CN113121337B - Phenoxyaromatic acid with cyclopropyl and pharmaceutically acceptable salt thereof, and preparation method and application thereof - Google Patents
Phenoxyaromatic acid with cyclopropyl and pharmaceutically acceptable salt thereof, and preparation method and application thereof Download PDFInfo
- Publication number
- CN113121337B CN113121337B CN201911425031.0A CN201911425031A CN113121337B CN 113121337 B CN113121337 B CN 113121337B CN 201911425031 A CN201911425031 A CN 201911425031A CN 113121337 B CN113121337 B CN 113121337B
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- Prior art keywords
- cyclopropyl
- pharmaceutically acceptable
- salt
- acid
- salts
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- 150000003839 salts Chemical class 0.000 title claims abstract description 44
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 239000002253 acid Substances 0.000 title description 12
- -1 phenoxy aromatic acid Chemical compound 0.000 claims abstract description 53
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 18
- 239000003826 tablet Substances 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000008187 granular material Substances 0.000 claims description 11
- 239000004381 Choline salt Substances 0.000 claims description 9
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 7
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C62/30—Unsaturated compounds
- C07C62/38—Unsaturated compounds containing keto groups
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Hematology (AREA)
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- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a phenoxy aromatic acid with cyclopropyl and a preparation method thereof, a pharmaceutically acceptable salt of the phenoxy aromatic acid with cyclopropyl and a preparation method thereof, and also provides a preparation form of the phenoxy aromatic acid with cyclopropyl and the pharmaceutically acceptable salt thereof, and application of the phenoxy aromatic acid with cyclopropyl in medicines for treating hyperlipidemia diseases. The compound provided by the invention has better hypolipidemic drug effect, so that the compound has good application prospect.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a phenoxy aromatic acid hypolipidemic compound with cyclopropyl, a pharmaceutically acceptable salt thereof, and a preparation method and application thereof.
Background
Cardiovascular diseases are one of the most common and serious diseases which are harmful to human health (especially middle-aged and elderly people), dyslipidemia is an important risk factor of atherosclerosis, coronary heart disease and other cardiovascular and cerebrovascular diseases, and lipid regulating drugs can reduce the occurrence rate and death rate of the diseases and have positive effects and profound effects on the prevention and treatment of cardiovascular diseases. Statistics of the American IMSHealth company show that the global lipid regulating drug market in 2008 has reached 338.49 hundred million dollars, which is increased by 1.75% over the last year, and is 4.38% of the global drug market, which is an important second-order anti-tumor drug and the second-order important variety. In 2009, 15 lipid regulating drugs in 500 patients reach 285 hundred million dollars, which is increased by 1.11% over the last year, and the drug accounts for 6.6% of the total sales of 500 strong drugs, and the first 10 main varieties are the third varieties after tumor and hypertension drugs. Along with the improvement of the conversion level and the living standard of the life style of people, the incidence rate of cardiovascular diseases represented by dyslipidemia in China is obviously increased, and the basic clinical market is huge.
Fenofibrate (Fenofibrate) was first licensed to the FDA as a lipid regulating agent in 1993 and has been marketed abroad and domestically for many years to date for hypercholesterolemia and/or hypertriglyceridemia that cannot be controlled by appropriate and regular dietary therapy. At present, various preparations including common preparations, micronized preparations and corresponding various specifications are marketed at home and abroad, and the dosage of different dosage forms is different. Fenofibrate drug substances, tablets (specification 0.1 g) and capsules (specification 0.1 g) have been received in the chinese pharmacopoeia 2015 edition. Fenofibrate can obviously reduce triglyceride, moderately reduce total cholesterol and low-density lipoprotein cholesterol, and can raise high-density lipoprotein cholesterol to play a good role, so that the fenofibrate has wide clinical application. Fenofibrate or a derivative thereof has also been reported (patent CN 103417524 a) to be useful for preventing and/or treating retinopathy, particularly diabetic retinopathy.
Fenofibrate is usually orally administered, and is usually absorbed in the duodenum and other gastrointestinal tract after oral administration, and then metabolized to the active ingredient fenofibric acid. The biggest problem existing in fenofibrate at present is that the water solubility is extremely poor, so the fenofibrate is not easy to be absorbed by human bodies, and the bioavailability is extremely low.
Fenofibric acid is a metabolite of fenofibrate in vivo and is also an active form of a drug, has the effects of obviously reducing serum TC, TG and raising HDL-C levels, and can play a good lipid regulating role. Fenofibric Acid (Fenofibric Acid) is a novel phenoxy Acid derivative drug developed by us MUTUAL PHARM CO INC, which is approved by us FDA in 4 months of 2009 under the trade name of FIBRICOR, specification of 35mg and 105mg, and which has not yet been marketed in China. The medicine is used as a peroxisome proliferation activated receptor alpha (PPAR-alpha) agonist, is suitable for treating hypertriglyceridemia, can be singly used or can be used together with statin medicines, has excellent effect of controlling blood fat, and is a substitute medicine of fenofibrate.
Various attempts have been made to solve the problem of poor water solubility of fenofibrate drugs. The fenofibrate choline slow-release capsule is a chlorine Bei Dingsuan derivative blood lipid regulator marketed by AbVQIE (AbVIE) in the FDA in 2008 at 12 months, and the commercial product is sold under the trade name TRILIPIX and the specification: 45mg and 135mg have been marketed in multiple countries. Fenofibrate choline is a double salt formed by combining fenofibric acid (fenofibric acid) which is a metabolite of fenofibrate in vivo with choline, and the solubility of fenofibrate choline is obviously higher than that of fenofibrate choline under alkaline conditions. Can reduce Low Density Lipoprotein (LDL) and triglyceride levels, increase High Density Lipoprotein (HDL) levels, and can be used with statin drugs to improve hyperlipidemia. Proved by a large number of clinical experiments and drug researches: the hydrophobicity of the fenofibrate leads to low bioavailability, is greatly influenced by food, and in contrast to the fenofibrate, the fenofibrate choline has higher solubility in small intestine areas, so that the bioavailability of the fenofibric acid is increased, the bioavailability is not influenced by food, and simultaneously, the dosage is reduced, and the toxic and side effects are also reduced. The chemically modified fenofibrate choline is an ultimate solution for the bioavailability of the fenofibrate, and can be expected to replace all the prior fenofibrate preparations on the market, greatly improve the curative effect and reduce the toxicity. The present product is not marketed in China, and according to the statistics of PDB drug comprehensive database, the ebiferous fenofibrate choline slow release capsule is sold in 2014 for about 23,590 ten thousand dollars, and in 2015 for about 16,310 ten thousand dollars.
Although Trilipix solves the problem of water solubility to some extent, its efficacy is still not strong enough.
Disclosure of Invention
The present invention intends to further enhance the efficacy of such compounds by altering the electronic effect of the molecular structure of fenofibric acid. A phenoxy aromatic acid with cyclopropyl and its pharmaceutically acceptable salt, and their preparing process and application are disclosed. The phenoxy aromatic acid with cyclopropyl has obvious multiple activities of reducing cholesterol and resisting oxidization.
The technical scheme adopted by the invention is as follows: a phenoxy aromatic acid with cyclopropyl has a structural formula as shown in the following formula (I),
the invention also provides a preparation method of the phenoxy aromatic acid with cyclopropyl, which comprises the following steps:
(1) Taking 4-chlorobenzoyl chloride and anisole as starting materials, and carrying out Friedel-crafts acylation reaction under the action of anhydrous aluminum trichloride to obtain a compound shown in a formula (II):
(2) Reacting the compound of formula (II) obtained in step (1) with a dichloromethane solution of 1-bromocyclopropanecarboxylic acid under the catalysis of sodium hydroxide to obtain a compound of formula (I):
the invention further provides a pharmaceutically acceptable salt of the phenoxy aromatic acid with cyclopropyl. The pharmaceutically acceptable salts of the present invention are preferably base addition salts. The base addition salts include salts with inorganic bases including, but not limited to, alkali metal, alkaline earth metal or transition metal hydroxides or carbonates, or with organic bases including, but not limited to, ammonia, basic amino acids such as arginine and lysine, and amines such as methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, 1-amino-2-propanol, 3-amino-1-propanol or hexamethylenetetramine, saturated cyclic amines having 4 to 6 ring carbon atoms (including, but not limited to, piperidine, piperazine, pyrrolidine and morpholine), and other organic bases such as N-methylglucamine, sarcosine and tromethamine, and quaternary ammonium compounds (including, but not limited to, tetramethylammonium and the like). The salt with the organic base is preferably a salt with an amino acid, an amine or a saturated cyclic amine. Preferred salts with inorganic bases are preferably salts with cations of Na, K, mg and Ca.
Further, the pharmaceutically acceptable salt of the phenoxy aromatic acid having a cyclopropyl group is selected from the group consisting of choline salt, ethanolamine salt, diethanolamine salt, piperazine salt, calcium salt and tromethamine salt of the phenoxy aromatic acid having a cyclopropyl group.
The invention further provides a preparation method of the pharmaceutically acceptable salt of the phenoxy aromatic acid with the cyclopropyl, which comprises the following steps: adding phenoxy aromatic acid of cyclopropyl, a solvent and salt into a reaction bottle, heating and stirring to perform a reaction; and after the reaction is finished, naturally cooling to room temperature, precipitating solid, and drying to obtain pharmaceutically acceptable salt of the ciprofloxacin.
Preferably, in the preparation method of the phenoxy aromatic acid with cyclopropyl in the pharmaceutically acceptable salt, the solvent is one or more selected from isopropanol, ethyl acetate and ethanol.
The invention further provides a preparation method of the pharmaceutically acceptable salt of the phenoxy aromatic acid with the cyclopropyl, which comprises the following steps: adding phenoxy aromatic acid with cyclopropyl, solvent and salt into a reaction bottle, heating and stirring to react; and after the reaction is finished, naturally cooling to room temperature, precipitating solid, and drying to obtain pharmaceutically acceptable salt of the ciprofloxacin.
Preferably, in the preparation method of the phenoxy aromatic acid with cyclopropyl in the pharmaceutically acceptable salt, the solvent is one or more selected from isopropanol, ethyl acetate and ethanol.
More preferably, in the preparation method of the phenoxy aromatic acid with cyclopropyl in the pharmaceutically acceptable salt, the molar ratio of the ciprofloxacin to the salt is 1:1-1:1.2.
The invention further provides a phenoxy aromatic acid crystal with cyclopropyl, and the chemical structural formula of the phenoxy aromatic acid crystal with cyclopropyl is as follows:
the invention further provides a choline phenoxy-aromatic acid salt crystal with cyclopropyl, which has a chemical structural formula as follows:
the medicament of the present invention may be any form of pharmaceutical formulation suitable for phenoxy aromatic acids and salts thereof having cyclopropyl groups.
In addition to the phenoxy aromatic acid having a cyclopropyl group or its salt, the formulation may contain one or more other active substances, in particular those having a similar effect to that of fenofibrate, such as active substances selected from the group consisting of other lipid modulators, for example but not limited to further fibric acids (fibrates; fibrates) such as bezafibrate, ciprofibrate and gemfibrozil, or statins such as lovastatin, mevinolin, pravastatin, fluvastatin, atorvastatin, mevastatin, rosuvastatin, shu Jiangzhi (velostatin), simvastatin (simvastatin) and cerivastatin, as well as other types of advantageous active substances.
The phenoxy aromatic acid or salt thereof of the cyclopropyl group generally represents from 5% to 60%, preferably from about 7% to 40%, in particular from about 10% to 30% of the total weight of the formulation.
The formulations of the present invention comprise pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are those excipients known to be useful in the pharmaceutical arts and in similar fields, in particular those listed in the relevant pharmacopoeias (e.g. chinese pharmacopoeias, united states pharmacopoeias, european pharmacopoeias, international pharmacopoeias, national formulary), and other excipients whose properties do not impair physiological use.
The excipient is typically a conventional pharmaceutical excipient such as a filler, for example, but not limited to, sugar alcohols (e.g., lactose, microcrystalline cellulose, mannitol, sorbitol, and xylitol), isomalt, starch saccharification products, talc, sucrose, cereal corn, or potato starch, present at a concentration of about 0.02% to about 50%, preferably about 0.20% to about 20%, based on the total weight of the mixture; lubricants, glidants and mold release agents, such as, but not limited to, magnesium stearate, aluminum stearate and calcium stearate, talc and silicone, and animal or vegetable fats and oils, particularly those that are solid at room temperature and fats in hydrogenated form; fluidity modifiers such as colloidal silica (highly dispersed silica); dyes, such as but not limited to azo dyes, organic or inorganic pigments or dyes of natural origin, preferably inorganic pigments, such as iron oxides, if present, are present in a concentration of from about 0.001% to about 10%, preferably from about 0.1% to 3%, based on the total weight of the mixture; stabilizers such as, but not limited to, antioxidants, light stabilizers, hydrogen peroxide destroyers, radical scavengers, stabilizers against microbial attack; plasticizers, particularly those described below. Wetting agents, preservatives, disintegrants, adsorbents and surfactants, in particular anionic and nonionic surfactants, such as fatty acid salt surfactants and fatty acid salt-containing surfactants, alkyl sulfates and sulfonates, bile acid salts, alkoxylated fatty alcohols, alkoxylated alkylphenols, alkoxylated fatty acids and fatty acid glycerides (which may be alkoxylated), and solubilizing agents, such as (polyethoxylated castor oil), and vitamin E TPGS and (ethoxylated sorbitan fatty acid esters), may also be added. For the purposes of the present invention, excipients are also substances which are used to form solid solutions with the active substance. Examples of such excipients are pentaerythritol, pentaerythritol tetraacetate, urea, phospholipids such as egg phosphine esters, polymers such as polyethylene oxide and polypropylene oxide and their block copolymers (poloxamers), citric acid and succinic acid, bile acids, glyceryl stearate and other excipients.
In one embodiment, the pharmaceutical formulation useful in the present invention may comprise an enteric binder (entericbinder), which may be an enteric polymer, such as a binder selected from the group consisting of: hydroxypropyl methylcellulose phthalate, hydroxypropyl methyl-cellulose acetate succinate, carboxymethyl ethyl-cellulose, cellulose acetate phthalate, cellulose acetate trimellitate, and sodium carboxymethyl cellulose. Furthermore, the enteric polymer may be a copolymer, for example a copolymer of (meth) acrylic acid and at least one alkyl (meth) acrylate. The alkyl (meth) acrylate may be methyl methacrylate. The ratio of free carboxyl groups to esterified carboxyl groups of the copolymer may be about 2:1 to 1:3, preferably about 1:1.
The pharmaceutical preparation of the invention is mainly used for physiological practices, in particular to the field of human medicine. In this sense, the formulation is used as or in a dosage form, i.e. the formulation of the invention (together with other excipients, if necessary) has an advantageous morphology suitable for physiological practice. Thus, the term "dosage form" refers to any dosage form suitable for administration of an active substance to a human.
Conventional dosage forms include, but are not limited to, capsules, granules, pills, powders, suspensions, suppositories, and tablets. The granules comprise solid granules of the formulation of the invention, wherein each granule is an aggregate of a plurality of powder particles. The average particle size of the particles may be from about 0.12mm to about 2mm, preferably from about 0.2mm to about 0.7mm. The granules are preferably used as oral dosage forms. A single dose formulation may be provided to the user, for example, as particles packaged in a packet (pouch), paper packet or vial, or a multi-dose formulation requiring an appropriate measure may be provided to the user. However, in many cases, such granules are not actual dosage forms, but rather intermediates in the preparation of particular dosage forms, such as tablet granules which may be compressed into tablets, capsule granules which may be packaged into hard gelatin capsules, or granules for instant or oral suspension which may be put into water and then ingested. As capsules, the formulations of the invention are typically packaged in a hard shell consisting of two parts fitted together, or in a separate, closed soft shell, which can vary in shape and size. The formulations of the present invention may be encapsulated or embedded in a suitable polymer matrix, that is, microcapsules and microspheres. Hard and soft capsules consist mainly of gelatin, which may have a suitable content of plasticizing substances, such as glycerol or sorbitol. Hard gelatin capsules may be used to receive solid formulations of the invention, such as granules, powders or pellets. Soft gelatin capsules are suitable for semi-solid formulations, as well as viscous liquid formulations (if necessary).
In semi-solid formulations, the formulations of the present invention are absorbed into a suitable vehicle. Suitable matrices are known to those skilled in the art.
Suppositories are solid formulations for rectal, vaginal, urethral administration. To be suitable for this route of administration, the formulations of the present invention in these pharmaceutical forms must be absorbed into suitable excipients, such as fats (e.g., hard fats) which melt at body temperature, macrogols (i.e., polyethylene glycols having a molecular weight of from about 1000 to about 3000 in various proportions), glycerin, gelatin, and the like.
Tablets are solid formulations for oral administration. In particular, oral within the framework of the present invention means the term "oral", i.e. a tablet in which the active substance is absorbed or acts in the gastrointestinal tract. Particular embodiments include, but are not limited to, coated tablets, layered tablets, laminated tablets, tablets with improved release of active substance, matrix tablets, effervescent tablets or chewable tablets. The formulations of the present invention generally comprise at least a portion of the necessary tablet excipients, such as binders, fillers, glidants and lubricants, and disintegrants. If desired, tablets of the formulations of the invention may also contain other suitable excipients. Excipients which facilitate tabletting, such as lubricants and glidants, for example those mentioned above, are also used here, preference being given to flowability regulators such as silicon dioxide and/or lubricants such as magnesium stearate, in particular excipients for promoting compaction. The coated tablets additionally comprise suitable coating materials, such as film-coating agents with coating aids, in particular those mentioned below. Coated tablets include, but are not limited to, sugar coated tablets and film coated tablets.
When used as a dosage form and thus providing an effective amount of active substance, the formulations of the present invention are administered to the individual to be treated. Whether such treatment is needed and what form is taken depends on the individual's condition, a drug assessment (diagnosis) can be made that includes the signs, symptoms and/or dysfunctions that are present, the risk of developing certain signs, symptoms and/or dysfunctions, and other factors.
These formulations are typically administered together or alternately with other products so that the individual to be treated receives a daily dose of about 50mg to about 250mg of cyclopropyl phenoxyaromatic acid orally. In one embodiment of the invention, the daily dose is 200mg, 160mg, 145mg or 130mg.
Any delivery route may be employed for providing the patient with an effective amount of the cyclopropyl phenoxy aromatic acid or salt thereof. Preferred routes of delivery include, but are not limited to, oral or parenteral, such as rectal, vaginal, urethral, transdermal, and oral routes of delivery are preferred.
The invention also discloses application of the cyclopropyl phenoxy aromatic acid in preparing medicaments for treating hyperlipidemia diseases.
Compared with the prior art, the invention has the following beneficial technical effects:
the invention uses the isostere rule in chemistry to replace two methyl groups of fenofibric acid by cyclopropyl, changes the three-dimensional conformation and hydrophobicity of alkyl, and examines whether the two groups form more reasonable interaction with a hydrophobic pocket of a receptor binding point. In addition, the introduction of cyclopropyl contributes to the improvement of metabolic stability. So that the drug effect of the fenofibric acid molecules is further improved.
The disclosed phenoxy aromatic acid with cyclopropyl is a novel multifunctional active compound, which can be used for treating hyperlipidemia, can reduce blood lipid (triglyceride and cholesterol), can resist lipid peroxidation, and can improve oxidative stress under the symptom of hyperlipidemia.
The ciprofloxacin fenofibric acid disclosed by the invention has remarkable blood lipid reducing effect on hyperlipoidemia mice caused by Triton WR-1339, and can obviously reduce triglyceride level and total cholesterol level of the hyperlipoidemia mice.
The invention also discloses a preparation method of the phenoxy aromatic acid with cyclopropyl, and in addition, a series of pharmaceutically acceptable salts of the phenoxy aromatic acid with cyclopropyl are prepared on the basis.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Comparative example preparation of fenofibric acid and its choline salt
(1) Preparation of fenofibric acid
72.0g of fenofibrate and 360ml of absolute ethyl alcohol are added into a 500ml reaction bottle, and stirred and mixed uniformly. Heating to 60 ℃, keeping the temperature, stirring until the solid is dissolved into colorless transparent solution, dropwise adding 57.6g of 25% sodium hydroxide solution, keeping the temperature at about 60 ℃ during dropwise adding, heating to 80 ℃ after dropwise adding, and reacting for 1 hour, and ending the reaction; cooling the reaction solution to 0-5 ℃, dropwise adding concentrated hydrochloric acid to adjust the pH value of the reaction solution to 2-3, stirring for 30 minutes at 0-5 ℃ after the dropwise adding, filtering, washing the filter cake to be neutral by pure water, pumping, and drying at 65 ℃ to obtain 60.1g of fenofibric acid.
(2) Preparation of fenofibric acid choline
Fenofibric acid 10.0g was dissolved in 100ml isopropanol and heated to 65 ℃. A choline hydroxide/methanol solution (8.58 g, 45%) was diluted with 20ml of isopropanol and approximately 2/3 of the dilution was added dropwise to the fenofibric acid solution. A small amount of seed crystals can be added to the reaction solution to accelerate crystallization. After the funnel was rinsed with 15ml of isopropyl alcohol, the remaining 1/3 choline hydroxide dilution was added to the reaction solution. Stirred at 65℃for crystallization for 0.5 hours, cooled to 20℃for more than 5 hours, and then stirred at 20℃overnight. Filtered and rinsed with 30ml of isopropanol. The filter cake was dried in a vacuum oven at 35 c for about 24 hours. 11.83g of fenofibric acid choline are obtained.
EXAMPLE 1 preparation of ciprofloxacin
Into a three-neck flask, 11.2g of anhydrous aluminum trichloride, 42.4ml of toluene and 7.9ml of anisole are added, the mixture is stirred, the temperature is controlled below 40 ℃, 7.36ml of 4-chlorobenzoyl chloride is slowly added dropwise, and after the dropwise addition is completed, the temperature is slowly raised to reflux in an oil bath for reaction for 2 hours. TLC was followed by reaction, after completion of the reaction, cooled to room temperature, 50ml of water was slowly added dropwise with stirring, at which time a large amount of solid was precipitated, suction-filtered, the cake was washed with a suitable amount of water, and the obtained solid was recrystallized from ethanol to give 10.8g of compound (II).
8.0g of the compound (II) prepared in the previous step, 0.6g of sodium hydroxide and 96ml of butanone are added into a three-necked flask, the temperature is raised to 45-60 ℃ under stirring, the mixture is stirred for 30 minutes, 1.6g of purified water is added, the mixture is stirred for 1 hour, the temperature is kept at 45-60 ℃, then butanone solution of 1-bromocyclopropane carboxylic acid (8.0 g) is taken and slowly added into the reaction solution in a dropwise manner, and the reflux reaction is carried out for 3-5 hours after the dropwise addition is completed. After the reaction is finished, 50ml of water is added into the reaction liquid, stirring and washing are carried out, liquid separation is carried out, the water phase is discarded, 1mol/L hydrochloric acid is used for adjusting the pH value to 2-3 (room temperature), a large amount of solids are separated out, filtration is carried out, the filter cake is washed to pH value of 5-6 by purified water, filtration is carried out, the filter cake is collected, and vacuum drying is carried out at 40-60 ℃ to obtain 9.2g of crude ciprofloxacin fenofibric acid.
Adding the crude product of the ciprofloxacin bevacic acid obtained in the example 1 into a dry reaction bottle, adding 92g of ethanol, heating to 70 ℃ for stirring and dissolving, stirring for 30 minutes, filtering, cooling the filtrate to 5-10 ℃, stirring and crystallizing for 12 hours, filtering, collecting a filter cake, vacuum drying at 40-60 ℃, weighing and detecting the purity to obtain 7.84g of refined ciprofloxacin bevacic acid, and detecting the purity by HPLC to 99.9%.
EXAMPLE 2 preparation of Cycloprofenoxac acid choline salt
Into the reaction flask was charged 7.5g of ciprofloxacin, 75ml of isopropyl alcohol, 6.26g of choline hydroxide solution (45 wt%). Heating to 65deg.C, stirring for 1 hr, naturally cooling to room temperature, and separating out solid. The solid was collected and dried to give 6.88g of ciprofloxacin choline salt. m/z 418.14 (100.0%), 420.14 (32.0%), 419.15 (24.3%), 421.14 (7.8%), 420.15 (3.8%); elemental Analysis C,63.08; h,6.02; cl,8.46; n,3.34; o,19.10.
EXAMPLE 3 preparation of Cycloprofenoxac acid ethanolamine salt
7.5g of ciprofloxacin bevacizidine, 75ml of isopropanol and 1.59g of ethanolamine are added to the reaction flask. Heating to 65deg.C, stirring for 1 hr, naturally cooling to room temperature, and separating out solid. The solid was collected and dried to give 6.17g of ciprofloxacin ethanolamine salt. m/z 377.10 (100.0%), 379.10 (32.0%), 378.11 (21.0%), 380.10 (6.8%), 379.11 (3.1%); elemental Analysis C,60.40; h,5.34; cl,9.38; n,3.71; o,21.17.
EXAMPLE 4 preparation of Cycloprofenoxac acid diethanolamine salt
7.5g of ciprofloxacin bevacizumab acid, 75ml of isopropanol, 2.74g of diethanolamine are added to the reaction flask. Heating to 65deg.C, stirring for 1 hr, naturally cooling to room temperature, and separating out solid. The solid was collected and dried to give 7.04g of the diethanolamine salt of ciprofloxacin. m/z 421.13 (100.0%), 423.13 (33.3%), 422.13 (23.3%), 424.13 (7.4%), 423.14 (2.6%), 425.13 (1.2%); elemental Analysis C,59.79; h,5.73; cl,8.40; n,3.32; o,22.75.
EXAMPLE 5 preparation of piperazine salt of ciprofloxacin
7.5g of ciprofloxacin bevacizide, 75ml of isopropanol, and 1.12g of piperazine were added to the reaction flask. Heating to 65deg.C, stirring for 1 hr, naturally cooling to room temperature, and separating out solid. The solid was collected and dried to give 5.52g of piperazine ciprofloxacin. m/z 714.15 (100.0%), 716.15 (64.2%), 715.16 (41.8%), 717.15 (27.0%), 718.15 (11.5%), 716.16 (10.1%), 718.16 (5.6%), 719.15 (4.3%), 717.16 (2.1%), 719.16 (1.2%), 720.15 (1.0%); elemental Analysis C,63.78; h,4.51; cl,9.91; n,3.91; o,17.89.
EXAMPLE 6 preparation of ciprofloxacin
7.5g of ciprofloxacin, 75ml of isopropanol, and 3.16g of tromethamine were added to the reaction flask. Heating to 65deg.C, stirring for 1 hr, naturally cooling to room temperature, and separating out solid. The solid was collected and dried to give 6.38g of ciprofloxacin tromethamine salt. m/z 437.12 (100.0%), 439.12 (32.0%), 438.13 (23.3%), 440.12 (7.4%), 439.13 (4.0%), 441.13 (1.3%); elemental Analysis C,57.60; h,5.52; cl,8.10; n,3.20; o,25.58.
EXAMPLE 7 preparation of ciprofloxacin sodium salt
7.5g of ciprofloxacin bevacizc acid, 75ml of isopropanol, 1.30g of sodium carbonate were added to the reaction flask. Heating to 65deg.C, stirring for 1 hr, naturally cooling to room temperature, and separating out solid. The solid was collected and dried to give 5.66g of ciprofloxacin sodium salt. m/z 338.03 (100.0%), 340.03 (32.0%), 339.04 (18.7%), 341.03 (5.9%), 340.04 (2.5%); elemental Analysis C,60.28; h,3.57; cl,10.47; na,6.79; o,18.89.
EXAMPLE 8 lipid-lowering action of ciprofloxacin
The compounds disclosed by the invention are novel hypolipidemic candidate compounds, and the hypolipidemic drug effect evaluation method is to observe the hypolipidemic effect of the compounds according to the technical requirements of new pharmacodynamics research by adopting rats through continuous repeated administration experiments. The specific method comprises the following steps:
the compounds disclosed by the invention are novel hypolipidemic candidate compounds, and the hypolipidemic efficacy evaluation method is to observe the hypolipidemic effect of the compounds according to the technical requirements of new pharmacodynamics research by adopting male C57 mice through continuous repeated administration experiments. The specific method comprises the following steps:
1. the C57 mice are bred in SPF class animal houses, the temperature is controlled to be 20-25 ℃, the relative humidity is 55+/-15 percent, ventilation is carried out 10 times per hour, illumination is controlled manually, and 12 hours are alternated day and night. The mice were randomly grouped according to body weight, normally fed with diet, and after 1 week of acclimation, each group of mice was fed with high fat diet except for the normal control group.
2. Mice were fed with high fat diet for 26 days and were each fed with 100mg/kg of fenofibric acid, 100mg/kg of fenofibric acid salt and test compound. The doses of the test compounds were 10, 30 and 100mg/kg, respectively. The volume of administration was 0.1ml/10g, n=8, for 4 days.
3. After 5-6 hours after the last administration, blood is taken, left to stand at room temperature to fully coagulate, centrifuged at 10000rpm for 5 minutes, the supernatant is transferred, and the serum sample is stored at 4 ℃ for measuring the serum triglyceride, total cholesterol, high density lipoprotein and low density lipoprotein level.
4. Statistical analysis: the serum triglyceride, total cholesterol, high density lipoprotein, and low density lipoprotein levels of mice are expressed as mean ± standard deviation, and the differences between groups were first examined by statistical analysis of one-way variance between groups and then by Student's t-test.
The compounds of the examples of the present invention were evaluated by the pharmacodynamics of the animals described above and the results are shown in the following table:
table 1 effect of drug on serum blood lipid levels in C57 mice
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The above comparison of the results of the specific examples of the present invention with the comparative examples on the serum blood lipid level of C57 mice shows that the effect of the fenofibric acid and the salt thereof with cyclopropyl on lowering blood lipid is remarkable and superior to that of the fenofibric acid and the choline salt thereof; the lipid lowering effect of the choline salt of fenofibric acid with cyclopropyl is superior to that of ethanolamine salt, diethylamine salt, piperazine salt, tromethamine salt and sodium salt.
Example 9 samples of examples 1-7 of the present invention were compared for hygroscopicity and solubility.
Referring to the four hygroscopicity and solubility tests of chinese pharmacopoeia 2015 edition, the hygroscopicity and solubility of the samples of examples 1-7 were measured and the results are shown in the following table:
examples | Moisture-wicking property (%) | Solubility in water (mg/ml) |
Example 1 | 0.1 | 80 |
Example 2 | 0.1 | 800 |
Example 3 | 3.0 | 100 |
Example 4 | 5.8 | 250 |
Example 5 | 4.3 | 300 |
Example 6 | 3.5 | 200 |
Example 7 | 8.5 | 600 |
The test results show that: the samples of examples 3-7 all have certain hygroscopicity, and the sodium salt sample of example 7 has the most hygroscopicity although the solubility is also possible; examples 1-2 were free of hygroscopicity; example 2 (choline salt of example 1) has the best solubility.
EXAMPLE 10 stability control of the inventive examples
The samples of examples 1-7 were subjected to the following stability comparisons and the results for the relevant substances are shown in the following table:
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as can be seen from the above table, the samples of examples 1 and 2 prepared according to the present invention are most stable under strong light, high heat and high humidity. The results show that the choline salt stability of the product is superior to other salts.
While the specific embodiments of the present invention have been described above, the present invention is not limited to the above embodiments, and various modifications can be made within the technical gist of the present invention as long as the general knowledge is known in the technical field of the present invention.
Claims (9)
1. A phenoxy aromatic acid with cyclopropyl and its medicinal salt, which has the structural formula as follows,
2. the phenoxy aromatic acid having cyclopropyl and pharmaceutically acceptable salts thereof according to claim 1, characterized in that the preparation method comprises the steps of:
(1) Taking 4-chlorobenzoyl chloride and anisole as starting materials, and carrying out Friedel-crafts acylation reaction under the action of anhydrous aluminum trichloride to obtain a compound shown in a formula (II):
(2) Reacting the compound of formula (II) obtained in step (1) with a dichloromethane solution of 1-bromocyclopropanecarboxylic acid under the catalysis of sodium hydroxide to obtain a compound of formula (I):
3. the phenoxy aromatic acid having a cyclopropyl group and pharmaceutically acceptable salts thereof according to claim 1, wherein the pharmaceutically acceptable salt is a base addition salt comprising a salt with an inorganic base comprising an alkali metal, alkaline earth metal or transition metal hydroxide or carbonate, or a salt with an organic base comprising arginine, lysine, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, 1-amino-2-propanol, 3-amino-1-propanol, hexamethylenetetramine, piperidine, piperazine, pyrrolidine, morpholine, N-methylglucamine, sarcosine, tromethamine or tetramethylammonium.
4. A pharmaceutically acceptable salt according to claim 3, selected from the group consisting of choline salts, ethanolamine salts, diethanolamine salts, piperazine salts, calcium salts and tromethamine salts of phenoxy aromatic acids having cyclopropyl groups.
5. A pharmaceutical formulation comprising a phenoxy aromatic acid having a cyclopropyl group according to claim 1 and pharmaceutically acceptable salts thereof.
6. The pharmaceutical preparation according to claim 5, wherein the phenoxy aromatic acid having cyclopropyl group as the main active ingredient or a pharmaceutically acceptable salt thereof accounts for 5 to 60% of the total weight of the preparation.
7. Pharmaceutical formulation according to claims 5-6, characterized in that it comprises pharmaceutically acceptable excipients, which are excipients known to be useful in the pharmaceutical technical field and in the similar field, including those listed in the chinese pharmacopoeia, the united states pharmacopeia, the european pharmacopeia, the international pharmacopeia, the national formulary set of prescriptions, and excipients whose properties do not impair the physiological use.
8. The pharmaceutical formulation of claim 5, wherein the pharmaceutical formulation comprises a capsule, granule, pill, powder, suspension, suppository, or tablet.
9. The pharmaceutical formulation of claim 5, wherein the route of administration comprises intravenous injection and gastrointestinal delivery routes.
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