CN109879840A - 4- piperazine methyl -7- hydroxyl benzofuran class compound and its medical usage - Google Patents
4- piperazine methyl -7- hydroxyl benzofuran class compound and its medical usage Download PDFInfo
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Abstract
4- piperazine methyl -7- hydroxyl benzofuran class compound and its medical usage, it is related to a kind of compound and its medical usage, the compound includes a kind of 4- piperazine methyl -7- hydroxyl benzofuran class compound of formula I and the stereoisomer and its pharmaceutically acceptable salt of above compound:
Description
Technical field
The present invention relates to a kind of compound and its medical usages, more particularly to a kind of 4- piperazine methyl -7- hydroxy benzo
Furfuran compound and its medical usage.
Background technique
Obesity is a kind of worldwide common disease, in recent years in, the obesity of the whole world especially developed country is sent out
Sick rate is increasing.Due to the continuous improvement of economic fast development and living standard, exist always in modern life mode
Exercise lack and ingest energy relative surplus the problem of, the intake which results in numerous modern's human body energies has been more than energy
Consumption understands some in superfluous energy as depot fat in adipose tissue, leads to obesity, and obesity can cause it is a variety of
Metabolic disorder is one of the Major Risk Factors of diabetes and cardiovascular disease, and with the disease incidence of cardiovascular patient and death
Rate increases related.Currently, being traditionally based on diet and movement often extremely has the long-term efficacy of the non-drug therapy of obesity
Limit, Chinese materia medica preparation there is no kind curative for effect in drug therapy, and the treatment of obesity essentially consists in exploitation increase energy and disappears
The drug of consumption or the drug for reducing caloric intake.Wherein, the main method for reducing caloric intake be exactly reduce body digestion and
Nutriment in assimilating food, it is especially fatty.Pancreatic lipase is enzyme necessary to fat digestion absorbs in enteron aisle, in food
Fat pancreatic lipase effect under be hydrolyzed to monoacylglycerol and free fatty acid, after enteron aisle is reuptaked, in vivo
Synthctic fat again causes fat accumulation as energy stores, eventually leads to fat and associated hyperlipidemia, diabetes
The generation of equal metabolic diseases.Pancreatic lipase inhibitor can be effectively suppressed pancreatic lipase in enteron aisle and make to the catalytic decomposition of fat
With, achieve the purpose that reduce fat absorption into fat with treatment, thus the effective pancreatic lipase inhibitor of development and application by
The common concern of people.Pancreatic lipase inhibitor salable is Xenical currently on the market, active strong, and stability is good etc.
Feature, but also have the shortcomings that simultaneously uncontrollable bowel symptoms, oil just with vomiting abdominal distension.Therefore new pancreatic lipase is found
Inhibitor has great importance to the prevention and treatment of the metabolic diseases such as fat and diabetes.
Summary of the invention
The purpose of the present invention is to provide a kind of 4- piperazine methyl -7- hydroxyl benzofuran class compounds and its pharmaceutical
On the way, application of the compounds of this invention as effective lipase inhibitors object space face, especially as novel reduction nutrient absorption
Agent may act on gastrointestinal tract, prevent the catalytic decomposition of lipase, and the partial fat taken in by diet is inhibited to absorb, and be suitable for fertilizer
Fat disease including heathy obesity subjects and has the overweight peoples of adult-onset diabetes, that is, by a effective amount of present inventionization
Close object administration.
The purpose of the present invention is what is be achieved through the following technical solutions:
4- piperazine methyl -7- hydroxyl benzofuran class compound, the compound include a kind of 4- piperazine methyl -7- hydroxyl of formula I
The stereoisomer and its pharmaceutically acceptable salt of base benzofuran compounds and above compound:
Wherein Ar independently is selected from phenyl, the alkyl-substituted phenyl of C1-C4, the phenyl that C1-C4 alkoxy replaces, halogen substitution
Phenyl, cyano replace phenyl；
Further, the present invention preferably has following formula (1) compound and its pharmaceutically acceptable salt:
Ar independently be selected from phenyl, 4- aminomethyl phenyl, 2- aminomethyl phenyl, 4- methoxyphenyl, 4- chlorphenyl, 4- bromophenyl,
4- fluorophenyl, 4- cyano-phenyl.
4- piperazine methyl -7- hydroxyl benzofuran class compound and its medical usage, described the composition contain effective quantity such as
On compound or pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
4- piperazine methyl -7- hydroxyl benzofuran class compound the medical usage, the medical usage are the chemical combination
Application of the object in the drug that preparation prevents and treats disease related with lipase.
It is prepared by the 4- piperazine methyl -7- hydroxyl benzofuran class compound medical usage, described pharmaceutical composition
Prevent and treat the application in the drug of disease related with lipase.
4- piperazine methyl -7- hydroxyl benzofuran class compound the medical usage, the disease related with lipase
Disease include include heathy obesity subjects and the overweight people for having adult-onset diabetes.
4- piperazine methyl -7- hydroxyl benzofuran class compound the medical usage, the lipase inhibitor is one
Kind has high selectivity, long-acting gastrointestinal lipases inhibitor, the serine with lipase active sites in stomach and pancreas
Residue covalent bonding does not influence other enzymatic activitys of nervous system and gastrointestinal tract to block the absorption of fat and water；The fat
Enzyme inhibitor is chemical synthesis compound, this lipase inhibitor is by inhibiting the activity of lipase to reach weight-reducing.
It is an object of the present invention to provide new 4- piperazine methyl -7- hydroxyl benzofuran class compounds and above-mentioned
The stereoisomer and its pharmaceutically acceptable salt of compound: the compound has significant inhibition pancreatic lipase effect.
The present invention relates to the compounds of following formula I:
Wherein Ar can independently be selected from phenyl, the alkyl-substituted phenyl of C1-C4, the phenyl that C1-C4 alkoxy replaces, halogen
Substituted phenyl, the phenyl that cyano replaces.
Further, Ar can independently be selected from phenyl, 4- aminomethyl phenyl, 2- aminomethyl phenyl, 4- methoxyphenyl, 4-
Chlorphenyl, 4- bromophenyl, 4- fluorophenyl, 4- cyano-phenyl.
The present invention includes stereoisomer and optical isomer, such as mixture of enantiomers and each enantiomer and non-right
Body is reflected, Producing reason is the structural asymmetry in the selected series compound.The compounds of this invention can also have
There is polymorphic, all polymorphics are also included in the present invention.
The compounds of this invention is also possible to the form of solvate, especially hydrate.Hydration can occur in compound
Or in the production process of the composition comprising compound, or due to the hygroscopicity of compound, water can occur by certain time
It closes.
Certain compounds of the compounds of this invention are the derivatives for being referred to as prodrug.
The pharmaceutically acceptable salt of the compounds of this invention is (with water-soluble or oil-soluble products or dispersible product shape
Formula) it include conventional non-toxic salt or quaternary ammonium salt, they are, for example, to generate from inorganic or organic acid or alkali.The reality of acid-addition salts
Example includes malate, maleate, sulfanilate, hydrochloride, acetate, adipate, alginates, asparagus fern
Propylhomoserin salt, benzoate, benzene sulfonate, tosilate, disulfate, butyrate, citrate, camphor hydrochlorate, camphor
Sulfonate, cipionate, digluconate, lauryl sulfate, esilate, fumarate, gluceptate are sweet
Oleophosphoric acid salt, Hemisulphate, enanthate, caproate, hydrogen chlorate, hydrobromate, hydriodate, 2- isethionate, cream
Hydrochlorate, maleate, mesylate, 2- naphthalene sulfonate, nicotinate, nitrate, oxalates, pamoate, pectinic acid salt, over cure
Hydrochlorate, 3- phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, sulfate, tartrate, rhodanate,
Toluene fulfonate and undecylate etc..Alkali salt include ammonium salt, alkali metal salt, such as sodium and sylvite, alkali salt, such as calcium and
Magnesium salts, the salt of organic base, such as dicyclohexyl amine salt, the salt of N- methyl-D-glucamine salt and amino acid, such as arginine rely ammonia
Acid etc., moreover, Basic nitrogen-containing groups can be quaternized with such reagent, such as elementary alkyl halide, such as methyl, ethyl,
The chlorine of propyl and butyl, bromine and iodide；Dialkyl sulfate, such as dimethyl suflfate, diethylester, dibutyl ester and diamyl ester；It is long
The chlorine of chain halide, such as decyl, lauryl, myristyl and stearyl, bromine and iodide；Aralkyl halide, such as benzyl
With the bromide of phenethyl etc..It is preferred for generating the acid of acid-addition salts including hydrochloric acid and acetic acid.
For their application, the effect of the enzyme rejection characteristic of the compounds of this invention and other biochemical parameters are according to this
Standard biochemical technique known to field is subject to determining.The actual dose range of application depends on treated patient or animal disease
The property and seriousness of diseased state, these are determined by the diagnostician of follow-up.It is expected that useful dosage range will be
About 0.01-10mg/Kg is daily, that is, can reach effective therapeutic effect.
The compounds of this invention can be combined or be embedded in soluble and/or biodegradable polymer, be then coated in
On stent moulage.Such polymer may include polyvinylpyrrolidone, poly- hydroxyl-propyl methacrylamide-
Phenol, poly-hydroxyethyl-asparagine-phenol, the polyethyleneoxide-polylysine replaced by palmitoyl residues, polylactic acid are gathered
The copolymer of glycolic, polylactic acid and polyglycolic acid, poly-epsilon-caprolactone, polyhydroxybutyrate gather original ester, polyacetals, poly- dihydro pyrrole
It mutters, the crosslinking of polybutylcyanoacrylate and hydrogel or amphiphilic block copolymer.
When being used as lipase inhibitor, the effective quantity of the compounds of this invention administration can be in about 0.1-500mg/Kg weight
Dosage range in, preferably 0.1-10mg/Kg weight range, dosage regimen is once a day or 2-4 times.
Lipase inhibitor can be coupled with soluble polymer, and the latter is as orientable pharmaceutical carrier.It is such poly-
Closing object may include polyvinylpyrrolidone, pyran co-polymer, poly- hydroxyl-propyl methacrylamide-phenol, poly-hydroxyethyl-day
Winter glutamine-phenol, or the polyethyleneoxide-polylysine replaced by palmitoyl residues.Moreover, lipase inhibitor can be with
A kind of biodegradable polymer coupling, the latter can be used for realizing that the control of drug discharges, such as polylactic acid, polyglycolic acid,
The copolymer of polylactic acid and polyglycolic acid, poly epsilon caprolactone lactone, polyhydroxybutyrate gather original ester, polyacetals, poly- dihydropyran, paracyanogen base
The crosslinking of acrylate and hydrogel or amphiphilic block copolymer.
Pharmaceutical composition of the invention can be administered by any way.For example, administration can by parenteral, subcutaneously,
Intravenously, intramuscular, transdermal in peritonaeum, cheek or ocular route.Alternatively, oral route concurrent, administration can be passed through.Dosage
It will depend on the age of subject, health status and weight, the type (if yes) of concurrent treatment, therapeutic frequency and institute
Need the property of effect.
Other than reactive compound pharmaceutically, the pharmaceutical preparation is also containing suitable pharmaceutically acceptable load
Body, including the excipient and auxiliary agent for being conducive to for reactive compound to be processed into preparation that can be medicinal.
Pharmaceutical preparation of the invention is granulated, pelletization by conventional mixing, dissolution or freeze-drying process.Therefore, pass through
Reactive compound is mixed into available oral drug preparation with solid excipient, suitable auxiliary agent can be added, then grinds institute
Mixture is obtained, granulate mixture is processed into tablet or pastille core.
Suitable excipient especially filler, such as carbohydrate, such as lactose or sucrose, mannitol or D-sorbite are fine
Plain preparation and/or calcium phosphate are tieed up, such as tricalcium phosphate or calcium monohydrogen phosphate and adhesive, such as gelatinized corn starch, such as cornstarch is small
Wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose
Plain sodium and/or polyvinylpyrrolidone.Disintegrating agent, starch as escribed above and carboxymethyl starch can also be added, be crosslinked poly- second
Alkene pyrrolidone, agar, alginic acid or its salt, such as mosanom.Auxiliary agent especially glidant and lubricant, such as silica are sliding
Stone, stearic acid or its salt, such as magnesium stearate or calcium stearate and/or polyethylene glycol.It is eligible containing Arabic gum, talcum,
Polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, paint solution and suitable organic solvent or solvent mixture.For
The coating for forming tolerance gastric acid, uses the solution of suitable cellulose preparation, such as cellulose acetate phthalate or neighbour
Hydroxypropyl methylcellulose phthalate.Dyestuff or pigment can be added into the coating of tablet or dragee, for example, being used for
Identify or in order to describe the combination of each dose of reactive compound.
Other pharmaceutical preparations that can be administered orally include formula capsule is pushed and fitted made of gelatin, and by gelatin and
Soft seal capsule made of the plasticizer such as glycerol or D-sorbite.The formula capsule of being pushed and fitted can contain the activation of particle form
Object is closed, they can be with fillers, the adhesives such as starch and/or the lubricants such as talcum or magnesium stearate such as lactose and optional
Stabilizer mixing.In soft capsule, reactive compound is preferably dissolved or suspended in suitable liquid, such as fat oil or liquid
Paraffin.Alternatively, it is also possible to which stabilizer is added.
The preparation for being suitable for parenteral administration includes the aqueous solution of water soluble active compound, such as water soluble salt, alkalinity
Solution and cyclodextrin encapsulated complex compound.Especially preferred basic salt is ammonium salt, e.g. use Tris, bursine,
Bis-Tris propane, N-METHYL-ALPHA-L-GLUCOSAMINE or arginine preparation.One or more modifications or unmodified ring paste can be used
Essence is come the water solubility for the compounds of this invention that stabilizes and increases.
It is administered in addition, reactive compound can be used as oily injection appropriate with suspension.Suitable lipophilic solvent or
Carrier includes fat oil, such as sesame oil, or the aliphatic ester of synthesis, such as ethyl oleate or triglycerides or polyethylene glycol-400
(compound dissolves in PEG-400).Aqueous injection suspensions can contain the substance for increasing suspension viscosity, such as carboxymethyl
Sodium cellulosate, D-sorbite and/or glucan.Optionally, suspension can also contain stabilizer.
Using exchange reaction, the compounds of this invention can be marked with radioiodine.As known in the art with hot iodine
Exchange cold iodine.
The present invention also include can be used for body fat imaging composition, wherein the composition be by with radioactive atom network
The compounds of this invention composition of conjunction, or by forming with the invention compound of the present invention that paramagnetic atom is complexed.It uses
Complexing technology well known in the art obtains.
The present invention also includes the diagnosis composition that can be used for body fat imaging, and the composition includes pharmaceutically acceptable
The composition of a effective amount of the compounds of this invention on carrier and diagnostics.
The composition of " effective quantity in diagnostics " needed for every dose will depend on administration route, the type treated and be examined
The specific corporal characteristic considered.These factors and its relationship between determining dosage are that area of medical diagnostics technical staff institute is ripe
Know.And effective quantity and medication in adjustable diagnostics, optimum curative effect is reached, but is also depended on many
The other factors that factor, such as weight, diet, parallel drug therapy and medical domain technical staff will consider.Any
Aspect, the dosage for imaging should be enough to detect the presence of the preparation in targeted fat sites.In general, radiophotography is wanted
Seeking dosage provided by pharmaceutical composition of the present invention is about 5-20 μ Ci, preferably from about 10 μ Ci.Magnetic resonance imaging requires to be provided
Dosage be about 0.001-5mmol/Kg, the chemical combination of the present invention of preferably from about 0.005-0.5mmol/Kg and paramagnetic atoms complexing
Object.In both cases, actual dose known in the art will depend on the position of lipase.
It is known to pharmaceutical field for intracorporal " pharmaceutically acceptable carrier ".Pharmaceutical composition of the invention can
To be configured to the sterile solution or suspension for drug administration by injection with pharmaceutically acceptable carrier, it is suitable for dissolving before the injection
Or the solid form or lotion to float on a liquid.Suitable excipient such as water, salt water, glucose, mannitol, cream
Sugar, lecithin, albumin, sodium glutamate, cysteine hydrochloride etc..In addition, the pharmaceutical composition of injectable can be containing a small amount of
Nontoxic auxiliary substance, such as wetting agent, pH buffer etc..If necessary, can be used sorbefacient preparation (such as
Liposome).
The diagnosis composition that the present invention is also covered by storing or to be administered and prepare, in addition they contain preservative, stabilizer
And stain.For example, sodium benzoate, the ester of sorbic acid and P-hydroxybenzoic acid can be added as preservative.Further, it is possible to use
Antioxidant and suspending agent.
In-vivo imaging method of the invention also provides several the advantages of being better than pervious imaging process, these imaging process
For detecting or monitoring the presence of lipase, size subsides or increases.Compound especially provided by the present invention, composition
Be designed to extremely closely be combined with lipase with diagnosis composition, lipase be it is associated with obesity, to subtract
Few circulation radioactivity or paramagnetism " background " generated by unbonded preparation.Moreover, passing through the intracoronary injection present inventionization
The in-vivo imaging for closing object, composition or diagnosis composition and carrying out is expected almost instantaneous, this is because these preparation meetings
Saturated fat enzyme immediately.
Therefore, the present invention also includes the method for body fat imaging, and this method includes the following steps: that (1) will diagnose
The intracorporal fat of people is detected in the compounds of this invention of acceptable amount on, composition or diagnosis composition administration, and (2).With
In the method for monitoring fatty size, position and quantity and lipase dissolution or growth.This method uses compound, group in vivo
When closing object or diagnosis composition, " administration " is realized by parental routes, in a manner of whole body or local orientation.It is real
The method of existing Formulations for systemic administration is by the compounds of this invention, and composition or diagnosis composition are injected into suitable and available vein or dynamic
In arteries and veins.The method for realizing local orientation's administration is the speed by the compounds of this invention, composition or diagnosis composition to approach blood flow
Degree is injected under a cloud in the vein for containing thrombus far from injection site or intra-arterial.This includes but is not limited to be injected directly into hat
In shape arterial vasculature, coronary artery fat is imaged, is injected directly into arteria carotis, makes the fat imaging in brain vascular system,
Or it is injected directly into foot intravenously, leg Deep venou fat is imaged.
Delivery mode from the present composition to lipase position also in the range of term " administration " is considered.For example,
Radioactive atom can be injected later, thus in lipase position body by the compound injection for being connected with chelating unit in vivo
The interior composition for forming the compound comprising being complexed with radioactive atom.Alternatively, can will be comprising being complexed with radioactive atom
The composition of compound is injected into vivo.
As previously mentioned, with compound in the methods of the invention, composition or diagnosis composition it is " effective in diagnostics
Amount " will depend on administration route, the type treated and the specific corporal characteristic treated.These factors and its with determine dosage
Between relationship be known to area of medical diagnostics technical staff.It in any way, should be sufficient for the dosage of in-vivo imaging
To detect the presence of the imaging dosage in targeted lipase position.In general, radiophotography requires pharmaceutical composition institute of the present invention
The dosage of offer is about 5-20 μ Ci, preferably from about 10 μ Ci.It is about 0.001- that magnetic resonance imaging, which requires provided dosage,
The compounds of this invention of 5mmol/Kg, preferably from about 0.005-0.5mmol/Kg and paramagnetic atoms complexing.In both cases, originally
Actual dose known to field will depend on the position of fat.
The advantages and effects of the present invention are:
Application of the novel compound of present invention as effective lipase inhibitors object space face, especially as novel reduction nutrition
Absorbent may act on gastrointestinal tract, prevent the catalytic decomposition of lipase, and the partial fat taken in by diet is inhibited to absorb, and be applicable in
In obesity, including heathy obesity subjects and there is the overweight peoples of adult-onset diabetes, that is, a effective amount of is sent out
Bright compound administration.
The synthetic method of this kind of compound of the invention is simple, adapts to industrialized production, more relative to natural analog
Add stabilization, biological activity test shows that such compound has and inhibits pancreatic lipase activity, can be used as a kind for the treatment of or prevention
Obesity drug is applied to clinic.
The compounds of this invention can be used for a variety of therapeutic purposes.The compounds of this invention is a kind of with high selectivity, length
The gastrointestinal lipases inhibitor of effect, the serine residue covalent bonding with lipase active sites in stomach and pancreas, to hinder
The absorption of disconnected fat and water, does not influence other enzymatic activitys of nervous system and gastrointestinal tract.The compounds of this invention is chemical synthesis
Close object, it is different from other slimming drugs, do not act on nervous system, have no adverse effects to angiocarpy, act on gastrointestinal tract, but not by
Gastrointestinal tract absorbs.Lipase inhibitor of the invention is by inhibiting the activity of lipase to achieve the purpose that weight-reducing.
Specific embodiment
The following describes the present invention in detail with reference to examples.
The following example illustrates the method and composition being not intended to limit the present invention.Other of different condition and parameter are suitably repaired
Changing and adjusting is also normally, it is evident to the person skilled in the art that also within the scope of the invention.
The compound of the present invention can be prepared according to general approach below using suitable substance, and be passed through then
Specific embodiment further illustrates.However, the compound enumerated in embodiment is not interpreted to form the present invention
The substance uniquely approved.The condition of following preparation step and the various known variants of method can be used for preparing these chemical combination
Object.All temperature are degree Celsius, unless otherwise specified.
What the several representative embodiments of the present invention were described below prepares reaction process.
The preparation of embodiment 1:4- [(4- phenylpiperazine -1- base) methyl] -7- hydroxyl benzofuran (B01)
By 4.0 g of 7- hydroxyl benzofuran (0.030mol), 4.9 g of 1-php (0.030mol), 37% formalin
Reaction flask is added in 2.4 mL (0.033mol), glacial acetic acid 1mL, and ethanol in proper amount makees solvent, is heated to reflux 4 ~ 8h, and TLC monitoring is anti-
Process is answered, to which after reaction, cooling, revolving removing ethyl alcohol obtains yellow oil, with ethyl acetate: petroleum ether (1:5) is
Eluant, eluent carries out column chromatographic isolation and purification, and revolving removes solvent, and faint yellow solid 3.0g, yield 32.5% is precipitated in freezing.ESI-MS
M/z:309.2；1H-NMR (CDCl3) δ (ppm): 2.62-2.67 (4H, m), 3.16-3.20 (4H, m), 3.56
(2H, s), 6.70(1H, m), 6.80(1H, d, J=8.1 Hz), 6.98-7.08(2H, m), 7.16-7.22 (4H,
m), 7.68(1H, d, J=8.1 Hz)。
The preparation of embodiment 2:4- { [4- (4- aminomethyl phenyl) piperazine -1- base] methyl } -7- hydroxyl benzofuran (B02)
According to the preparation method of example 1, faint yellow solid, yield 22.7% are obtained.ESI-MS m/z:351.4；1H-NMR
(CDCl3) δ (ppm): 2.28 (3H, s), 2.67-2.72 (4H, m), 3.20-3.35 (4H, m), 3.60 (2H,
s), 6.70(1H, d, J=8.1 Hz), 6.96 (2H, d, J = 8.2 Hz), 7.00-7.06(2H, m), 7.16
(2H, d, J=8.2 Hz), 7.72(1H, d, J=8.1 Hz)。
The preparation of embodiment 3:4- { [4- (2- aminomethyl phenyl) piperazine -1- base] methyl } -7- hydroxyl benzofuran (B03)
According to the preparation method of example 1, faint yellow solid, yield 23.8% are obtained.ESI-MS m/z:351.4；1H-NMR
(CDCl3) δ (ppm): 2.30 (3H, s), 2.60-2.68 (4H, m), 3.28-3.36 (4H, m), 3.66 (2H,
s), 6.56-6.64 (1H, m), 6.77(1H, d, J=8.1 Hz), 6.94-7.03(3H, m), 7.08-7.13(2H,
m), 7.82(1H, d, J=8.1 Hz)。
The preparation of embodiment 4:4- { [4- (4- methoxyphenyl) piperazine -1- base] methyl } -7- hydroxyl benzofuran (B04)
According to the preparation method of example 1, faint yellow solid, yield 37.3% are obtained.ESI-MS m/z:367.3；1H-NMR
(CDCl3) δ (ppm): 2.60-2.66 (4H, m), 3.34-3.40 (4H, m), 3.68 (2H, s), 3.90 (3H,
s), 6.74(1H, d, J=7.8 Hz), 6.84(2H, d, J = 8.1 Hz), 6.90-6.99(1H, m), 7.04
(2H, d, J=8.1 Hz), 7.74(1H, d, J= 7.8 Hz)。
The preparation of embodiment 5:4- { [4- (4- chlorphenyl) piperazine -1- base] methyl } -7- hydroxyl benzofuran (B05)
According to the preparation method of example 1, faint yellow solid, yield 62.6% are obtained.ESI-MS m/z:343.1；1H-NMR
(CDCl3) δ (ppm): 2.68-2.74 (4H, m), 3.34-3.42 (4H, m), 3.64 (2H, s), 6.72 (1H,
d, J= 8.1 Hz), 6.85-6.91(2H, m), 6.96(2H, d, J=8.4 Hz), 7.24(2H, d, J = 8.4
Hz), 7.74(1H, d, J= 8.1 Hz)。
The preparation of embodiment 6:4- { [4- (4- bromophenyl) piperazine -1- base] methyl } -7- hydroxyl benzofuran (B06)
According to the preparation method of example 1, faint yellow solid, yield 32.1% are obtained.ESI-MS m/z:387.1,389.1；1H-
NMR (CDCl3) δ (ppm): 2.58-2.64 (4H, m), 3.38-3.46 (4H, m), 3.68 (2H, s), 6.78 (1H,
d, J= 7.8 Hz), 6.86-6.98(3H, m), 7.34(2H, d, J = 8.4 Hz), 7.78(1H, d, J= 8.1
Hz)。
The preparation of embodiment 7:4- { [4- (4- fluorophenyl) piperazine -1- base] methyl } -7- hydroxyl benzofuran (B07)
According to the preparation method of example 1, faint yellow solid, yield 34.5% are obtained.ESI-MS m/z:327.2；1H-NMR
(CDCl3) δ (ppm): 2.70-2.84 (4H, m), 3.21-3.25 (4H, m), 3.62 (2H, s), 6.72 (1H,
d, J= 8.1 Hz), 6.84-6.88 (2H, m), 7.02-7.09(4H, m), 7.78(1H, d, J= 8.1 Hz)。
The preparation of embodiment 8:4- { [4- (4- benzonitrile base) piperazine -1- base] methyl } -7- hydroxyl benzofuran (B08)
According to the preparation method of example 1, faint yellow solid, yield 28.0% are obtained.ESI-MS m/z:334.2；1H-NMR
(CDCl3) δ (ppm): 2.77-2.78 (4H, m), 3.33-3.38 (4H, m), 3.68 (2H, s), 6.74 (1H,
d, J= 8.1 Hz), 6.86-6.94 (2H, m), 7.03(2H, d, J=8.4 Hz), 7.58(2H, d, J = 8.4
Hz), 7.72(1H, d, J= 8.1 Hz)。
Embodiment 9: the measurement of lipase inhibiting activity
The measurement of lipase active using the 4-methyl umbelliferone of fluorescence in substrate oleate (4-UMO), by measurement by
The fluorescence for reacting the 4-methyl umbelliferone generated carries out.
When measurement, buffer is using the 13mM Tris-HCl(pH value containing 150mM NaCl, 1.36mM CaCl2
8.0).It is that the DMSO solution for the 0.1M that will be prepared dilutes 1000 times of product and rouge with above-mentioned buffer by substrate 4-UMO
Fat enzyme, for pancreatic lipase is equally used for enzymatic determination with the product that 400U/mL solution is made in above-mentioned buffer.
The 4-UMO buffer soln and 25 μ l of 50 μ l are added in 96 hole elisa Plates, mixed to enzyme reaction under the conditions of 250C
Distilled water (or sample aqueous solution) after, by add 25 μ l lipase buffer soln make reaction.Reaction carries out 30 points
The 0.1M citrate buffer solution (pH value 4.2) of Zhong Hou, 100 μ l of addition stop reaction, the 4- methylumbelliferyl that reaction is generated
The fluorescence (excitation wavelength 355nm, launch wavelength 460nm) of ketone is measured with fluorescence analyser.
The inhibitory activity of tested sample, relative to the activity of control (distilled water), using the sample size of inhibition 50% as IC50
(μM) is found out.
Representative compound of the present invention is measured according to the method described above, as a result shown in table 1:
Embodiment 10: antiobesity action of the compounds of this invention to Zucker obese rat
Zucker obese rat (heredity obese rat), male, 6 week old.Normal Zucker rat 8 is taken, as blank pair
According to group.Zucker obese rat is divided into 2 groups, i.e. model control group and administration group, every group 8.The compounds of this invention is with 0.5%
CMC-Na hydrotropy, dosage 120mg/Kg；Blank and model control group give the 0.5%CMC-Na of equal volume, and oral administration gavage is given
Medicine two weeks.Periodic detection diet and weight.
The compounds of this invention is shown in table 2 to the influence result of Zucker obese rat weight and diet:
From table 2 it can be seen that the compounds of this invention obviously inhibits Zucker obese rat weight gain, there is antiobesity action,
Do not have a significant impact to diet, and rat excrement shape no abnormality seen.
Embodiment 11: gelatine capsule
The preparation of hard gelatin capsule uses:
Above-mentioned preparation can be improved according to provided reasonable change.
Embodiment 12: tablet
The preparation of tablet uses
By said components mix and it is tabletted.
Embodiment 13: tablet
Tablet preparation in every containing 2.5-1000mg active component is as follows:
So that active constituent, starch and cellulose is passed through No. 45 meshes and is thoroughly mixed.By polyvinylpyrrolidonesolution solution and gained
Powder mixing, through No. 14 meshes after.The particle of generation is dried at 50-60 DEG C and through No. 18 meshes.60 will be first passed through in advance
Sodium carboxymethylcellulose, magnesium stearate and the talcum powder of number mesh are added in above-mentioned particle, are then mixed, are pressed on tablet press machine
Tablet is made.
Embodiment 14: suspension
The suspension preparation that every 5ml contains 0.1-1000mg drug is as follows:
Drug is enabled to be mixed to form smooth paste through No. 45 meshes and with sodium carboxymethylcellulose and syrup.By benzoic acid solution,
Corrigent and colorant are diluted with some water and aforesaid paste are added under stiring.Enough water is added then to reach required
Volume.
Embodiment 15: combined tablet-preparation
So that active constituent, starch and cellulose is passed through No. 45 meshes and is thoroughly mixed.By polyvinylpyrrolidonesolution solution and gained
Powder mixing, through No. 14 meshes after.The particle of generation is dried at 50-60 DEG C and through No. 18 meshes.60 will be first passed through in advance
Sodium carboxymethylcellulose, magnesium stearate and the talcum powder of number mesh are added in above-mentioned particle, are then mixed, are pressed on tablet press machine
Tablet is made.
Fat intake excessively may cause the metabolism such as obesity and diabetes relevant to obesity, hyperlipidemia, fatty liver
Dysfunctional disease.The decomposition for inhibiting pancreatic lipase that can inhibit fat in small intestine, to inhibit the absorption of fat.Chemical combination of the present invention
Object has antiobesity action as pancreatic lipase inhibitor, can be used for preventing or treating the diseases such as obesity.
Claims (6)
1.4- piperazine methyl -7- hydroxyl benzofuran class compound, which is characterized in that the compound includes a kind of 4- of formula I
The stereoisomer of piperazine methyl -7- hydroxyl benzofuran class compound and above compound and its pharmaceutically acceptable
Salt:
Wherein Ar independently is selected from phenyl, the alkyl-substituted phenyl of C1-C4, the phenyl that C1-C4 alkoxy replaces, halogen substitution
Phenyl, cyano replace phenyl；
Further, the present invention preferably has following formula (1) compound and its pharmaceutically acceptable salt: Ar independently is selected
From phenyl, 4- aminomethyl phenyl, 2- aminomethyl phenyl, 4- methoxyphenyl, 4- chlorphenyl, 4- bromophenyl, 4- fluorophenyl, 4- cyano benzene
Base.
2.4- piperazine methyl -7- hydroxyl benzofuran class compound and its medical usage, which is characterized in that described the composition contains
Effective quantity compound as above or pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
3. 4- piperazine methyl -7- hydroxyl benzofuran class compound medical usage according to claim 2, feature exist
In the medical usage is application of the compound in the drug that preparation prevents and treats disease related with lipase.
4. 4- piperazine methyl -7- hydroxyl benzofuran class compound medical usage according to claim 2, feature exist
In application of the described pharmaceutical composition in the drug that preparation prevents and treats disease related with lipase.
5. 4- piperazine methyl -7- hydroxyl benzofuran class compound medical usage as described in claim 3 or 4, feature exist
In the disease related with lipase includes heathy obesity subjects and the overweight people for having adult-onset diabetes.
6. 4- piperazine methyl -7- hydroxyl benzofuran class compound medical usage as claimed in claim 5, which is characterized in that
The lipase inhibitor has high selectivity, long-acting gastrointestinal lipases inhibitor, with lipase activity in stomach and pancreas
Property site serine residue covalent bonding do not influence nervous system and gastrointestinal tract its to block the absorption of fat and water
His enzymatic activity；The lipase inhibitor be chemical synthesis compound, this lipase inhibitor by inhibit lipase activity from
And reach weight-reducing.
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| CN114853706A (en) * | 2022-05-06 | 2022-08-05 | 西南民族大学 | Benzophenone dimer compound and use thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006062481A1 (en) * | 2004-12-09 | 2006-06-15 | Biovitrum Ab | New benzofuran derivatives and their use in the treatment of obesity, type ii diabetes and cns disorders . |
| CN101829079A (en) * | 2009-03-13 | 2010-09-15 | 复旦大学 | Application of compound of (E)-5-[6-hydroxy-5-(3-methyl-1-butenyl)-2-benzofuranyl] phenyl-1, 3-diol to preparation of pancrelipase inhibitor |
| CN107987042A (en) * | 2017-12-11 | 2018-05-04 | 沈阳大学 | A kind of acetylpiperazine class compound containing benzofuranyl and its applied to medicine |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006062481A1 (en) * | 2004-12-09 | 2006-06-15 | Biovitrum Ab | New benzofuran derivatives and their use in the treatment of obesity, type ii diabetes and cns disorders . |
| CN101829079A (en) * | 2009-03-13 | 2010-09-15 | 复旦大学 | Application of compound of (E)-5-[6-hydroxy-5-(3-methyl-1-butenyl)-2-benzofuranyl] phenyl-1, 3-diol to preparation of pancrelipase inhibitor |
| CN107987042A (en) * | 2017-12-11 | 2018-05-04 | 沈阳大学 | A kind of acetylpiperazine class compound containing benzofuranyl and its applied to medicine |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114853706A (en) * | 2022-05-06 | 2022-08-05 | 西南民族大学 | Benzophenone dimer compound and use thereof |
| CN114853706B (en) * | 2022-05-06 | 2023-04-25 | 西南民族大学 | Benzophenone dimer compounds and uses thereof |
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