CN106946879A - It is a kind of for medicine of reducing blood lipid and preparation method thereof - Google Patents
It is a kind of for medicine of reducing blood lipid and preparation method thereof Download PDFInfo
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- CN106946879A CN106946879A CN201710149506.2A CN201710149506A CN106946879A CN 106946879 A CN106946879 A CN 106946879A CN 201710149506 A CN201710149506 A CN 201710149506A CN 106946879 A CN106946879 A CN 106946879A
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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 present invention relates to a kind of for medicine of reducing blood lipid and preparation method thereof.The invention discloses a kind of medicine for being used to treat hyperlipidemia and/or treat atherosclerosis.Compound of the present invention can increase uptake ratio of the liver cell to low-density lipoprotein, the serum total cholesterol, serum triglyceride, serum LDL cholesterol of rat can be significantly reduced, action effect is suitable with Simvastatin, show that the compounds of this invention has excellent hypolipidemic activity, in the treatment that hyperlipemia and atherosclerosis can be applied to.
Description
Technical field
The invention belongs to medicinal chemistry art, more specifically, it is related to the jeterocyclic chemistry with hypolipidemic activity of a class newly
Compound, its preparation method and its for prepare reducing blood lipid and/or treat atherosclerosis medicine in purposes.
Background technology
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 factorses again can as hyperlipidemia a kind of intermediate link or promotive factor, cause Artery Endothelial function to damage, cause in
The damage of chrotoplast dysfunction or vascular wall function and structure, influences vascular function, caused by exacerbation and promotion hyperlipidemia
Pathological change and clinical symptoms.Research shows that hyperlipidemia is the primary hazards of atherosclerosis, and 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
Treatment hyperlipidemia has become one of focus of Medical research.
Clinical mainstream medicine mainly has HMG-CoA reductase inhibitor, nicotinic acid and its derivative, fibrates in the market
Medicine.HMG-CoA reductase inhibitor class medicine includes Lovastatin, Simvastatin, Atorvastatin, Fluvastatin, general cut down
Statin etc., nicotinic acid and its derivative have nicotinic acid, Acipimox, hexanicit, and fibrate includes fenofibrate, chlorine shellfish fourth
Ester, ciprofibrate etc..All there is certain defect, such as fenofibrate in these medicines, due to being practically insoluble in water, only make in itself
Into special pharmaceutical preparation, to ensure good bioavilability, but because fenofibrate is insoluble in water, preparation release
During exist recrystallization trend, have impact on bioavilability.
In summary, this area is in the urgent need to providing the new compound with hypolipidemic activity.
The content of the invention
It is an object of the invention to provide the compound with hypolipidemic activity of a class newly.
There is provided a kind of compound of formula 1, or its pharmaceutically acceptable salt for the first aspect of the present invention：
In Formulas I,
A represents heterocyclic radical, its be optionally selected from halogen, oxo, cyano group, nitro, hydroxyl, amino, carboxyl, C1-4 alkyl,
C3-8 cycloalkyl, halogenated c1-4 alkyl, C1-4 alkoxies, C1-4 alkylthio groups, C1-4 alkoxy C 1-4 alkyl, C1-4 alkyl sulfonyls
Base, C1-4 alkyl aminos, the group of two (C1-4 alkyl) amino, C1-4 alkyl-carbonyls and C1-4 alkoxy carbonyls are replaced；
R1Represent：Hydroxyl, amino, C1-4 alkoxies, C1-4 alkyl, C3-8 cycloalkyl, halogenated c1-4 alkyl, C1-4 alcoxyls
Base C1-4 alkyl, aryl, aryl C1-2 alkyl, heterocyclic radical, heterocyclic radical C1-2 alkyl；
R2Represent：Hydrogen, hydroxyl, amino, C1-4 alkyl, halogenated c1-4 alkyl, the C1-4 alkyl of hydroxyl substitution, C3-8 cycloalkanes
Base, C1-4 alkyl-carbonyls, C1-4 alkoxy carbonyls, aryl, aryl C1-2 alkyl, heterocyclic radical, heterocyclic radical C1-2 alkyl；
L is represented：-(CR3R4) n-, wherein each R3、R4Hydrogen or C1-4 alkane can be each independently selected from identical or different
Base；
N represents 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 heteroaryls.
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 Heterocyclylalkyls.
In one embodiment of the invention, the aryl represents C6-14 aryl.
In one embodiment of the invention, the R1Represent：Hydroxyl, C1-4 alkoxies, C1-4 alkoxy C 1-4 alkane
Base.
In one embodiment of the invention, the R1Represent：Heterocyclic radical C1-2 alkyl.
In one embodiment of the invention, the R2Represent：C1-4 alkyl or halogenated c1-4 alkyl.
In one embodiment of the invention, the A represents piperazine -1- bases, thio code quinoline -1- bases.
In one embodiment of the invention, the A represents pyridine -2- bases.
In one embodiment of the invention, the A is unsubstituted.
In one embodiment of the invention, the A is selected from halogen, oxo, cyano group, nitro, hydroxyl, amino, carboxylic
Base, C1-4 alkyl, C3-8 cycloalkyl, halogenated c1-4 alkyl, C1-4 alkoxies, C1-4 alkylthio groups, C1-4 alkoxy C 1-4 alkyl,
C1-4 alkyl sulphonyls, C1-4 alkyl aminos, the base of two (C1-4 alkyl) amino, C1-4 alkyl-carbonyls and C1-4 alkoxy carbonyls
Group is replaced.
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, alkyl of the carbon number of straight-chain or branch's chain state for 1-4, such as first can be enumerated
Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group.Wherein, preferably carbon number is 1-2 alkyl.
As " cycloalkyl " in the present invention, the cycloalkyl that carbon number is 3-8, such as cyclopropyl, cyclobutyl, ring can be enumerated
Amyl group, cyclohexyl, suberyl, cyclooctyl.Wherein, preferably carbon number is 5-7 cycloalkyl.
As " aryl " in the present invention, the aromatic hydrocarbyl that carbon number is 6-14 can be enumerated, such as phenyl, naphthyl.
As " heterocyclic radical " in the present invention, following (1) or (2) can be enumerated：
(1) heteroaryl, refers to the hetero atom that O, N and S are selected from 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 O, N and S hetero atom are selected from containing at least one, optionally containing 1-
4 be independently selected from O, N and S heteroatomic nine yuan other or ten membered bicyclic aromatic ring structures.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, oxazolyls, imidazole radicals, pyrazolyl, isoxazolyls, isothiazolyl, triazolyl, thiadiazolyl group, pyridine
Base, pyridazinyl, pyrimidine radicals, pyrazinyl, pyranose, indolizine base, indyl, isoindoline base, indazolyl, benzofuranyl,
Benzothienyl, benzimidazolyl, benzothiazolyl, purine radicals, quinolizine base, quinolyl, isoquinolyl, isothiazolyl, cinnolines
Base, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridines base, pteridyl etc..
(2) Heterocyclylalkyl, refers to containing at least one hetero atom selected from O, N and S, 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 unsaturation ring structure；Or containing selected from O, N and S
At least one hetero atom, nine yuan optionally containing 1-4 additional heteroatom for being independently selected from O, N and S or ten yuan of saturations, parts are not
Saturation or the bicyclic loop system of partially aromatic.Heterocyclylalkyl can be connected on any hetero atom of ring or carbon atom, so that produce steady
Fixed structure.The example of appropriate Heterocyclylalkyl includes, but not limited to pyrrolinyl, pyrrolidinyl, dioxolanyl, imidazoles miaow
Base, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidyl, dioxane base, morpholinyl, dithiane base, thio-morpholinyl, piperazine
Piperazine base, trithiane base, indolinyl, chromene base.
When the compound according to the present invention has at least one chiral centre, they correspondingly can be deposited with enantiomeric form
.When compound has 2 or more chiral centres, they correspondingly can exist with diastereomeric form.Should
Understand, all such isomers and its mixture are included within the scope of the present invention.In addition, some knots of compound
Crystalline form can exist with polymorph form, and these are also intended to including within the scope of the invention.Further, some 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 in the range of it.Typically, such prodrug will be the compound
Functional derivatives, it is easy to be converted into required compound in vivo.Therefore.In subject treatment method, term " is given
Give " by including with specifically disclosed compound or with may be without not specifically disclosed but can be converted in vivo after being administered to patient
For a variety of disease diseases described by the compounds for treating of specific compound.Select and prepare the conventional journey of suitable prodrug derivant
Sequence, for example, " Design of Prodrugs ", H.Bundgaard, Elsevier writes, described in 1985.
In order to apply in medicine, the salt of the compounds of this invention is considered as avirulent " pharmaceutically acceptable salt ".
However, other salt can be used for preparing the compound according to the present invention, or prepare the pharmaceutically acceptable of them.The chemical combination
The suitable pharmaceutically acceptable salt of thing include acid-addition salts, its can, for example, by by the compound solution with 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, when the compounds of this invention carries the part of acid, then it is suitable pharmaceutically
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
The salt that organic ligand is formed, such as quaternary ammonium salt.Thus, representational 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.
Include available for the representational bronsted lowry acids and bases bronsted lowry for preparing pharmaceutically acceptable salt as follows：
Acid, including acetic acid, 2,2- dichloroacetic acid, the amino acid of acylation, aliphatic acid, alginic acid, ascorbic acid, L- asparagus fern ammonia
Acid, benzene sulfonic acid, benzoic acid, 4- acetaminobenzoic acids, (+)-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-ethanes 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 acids, Loprazolam, naphthalene -2- sulphurs
Acid, naphthalene -1,5- disulfonic acid, 1- hydroxyl -2- naphthoic acids, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphorus
Acid, L-Glutimic acid, salicylic acid, 4- amino-salicylics, 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)-ethanol, monoethanolamine, ethylenediamine, N- methyl-glucamines, extra large bar amine, 1H- miaows
It is azoles, 1B, magnesium hydroxide, 4- (2- ethoxys)-morpholine, piperazine, potassium hydroxide, 1- (2- ethoxys)-pyrrolidines, secondary
Amine, NaOH, triethanolamine, tromethamine and zinc hydroxide.
The second aspect of the present invention prepares the above-mentioned compound of formula 1 or the side of its pharmaceutically acceptable salt there is provided a kind of
Method, the described method comprises the following steps：
Step one：
The step includes making Formula II compound react in atent solvent with formula IV compounds with formula III compound.
Solvent for the step can be alcohol, such as methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, tertiary fourth
Alcohol, isoamyl alcohol, octanol, cyclohexanol, 2-methyl cellosolve, diethylene glycol (DEG) or glycerine；Aromatic hydrocarbons, such as benzene, toluene or dimethylbenzene；Or it
Mixed solvent.Solvent is preferably alcohol, more preferably ethanol.
The reaction temperature of the step is preferably 20 DEG C to 150 DEG C, more preferably 50 DEG C of reflux temperatures to solvent.
The reaction time of the step is preferably 10 minutes to 24 hours, more preferably 1 hour to 5 hours.
Step 2：
The step includes making formula IV compound react 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, ethanol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, tertiary fourth
Alcohol, isoamyl alcohol, octanol, cyclohexanol, 2-methyl cellosolve, diethylene glycol (DEG) or glycerine；Aromatic hydrocarbons, such as benzene, toluene or dimethylbenzene；Or it
Mixed solvent.Solvent is preferably alcohol, more preferably ethanol.
The reaction temperature of the step is preferably 0 DEG C to 150 DEG C, more preferably 20 DEG C of reflux temperatures to solvent.
The reaction time of the step is preferably 30 minutes to 24 hours, more preferably 1 hour to 6 hours.
Step 3：
The step includes making Formula IV compound react to make in atent solvent with Formula VII compound and alkali, catalyst
The standby compound of formula 1.
Solvent for the step can be alcohol, such as methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, tertiary fourth
Alcohol, isoamyl alcohol, octanol, cyclohexanol, 2-methyl cellosolve, diethylene glycol (DEG) or glycerine；Aromatic hydrocarbons, such as benzene, toluene or dimethylbenzene；Halo
Hydrocarbon, such as chloroform, dichloromethane；Or their mixed solvent.Solvent is preferably aromatic hydrocarbons, more preferably toluene.
Alkali for the step can be hydroxide, such as NaOH, potassium hydroxide；Carbonate, such as sodium carbonate, carbon
Sour potassium；Bicarbonate, such as sodium acid carbonate, saleratus；Acetate, such as sodium acetate or potassium acetate.Alkali is preferably bicarbonate
Salt, more preferably saleratus.
Catalyst for the step can be cuprous salt, such as cuprous iodide.
Optional step four：
In case there is a need, the compound of the formula 1 experience salt-forming steps are made to prepare its pharmaceutically acceptable salt.
In above-mentioned steps, A, R1、R2, L is as described above, X represents halogen, preferably chlorine or bromine；R represents C1-4 alkyl.
The third aspect of the present invention is there is provided a kind of pharmaceutical composition, and it includes at least one chemical combination of formula 1 of the present invention
Thing 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
Close, the Pharmaceutical composition containing one or more the compounds of this invention described herein, as active component can be prepared.According to institute
Approach to be administered is (e.g., oral, parenteral) different, and extensive types of carrier can be used.Thus, for liquid oral medicine,
Such as supensoid agent, elixir and solution, suitable carrier and additive include water, glycol, oil, alcohol, flavor enhancement, preservative, steady
Determine agent, colouring agent 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, disintegrant etc..Also working substance, such as sugared that solid orally ingestible is entered
Row is coated or carries out enteric coating, to adjust major absorption site.For parenteral, carrier is by generally by that can add increase
Dissolubility or the aqua sterilisa of keeping quality or other compositions composition.Aqueous carrier can also be used together with appropriate additive, system
The supensoid agent 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 supensoid agent, 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.Or, form that composition can be suitably, that weekly administration once or is monthly administered once is presented；For example, reactive compound
Insoluble salt, such as caprate can be adapted to provide for depot formulations, for intramuscular injection.
Advantageously, the compounds of this invention can be administered in single daily dosage form, or is divided into often per total daily dose
Day twice, three times or four dosage administrations.Furthermore, it is possible to be given through intranasal form via local using suitable intranasal instrument
The compounds of this invention, or give the compounds of this invention via percutaneous plaster known to those of ordinary skill in the art.In order to saturating
The form administration of skin transmission system, dosage will be continuous and intermittent certainly in whole dosage regimen.
The daily dosage of this product can change in very large range, from every daily 0.01-1000mg of adult.For orally giving
Medicine, preferably provides the composition of tablet form, the tablet is containing 0.01,0.05,0.1,0.5,1.0,2.5,5.0,10.0,
15.0th, 25.0,50.0,100,150,200,250 and 500 milligrams of active component, is the agent that patient to be treated carries out symptom
Amount adjustment.The general dosage level in about 0.01mg/kg- about 300mg/kg body weight daily provides the effective dose of medicine.Preferably,
The scope is from about 0.5- about 5.0mg/kg body weight daily, most preferably, from about 1.0- about 3.0mg/kg body weight daily.According to
Prescription case, this compound can be given daily 1-4 times.
The optimal dose of administration can be easy to determine and by according to specifically used compound, administration by those skilled in the art
Pattern, the intensity of preparation, the progress of administering mode and disease condition are different and different.In addition, having with specifically treated patient
The factor of pass, including patient age, body weight, diet and administration number of times, it will produce the demand of adjustment dosage.
The fourth aspect of the present invention is there is provided the compound of formula 1 of the present invention or its pharmaceutically acceptable salt in treatment
Application in hyperlipemia, it includes giving at least one compound of formula 1 of the present invention of effective dose to individual in need
Or its pharmaceutically acceptable salt.
The fifth aspect of the present invention is there is provided the compound of formula 1 of the present invention or its pharmaceutically acceptable salt in treatment
Application in atherosclerosis, it includes changing at least one formula 1 of the present invention that individual in need gives effective dose
Compound or its pharmaceutically acceptable salt.
The fifth aspect of the present invention is being prepared there is provided the compound of formula 1 of the present invention or its pharmaceutically acceptable salt
Application in medicine, the medicine is used to treat hyperlipemia.
The fifth aspect of the present invention is being prepared there is provided the compound of formula 1 of the present invention or its pharmaceutically acceptable salt
Application in medicine, the medicine is used to treat atherosclerosis.
The compounds of this invention can increase uptake ratio of the liver cell to low-density lipoprotein, can significantly reduce the blood of rat
Clear T-CHOL, serum triglyceride, serum LDL cholesterol, action effect are suitable with Simvastatin, show this
Invention compound has excellent hypolipidemic activity, in the treatment that can be applied to hyperlipemia and atherosclerosis.
Embodiment
The present invention is described below in more detail to contribute to 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 of many present invention, and be considered as preparing other methods of compound of the invention in model of the invention
Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention
Completed by method of modifying, such as appropriate protection interference group, by using other known reagent except 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 applied to the preparation of other compounds of the invention.
Embodiment 1：1- ((3- methoxyl group -4- methyl -6- oxo -4,5,6,7- tetrahydrochysene -2H- pyrazoles [3,4-b] pyridines -2-
Base) methyl) -3- (piperidin-1-yl) urea (compound I)
Step one：Bromomethyl hydrazine (2.46g, 20.0mmol) is added to 2- malonic methyl ester nitriles (1.98g, 20.0mmol)
Solution in ethanol (100mL), and stir mixture 2 hours at 50 DEG C.Concentrated reaction solution, the residual of acquisition under reduced pressure
Thing is separated into organic layer and water layer by adding the sodium bicarbonate aqueous solution and ethyl acetate of saturation.With salt water washing organic layer simultaneously
Dry, and under reduced pressure distill out solvent on anhydrous sodium sulfate.The residue obtained with Gossypol recrystallized from chloroform is to obtain 1- (bromines
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) that is prepared in step one-
The ethanol 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.
Recrystallize the residue of acquisition to obtain 2- (bromomethyl) -3- methoxyl group -4- methyl -4,5- dihydro -2H- pyrazoles with tetrahydrofuran
[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- bases) urea (0.86g, 6.0mmol), 2- (bromomethyl) -3- methoxyl group -4- methyl -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) are mixed, and are being heated to reflux lower stirring 6 hours.Room temperature is cooled to, by gained
Reactant mixture be extracted with ethyl acetate.Organic layer is washed with water, then with anhydrous sodium sulfate drying, is concentrated under decompression；Thick production
Thing silica gel column chromatogram separating purification, eluant, eluent is Ethyl acetate-cyclohexane (1:2) title compound of white solid, is obtained
1.42g, yield is 84%, content 99%.
ESI-MS：338.19[M+H]+
Elementary 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- bases) methyl) -4- (methyl fluoride) -6- oxos -4,5,6,7- four
Hydrogen -2H- pyrazoles [3,4-b] pyridine -2- bases) methyl) -3- thio-morpholinyl ureas (compound II)
According to the method for embodiment 1,2- cyanoacetic acid first is replaced with 3- oxos -4- (2H-1,2,3- triazole -2- bases) butyronitrile
Ester, 1- fluorine acetaldehyde methyl hemiacetal replaces acetaldehyde methyl hemiacetal, and 1- (piperazine -1- are replaced with 1- (thiomorpholine -4- bases) urea
Base) urea, obtain the title compound of faint yellow solid, three step gross production rates 38%.
ESI-MS：424.16[M+H]+
Elementary 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- bases) -3- ((3- (2- ethoxyethyl groups) -6- oxos -4- (trifluoromethyl) -4,
5,6,7- tetrahydrochysene -2H- pyrazoles [3,4-b] pyridine -2- bases) methyl) urea (compound III)
According to the method for embodiment 1,2- malonic methyl ester nitriles, trifluoro acetaldehyde first are replaced with 5- ethyoxyl -3- oxopentanenitriles
Base hemiacetal replaces acetaldehyde methyl hemiacetal, replaces 1- (piperazine -1- bases) urea with 1- (the chloro- pyridine -2- bases of 3-) urea, obtains white
The title compound of solid, three step gross production rates 35%.
ESI-MS：461.12[M+H]+
Elementary 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 compounds of this invention hypolipidemic activity is tested
1. the facilitation that target compound is absorbed to liver cell low-density lipoprotein
With compound I, II, III and (final concentration of 5 μM) of positive control Simvastatin processing degreasing serum starvation 12 hours
HepG2 cells 24 hours, add the μ g/ml of low-density lipoprotein (DiI-LDL) 20 of fluorescence labeling, 37 DEG C are incubated 4 hours, use
Phosphate buffer, which is gently washed, uses isopropyl alcohol extracting lipid after cell 5 times, in determining fluorescence reading (exciting light on ELIASA：
520nm；Launch light 570nm).Then 0.2M NaOH cell lysis is used, protein content is determined, calculates fluorescence/albumen
Numerical value.Experimental result is shown in Table 1.
Table 1：The effect that target compound is absorbed to liver cell low-density lipoprotein
| Compound | Consumption | 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
Result of the test shows that 3 compounds of the invention can dramatically increase liver cell HepG2 to low close under 5 μM of concentration
Spend lipoprotein LDL intake.
2. the dose dependent that target compound is absorbed to liver cell low-density lipoprotein
With the compound I of various concentrations (concentration is respectively 5,10,20 μM) the processing degreasing serum starvation HepG2 of 12 hours
Cell 24 hours, calculates uptake ratio of the cell to low-density lipoprotein as stated above, investigates compound I dosage and activity
Between relation.Experimental result is shown in Table 2.
Table 2：The effect that various concentrations compound is absorbed to liver cell low-density lipoprotein
| Compound | Consumption | 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
Result of the test shows that there is the compounds of this invention I increase HepG2 cell phagocytosiss LDL obvious dose dependent to close
System, can very significantly increase intakes (P ＜ 0.01) of the liver cell HepG2 to low-density lipoprotein LDL under 20 μM of concentration,
And the effect of increase LDL intakes is suitable with Simvastatin.
3. internal reducing blood lipid drug efficacy study is administered orally in target compound
3.1 experimental animals
Male SD rat, 200 ± 10g of body weight.
3.2 medicines are prepared
Compound I, II, III and Simvastatin 5%DMSO, 2%Tween80 and 93% normal saline into
15mg/ml suspension decoction, is mixed using preceding ultrasound；Every animal gives 200 μ l/100g administered volume, and dosage is
20mg/kg。
3.3 experimental methods
Male SD rat adaptability is grouped after raising one week according to its initial blood fat and weight levels stochastic averagina, every group 10
Only.Hyperlipidemia model group and administration group give high lipid food, administration group given in the way of abdominal cavity is injected 20mg/kg compound I,
II, III, positive controls give 20mg/kg compound Simvastatin in the way of abdominal cavity is injected, and hyperlipidemia model group is orally given
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 methods)
Determine serum total cholesterol (TC)；Serum triglyceride (TG) is determined with enzymatic end pointassay (GPO-PAP methods)；Use polyvinyl sulfuric acid salt
PVS Precipitation Determinations 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 groups | 1.93 ± 0.24 (33.9%) * * | 1.24 ± 0.08 (14.5%) * | 1.01 ± 0.31 (45.1%) * * |
| Compound II groups | 2.16 ± 0.28 (26.0%) * * | 1.36 ± 0.10 (6.2%) * | 1.22 ± 0.28 (33.7%) * * |
| Compound III groups | 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
Result of the test shows, after 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 with significant difference (P ＜ 0.05 or 0.01), decline degree is with giving pungent cut down
The positive controls of statin are similar, point out the compounds of this invention to have significant effect for reducing blood fat, action effect and Simvastatin
Quite.
Above-mentioned pharmacological testing shows that the compounds of this invention can increase uptake ratio of the liver cell to low-density lipoprotein, energy
Enough significantly reduce the serum total cholesterol, serum triglyceride, serum LDL cholesterol of rat, action effect with it is pungent
Cut down statin quite, show that the compounds of this invention has excellent hypolipidemic activity, hyperlipemia can be applied to and artery congee is hard
In the treatment of change.
The preferred embodiment for the present invention is the foregoing described, so it is not limited to the present invention.Those skilled in the art couple
Embodiment disclosed herein can carry out improvement and the change without departing from scope and spirit.
Claims (10)
1. a kind of compound of formula 1, or its pharmaceutically acceptable salt：
In Formulas I,
A represents heterocyclic radical, and it is optionally selected from halogen, oxo, cyano group, nitro, hydroxyl, amino, carboxyl, C1-4 alkyl, C3-8
Cycloalkyl, halogenated c1-4 alkyl, C1-4 alkoxies, C1-4 alkylthio groups, C1-4 alkoxy C 1-4 alkyl, C1-4 alkyl sulphonyls,
C1-4 alkyl aminos, the group of two (C1-4 alkyl) amino, C1-4 alkyl-carbonyls and C1-4 alkoxy carbonyls are replaced；
R1Represent：Hydroxyl, amino, C1-4 alkoxies, C1-4 alkyl, C3-8 cycloalkyl, halogenated c1-4 alkyl, C1-4 alkoxy Cs 1-
4 alkyl, aryl, aryl C1-2 alkyl, heterocyclic radical, heterocyclic radical C1-2 alkyl；
R2Represent：Hydrogen, hydroxyl, amino, C1-4 alkyl, halogenated c1-4 alkyl, hydroxyl substitution C1-4 alkyl, C3-8 cycloalkyl,
C1-4 alkyl-carbonyls, C1-4 alkoxy carbonyls, aryl, aryl C1-2 alkyl, heterocyclic radical, heterocyclic radical C1-2 alkyl；
L is represented：-(CR3R4) n-, wherein each R3、R4Hydrogen or C1-4 alkyl can be each independently selected from identical or different；
N represents 1,2,3,4 or 5.
2. compound according to claim 1, it is characterised in that preferred, five yuan of the heterocycle basis representation or hexa-atomic list
Ring heteroaryl, or nine yuan or ten membered bicyclic heteroaryls.
3. compound according to claim 1, it is characterised in that five yuan of the heterocycle basis representation to seven unit monocycle heterocycle alkane
Base, or nine yuan or ten membered bicyclic Heterocyclylalkyls.
4. compound according to claim 1, it is characterised in that the aryl represents C6-14 aryl.
5. compound according to claim 1, it is characterised in that the R1Represent：Hydroxyl, C1-4 alkoxies, C1-4 alcoxyls
Base C1-4 alkyl；The R2Represent：C1-4 alkyl or halogenated c1-4 alkyl.
6. compound according to claim 1, it is selected from：
7. a kind of prepare the compound of formula 1 according to claim 1 or the method for its pharmaceutically acceptable salt, methods described
Comprise the following steps：
Step one：
The step includes making Formula II compound react in atent solvent with formula IV compounds with formula III compound；
Step 2：
The step includes making formula IV compound react with formula in atent solvent with Formula V compound and Meldrum ' s acid
VI compounds；
Step 3：
The step includes making Formula IV compound react in atent solvent with formula 1 with Formula VII compound and alkali, catalyst
Compound；
Alkali for the step can be hydroxide, such as NaOH, potassium hydroxide；Carbonate, such as sodium carbonate, carbonic acid
Potassium；Bicarbonate, such as sodium acid carbonate, saleratus；Acetate, such as sodium acetate or potassium acetate；Alkali is preferably bicarbonate,
More preferably saleratus；
Catalyst for the step can be cuprous salt, such as cuprous iodide；
Optional step four：
In case there is a need, the compound of the formula 1 experience salt-forming steps are made to prepare its pharmaceutically acceptable salt；
In above-mentioned steps, A, R1、R2, L as described in the appended claim 1, X represents halogen, preferably chlorine or bromine；R represents C1-4 alkyl.
8. a kind of pharmaceutical composition, it includes at least one compound of formula 1 according to claim any one of 1-6 or its medicine
Acceptable salt on, and pharmaceutically acceptable carrier.
9. the compound of formula 1 or its pharmaceutically acceptable salt according to claim any one of 1-6 are in medicine is prepared
Using the medicine is used to treat hyperlipidemia.
10. the compound of formula 1 or its pharmaceutically acceptable salt according to claim any one of 1-6 are in medicine is prepared
Using the medicine is used to treat atherosclerosis.
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| US20040266815A1 (en) * | 2003-06-27 | 2004-12-30 | Pfizer Inc | Pyrazolo[3,4-b]pyridin-6-ones as GSK-3 inhibitors |
| WO2013176970A1 (en) * | 2012-05-22 | 2013-11-28 | Merck Sharp & Dohme Corp. | TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF |
| CN104311575A (en) * | 2014-09-19 | 2015-01-28 | 广东东阳光药业有限公司 | Pyrazolo piperidone compound containing condensed ring and composition and application thereof |
| CN104327074A (en) * | 2014-09-19 | 2015-02-04 | 广东东阳光药业有限公司 | Lactam substituent-containing pyrazolo piperidone compound and composition and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040266815A1 (en) * | 2003-06-27 | 2004-12-30 | Pfizer Inc | Pyrazolo[3,4-b]pyridin-6-ones as GSK-3 inhibitors |
| WO2013176970A1 (en) * | 2012-05-22 | 2013-11-28 | Merck Sharp & Dohme Corp. | TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF |
| CN104311575A (en) * | 2014-09-19 | 2015-01-28 | 广东东阳光药业有限公司 | Pyrazolo piperidone compound containing condensed ring and composition and application thereof |
| CN104327074A (en) * | 2014-09-19 | 2015-02-04 | 广东东阳光药业有限公司 | Lactam substituent-containing pyrazolo piperidone compound and composition and use thereof |
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