conclusion there is an urgent need in the art to provide the new compound with hypolipidemic activity.
Summary of the invention
The object of the present invention is to provide a new class of compounds with hypolipidemic activity.
The first aspect of the present invention provides a kind of 1 compound of formula or its pharmaceutically acceptable salt：
In Formulas I,
A indicate heterocycle, optionally by selected from halogen, oxo, cyano, nitro, hydroxyl, amino, carboxyl, C1-4 alkyl,
C3-8 naphthenic base, halogenated c1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio group, C1-4 alkoxy C 1-4 alkyl, C1-4 alkyl sulfonyl
Base, C1-4 alkyl amino, two (C1-4 alkyl) amino, C1-4 alkyl-carbonyl and C1-4 alkoxy carbonyl group replaced；
R1It indicates：Hydroxyl, amino, C1-4 alkoxy, C1-4 alkyl, C3-8 naphthenic base, halogenated c1-4 alkyl, C1-4 alcoxyl
Base C1-4 alkyl, aryl, aryl C1-2 alkyl, heterocycle, heterocycle C1-2 alkyl；
R2It indicates：C1-4 alkyl, the C3-8 cycloalkanes that hydrogen, hydroxyl, amino, C1-4 alkyl, halogenated c1-4 alkyl, hydroxyl replace
Base, C1-4 alkyl-carbonyl, C1-4 alkoxy carbonyl, aryl, aryl C1-2 alkyl, heterocycle, heterocycle C1-2 alkyl；
L is indicated：-(CR3R4) n-, wherein each R3、R4Can be identical or different, it is each independently selected from hydrogen or C1-4 alkane
Base；
N indicates 1,2,3,4 or 5.
In one embodiment of the invention, five yuan of the heterocycle basis representation or single six-membered rings heteroaryl or nine yuan
Or ten membered bicyclic heteroaryl.
In one embodiment of the invention, five yuan of the heterocycle basis representation is to seven unit monocycle Heterocyclylalkyls or nine yuan
Or ten membered bicyclic Heterocyclylalkyl.
In one embodiment of the invention, the aryl indicates C6-14 aryl.
In one embodiment of the invention, the R1It indicates：Hydroxyl, C1-4 alkoxy, C1-4 alkoxy C 1-4 alkane
Base.
In one embodiment of the invention, the R1It indicates：Heterocycle C1-2 alkyl.
In one embodiment of the invention, the R2It indicates：C1-4 alkyl or halogenated c1-4 alkyl.
In one embodiment of the invention, the A indicates piperazine -1- base, thio code quinoline -1- base.
In one embodiment of the invention, the A indicates pyridine -2- base.
In one embodiment of the invention, the A is unsubstituted.
In one embodiment of the invention, the A is selected from halogen, oxo, cyano, nitro, hydroxyl, amino, carboxylic
Base, C1-4 alkyl, C3-8 naphthenic base, halogenated c1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio group, C1-4 alkoxy C 1-4 alkyl,
C1-4 alkyl sulphonyl, C1-4 alkyl amino, two (C1-4 alkyl) amino, C1-4 alkyl-carbonyl and C1-4 alkoxy carbonyl base
Replaced group.
Currently preferred compound is：
As " halogen " in the present invention, such as fluorine, chlorine, bromine, iodine can be enumerated.
As " alkyl " in the present invention, the carbon number that can enumerate straight-chain or branch's chain state is the alkyl of 1-4, such as first
Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl.Wherein, preferably carbon number be 1-2 alkyl.
As " naphthenic base " in the present invention, the naphthenic base that carbon number is 3-8, such as cyclopropyl, cyclobutyl, ring can be enumerated
Amyl, cyclohexyl, suberyl, cyclooctyl.Wherein, preferably carbon number be 5-7 naphthenic base.
As " aryl " in the present invention, the aromatic hydrocarbyl, such as phenyl, naphthalene etc. that carbon number is 6-14 can be enumerated.
As " heterocycle " in the present invention, (1) or (2) below can be enumerated：
(1) heteroaryl refers to the hetero atom for being selected from O, N and S containing at least one, is optionally independently selected from the another of O, N and S containing 1-3
Outer heteroatomic any five yuan or single six-membered rings aromatic ring structure；Or the hetero atom of O, N and S are selected from containing at least one, optionally contain 1-
4 are independently selected from heteroatomic nine yuan other or the ten membered bicyclic aromatic ring structures of O, N and S.The heteroaryl is attached to ring
Any hetero atom or carbon atom on, to form stable structure.The example of suitable heteroaryl includes, but are not limited to pyrroles
Base, furyl, thienyl, oxazolyl, imidazole radicals, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl group, pyridine
Base, pyridazinyl, pyrimidine radicals, pyrazinyl, pyranose, indolizine base, indyl, isoindoline base, indazolyl, benzofuranyl,
Benzothienyl, benzimidazolyl, benzothiazolyl, purine radicals, quinazinyl, quinolyl, isoquinolyl, isothiazolyl, cinnolines
Base, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridines base, pteridyl etc..
(2) Heterocyclylalkyl, refer to containing selected from O, N and S at least one hetero atom, optionally containing being independently selected from O, N and S
Any five yuan of 1-3 additional heteroatom are to seven unit monocycles, saturation or part unsaturated ring structure；Or containing selected from O, N and S
At least one hetero atom, nine yuan or ten yuan saturations, parts optionally containing 1-4 additional heteroatom for being independently selected from O, N and S are not
Saturation or the bicyclic loop system of partially aromatic.Heterocyclylalkyl can be connected on any hetero atom or carbon atom of ring, so that generate steady
Determine structure.The example of Heterocyclylalkyl appropriate includes, but are not limited to pyrrolinyl, pyrrolidinyl, dioxolanyl, imidazoles miaow
Base, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidyl, dioxane, morpholinyl, dithianyl, thio-morpholinyl, piperazine
Piperazine base, trithiane base, indolinyl, chromene base.
When compound according to the present invention has at least one chiral centre, they can correspondingly be deposited with enantiomeric form
?.When compound has 2 or more chiral centres, they can correspondingly exist with diastereomeric form.It should
Understand, all such isomers and its mixture are included within the scope of the present invention.In addition, certain knots of compound
Crystalline form can exist with polymorph form, and these are also intended to including within the scope of the invention.Further more, certain compounds can
Solvate is formed with water (i.e. hydrate) or with ordinary organic solvents, and such solvate is also intended to including the present invention
Within the scope of.
The present invention includes the prodrug of the compounds of this invention within its scope.Generally, such prodrug will be the compound
Functional derivatives are easy to be converted into required compound in vivo.Therefore.In subject treatment method, term " is given
Give " it will include with specifically disclosed compound or with may be without not specifically disclosed but can be converted in vivo after being administered to patient
Described a variety of disease diseases are treated for the compound of specific compound.The conventional journey for the prodrug derivant that selection and preparation are suitable for
Sequence, for example, " Design of Prodrugs ", H.Bundgaard, Elsevier is write, and describes in 1985.
In order to apply in drug, the salt of the compounds of this invention is considered as avirulent " pharmaceutically acceptable salt ".
However, other salt can be used for preparing compound according to the present invention, or prepare the pharmaceutically acceptable of them.The chemical combination
The suitable pharmaceutically acceptable salt of object includes acid-addition salts, can, for example, by by the compound solution and pharmaceutically
Acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, winestone
The solution of acid, carbonic acid or phosphoric acid is mixed to form.In addition, then its is suitable pharmaceutically when part of the compounds of this invention with acid
Acceptable salt may include alkali metal salt, e.g., sodium salt or sylvite；Alkali salt, e.g., calcium salt or magnesium salts；And with it is suitable
Organic ligand is formed by salt, such as quaternary ammonium salt.Thus, representative pharmaceutically acceptable salt includes as follows：
Acetate, benzene sulfonate, benzoate, bicarbonate, disulfate, biatrate, borate, bromide,
Ca-EDTA, camsilate, carbonate, chloride, Clavulanate, citrate, dihydrochloride, edetate, second sulphur
Hydrochlorate, fumarate, gluceptate, gluconate, glutamate, extra large bar amine, hydrobromate, hydrochloride, hydroxyl naphthalene first
Hydrochlorate, iodide, different thiosulfate, lactate, Lactobionate, laruate, malate, maleate, almond
Hydrochlorate, mesylate, bromomethane, first nitrate, metilsulfate, mucus hydrochlorate, naphthalene sulfonate, nitrate, N-METHYL-ALPHA-L-GLUCOSAMINE
Ammonium salt, oleate, palmitate, pantothenate, phosphate/diphosphate, Polygalacturonate, salicylate, stearate,
Sulfate, basic acetate, succinate, tannate, tartrate, toluene fulfonate and valerate.
It includes as follows for can be used for preparing the representative bronsted lowry acids and bases bronsted lowry of pharmaceutically acceptable salt：
Acid, including acetic acid, 2,2- dichloroacetic acid, the amino acid of acylation, fatty acid, alginic acid, ascorbic acid, L- asparagus fern ammonia
Acid, benzene sulfonic acid, benzoic acid, 4- acetaminobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor -10- sulfonic acid,
Capric acid, caproic acid, octanoic acid, cinnamic acid, citric acid, cyclohexane sulfamic acid, dodecyl sulphate, ethane -1,2- disulfonic acid, ethane
Sulfonic acid, 2- hydroxy-ethane sulfonic acid, formic acid, fumaric acid, galactosaccharic acid, gentianic acid, glucoheptonic acid, maltonic acid, D-
Glucuronic acid, Pidolidone, alpha-oxo-glutaric acid, glycolic, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-Pfansteihl, (±)-
DL-LACTIC ACID, lactobionic acid, maleic acid, (-)-L MALIC ACID, malonic acid, (±)-DL- mandelic acid, Loprazolam, naphthalene -2- sulphur
Acid, naphthalene -1,5- disulfonic acid, 1- hydroxyl -2- naphthoic acid, niacin, nitric acid, oleic acid, orotic acid, oxalic acid, palmitinic acid, pamoic acid, phosphorus
Acid, L-Glutimic acid, salicylic acid, 4- amino-salicylic, decanedioic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L- wine
Stone acid, thiocyanic acid, p- toluenesulfonic acid and undecenoic acid；And alkali, including ammonia, L-arginine, calcium hydroxide, choline, deanol,
Diethanol amine, diethylamine, 2- (diethylamino)-ethyl alcohol, ethanol amine, ethylenediamine, N- methyl-glucamine, extra large bar amine, 1H- miaow
It is azoles, L-lysine, magnesium hydroxide, 4- (2- ethoxy)-morpholine, piperazine, potassium hydroxide, 1- (2- ethoxy)-pyrrolidines, secondary
Amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.
The second aspect of the present invention provides a kind of side for preparing above-mentioned 1 compound of formula or its pharmaceutically acceptable salt
Method the described method comprises the following steps：
Step 1：
The step includes reacting Formula II compound in atent solvent with preparation formula IV compound with formula III compound.
Solvent for the step can be alcohol, such as methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, tertiary fourth
Alcohol, isoamyl alcohol, octanol, cyclohexanol, 2-methyl cellosolve, diethylene glycol (DEG) or glycerol；Aromatic hydrocarbons, such as benzene, toluene or dimethylbenzene；Or it
Mixed solvent.Solvent is preferably alcohol, more preferable ethyl alcohol.
The reaction temperature of the step is preferably 20 DEG C to 150 DEG C, more preferable 50 DEG C of reflux temperatures to solvent.
The reaction time of the step is preferably 10 minutes to 24 hours, and more preferable 1 hour to 5 hours.
Step 2：
The step includes reacting formula IV compound in atent solvent to make with Formula V compound and Meldrum ' s acid
Standby Formula IV compound.
Solvent for the step can be alcohol, such as methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, tertiary fourth
Alcohol, isoamyl alcohol, octanol, cyclohexanol, 2-methyl cellosolve, diethylene glycol (DEG) or glycerol；Aromatic hydrocarbons, such as benzene, toluene or dimethylbenzene；Or it
Mixed solvent.Solvent is preferably alcohol, more preferable ethyl alcohol.
The reaction temperature of the step is preferably 0 DEG C to 150 DEG C, more preferable 20 DEG C of reflux temperatures to solvent.
The reaction time of the step is preferably 30 minutes to 24 hours, and more preferable 1 hour to 6 hours.
Step 3：
The step includes reacting Formula IV compound in atent solvent to make with Formula VII compound and alkali, catalyst
Standby 1 compound of formula.
Solvent for the step can be alcohol, such as methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, tertiary fourth
Alcohol, isoamyl alcohol, octanol, cyclohexanol, 2-methyl cellosolve, diethylene glycol (DEG) or glycerol；Aromatic hydrocarbons, such as benzene, toluene or dimethylbenzene；It is halogenated
Hydrocarbon, such as chloroform, methylene chloride；Or their mixed solvent.Solvent is preferably aromatic hydrocarbons, more preferable toluene.
Alkali for the step can be hydroxide, such as sodium hydroxide, potassium hydroxide；Carbonate, such as sodium carbonate, carbon
Sour potassium；Bicarbonate, such as sodium bicarbonate, saleratus；Acetate, such as sodium acetate or potassium acetate.Alkali is preferably bicarbonate
Salt, more preferable saleratus.
Catalyst for the step can be cuprous salt, such as cuprous iodide.
Optional step four：
In case there is a need, make 1 compound of the formula experience salt-forming steps to prepare its pharmaceutically acceptable salt.
In above-mentioned steps, A, R1、R2, L is as described above, X indicates halogen, preferably chlorine or bromine；R indicates C1-4 alkyl.
The third aspect of the present invention provides a kind of pharmaceutical composition, and it includes at least one 1 chemical combination of formula of the present invention
Object or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
According to conventional medicinal compound technology, by the way that one or more compounds are finely mixed with pharmaceutically acceptable carrier
It closes, the Pharmaceutical composition containing one or more the compounds of this invention described herein, as active constituent can be prepared.According to institute
Approach (e.g., take orally, is parenteral) to be administered is different, and extensive types of carrier can be used.Thus, for liquid oral medicine,
Such as suspension, elixir and solution, suitable carrier and additive include water, glycol, oil, alcohol, flavoring agent, preservative, steady
Determine agent, colorant etc.；For solid orally ingestible, such as pulvis, capsule and tablet, suitable carrier and additive include forming sediment
Powder, sugar, diluent, granulating agent, lubricant, adhesive, disintegrating agent etc..Also working substance, such as sugar to solid orally ingestible into
Row coating carries out enteric coating, to adjust major absorption site.For parenteral, carrier will be usually by that can be added increase
The aqua sterilisa of dissolubility or keeping quality is other at being grouped as.Aqueous carrier can also be used together with additive appropriate, system
The suspension or solution of standby injectable.
Preferably, these compositions are presented with unit dosage forms, and the unit dosage forms are such as tablet, pill, capsule, powder
Agent, granule, sterilizing parenteral solutions or suspension, the aerosol of metering or liquid spray, drops, ampoule, self note
Mapper arrangement or suppository；Agent for parenteral, intranasal, the sublingual or rectally in oral cavity or for sucking or spraying administration
Type.Alternatively, that composition can be suitable for, weekly administration is primary or the form that is monthly administered once is presented；For example, reactive compound
Insoluble salt, such as caprate can be adapted to provide for depot formulations, be used for intramuscular injection.
Advantageously, the compounds of this invention can be administered in the form of single daily dosage or every total daily dose can be divided into often
Day twice, three times or four dosage administrations.Furthermore, it is possible to be given through intranasal form via the intranasal tool that local use is suitable for
The compounds of this invention, or the compounds of this invention is given via percutaneous plaster known to those of ordinary skill in the art.In order to saturating
The form of skin transmission system is administered, and dosage will be continuous and intermittent certainly in entire dosage regimen.
The daily dosage of this product can change in very large range, from every daily 0.01-1000mg of adult.For take orally to
Medicine, preferably provides the composition of tablet form, the tablet containing 0.01,0.05,0.1,0.5,1.0,2.5,5.0,10.0,
15.0,25.0,50.0,100,150,200,250 and 500 milligrams of active constituent carries out the agent of symptom for patient to be treated
Amount adjustment.Generally the effective quantity of drug is provided in the dosage level of about 0.01mg/kg- about 300mg/kg weight daily.Preferably,
The range is from about 0.5- about 5.0mg/kg weight daily, most preferably, from about 1.0- about 3.0mg/kg weight daily.According to giving
Prescription case can be given once daily this compound 1-4 times.
The optimal dose of administration can be easy to determine by those skilled in the art and will be according to specifically used compound, administration
Mode, the intensity of preparation, the progress of administration mode and disease condition are different and different.In addition, having with the patient being specifically treated
The factor of pass, including patient age, weight, diet and administration number of times, it will generate the demand of adjustment dosage.
The fourth aspect of the present invention, provides 1 compound of formula of the present invention or its pharmaceutically acceptable salt is being treated
Application in hyperlipemia comprising give a effective amount of at least one 1 compound of formula of the present invention to individual in need
Or its pharmaceutically acceptable salt.
The fifth aspect of the present invention, provides 1 compound of formula of the present invention or its pharmaceutically acceptable salt is being treated
Application in atherosclerosis comprising give a effective amount of at least one formula 1 of the present invention to individual in need and change
Close object or its pharmaceutically acceptable salt.
The fifth aspect of the present invention, provides 1 compound of formula of the present invention or prepared by its pharmaceutically acceptable salt
Application in drug, the drug is for treating hyperlipemia.
The fifth aspect of the present invention, provides 1 compound of formula of the present invention or prepared by its pharmaceutically acceptable salt
Application in drug, the drug is for treating atherosclerosis.
The compounds of this invention can increase liver cell to the uptake ratio of low-density lipoprotein, can significantly reduce the blood of rat
Clear total cholesterol, serum triglyceride, serum LDL cholesterol, function and effect are suitable with Simvastatin, show this
Invention compound is with excellent hypolipidemic activity, in the treatment that can be applied to hyperlipemia and atherosclerosis.
Specific embodiment
The present invention is described below in more detail to facilitate the understanding of the present invention.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used to suitably prepare perhaps
Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention
Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention
It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention
, or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged
Ground is suitable for the preparation of other compounds of the invention.
Embodiment 1：1- ((3- methoxyl group -4- methyl -6- oxo -4,5,6,7- tetrahydro -2H- pyrazoles [3,4-b] pyridine -2-
Base) methyl) -3- (piperidin-1-yl) urea (compound I)
Step 1：Bromomethyl hydrazine (2.46g, 20.0mmol) is added to 2- malonic methyl ester nitrile (1.98g, 20.0mmol)
Solution in ethyl alcohol (100mL), and 50 DEG C stirring mixture 2 hours.It is concentrated under reduced pressure reaction solution, the residual of acquisition
Object is separated into organic layer and water layer by the sodium bicarbonate aqueous solution and ethyl acetate of addition saturation.It is washed with brine organic layer simultaneously
It dries, and under reduced pressure distills out solvent on anhydrous sodium sulfate.The residue obtained with Gossypol recrystallized from chloroform is to obtain 1- (bromine
Methyl) -5- methoxyl group -1H- pyrazoles -3- amine 2.93g, yield：72%, content 99%.ESI-MS：205.99[M+H]+。
Step 2：Acetaldehyde methyl hemiacetal (0.76g, 20.mmol) is added to the 1- (bromomethyl)-prepared in step 1
The ethyl alcohol of 5- methoxyl group -1H- pyrazoles -3- amine (2.05g, 10.0mmol) and Meldrum ' s sour (2.88g, 20.0mmol)
In (40mL) solution, and mixture is being heated to reflux lower stirring 5 hours.The solvent in reaction solution is distilled out under reduced pressure.
The residue obtained with tetrahydrofuran recrystallization is to obtain 2- (bromomethyl) -3- methoxyl group -4- methyl -4,5- dihydro -2H- pyrazoles
[3,4-b] pyridine -6 (7H) -one 1.78g, yield：65%, content 98%.ESI-MS：274.01[M+H]+。
Step 3：By 1- (piperazine -1- base) urea (0.86g, 6.0mmol), methyl -4 2- (bromomethyl) -3- methoxyl group -4-,
5- dihydro -2H- pyrazoles [3,4-b] pyridine -6 (7H) -one (1.37g, 5.0mmol), KHCO3(1.38g,10.0mmol)、CuI
(0.19g, 1.0mmol) and toluene (30ml) mix, and are being heated to reflux lower stirring 6 hours.It is cooled to room temperature, by gained
Reaction mixture be extracted with ethyl acetate.Organic layer is washed with water, then dry with anhydrous sodium sulfate, depressurizes lower concentration；It is thick to produce
Object silica gel column chromatogram separating purification, eluant, eluent are Ethyl acetate-cyclohexane (1:2) title compound of white solid, is obtained
1.42g, yield 84%, content 99%.
ESI-MS：338.19[M+H]+
Elemental analysis：Theoretical value/measured value, C (49.84/49.71), H (6.87/6.77), N (29.06/29.19), O
(14.23/14.33)
1H NMR(400MHz,DMSO-D6)δ8.09(s,1H),6.05(s,1H),5.95(s,1H),5.61(s,2H),
4.08(s,3H),3.17(m,1H),2.65(t,8H),2.51(q,1H),2.31(q,1H),2.11(s,1H),1.31(d,3H)。
Embodiment 2：1- ((3- ((2H-1,2,3- triazole -2- base) methyl) -4- (methyl fluoride) -6- oxo -4,5,6,7- four
Hydrogen -2H- pyrazoles [3,4-b] pyridine -2- base) methyl) -3- thio-morpholinyl urea (compound II)
According to the method for embodiment 1,2- cyanoacetic acid first is replaced with 3- oxo -4- (2H-1,2,3- triazole -2- bases) butyronitrile
Ester, 1- fluorine acetaldehyde methyl hemiacetal replace acetaldehyde methyl hemiacetal, replace 1- (piperazine -1- with 1- (thiomorpholine -4- base) urea
Base) urea, obtain the title compound of faint yellow solid, three step gross production rates 38%.
ESI-MS：424.16[M+H]+
Elemental analysis：Theoretical value/measured value, C (45.38/45.48), H (5.24/5.29), F (4.49/4.53), N
(29.77/29.64), O (7.56/7.51), S (7.57/7.55)
1H NMR(400MHz,DMSO-D6)δ8.04(s,1H),7.62(d,2H),6.03(s,1H),5.97(s,1H),
5.61(s,2H),4.99(s,2H),4.55(q,1H),4.25(q,1H),3.25(m,1H),2.91(t,4H),2.72(t,4H),
2.61(q,1H),2.31(q,1H)。
Embodiment 3：1- (3- chloropyridine -2- base) -3- ((3- (2- ethoxyethyl group) -6- oxo -4- (trifluoromethyl) -4,
5,6,7- tetrahydro -2H- pyrazoles [3,4-b] pyridine -2- base) methyl) urea (compound III)
According to the method for embodiment 1,2- malonic methyl ester nitrile, trifluoro acetaldehyde first are replaced with 5- ethyoxyl -3- oxopentanenitrile
Base hemiacetal replaces acetaldehyde methyl hemiacetal, replaces 1- (piperazine -1- base) urea with 1- (the chloro- pyridine -2- base of 3-) urea, obtains white
The title compound of solid, three step gross production rates 35%.
ESI-MS：461.12[M+H]+
Elemental analysis：Theoretical value/measured value, C (46.91/46.78), H (4.37/4.31), Cl (7.69/7.78), F
(12.37/12.47), N (18.24/18.34), O (10.42/7.32)
1H NMR(400MHz,DMSO-D6)δ9.54(s,1H),8.04(s,1H),8.12(d,1H),7.62(d,1H),
6.81(q,1H),6.08(s,1H),5.63(s,2H),3.89(q,1H),3.55(t,2H),3.47(q,2H),2.75(t,2H),
2.61(q,1H),2.32(q,1H),1.11(t,3H)。
Pharmacological examples Example：The test of the compounds of this invention hypolipidemic activity
1. the facilitation that target compound absorbs liver cell low-density lipoprotein
It is handled degreasing serum starvation 12 hours with compound I, II, III and (final concentration of 5 μM) of positive control Simvastatin
HepG2 cell 24 hours, the 20 μ g/ml of low-density lipoprotein (DiI-LDL) of fluorescent marker is added, 37 DEG C are incubated for 4 hours, use
Phosphate buffer uses isopropyl alcohol extracting lipid after gently washing cell 5 times, in measurement fluorescence reading (exciting light in microplate reader：
520nm；Emit light 570nm).Then 0.2M sodium hydroxide lytic cell is used, protein content is measured, calculates fluorescence/albumen
Numerical value.Experimental result is shown in Table 1.
Table 1：The effect that target compound absorbs liver cell low-density lipoprotein
| Compound | Dosage | Low-density lipoprotein uptake ratio |
| Blank group (DMSO) | - | 1 |
| Positive control Simvastatin | 5μM | 1.22* |
| Compound I | 5μM | 1.28* |
| Compound II | 5μM | 1.21* |
| Compound III | 5μM | 1.25* |
Note：Compared with blank group, * P < 0.05
Test result shows that 3 compounds of the invention can dramatically increase liver cell HepG2 to low close under 5 μM of concentration
Spend the intake of lipoprotein LDL.
2. the dose dependent that target compound absorbs liver cell low-density lipoprotein
12 hours HepG2 of degreasing serum starvation are handled with the compound I (concentration is respectively 5,10,20 μM) of various concentration
Cell 24 hours, cell was calculated according to the above method to the uptake ratio of low-density lipoprotein, investigates the dosage and activity of compound I
Between relationship.Experimental result is shown in Table 2.
Table 2：The effect that various concentration compound absorbs liver cell low-density lipoprotein
| Compound | Dosage | Low-density lipoprotein uptake ratio |
| Blank group (DMSO) | - | 1 |
| Positive control Simvastatin | 20μM | 1.59** |
| Compound I | 5μM | 1.28* |
| Compound I | 10μM | 1.41** |
| Compound I | 20μM | 1.63** |
Note：Compared with blank group, * P < 0.05, * * P < 0.01
Test result shows that the compounds of this invention I increases HepG2 cell phagocytosis LDL and closes with apparent dose dependent
System, can very significantly increase intake (P < 0.01) of the liver cell HepG2 to low-density lipoprotein LDL under 20 μM of concentration,
And the effect for increasing LDL intake is suitable with Simvastatin.
3. internal reducing blood lipid drug efficacy study is administered orally in target compound
3.1 experimental animal
Male SD rat, 200 ± 10g of weight.
3.2 drugs are prepared
Compound I, II, III and Simvastatin 5%DMSO, 2%Tween80 and 93% normal saline at
The suspension medical fluid of 15mg/ml is mixed using preceding ultrasound；Every animal gives the administered volume of 200 μ l/100g, and dosage is
20mg/kg。
3.3 experimental method
Male SD rat adaptive feeding is grouped according to its initial blood lipid and weight levels stochastic averagina after a week, and every group 10
Only.Hyperlipidemia model group and administration group give high lipid food, administration group given in a manner of being injected intraperitoneally 20mg/kg compound I,
II, III, positive controls give the compound Simvastatin of 20mg/kg in a manner of being injected intraperitoneally, hyperlipidemia model group take orally to
The solvent of equal volume is given, chow diet control group gives chow diet.Broken end took blood on 5th, was surveyed with enzyme process (GPO-PAP method)
Determine serum total cholesterol (TC)；Serum triglyceride (TG) is measured with enzymatic end pointassay (GPO-PAP method)；With polyvinyl sulfuric acid salt
PVS Precipitation Determination serum LDL cholesterol (LDL-C).Experimental result is shown in Table 3.
Table 3：Effect of the target compound to TC, TG, LDL-C
| Group | TC(mmol/l) | TG(mmol/l) | LDL-C(mmol/l) |
| Hyperlipidemia model group | 2.92±0.31 | 1.45±0.11 | 1.84±0.41 |
| Positive controls | 2.08 ± 0.27 (28.8%) * * | 1.31 ± 0.09 (9.6%) * | 1.14 ± 0.29 (38.1%) * * |
| Compound I group | 1.93 ± 0.24 (33.9%) * * | 1.24 ± 0.08 (14.5%) * | 1.01 ± 0.31 (45.1%) * * |
| Compound II group | 2.16 ± 0.28 (26.0%) * * | 1.36 ± 0.10 (6.2%) * | 1.22 ± 0.28 (33.7%) * * |
| Compound III group | 2.02 ± 0.24 (30.1%) * * | 1.28 ± 0.12 (11.7%) * | 1.09 ± 0.25 (40.1%) * * |
Note：Compared with hyperlipidemia model group, * P < 0.05, * * P < 0.01
After test result shows that the rat of high fat diet gives the compounds of this invention for a period of time, with hyperlipidemia model group phase
Than, TC, TG, LDL-C level are remarkably decreased, and have significant difference (P < 0.05 or 0.01), decline degree with give pungent cut down
The positive controls of statin are similar, and the compounds of this invention is prompted to have significant effect for reducing blood fat, function and effect and Simvastatin
Quite.
Above-mentioned pharmacological testing shows that the compounds of this invention can increase liver cell to the uptake ratio of low-density lipoprotein, energy
Enough significantly reduce rat serum total cholesterol, serum triglyceride, serum LDL cholesterol, function and effect with it is pungent
It cuts down that statin is suitable, shows that the compounds of this invention has excellent hypolipidemic activity, can be applied to hyperlipemia and artery congee is hard
In the treatment of change.
The foregoing describe the preferred embodiment for the present invention, and however, it is not to limit the invention.Those skilled in the art couple
Embodiment disclosed herein can carry out the improvements and changes without departing from scope and spirit.
Claims (6)
1. a kind of 1 compound of formula or its pharmaceutically acceptable salt：
In Formulas I,
A indicates heterocycle, optionally by selected from halogen, oxo, cyano, nitro, hydroxyl, amino, carboxyl, C1-4 alkyl, halogenated
C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio group, C1-4 alkoxy C 1-4 alkyl, C1-4 alkyl sulphonyl, C1-4 alkyl ammonia
Base, two (C1-4 alkyl) amino, C1-4 alkyl-carbonyl and C1-4 alkoxy carbonyl group replaced；
R1It indicates：Hydroxyl, amino, C1-4 alkoxy, C1-4 alkyl, C3-8 naphthenic base, halogenated c1-4 alkyl, C1-4 alkoxy C 1-
4 alkyl；
R2It indicates：Hydrogen, hydroxyl, amino, C1-4 alkyl, halogenated c1-4 alkyl, hydroxyl replace C1-4 alkyl, C3-8 naphthenic base,
C1-4 alkyl-carbonyl, C1-4 alkoxy carbonyl；
L is indicated：-(CR3R4) n-, wherein each R3、R4Can be identical or different, it is each independently selected from hydrogen or C1-4 alkyl；
N indicates 1,2,3,4 or 5；
Wherein the heterocycle indicate five yuan to seven unit monocycle Heterocyclylalkyls or nine yuan or ten membered bicyclic Heterocyclylalkyls；
The aryl indicates C6-14 aryl.
2. compound according to claim 1, is selected from：
3. a kind of method for preparing 1 compound of formula according to claim 1 or its pharmaceutically acceptable salt, the method
Include the following steps：
Step 1：
The step includes reacting Formula II compound in atent solvent with preparation formula IV compound with formula III compound；
Step 2：
The step includes reacting formula IV compound with preparation formula in atent solvent with Formula V compound and Meldrum ' s acid
VI compound；
Step 3：
The step includes reacting Formula IV compound in atent solvent with preparation formula 1 with Formula VII compound and alkali, catalyst
Compound；
Alkali for the step is hydroxide；
Catalyst for the step is cuprous salt；
Optional step four：
In case there is a need, make 1 compound of the formula experience salt-forming steps to prepare its pharmaceutically acceptable salt；
In above-mentioned steps, A, R1、R2, L as described in the appended claim 1, X indicate halogen；R indicates C1-4 alkyl.
4. a kind of pharmaceutical composition, it includes at least one 1 compound of formula according to claim 1 or 2 or its pharmaceutically
Acceptable salt and pharmaceutically acceptable carrier.
5. the application of 1 compound of formula according to claim 1 or 2 or its pharmaceutically acceptable salt in medicine preparation,
The drug is for treating hyperlipidemia.
6. the application of 1 compound of formula according to claim 1 or 2 or its pharmaceutically acceptable salt in medicine preparation,
The drug is for treating atherosclerosis.
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