CN103087009B - Carboxylic acid derivative compound and its preparation method and application - Google Patents
Carboxylic acid derivative compound and its preparation method and application Download PDFInfo
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Abstract
The invention provides carboxylic acid derivant compound, the compound shown in formula (I) or its pharmaceutically acceptable salt that the present invention provides are possible not only to reduce the level of triglyceride in hyperlipidemia model animal blood, but also there is good reduction cholesterol and the effect of low density lipoprotein, LDL, and there is promotion bile secretion, reduce the content of bile cholesterol, increase the content of bile acid, and cause, on stone model, have the effect preventing and treating cholelithiasis in Golden Hamster.It is of particular importance that the toxicity of the compound of present invention offer or its pharmaceutically acceptable salt is relatively low.
Description
Technical field
The present invention relates to novel Carboxylic acid derivative compound of a class and its preparation method and application.Specifically select to close
A kind of novel carboxylic acid derivatives compounds that suitable raw material (such as aminated compounds or halides) and carboxylic acid compound are constituted
And its preparation method and application.
Background technology
Cardiovascular and cerebrovascular disease is currently harm human life and the most serious healthy disease, be middle-aged and elderly people commonly encountered diseases and
Frequently-occurring disease.It is the first place of M & M in many countries.Atherosclerosis is the basis of many cardiovascular and cerebrovascular diseases,
Substantial amounts of experiment and clinical data prove that atherosclerosis is closely related with the exception of blood lipid metabolism.Therefore, lipid lowering agent
Become the key areas of current new drug research.
By perspective, immediately with comparison clinical research, it has proved that some statinses can reduce tremulous pulse medicated porridge
Sample hardening and the generation of coronary heart disease, reduce the mortality rate caused by coronary heart disease, reduce the incidence rate of myocardial infarction.And enter one
The treatment that walking proves to be down to medicine can reduce the content of atherosclerotic plaque inner lipid.Reinforce ferry grease and stable speckle, subtract
The myocardial infarction lacking plaque rupture and cause and cerebral infarction etc. matters of aggravation.Additionally, lipid regulating agent also can recover damaged blood vessels
The function of endotheliocyte, strengthens fibrinolytic and prevents thrombosis, and delay the atherosclerotic progress of people and disappear
Established speckle.Therefore, actively using lipid lowering agent treatment is to alleviate atherosclerosis and reduce the generation of coronary heart disease
Important measures.
The types of drugs of the most clinical and conventional regulation blood fat is more, such as HMG-CoA reductase inhibitor class, benzene oxygen
Aromatic acids, ion exchange resin or cholic acid chelating agent, nicotinic acid class and other Adjust-blood lipid class medicines.Wherein statins is (i.e.
HMG-CoA reductase inhibitor class) the most noticeable.
Statins is the inhibitor of cholesterol synthase.HMG-CoA is changed under the effect of HMG-CoA reductase
The acid of methoxy dragon, statins is that the open acid part of chemical constitution is similar to HMG-CoA, its contestable suppression methoxy dragon acid
Formed, thus reduce the synthesis of cholesterol, thus Blood Cholesterol and low density lipoprotein, LDL (LDL-C) water can be reduced
Flat, further clinical research proves, even if the level of patients with coronary heart disease cholesterol in serum and low density lipoprotein, LDL is the highest
Or normal, the generation of statins equally prevention of arterial atherosclerotic plaque, develop and reduce seriously facing of coronary heart disease
Bed event.But statins long-term taking is in addition to having the gastrointestinal symptoms such as epigastric discomfort, considerable part patient can produce
Raw liver function injury, transaminase raises, myalgia, and creatine kinase raises.
Therefore, objectively there are the needs of the novel lipid lowerers that continual exploitation is effective, side effect is little.
Summary of the invention
The present invention selects suitable raw material (aminated compounds or halides) to pass through condensation reaction with carboxylic acid compound, with
The form of ester bond or amido link connects, thus provides a kind of and play Adjust-blood lipid in vivo and/or prevent and treat the new of calculus effect
Compound.This compound is possible not only to reduce the level of triglyceride in hyperlipidemia model animal blood, but also has good fall
Low cholesterol and the effect of low density lipoprotein, LDL, and cause, on stone model, have the effect preventing and treating cholelithiasis in Golden Hamster.Especially
It is essential that the toxicity of the compound of present invention offer is relatively low.
First purpose of the present invention is to provide the compound shown in following formula (I) or its pharmaceutically acceptable salt,
Wherein:
R1Selected from phenyl, mono-substituted phenyl and polysubstituted phenyl, the substituent group of phenyl includes halogen, hydroxyl, C1-C10
Alkyl, C1-C10Alkoxyl, C3-C10Cycloalkyl, band C5-C10The C of aryl1-C10Alkyl, C5-C10Aryl, contain
Have 1-3 independently selected from the heterocyclic radical of the heteroatomic 3-10 unit of N, O or S or containing 1-3 independently selected from N, O or
The heteroaryl of heteroatomic 5-10 unit of person S, substituted C1-C10Alkyl, substituted C3-C10Cycloalkyl or substituted formyl
Base, containing C1-C10Alkyl, C1-C10Alkoxyl, C3-C10Cycloalkyl, band C5-C10The C of aryl1-C10Alkyl, band
C5-C10The C of aryl1-C10Alkoxyl, band C5-C10The C of aryl1-C10Thiazolinyl, band C5-C10Aryl ester group and
P is selected from C1-C10Alkyl, C1-C10Alkoxyl, C3-C10Cycloalkyl, band C5-C10The C of aryl1-C10Alkane
Base, C5-C10Aryl, containing 1-3 independently selected from the heterocyclic radical of the heteroatomic 3-10 unit of N, O or S or containing 1-3
Individual independently selected from the heteroaryl of heteroatomic 5-10 unit of N, O or S, substituted C1-C10Alkyl ,-(CH2)nO-R2And
L is selected from
R2、R6Selected from phenyl, mono-substituted phenyl and polysubstituted phenyl, the substituent group of phenyl includes halogen, hydroxyl, C1-
C10Alkyl, C1-C10Alkoxyl, C3-C10Cycloalkyl, band C5-C10The C of aryl1-C10Alkyl, C5-C10Aryl,
Independently selected from the heterocyclic radical of the heteroatomic 3-10 unit of N, O or S or 1-3 is contained independently selected from N, O containing 1-3
Or the heteroaryl of heteroatomic 5-10 unit of S, substituted C1-C10Alkyl, substituted C3-C10Cycloalkyl and substituted first
Acyl group；
R3Selected from H, substituted or unsubstituted C1-C10Alkyl and C3-C10Cycloalkyl；
R4Selected from H, substituted or unsubstituted C1-C10Alkyl and C3-C10Cycloalkyl；
R5Selected from H, substituted or unsubstituted C1-C10Alkyl and C3-C10Cycloalkyl；
R7Selected from hydrogen atom and
Q is selected from C1-C6Straight chain, side chain and ring-type alkyl；
T is selected from C1-C6Straight chain, the aliphatic chain of straight chain and C6-C10Fragrant chain；
H is the integer of 0 or 1；
M is the integer of 0-10；
N is the integer of 0-10；
The above-mentioned substituent group being not specifically noted is selected from halogen, C1-C10Alkyl, C3-C10Cycloalkyl, band C5-C10's
The C of aryl1-C10Alkyl, C5-C10Aryl, containing 1-3 independently selected from heteroatomic 3-10 unit miscellaneous of N, O or S
Ring group, containing 1-3 independently selected from heterocyclic base, benzoyl and the amide groups of the heteroatomic 5-10 unit of N, O or S.
Compound shown in formula (I), the particularly preferred compound 1-38 being as follows:
Except as otherwise noted, the following term occurred in description of the invention and claims has the meaning that
" alkyl " used in the present invention means to include having appointment carbon number purpose side chain and the radical of saturated aliphatic of straight chain
Alkyl.Such as, C1-C10, as at " C1-C10Alkyl " defined in for be included in straight chain or branched structure have 1,2,3,4,5,
6, the group of 7,8,9 or 10 carbon atoms.Such as, " C1-C10Alkyl " specifically include methyl, ethyl, n-pro-pyl, isopropyl,
Normal-butyl, the tert-butyl group, isobutyl group, amyl group, hexyl, heptyl, octyl group, nonyl and decyl etc..
Term " cycloalkyl " refers to have the monocycle radical of saturated aliphatic alkyl specifying number carbon atom.Such as, " cycloalkyl " bag
Include cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyI-cyclopentyl and cyclohexyl etc..
Term " alkoxyl " represents that described carbon number purpose is ring-type or acyclic alkyl groups by having of connecing of oxygen bridging.
Thus, " alkoxyl " comprises the definition of above alkyl and cycloalkyl.
Term " thiazolinyl " refers to containing specifying number carbon atom and the straight chain of at least one carbon-carbon double bond, side chain or ring-type
Non-aromatic alkyl.Preferably there is a carbon-carbon double bond, and up to four non-aromatic carbon-carbon double bonds can be there are.Such as, " C2-
C10Thiazolinyl " refer to the thiazolinyl with 2-10 carbon atom.“C2-C6Thiazolinyl " refer to the thiazolinyl with 2-6 carbon atom, including second
Thiazolinyl, acrylic, cyclobutenyl, 2-methyl butene base and cyclohexenyl group.The straight chain of thiazolinyl, side chain or loop section can be containing double
Key, and if be shown to be substituted alkenyl, then can be replaced.
Term " alkynyl " refers to containing specifying number carbon atom and the straight chain of at least one triple carbon-carbon bonds, side chain or ring-type
Alkyl.Wherein can there are up to three triple carbon-carbon bonds.Such as, " C2-C10Alkynyl " refer to the alkynyl with 2-10 carbon atom.
“C2-C6Alkynyl " refer to the alkynyl with 2-6 carbon atom, including acetenyl, propinyl, butynyl and 3-methylbutynyl etc.
Deng.
Term " cycloalkyl " refers to the unsaturated monocycle of saturated or part, multi-ring or bridge joint carbocyclic ring substituent group.Such as, tool
The ring having 3-20 carbon atom can be expressed as C3-20Cycloalkyl；The ring with 5-15 carbon atom can be expressed as C5-15Cycloalkanes
Base；The ring with 3-8 carbon atom can be expressed as C3-8Cycloalkyl, etc..This term includes but not limited to cyclopropyl, ring fourth
Base, cyclopenta, cyclohexyl, suberyl, ring octyl group, 1H-indenyl, indanyl, 1,2,3,4-tetrahydro-naphthalenyl, 5,6,
7,8-tetrahydro-naphthalenyl, 8,9-dihydro-7H-benzo ring heptene-6-base, 6,7,8,9-tetrahydrochysene-5H-benzocyclohepta thiazolinyl, 5,6,7,
8,9,10-hexahydro-benzo ring octenyl, fluorenyl, bicyclo-[2.2.1] heptyl, bicyclo-[2.2.1] heptenyl, bicyclo-[2.2.2] are pungent
Base, bicyclo-[3.1.1] heptyl, bicyclo-[3.2.1] octyl group, bicyclo-[2.2.2] octenyl, bicyclo-[3.2.1] octenyl, diamantane (obsolete)
Base, octahydro-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-pentalene base etc..Naphthenic substituent is permissible
It is connected on central element through any suitable carbon atom, and it can be further substituted with when permitted.
" aryl " as used herein refers to any stable monocycle that may be up to 7 atoms in each ring or dicyclo carbon
Ring, at least one of which ring is aromatic rings.The example of above-mentioned aryl unit includes phenyl, naphthyl, tetralyl, 2,3-dihydro
Indenyl, xenyl, phenanthryl, anthryl or acenaphthenyl (acenaphthyl).It is appreciated that at aryl substituent be two ring substituents,
And one of them ring is in the case of non-aromatic ring, connection is carried out by aromatic ring.
Term as used herein " heterocyclic base " represents stable monocycle or the bicyclo-that may be up to 7 atoms in each ring, wherein
At least one ring is aromatic rings and contains 1-4 the hetero atom selected from O, N and S.Heteroaryl within the range defined herein includes
But it is not limited to: acridinyl, carbazyl, cinnolines base, quinoxalinyl, pyrazolyl, indyl, benzotriazole base, furyl, thiophene
Base, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indyl, pyrazinyl, pyridazine
Base, pyridine radicals, pyrimidine radicals, pyrrole radicals, tetrahydroquinoline.As the definition of following heterocycle, " heteroaryl " it should also be understood that into
N-oxide derivative including any nitrogen-containing hetero aryl.Heteroaryl substituent is two ring substituents and a ring is wherein
Non-aromatic ring or do not comprise heteroatomic in the case of, it will be understood that connect respectively by aromatic ring or by comprising the miscellaneous of ring
Atom is carried out.
Term as used herein " heterocycle " or " heterocyclic radical " represent containing 1-4 the heteroatomic 5-10 selected from O, N and S
Unit's fragrance or nonaromatic heterocycles, and include bicyclic groups.Therefore, " heterocyclic radical " include above-mentioned heteroaryl and its dihydro or
Person's tetrahydrochysene analog.Other example of " heterocyclic radical " includes but not limited to following: benzimidazolyl, benzofuranyl, benzo furan
Our base, benzopyrazoles base, benzotriazole base, benzothienyl, benzoxazolyl group, carbazyl, carbolinyl, cinnolines base, furyl,
Imidazole radicals, indolinyl, indyl, indazolyl, isobenzofuran-base, isoindolyl, isoquinolyl, isothiazolyl, different
Oxazolyl, naphthalene pyrimidine radicals, di azoly, oxazolyl, oxazoline, isoxazolines, oxygen cyclobutyl, pyranose, pyrazinyl, pyrazoles
Base, pyridazinyl, pyridopyridine base, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, quinazolyl, quinolyl, quinoxalinyl,
THP trtrahydropyranyl, tetrazole radical, tetrazolo pyridine radicals, thiadiazolyl group, thiazolyl, thienyl, triazolyl, azetidinyl, 1,
4-dialkyl group, hexahydro azatropylidene base, piperazinyl, piperidyl, pyrrolidinyl, morpholinyl, thio-morpholinyl, dihydrobenzo imidazoles
Base, dihydro benzo furyl, dihydrobenzo thienyl, dihydrobenzo oxazolyl, dihydrofuran base, glyoxalidine base, dihydro Yin
Diindyl base, dihydro isoxazolyl, dihydro isothiazolyl, dihydrooxadiazole base, dihydro oxazolyl, dihydro pyrazinyl, pyrazoline base,
Dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, dihydroquinoline base, dihydro tetrazole radical, thiodiazoline base, thiazoline
Base, dihydro-thiophene base, dihydro triazolyl, dihydro azetidinyl, methylenedioxyphenyl formoxyl, tetrahydrofuran base and four
Hydrogen thienyl and N-oxide thereof.Heterocyclyl substituent can be attached through carbon atom or hetero atom.
In the present invention, described pharmaceutically acceptable salt is preferably the compounds of this invention and pharmaceutically acceptable acid
Carry out the acid-addition salts that reaction prepares, or wherein there is compound and the salt of alkali compounds reaction generation of acidic-group.
Wherein, described acid is preferably selected from mineral acid (example hydrochloric acid, sulphuric acid, phosphoric acid or hydrobromic acid etc.), and organic acid is (such as oxalic acid, horse
Come sour, fumaric acid, malic acid, tartaric acid, citric acid or benzoic acid etc.)；Described alkali compounds is preferably selected from hydroxide
Sodium, potassium hydroxide, calcium hydroxide, sodium carbonate or potassium bicarbonate etc..Above-mentioned pharmaceutically acceptable salt can be easily separated, and often can use
Rule separation method purifies, such as solvent extraction, dilution, recrystallization, column chromatography with prepare thin layer chromatography etc..
Second object of the present invention is to provide above-mentioned compound shown in formula I or the system of its pharmaceutically acceptable salt
Preparation Method.
Compound shown in Formulas I or the preparation method of its pharmaceutically acceptable salt,
Wherein R1、R2、R3、R4、R5、R6、R7, Q, L, P, T, h, m, n described above；
Method one:
When h is 1, by the acid represented by II and the aminated compounds represented by III in the presence of condensing agent and solvent directly
It is condensed to yield:
One according to the present invention is preferred embodiment, and the condensing agent described in method one is conventional ester condensation agent, as
N, N '-carbonyl dimidazoles, dicyclohexylcarbodiimide or DIC etc..
One according to the present invention preferred embodiment, can add the catalysis of nitrogenous class in reaction described in said method one
Agent, such as N, N-dimethylamino naphthyridine, accelerates response speed.
Method two:
When h is 1, the halogenide represented by the carboxylic acid represented by IV, thiocarboxylic acid or carboxylate and V is condensed in a solvent
Reaction:
One according to the present invention preferred embodiment, and the solvent described in said method two is selected from halogenated hydrocarbons, such as dichloro
Methane, dichloroethanes, chloroform etc.；Esters solvent such as ethyl acetate, isopropyl acetate etc..
One according to the present invention preferred embodiment, can add inorganic base or organic in said method two condensation reaction
Alkali, inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate etc.；Organic base such as triethylamine, pyridine etc., increase reaction speed
Degree.
Method three:
When h is 0 or 1, by the halogenide represented by the amine represented by VI, alcohols, sulfur alcohol compound or its salt and VII
Condensation reaction in a solvent:
One according to the present invention preferred embodiment, and the solvent described in said method three is selected from halogenated hydrocarbons, such as dichloro
Methane, dichloroethanes, chloroform etc.；Esters solvent such as ethyl acetate, isopropyl acetate etc.；Ether solvent, such as oxolane, methyl
Oxolane, methyl tertiary butyl ether(MTBE) etc..
One according to the present invention preferred embodiment, can add inorganic base in the condensation reaction described in said method three
Or organic base, inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate etc.；Organic base such as triethylamine, pyridine etc., increase
Response speed.
Method four:
When h is 1, the acid represented by Formula II and halide reagent reaction, prepare carboxylic acid halides VIII；Described carboxylic acid halides VIII is again and formula IV
Represented substituted aminated compounds carries out condensation reaction in a solvent:
One according to the present invention is preferred embodiment, the halide reagent described in said method four include oxalyl chloride, two
Chlorine sulfoxide, Phosphorous chloride., phosphorus pentachloride, dibromo sulfoxide and phosphorus tribromide.
One according to the present invention preferred embodiment, and the solvent described in said method four is selected from halogenated hydrocarbons, such as dichloro
Methane, dichloroethanes, chloroform etc.；Esters solvent such as ethyl acetate, isopropyl acetate etc..
One according to the present invention preferred embodiment, and said method four can add inorganic base or organic in the condensation reaction
Alkali, inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate etc.；Organic base such as triethylamine, pyridine etc., increase reaction speed
Degree.
Third object of the present invention is to provide a class pharmaceutical composition, by compound shown in Formulas I or its pharmaceutically can connect
The salt being subject to forms with pharmaceutically acceptable additive.
The compound of the present invention can make medicine group with the most various typical additives (such as diluent and excipient etc.)
Compound.According to therapeutic purposes, pharmaceutical composition can be made various types of administration unit dosage forms, as tablet, pill, powder,
Liquid, suspension, emulsion, granule, capsule, suppository and injection (solution and suspension) etc..
In order to make the pharmaceutical composition of tablet form shape, any of and widely used figuration in this area can be used
Agent.Such as, carrier, such as lactose, white sugar, sodium chloride, glucose, carbamide, starch, calcium carbonate, Kaolin, crystalline cellulose and silicon
Acid etc.；Binding agent, such as water, ethanol, propanol, common syrup, glucose solution, starch solution, penetrating judgment solution, carboxymethyl cellulose
Element, lac, methylcellulose and potassium phosphate, polyvinylpyrrolidone etc.；Disintegrating agent, such as dried starch, sodium alginate, agar powder and sea
Band powder, sodium bicarbonate, calcium carbonate, the fatty acid ester of polyethylene sorbitan, sodium lauryl sulphate, stearic acid monoglycerides,
Starch and lactose etc.；Disintegrate inhibitor, such as white sugar, glycerol tristearate, Oleum Cocois and hydrogenated oil and fat；Adsorption enhancer, such as season
Amine base and sodium lauryl sulphate etc.；Wetting agent, such as glycerol, starch etc.；Adsorbent, such as starch, lactose, Kaolin, bentonite
With colloid silicic acid etc.；And lubricant, such as pure Talcum, stearate, boric acid powder and Polyethylene Glycol etc..If needed
Words, it is also possible to make tablet as sugar coated tablet with common coated material, be coated with gelatin film tablet, enteric coated tablets, film coated tablets, double
Tunic tablet and multilayer tablet.
In order to make the pharmaceutical composition of pill shape, any of and widely used inborn nature in this area can be used
Agent, such as, carrier, such as lactose, starch, Oleum Cocois, hardened vegetable oils, Kaolin and Talcum etc.；Binding agent, such as Radix Acaciae senegalis
Powder, yellow work rubber powder, gelatin and ethanol etc.；Disintegrating agent, such as agar and Kelp Powder etc..
In order to make the pharmaceutical composition of suppository form shape, this area can be used any known and widely used inborn nature
Agent, such as, Polyethylene Glycol, Oleum Cocois, higher alcohol, the ester of higher alcohol, gelatin and semisynthetic glyceride etc..
In order to prepare the pharmaceutical composition of injection form, solution and suspension can be sterilized, and be preferably added appropriate chlorine
Change sodium, glucose or glycerol etc., make injection isotonic with blood.When preparing injection, it is possible to use any in this area
Conventional carrier.Such as, water, ethanol, propylene glycol, the isooctadecanol of ethoxylation, the isooctadecanol of polyoxy and polyethylene
The fatty acid ester etc. of anhydro sorbitol.Additionally, common lytic agent, buffer agent and analgesic etc. also can be added.As required, exist
During treatment schizophrenia, it is possible to add coloring agent, preservative, spice, flavoring agent, sweetening agent and other medicines etc..
Compound shown in the Formulas I of the present invention and pharmaceutically acceptable salt thereof the content in pharmaceutical composition is without special
Limit, can select in a wide range, generally can be mass percent 1-70%, be preferably mass percent 1-
30%。
In the present invention, the medication of described pharmaceutical composition is not particularly limited.Can according to patient age, sex and
Other condition and symptom, select the preparation of various dosage form to be administered.Such as, tablet, pill, solution, suspension, emulsion, granule
It is oral administration with capsule；Injection can be individually dosed, or (as molten in glucose solution and aminoacid with injection conveying liquid
Liquid) it is mixed into row vein injection, injection in muscle, Intradermal, subcutaneous or abdomen can be carried out by simple injection if necessary；Suppository is
It is administered into rectum.
In the present invention, use can be properly selected according to method of administration, patient age, sex and other condition and symptom
Pharmaceutical quantities.Common dosage can be: about 0.1-300mg active constituents of medicine/kg body weight/day.In general, each administration
Unit dosage forms can contain the active constituents of medicine of 1-200mg.
Fourth object of the present invention is to provide compound shown in Formulas I or its pharmaceutically acceptable salt at preparation regulation blood
Fat and/or the application in preventing and treating the medicine of cholelithiasis.This compound or its pharmaceutically acceptable salt are possible not only to reduce high fat
The level of triglyceride in animal pattern blood, but also there is good reduction cholesterol and the effect of low density lipoprotein, LDL, and
And cause, on stone model, have the effect preventing and treating cholelithiasis in Golden Hamster.It is of particular importance that the present invention provide compound or its
The toxicity of pharmaceutically acceptable salt is relatively low.
Compound in this patent proves to reduce blood cholesterol, the effect of low density lipoprotein, LDL after deliberation, and has
Promote bile secretion, reduce the content of bile cholesterol, increase the content of bile acid, thus have the effect of preventing and treating cholelithiasis.
Detailed description of the invention
Embodiment 1: the preparation of compound 1
Bezafibrate 1g, dicyclohexylcarbodiimide 0.74g, 1-Boc piperazine 0.52g, dichloromethane 60ml are placed in 100ml
In single port bottle, react 4 hours under room temperature, solvent evaporated, ethyl alcohol recrystallization, obtain white solid 1.22g, insert 50ml single port bottle
In, adding dichloromethane 20ml, trifluoroacetic acid 4ml, stir 1 hour, 1mol/L wet chemical adjusts system pH to be alkalescence, has
Machine layer is dried, and concentrates, ethyl alcohol recrystallization, obtains white solid 0.7g, insert in 50ml single port bottle, and oxolane 30ml, 2-amido-
1-(4-hydroxy phenyl) ethyl ketone 0.35g, potassium carbonate 0.5g, TLC monitor reaction end, and column chromatography obtains target compound 790mg.
MS(ESI): 564(M+H+).
Embodiment 2-6: the preparation of compound 2-compound 6
Utilize the raw material corresponding with target compound 2-6, prepared by the operational approach of embodiment 1. and concrete steps save herein
Slightly.
Embodiment 7: the preparation of compound 7
Butyl chloride 1g, 2-amido-1-(4-hydroxy phenyl) ethyl ketone 0.71g, triethylamine 2.1g, dichloromethane 60ml are placed in
In 100ml single port bottle, reacting 4 hours under room temperature, solvent evaporated, column chromatography obtains target compound 2.63g.MS(ESI): 292
(M+H+).
Embodiment 8-10: the preparation of compound 8-compound 10
Utilize the raw material corresponding with target compound 8-10, prepared by operational approach similar described in embodiment 7. and concrete
Step is omitted herein.
Embodiment 11: the preparation of compound 11
Compound 101g, sodium hydroxide 0.13g, dichloromethane 60ml are placed in 100ml single port bottle, react 4 little under room temperature
Time, solvent evaporated, column chromatography obtains target compound 612mg.MS(ESI): 236(M+H+).
Embodiment 12: the preparation of compound 12
The bromo-1-of 2-(4-hydroxy phenyl) ethyl ketone 1g, acetic anhydride 1.05, oxolane 60ml, potassium carbonate 1.42g, it is placed in
In 100ml single port bottle, reacting 4 hours under room temperature, solvent evaporated, column chromatography obtains target compound 0.98g.MS(ESI): 237
(M+H+).
Embodiment 13: the preparation of compound 13
Gemfibrozil 1g, dicyclohexylcarbodiimide 1.07g, 1-Boc ethylenediamine 0.64g, dichloromethane 60ml are placed in
In 100ml single port bottle, react 4 hours under room temperature, solvent evaporated, ethyl alcohol recrystallization, obtain white solid 1.44g, 50ml single port
In Ping, adding dichloromethane 20ml, trifluoroacetic acid 4ml, after 1 hour, 1mol/L wet chemical adjusts pH to be alkalescence, organic layer
It is dried, solvent evaporated, ethyl alcohol recrystallization, obtains in white solid 0.94g, 50ml single port bottle, the bromo-1-of 2-(4-hydroxy phenyl) second
Ketone 1.37g, potassium carbonate 3.5g, TLC monitor reaction end, and column chromatography obtains target compound 1.64g.MS(ESI): 561(M+H+).
Embodiment 14: the preparation of compound 14
5-(2,5-dimethyl phenoxy)-N-(2-(4-hydroxy phenyl)-2-oxoethyl)-2,2-dimethyl-penten acid amide
1g, isoveryl chloride 0.32g, triethylamine 0.3g, dichloromethane 60ml are placed in 100ml single port bottle, react 4 hours under room temperature, steam
Dry solvent, column chromatography obtains target compound 1.09g.MS(ESI): 468(M+H+).
Embodiment 15-27,32: compound 15-compound 27, the preparation of compound 32
Utilize the raw material corresponding with target compound 15-27,32, operational approach system similar described in embodiment 14
Standby. concrete steps are omitted herein.
Embodiment 28: the preparation of compound 28
5-(2,5-dimethyl phenoxy)-2,2-dimethyl-penten acyl chlorides 1g, 2-amido-1-(4-(methyl mercapto) phenyl) second
Ketone 0.67g, triethylamine 0.38g, dichloromethane 60ml are placed in 100ml single port bottle, react 4 hours, solvent evaporated, post under room temperature
Chromatography target compound 1.35g.MS(ESI): 414(M+H+).
Embodiment 29: the preparation of compound 29
Utilize the raw material corresponding with target compound 29, prepared by operational approach similar described in embodiment 28. and concrete
Step is omitted herein.
Embodiment 30: the preparation of compound 30
Succinic acid 0.5g, dicyclohexylcarbodiimide 2g, 2-amido-1-(4-hydroxy phenyl) ethyl ketone 1.15g, dichloromethane
60ml is placed in 100ml single port bottle, reacts 4 hours under room temperature, and solvent evaporated, column chromatography obtains target compound 1.23g.MS
(ESI): 385(M+H+).
Embodiment 31: the preparation of compound 31
Benzyloxy chloroacetic chloride 1g, 2-amido-1-(4-hydroxy phenyl) ethyl ketone 0.82g, triethylamine 0.55, dichloromethane 60ml puts
In 100ml single port bottle, reacting 4 hours under room temperature, solvent evaporated, column chromatography obtains target compound 0.9g.MS(ESI): 300
(M+H+).
Embodiment 33: the preparation of compound 33
The bromo-1-of bezafibrate 1g, 2-(4-hydroxy phenyl) ethyl ketone 0.6g, potassium carbonate 0.84g, oxolane 50ml, room temperature
Reacting 3.5 hours, filter, filtrate is evaporated column chromatography and obtains target compound 0.93g.MS(ESI): 496(M+H+)
Embodiment 34-35
Utilize the raw material corresponding with target compound 34-35, prepared by operational approach similar described in embodiment 33. tool
Body step is omitted herein.
Embodiment 36: the preparation of compound 36
Bezafibrate 1g, N, N-carbonyl dimidazoles (CDI) 0.49g, DMF (DMF) 50ml, room temperature stirs
Mix 4h, be passed through hydrogen sulfide gas, solvent evaporated after 20 minutes, add ethyl acetate 20ml, cold diluted hydrochloric acid aqueous solution 20ml, have
Machine layer is dried concentration, is evaporated, and obtains yellow solid crude product.The bromo-1-of 2-(4-hydroxy phenyl) ethyl ketone 0.47g, potassium carbonate 0.84g, on
Stating prepared yellow crude, oxolane 50ml, normal-temperature reaction, 3 hours, filter, filtrate is evaporated column chromatography and obtains target compound
0.7g.MS(ESI): 512(M+H+)
Embodiment 37-38: the preparation of compound 37-38
Utilize the raw material corresponding with target compound 37-38, prepared by operational approach similar described in embodiment 36. tool
Body step is omitted herein.
Experimental example 1: carry out the preparation-obtained screening compound of embodiment 1-38 with SD hyperlipemia model of rats
Material and method
1 reagent
Simvastatin Tablets (20mg*7, Hangzhou Mo Shadong pharmaceutical Co. Ltd, lot number: 20090115)
Ursodesoxycholic acid (Bio Basic Inc., Lot:YY0201B207Y)
Adeps Sus domestica is commercially available；Cholesterol (upper sea blue season development in science and technology company limited, lot number: 090720)；Propylthiouracil
(upper sea blue season development in science and technology company limited, lot number: 090505)；Deoxycholic acid (upper sea blue season development in science and technology company limited, batch
Number: 090615)；Tween 80 (Chemical Reagent Co., Ltd., Sinopharm Group, CP, lot number: F20090507)；1,2-propylene glycol (traditional Chinese medicines
Chemical reagent company limited of group, AR, lot number: T20070125)；
2 animals
SD rat, male, 150-180g, Shanghai Si Laike laboratory animal responsibility company limited provide.
3 instruments
YP2001N electronic balance, Shanghai Precision Scientific Apparatus Co., Ltd.
Hitachi's automatic biochemistry analyzer 7080.
4 methods
Lipomul preparation method: take Adeps Sus domestica 500g, is placed in container, heating, after thawing, when temperature is raised to 100 DEG C,
Add 200g cholesterol, be completely dissolved, add 20g propylthiouracil, fully stir evenly, after dissolving, be subsequently adding 500ml tween
80, make oil phase.Meanwhile, take 600ml distilled water and 1,2-PD 400ml, water-bath is heated to 60 DEG C, is subsequently adding 40g
NaTDC, is sufficiently agitated until and is completely dissolved, and makes aqueous phase.Aqueous phase adds oil phase, fully mixes, i.e. makes fat milk
Agent.
Compound solution compound method: take appropriate compound, with the appropriate grinding distribution of Tween 80 uniformly after, add enough
CMC-Na liquid, is fully ground, suspendible and get final product.
Animal adaptability is fed 3 days, separates 8 according to body weight and is only used as blank group (Control), remaining animal every day
The morning 9:00-11:00 gavage fat milk, 1ml/100g body weight, continuous gavage 2 weeks, animal fasting 12h, eye socket blood sampling 1ml, adopt
Serum cholesterol (CHO), triglyceride (TG), low density lipoprotein, LDL (LDL-C) is measured with Hitachi's automatic biochemistry analyzer 7080
With high density lipoprotein (HDL-C), take the animal that CHO is 4-7mmol/L and test.
It is divided into model group (Model), simvastatin group (Sim, 10mg/ by giving the lipomul animal of 2 weeks according to body weight
Kg), each compound group (40mg/kg).Continue gavage lipomul, be administered simultaneously group and give the medicine of corresponding dosage, model group
Give equal-volume solvent.The morning, sink grease fat emulsion, was administered afternoon.Weigh on every Mondays, observe animal situation.Successive administration 21
My god, animal fasting 12h, eye socket blood sampling 1ml.Expose liver, observe hepatic pathology situation, take that to put into 4% formaldehyde after weighing molten
Liquid is fixed, pathological examination to be done.
Hitachi's automatic biochemistry analyzer 7080 is used to measure serum cholesterol (CHO), triglyceride (TG), low-density lipoprotein
(LDL-C) and high density lipoprotein (HDL-C) in vain.
5 data statisticss
Experimental data withRepresenting, between each group, experimental data compares employing t inspection.
6 results and discussion
The impact of the blood fat of 6.1 compound on animals, is shown in Table 1
Serum Lipids in Experimental HypercholesterolemicRats (X ± SD, mmol/L) after table 1 administration
Be can be seen that compound 01 has certain effect for reducing blood fat substantially to compound 38 by result, and gallbladder can be reduced simultaneously
Sterin, triglyceride and low density lipoprotein, LDL.
Test example 2: carry out screening compound with Golden Hamster cholelithiasis model
Material and method
Reagent: Simvastatin Tablets (20mg*7, Hangzhou Mo Shadong pharmaceutical Co. Ltd, lot number: 20090115) ursodeoxycholic
Acid (Bio Basic Inc., Lot:YY0201B207Y)
Animal: Golden Hamster, male, 68,50-60g, Shanghai Si Laike laboratory animal responsibility company limited provide.
Instrument: YP2001N electronic balance, Shanghai Precision Scientific Apparatus Co., Ltd.Hitachi's automatic biochemistry analyzer 7080.
Method: Animal adaptability is fed 3 days, separates 8 according to body weight and is only used as blank group (Control).Matched group
Giving normal mice feedstuff, remaining animal gives to cause stone feedstuff (sucrose 32.1%, cheese 64.2%, cholesterol 0.2%, Sal 3%, dimension
Raw element B120.1%, Concentrated Cod-liver Oil 0.4%), readaptability is fed 7 days, is divided into model group (Model) according to body weight, pungent cuts down him
Spit of fland group (Sim, 10mg/kg), ursodesoxycholic acid group (UDCA, 40mg/kg), administration group, often group 6.
Sim group gives simvastatin 10mg/kg, and UDCA group gives ursodesoxycholic acid 40mg/kg, and administration group gives 40mg/
kg.All starting oral administration the same day in packet, every afternoon, 2:00-3:00 was administered.Weigh on every Mondays, observe animal wool
Color, feces, active degree change.
Successive administration 45 days, animal fasting 12h, barbose 30mg/kg intraperitoneal injection of anesthesia, ventral aorta is taken a blood sample
1ml.Expose gallbladder, hold ophthalmic tweezers and clamp gallbladder mouth, draw intracapsular bile of gallbladder with 1ml syringe.
Biochemical of bile measures
Hitachi's automatic biochemistry analyzer 7080 is used to measure biliary cholesterol (CHO), total bile pigments (TBIL), TOTAL BILE ACID TBA
(TBA), total protein (TP).
Data statistics
Experimental data withRepresenting, measuring experimental data between each group and compare employing t inspection, enumeration data uses non-
Parametric test.
Experimental result is shown in Table 2-10
Table 2-10 Golden Hamster bile components level
Table 2-10 Level of CHO,TBA,TBIL,TP in Gallbladder
Remarks: CHO cholesterol, TBA TOTAL BILE ACID TBA, the total bile pigments of TBIL, TP total protein.
Bile studied result shows, in each compound group, Determination of Bile Acids is apparently higher than model group, raises bile acid
Effect is also better than simvastatin and ursodesoxycholic acid.
Test example 3: Mouse Acute Toxicity is tested
After compound dissolves with appropriate tween 80, it is uniformly dispersed with a certain amount of CMC-Na liquid suspendible, oral administration gavage 5g/kg
Dosage, has no that administration is xicity related, and Continuous Observation 14 days has no animal dead.Result shows, sample compound 01, compound
02, compound 03, compound 04, compound 05, compound 06, compound 07, compound 08, compound 09, compound 10, change
Compound 11, compound 12, compound 13, compound 14, compound 15, compound 16, compound 17, compound 18, compound
19, compound 20, compound 21, compound 22, compound 23, compound 24, compound 25, compound 26, compound 27, change
Compound 28, compound 29, compound 30, compound 31, compound 32 safety.
Embodiment 39: the preparation of tablet
| Prescription: | Consumption |
| Compound 26 | 200mg |
| Microcrystalline Cellulose | 200mg |
| Crospolyvinylpyrrolidone | 20mg |
| Pregelatinized Starch | 50mg |
| Magnesium stearate | 5mg |
Preparation method: by above-mentioned formula, compound 26, microcrystalline Cellulose, pregelatinized Starch and the friendship after pulverizing and sieving
Connection polyvinylpyrrolidone uniformly mixes, and then mixes with 5% ethanol solution, pelletizes, is dried, the most again with mix lubricant, and pressure
Sheet.Wherein, described compound 11 pulverizes and sieves as crossing 60 mesh sieves；Described microcrystalline Cellulose, pregelatinized Starch and friendship
Connection polyvinylpyrrolidone pulverizes and sieves as crossing 80 mesh sieves；The grain diameter size of described granulation is 20 mesh；Described is dried
Temperature be preferably 90 DEG C and control within biodiversity percentage ratios 3%.
Embodiment 40: the preparation of capsule
Preparation method: by upper table formula, by medicine and each raw material blending of adjuvant, fill to capsule shells.
Prepared by embodiment 41 injection
Preparation method: by above-mentioned formula, uses mortar, by uniform, then with wetting agent ground and mixed to compound 7 or its salt
Uniformly mix with suspending agent, preservative and water for injection, then grind.Wherein, the granular size of described grinding is 0.5 μ
m。
Claims (33)
1. such as compound or its pharmaceutically acceptable salt of following formula:
2. such as compound or its pharmaceutically acceptable salt of following formula:
3. such as compound or its pharmaceutically acceptable salt of following formula:
4. such as compound or its pharmaceutically acceptable salt of following formula:
5. such as compound or its pharmaceutically acceptable salt of following formula:
6. such as compound or its pharmaceutically acceptable salt of following formula:
7. such as compound or its pharmaceutically acceptable salt of following formula:
8. such as compound or its pharmaceutically acceptable salt of following formula:
9. such as compound or its pharmaceutically acceptable salt of following formula:
10. such as compound or its pharmaceutically acceptable salt of following formula:
The compound of 11. such as following formula or its pharmaceutically acceptable salt:
The compound of 12. such as following formula or its pharmaceutically acceptable salt:
The compound of 13. such as following formula or its pharmaceutically acceptable salt:
The compound of 14. such as following formula or its pharmaceutically acceptable salt:
The compound of 15. such as following formula or its pharmaceutically acceptable salt:
The compound of 16. such as following formula or its pharmaceutically acceptable salt:
The compound of 17. such as following formula or its pharmaceutically acceptable salt:
The compound of 18. such as following formula or its pharmaceutically acceptable salt:
The compound of 19. such as following formula or its pharmaceutically acceptable salt:
The compound of 20. such as following formula or its pharmaceutically acceptable salt:
Compound described in 21. claim 1-20 any one or its pharmaceutically acceptable salt, it is characterised in that: described
Pharmaceutically acceptable salt is that the compound described in claim 1-20 carries out, with pharmaceutically acceptable acid, the acid that reaction prepares
Addition salts, or wherein there is compound and the salt of alkali compounds reaction generation of acidic-group.
22. compound as claimed in claim 21 or its pharmaceutically acceptable salts, it is characterised in that: described is acceptable
Acid is selected from hydrochloric acid, sulphuric acid, phosphoric acid and hydrobromic acid.
Compound described in 23. claim 21 or its pharmaceutically acceptable salt, it is characterised in that: described acceptable acid
Selected from oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and benzoic acid.
Compound described in 24. claim 21 or its pharmaceutically acceptable salt, it is characterised in that: described alkali compounds
Selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate and potassium bicarbonate.
25. 1 kinds of pharmaceutical compositions, by the compound described in claim 1-20 any one or its pharmaceutically acceptable salt,
Pharmaceutically acceptable additive forms.
26. pharmaceutical compositions as claimed in claim 25, it is characterised in that: described pharmaceutically acceptable additive is normal
Diluent and/or excipient.
27. pharmaceutical compositions as claimed in claim 25, it is characterised in that: compound or its pharmaceutically acceptable salt quality
Percentage ratio is 1-70%.
28. pharmaceutical compositions as claimed in claim 27, it is characterised in that: compound or its pharmaceutically acceptable salt quality
Percentage ratio is 1-30%.
29. 1 kinds of pharmaceutical preparatioies, it is characterised in that: the pharmaceutical composition described in claim 26-28 any one is tablet, ball
Agent, powder, liquid, suspension, emulsion, granule, capsule, suppository or injection.
30. pharmaceutical preparatioies as claimed in claim 29, it is characterised in that: each administration unit dosage forms has containing 0.1-200mg's
Active constituents of medicine.
Compound or its pharmaceutically acceptable salt described in 31. claim 1-20 any one at regulation blood fat and/or are prevented
Control the application in the medicine preparation of cholelithiasis.
Pharmaceutical composition described in 32. claim 26-28 any one is regulating blood fat and/or is preventing and treating the medicine system of cholelithiasis
Application in Bei.
Pharmaceutical preparation described in 33. claim 29 or 30 regulation blood fat and/or prevent and treat cholelithiasis medicine preparation in should
With.
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| CN87100652A (en) * | 1986-02-07 | 1987-08-19 | 菲泽有限公司 | Anti-dysrhythmia agents |
| CN1381448A (en) * | 2002-05-08 | 2002-11-27 | 上海医药工业研究院 | Aralkylformylalkyl piperazine derivative and its application as brain nerve protector |
| CN1798733A (en) * | 2003-06-10 | 2006-07-05 | 凯利普西斯公司 | Carbonyl compounds as inhibitors of histone deacetylase for the treatment of disease |
| CN102093246A (en) * | 2009-12-15 | 2011-06-15 | 上海医药工业研究院 | Ester compound, preparation method and application thereof |
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| CN102838505B (en) * | 2011-06-24 | 2016-02-17 | 上海医药工业研究院 | Amides, its preparation method and application |
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| GB832286A (en) * | 1956-10-15 | 1960-04-06 | Philips Nv | Improvements in or relating to processes for producing substituted alkylamines and acid-addition salts thereof |
| CN87100652A (en) * | 1986-02-07 | 1987-08-19 | 菲泽有限公司 | Anti-dysrhythmia agents |
| CN1381448A (en) * | 2002-05-08 | 2002-11-27 | 上海医药工业研究院 | Aralkylformylalkyl piperazine derivative and its application as brain nerve protector |
| CN1798733A (en) * | 2003-06-10 | 2006-07-05 | 凯利普西斯公司 | Carbonyl compounds as inhibitors of histone deacetylase for the treatment of disease |
| CN102093246A (en) * | 2009-12-15 | 2011-06-15 | 上海医药工业研究院 | Ester compound, preparation method and application thereof |
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