CN110577475A - Ambroxol derivative, and preparation method, pharmaceutical composition and application thereof - Google Patents

Ambroxol derivative, and preparation method, pharmaceutical composition and application thereof Download PDF

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CN110577475A
CN110577475A CN201810584093.5A CN201810584093A CN110577475A CN 110577475 A CN110577475 A CN 110577475A CN 201810584093 A CN201810584093 A CN 201810584093A CN 110577475 A CN110577475 A CN 110577475A
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compound
pharmaceutically acceptable
ambroxol
acceptable salt
preparation
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安明
常珍
魏俊明
祝江业
龙敬伟
况斌
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BEIJING HUARUI DINGXIN TECHNOLOGY Co Ltd
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BEIJING HUARUI DINGXIN TECHNOLOGY Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/10—Expectorants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

The invention relates to the field of medicinal chemistry, in particular to ambroxol derivatives or pharmaceutically acceptable salts thereof, a preparation method thereof, a medicinal composition thereof and medical application thereof.

Description

ambroxol derivative, and preparation method, pharmaceutical composition and application thereof
Technical Field
The invention particularly relates to an ambroxol derivative, a preparation method of the ambroxol derivative, a pharmaceutical composition containing the ambroxol derivative and the ambroxol derivative, belonging to the field of pharmaceutical chemistry,
Technical Field
Ambroxol (Ambroxol), the chemical name is trans-4- [ (2-amino-3, 5-dibromo benzyl phenyl methyl) amino ] cyclohexanol, the compound structure is shown as formula A, by Germany Boringer Yiger John's large pharmaceutical factory research and development, its pharmaceutical form is Ambroxol hydrochloride, the trade name is "Mushutane", it is the expectorant commonly used at present, its toxicity is low, the curative effect is precise, expectorant action is stronger than bromhexine, it is commonly used in clinic for the acute and chronic bronchitis accompanied by abnormal secretion of respiratory tract, bronchial asthma and acute, chronic lung disease of expectorant dysfunction, the preventive treatment of postoperative lung complication, the treatment of infant respiratory distress syndrome of premature infant and neonate.
CN 105693764, CN101544572 and the like report that hydroxyl ends are subjected to esterification reaction to obtain modified ambroxol, and mainly aim at solving the problem of solubility of ambroxol. The structure of the compound disclosed in CN 105693764 is shown in formula B, a hydroxyl end is connected with a phosphate group, and the water solubility problem of the compound is improved by changing R1 and R2 into different basic ions or groups. The structure of the compound disclosed in CN101544572 is shown in formula C, and the amino acid is grafted into the hydroxyl end to obtain amino acid ester, so that the problem of water solubility is properly solved.
Although the scheme can increase the water solubility of the ambroxol, the drug effect is not improved.
US5352703A reports that an ambroxol amino-terminal modified compound is shown as a formula D, and the ambroxol amino-terminal modified compound is found to have certain cough relieving and sputum regulating activities. EP0150787A2 also reports that ambroxol amino-terminal modified compounds are shown as E, and are found to have certain drug effects on respiratory diseases.
Disclosure of Invention
The invention aims to provide the ambroxol derivative with stronger drug effect and higher bioavailability. Specifically, the ambroxol derivative is characterized in that: the ambroxol derivative is a compound shown in the following structure, and the specific structure is as follows:
Wherein R is selected from H, C1-6 straight chain or branched chain alkyl and C1-6 straight chain or branched chain alkanoyl.
H, C1-4 alkyl, C1-4 alkanoyl are preferred.
More preferably H, C1-2 alkyl group or C1-2 alkanoyl group.
Most preferred is H, methyl, ethyl or acetyl.
the C1-6 straight chain or branched chain alkyl group of the invention is preferably a C1-5 straight chain or branched chain alkyl group or a C2-6 straight chain or branched chain alkyl group; still more preferred are C1-4 straight or branched chain alkyl, C2-5 straight or branched chain alkyl, C3-6 straight or branched chain alkyl; more preferred are C1-3 straight or branched chain alkyl, C2-4 straight or branched chain alkyl, C3-5 straight or branched chain alkyl, C4-6 straight or branched chain alkyl; further preferred are C1-2 linear or branched alkyl groups, C2-3 linear or branched alkyl groups, C3-4 linear or branched alkyl groups, C4-5 linear or branched alkyl groups, C5-6 linear or branched alkyl groups.
The C1-6 straight chain or branched chain alkyl is selected from methyl, ethyl, propyl, butyl, pentyl and hexyl.
preferred C1-4 straight or branched chain alkyl groups are selected from methyl, ethyl, propyl, butyl.
More preferred C1-2 alkyl groups are selected from methyl and ethyl.
the propyl group comprises an n-propyl group and an isopropyl group;
The butyl comprises n-butyl, isobutyl, second butyl and tertiary butyl;
The amyl group comprises an n-amyl group, an isoamyl group and a neopentyl group.
The C1-6 straight chain or branched chain alkyl group of the invention is preferably a C1-5 straight chain or branched chain alkyl group or a C2-6 straight chain or branched chain alkanoyl group; still more preferred are C1-4 straight or branched chain alkanoyl, C2-5 straight or branched chain alkanoyl, C3-6 straight or branched chain alkanoyl; more preferred are C1-3 straight or branched chain alkanoyl, C2-4 straight or branched chain alkanoyl, C3-5 straight or branched chain alkanoyl, C4-6 straight or branched chain alkanoyl; further preferred is a C1-2 linear or branched alkanoyl group, a C2-3 linear or branched alkanoyl group, a C3-4 linear or branched alkanoyl group, a C4-5 linear or branched alkanoyl group, a C5-6 linear or branched alkanoyl group.
The C1-6 straight chain or branched chain alkanoyl is selected from formyl, acetyl, propionyl, butyryl, pentanoyl and hexanoyl.
Preferred C1-4 straight or branched chain alkanoyl groups are selected from formyl, acetyl, propionyl, butyryl.
More preferred C1-2 alkanoyl is selected from formyl, acetyl.
The propionyl group comprises n-propionyl group and iso-propionyl group;
The butyryl group comprises n-butyryl, isobutyryl, second butyryl and tertiary butyryl;
the valeryl comprises n-valeryl, isovaleryl and pivaloyl.
The compound also comprises pharmaceutically acceptable salts of ambroxol derivatives, wherein the salts comprise inorganic acid salts or organic acid salts.
The inorganic acid salt is hydrochloride, hydrobromide, phosphate or sulfate;
The organic acid salt is selected from acetate, trifluoroacetate, methanesulfonate, p-toluenesulfonate, lycinate, maleate, tartrate, fumarate, citrate or lactate.
in a second aspect, the present invention provides a process for preparing an ambroxol derivative or a pharmaceutically acceptable salt thereof, comprising the steps of:
1) Taking the compound 2 as a starting material, and protecting aldehyde groups by using a carbonyl protection reagent to obtain a compound 3;
2) Reacting the compound 3 with a compound 6, and removing a protecting group by using a deprotection agent to obtain a compound 4;
3) Reacting the compound 4 with trans-4-aminocyclohexanol to obtain a Schiff base compound 5;
4) Reducing the compound 5 by a reducing agent to obtain a compound I;
Wherein PG is a carbonyl protecting group;
R' is selected from C1-6 straight chain or branched chain alkyl, C1-6 straight chain or branched chain alkanoyl;
R is selected from H, C1-6 straight chain or branched chain alkyl and C1-6 straight chain or branched chain alkanoyl.
the carbonyl protecting reagent in step 1) is selected from alcohols. Preferred carbonyl protecting agents are selected from: methanol, ethanol, isopropanol, 1, 2-ethanediol and 1, 3-propanediol. More preferably, the carbonyl protecting agent is selected from 1, 2-ethanediol.
the deprotection agent in the step 2) is selected from acid. Preferred deprotecting agents are selected from: trifluoroacetic acid, glacial acetic acid, acetic acid water solution, hydrochloric acid and sulfuric acid. More preferably the deprotecting agent is selected from aqueous acetic acid.
the reducing agent in the step 4) is selected from a hydroboration reagent. Preferred reducing agents are selected from: sodium borohydride, potassium borohydride, sodium triacetoxyborohydride. More preferably the reducing agent is selected from sodium borohydride.
The preparation method of the compound 6 comprises the following steps of oxidizing a compound 8 serving as a starting raw material to generate a compound 7, and then carrying out chlorination, wherein the reaction route is as follows:
R' is selected from C1-6 straight chain or branched chain alkyl and C1-6 straight chain or branched chain alkanoyl.
the compound I can also be salified by a conventional method, and an acidifying reagent is an inorganic acid or an organic acid.
The inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid;
The organic acid is selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, lycic acid, maleic acid, tartaric acid, fumaric acid, citric acid or lactic acid.
The third aspect of the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of an ambroxol derivative or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
The invention also relates to a pharmaceutical composition using the compound as an active ingredient. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of from 0.1 to 95% by weight.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ophthalmic, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.
for example, in order to prepare the compound of the present invention into a solid oral preparation, tablets, capsules and granules can be prepared. In addition to an effective amount of the active ingredient compound I, conventional functional adjuvants such as disintegrants, fillers, binders, lubricants and glidants are added to the formulation. The preparation process comprises mixing conventional active ingredients with adjuvants, granulating by wet method, mixing with lubricant or glidant, and making into capsule or directly into small bag or tablet, wherein the tablet may be coated or uncoated.
For example, to formulate the compounds of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
For example, to encapsulate a dosage unit, the active ingredient of a compound of the present invention can be mixed with a diluent, glidant, and the mixture can be placed directly into a hard or soft capsule. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.
The compounds of the invention can also be formulated as liquid oral preparations, for example for the purpose of preparing oral suspensions, which are formulated with purified water as solvent in addition to the active ingredient compound I, and optionally with the flavoring agents mannitol or sorbitol, hypromellose or methylcellulose as suspending agent, the preservatives methyl and propyl parabens or sodium benzoate, and the cosolvent sodium lauryl sulfate. If desired, colorants may also be added.
in order to prepare the compound of the invention into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
in addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage range for a compound of the invention is from 0.001 to 150mg/Kg body weight, preferably from 0.01 to 100mg/Kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.
The fourth aspect of the invention also provides the pharmaceutical use of the ambroxol derivative or the pharmaceutically acceptable salt thereof.
For example, the ambroxol derivative or the pharmaceutically acceptable salt thereof can be applied to the preparation of expectorant drugs.
for example, the ambroxol derivative or the pharmaceutically acceptable salt thereof of the invention is used for preparing a medicament for preventing, treating or relieving respiratory diseases. The respiratory system disease is selected from acute and chronic lung diseases with sputum excretion dysfunction, acute and chronic bronchitis accompanied with abnormal secretion of respiratory tract, bronchial asthma, postoperative lung complications, infant respiratory distress syndrome of premature infant and newborn infant.
advantageous technical effects
therefore, the aniline group is amidated and modified to obtain another ambroxol modified drug which is rapidly hydrolyzed into ambroxol in vivo, and pharmacological toxicological experiments in animals show that the ambroxol modified drug has good safety and greatly improved bioavailability compared with currently marketed ambroxol hydrochloride, compound D in US5352703A and compound E in EP0150787A 2.
Detailed Description
The present invention is described in further detail with reference to the following examples, but the present invention is not limited thereto, and any equivalent replacement in the field made in accordance with the present disclosure is included in the scope of the present invention.
preparation example 1
Compound D hydrochloride is prepared with reference to the patent US5352703A synthesis: 9.2mL of benzoyl chloride was added to the toluene solution of ambroxol, 6.5mL of pyridine was added dropwise, and the reaction was stirred for 3 hours. Then extracting with purified water, drying with magnesium sulfate and concentrating to dryness, recrystallizing with ethanol, dissolving in acetone, adjusting pH with hydrochloric acid, stirring at room temperature for crystallizing for 2h, and filtering to obtain compound D hydrochloride.
preparation example 2
Compound E hydrochloride is prepared with reference to the synthesis method of patent EP0150787a 2: adding 14mL of triethylamine into 39g of ambroxol in toluene, dropwise adding 2-thiophenecarbonyl chloride while stirring, reacting at room temperature overnight, extracting with purified water, concentrating to dryness, dissolving in ethanol, and adjusting pH with hydrochloric acid to obtain compound E hydrochloride.
Example 1
Preparation of Compound Ia
Preparation example: preparation of 3-methoxy-4-acetoxybenzoyl chloride
The preparation route is as follows:
40g of 3-methoxy-4-acetoxybenzoic acid and 200g of toluene were put in a reaction flask, and 31.2g of thionyl chloride was added thereto. The mixture is heated and stirred for 2 hours, and the mixture is decompressed and concentrated to be dry, thus obtaining 35.6g of 3-methoxy-4-acetoxy benzoyl chloride.
step 1: preparation of 2, 4-dibromo-6- (1, 3-dioxolane) aniline
the preparation route is as follows:
100.0g of 2-amino-3, 5-dibromobenzaldehyde and 500.0g of ethylene glycol are added into a reaction bottle, stirred and heated to 100 ℃, reacted overnight, cooled, filtered to obtain solid, and dried by air blast for 4 hours to obtain 92.5g of white solid powder.
H1 NMR(600MHz，d6-DMSO)：δ3.96(m，2H)，4.05(m，2H)，5.79(s，1H)，6.27(s，2H)，7.21(s，1H)，7.68(s，1H)
Step 2: preparation of 4-acetoxyl-N- (2, 4-dibromo-6-aldehyde-phenyl) -3-methoxybenzamide
The preparation route is as follows:
52.5g of 2, 4-dibromo-6- (1, 3-dioxolane) aniline, 50.0g of pyridine200mL of chloroform was added to a reaction flask, and a chloroform solution of 896.6 g of 3-methoxy-4-acetoxybenzoyl chloride was added dropwise thereto, followed by reaction for 4 hours. Extracting with 10% hydrochloric acid, 5% sodium carbonate solution, purified water, anhydrous Na2SO4Drying, concentrating under reduced pressure to dryness to obtain white solid, adding glacial acetic acid 400.0g and purified water 100g, stirring, hydrolyzing for 4h, filtering, and drying to obtain white solid 51.6 g.
H1 NMR(600MHz，d6-DMSO)：δ2.28(s，3H)，3.83(s，3H)，7.36(s，1H)，7.57(s，1H)，7.69(s，1H)，8.06(s，1H)，8.25(s，1H)，10.36(s，1H)
And step 3: preparation of ethyl 4- ((2, 4-dibromo-6- ((E) - ((4-hydroxycyclohexyl) imine) methyl) phenyl) carbamoyl) -2-methoxyphenyl
the preparation route is as follows:
Adding 51.6g of 4-acetoxyl-N- (2, 4-dibromo-6-aldehyde-phenyl) -3-methoxybenzamide, 30.0g of trans-4-aminocyclohexanol and 500mL of absolute ethanol into a reaction bottle, stirring for reaction for 5 hours, cooling to 0 ℃ for crystallization for 2 hours after the reaction is finished, filtering out a solid, and drying in vacuum for 5 hours to obtain 65.6g of a light yellow solid.
And 4, step 4: preparation of Compound Ia
the preparation route is as follows:
And (3) dissolving the compound obtained in the step (3) in 400mL of anhydrous methanol, stirring to dissolve the compound, adding sodium borohydride, stirring to react for 1h, adjusting the pH value to about 7 by using glacial acetic acid, filtering and drying to obtain 51.6g of white solid powder.
H1 NMR(600MHz，d6-DMSO)：δ1.35(m，2H)，1.47(m，2H)，1.60(m，2H)，1.72(m，2H)，2.57(m，1H)，3.58(s，2H)，3.76(s，2H)，3.86(s，3H)，5.35(s，1H)，7.22(s，1H)，7.30(s，1H)，7.43(s，1H)，7.55(s，1H)，7.76(s，1H)，9.18(s，1H)
example 2
preparation of Compound Ib
The preparation route is as follows:
The compound obtained in the step 3 of the example 1 is dissolved in 500mL of 1, 2-dichloroethane, sodium triacetoxyborohydride is added for stirring and reaction for 2 hours, and the white solid compound is obtained by filtering, concentrating to dryness and carrying out column chromatography separation.
H1 NMR(600MHz，d6-DMSO)：δ1.35(m，2H)，1.47(m，2H)，1.61(m，2H)，1.72(m，2H)，2.28(s，3H)，2.57(m，1H)，3.17(m，1H)，3.58(s，1H)，3.76(s，2H)，3.83(s，3H)，7.30(s，1H)，7.36(s，1H)，7.56(s，1H)，7.69(s，1H)，7.79(s，1H)，9.15(s，1H)
Example 3
preparation example: preparation of 3, 4-dimethoxybenzoyl chloride
The preparation route is as follows:
30g of 3, 4-dimethoxybenzoic acid and 200g of toluene were put into a reaction flask, and 31.2g of thionyl chloride was added thereto. The mixture is stirred for 2 hours under the temperature rising condition, and is concentrated to be dry under the reduced pressure, and 31.6g of 3, 4-dimethoxy benzoyl chloride is obtained.
Step 1: preparation of 2, 4-dibromo-6- (1, 3-dioxolane) aniline
The preparation route is as follows:
100.0g of 2-amino-3, 5-dibromobenzaldehyde and 500.0g of ethylene glycol are added into a reaction bottle, stirred and heated to 100 ℃, reacted overnight, cooled, filtered to obtain solid, and dried by air blast for 4 hours to obtain 92.5g of white solid powder.
H1 NMR(600MHz，d6-DMSO)：δ3.96(m，2H)，4.05(m，2H)，5.79(s，1H)，6.27(s，2H)，7.21(s，1H)，7.68(s，1H)
Step 2: preparation of N- (2, 4-dibromo-6-aldehyde-phenyl) -3, 4-dimethoxybenzamide
The preparation route is as follows:
22.5g of 2, 4-dibromo-6- (1, 3-dioxolane) aniline, 50.0g of pyridine and 200mL of chloroform were put into a reaction flask, and a solution of 27.6g of 3, 4-dimethoxybenzoyl chloride in chloroform was added dropwise thereto and reacted for 6 hours. Extracting with 10% hydrochloric acid, 5% sodium carbonate solution, purified water, anhydrous Na2SO4drying, concentrating under reduced pressure to dry to obtain white solid, adding glacial acetic acid 300.0g and purified water 100g, stirring, hydrolyzing for 7h, filtering, and drying to obtain white solid 31.6 g.
H1 NMR(600MHz，d6-DMSO)：3.88(s，6H)，7.16(s，1H)，7.47(s，1H)，7.69(s，1H)，8.00(s，1H)，8.28(s，1H)，9.15(s，1H)，10.38(s，1H)
And step 3: preparation of N- (2, 4-dibromo-6- ((E) - ((4-hydroxycyclohexyl) imine) methyl) phenyl) -3, 4-dimethoxybenzamide
The preparation route is as follows:
Adding 30.6g of N- (2, 4-dibromo-6-aldehyde-phenyl) -3, 4-dimethoxybenzamide, 20.0g of trans-4-aminocyclohexanol and 500mL of absolute ethanol into a reaction bottle, stirring for reaction for 5 hours, cooling to 0 ℃ for crystallization for 2 hours after the reaction is finished, filtering out a solid, and drying in vacuum for 5 hours to obtain 45.6g of a light yellow solid.
And 4, step 4: preparation of Compound Ic
The preparation route is as follows:
and (3) dissolving the compound obtained in the step (3) in 400mL of absolute ethyl alcohol, stirring to dissolve the compound, adding sodium borohydride, stirring to react for 1h, adjusting the pH value to about 7 by using glacial acetic acid, filtering and drying to obtain 31.9g of white solid powder.
H1 NMR(600MHz，d6-DMSO)：δ1.38(m，2H)，1.51(m，2H)，1.64(m，2H)，1.77(m，2H)，2.51(m，1H)，3.18(m，1H)，3.78(s，1H)，3.86(d，6H)，7.12(s，1H)，7.33(s，1H)，7.48(s，1H)，7.65(s，1H)，7.76(s，1H)，9.10(s，1H)
Example 4
Preparation example: preparation of 3-ethoxy-4-methoxybenzoyl chloride
The preparation route is as follows:
50g of 3-ethoxy-4-methoxybenzoic acid and 200g of toluene were put in a reaction flask, and 31.2g of thionyl chloride was added thereto. The mixture is heated and stirred for 2 hours, and the mixture is decompressed and concentrated to be dry, thus obtaining 51.6g of 3-ethoxy-4-methoxybenzoyl chloride.
step 1: preparation of 2, 4-dibromo-6- (1, 3-dioxolane) aniline
The preparation route is as follows:
100.0g of 2-amino-3, 5-dibromobenzaldehyde and 500.0g of ethylene glycol are added into a reaction bottle, stirred and heated to 100 ℃, reacted overnight, cooled, filtered to obtain solid, and dried by air blast for 4 hours to obtain 92.5g of white solid powder.
H1 NMR(600MHz，d6-DMSO)：δ3.96(m，2H)，4.05(m，2H)，5.79(s，1H)，6.27(s，2H)，7.21(s，1H)，7.68(s，1H)
Step 2: preparation of 3-ethoxy-N- (2, 4-dibromo-6-aldehyde-phenyl) -4-methoxybenzamide
The preparation route is as follows:
32.5g of 2, 4-dibromo-6- (1, 3-dioxolane) aniline, 50.0g of pyridine and 200mL of chloroform were put into a reaction flask, and 37.6g of a chloroform solution of 3-ethoxy-4-methoxybenzoyl chloride was added dropwise thereto to conduct a reaction for 8 hours. Extracting with 10% hydrochloric acid, 5% sodium carbonate solution, purified water, anhydrous Na2SO4Drying, concentrating under reduced pressure to dry to obtain white solid, adding glacial acetic acid 300.0g and purified water 100g, stirring, hydrolyzing for 7h, filtering, and drying to obtain white solid 41.6 g.
H1 NMR(600MHz，d6-DMSO)：1.32(s，3H)，3.88(s，3H)，7.17(s，1H)，7.49(s，1H)，7.64(s，1H)，8.10(s，1H)，8.21(s，1H)，9.19(s，1H)，10.31(s，1H)
and step 3: preparation of 3-ethoxy-N- (2, 4-dibromo-6- ((E) - ((4-hydroxycyclohexyl) imine) methyl) phenyl) -4-methoxybenzamide
The preparation route is as follows:
Adding 40.1g of 3-ethoxy-N- (2, 4-dibromo-6-aldehyde-phenyl) -4-methoxybenzamide, 40.0g of trans-4-aminocyclohexanol and 400mL of absolute ethanol into a reaction bottle, stirring for reacting for 8 hours, cooling to 0 ℃ for crystallization for 2 hours after the reaction is finished, filtering out a solid, and drying in vacuum for 5 hours to obtain 65.6g of a light yellow solid.
And 4, step 4: preparation of Compound Id
The preparation route is as follows:
And (3) dissolving the compound obtained in the step (3) in 400mL of absolute ethyl alcohol, stirring to dissolve the compound, adding sodium borohydride, stirring to react for 1h, adjusting the pH value to about 7 by using glacial acetic acid, filtering and drying to obtain 48.9g of white solid powder.
H1 NMR(600MHz，d6-DMSO)：δ1.32(m，3H)，1.35(m，2H)，1.44(m，2H)，1.61(m，2H)，1.71(m，2H)，2.59(m，1H)，3.17(m，1H)，3.78(s，2H)，3.86(d，3H)，4.16(dd，2H)，7.17(s，1H)，7.30(s，1H)，7.44(s，1H)，7.61(s，1H)，7.77(s，1H)，9.17(s，1H)
Example 5
Preparation of Compound Ia tablets
mixing compound Ia, pregelatinized starch and sodium dodecyl sulfate, adding 5% polyvidone K3090% ethanol solution to obtain soft material, granulating with 16 mesh sieve, drying at 60 + -5 deg.C, adding hydroxypropyl cellulose, magnesium stearate and silicon dioxide, mixing, grading with 30 mesh sieve, and tabletting.
Example 6
Preparation of Compound Ia oral suspension
Dissolving the adjuvants in purified water, adding compound Ia, dissolving to obtain suspension, and bottling penicillin bottle with 4ml each.
Pharmacological test
Test example 1
Comparison of the results of the Pharmacology toxicological tests of Compound Ia with ambroxol hydrochloride, Compound D hydrochloride of preparation 1, and Compound E hydrochloride of preparation 2
the acute toxicity profiles of compound Ia and ambroxol hydrochloride, compound D hydrochloride, compound E hydrochloride were compared in rats and mice by the oral route of administration with the following results:
The test results show that the acute toxicity of compound Ia is comparable to that of ambroxol hydrochloride, compound D hydrochloride, compound E hydrochloride.
Test example 2
Comparison of antitussive Effect
The antitussive effect of compound Ia and ambroxol hydrochloride, compound D hydrochloride in preparation 1, compound E hydrochloride in preparation 2, was compared using the method of the literature "Screening methods in pharmacological-interactive agents" Academic Press.New York-chapt.23-219, 1965 and the method after modification of this method reported by S.Malandrino et al (Arezneim. Forsch. drug. REs 38, 1141, 1988) using citric acid to induce cough in guinea pigs as the test model, the results are shown in the following Table:
The test result shows that the antitussive effect of the compound Ia is greatly improved compared with that of ambroxol hydrochloride, compound D hydrochloride and compound E hydrochloride.
Test example 3
comparison of bioavailability test results of Compound Ia and ambroxol hydrochloride
The bioavailability of compound D hydrochloride from preparation 1 and compound E hydrochloride from preparation 2 were compared in rats orally administered compound Ia and 30mg ambroxol hydrochloride (as ambroxol), and the concentration of ambroxol in the blood was determined, with the results shown in the following table:
Compound (I) AUC0-t(h*ng/ml)
Compound Ia 885
Ambroxol hydrochloride 364
Compound D hydrochloride 432
Compound E hydrochloride 418
the test result shows that the bioavailability of the compound Ia is greatly improved compared with that of ambroxol hydrochloride, compound D hydrochloride and compound E hydrochloride.
The above description is only a preferred embodiment and a test example of the present invention, and is not intended to limit the present invention, and various modifications and changes may be made to the present invention by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (14)

1. An ambroxol derivative or a pharmaceutically acceptable salt thereof, characterized in that: the structure of the ambroxol derivative is shown as a general formula I
Wherein R is selected from H, C1-6 straight chain or branched chain alkyl and C1-6 straight chain or branched chain alkanoyl.
2. ambroxol derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: r is selected from H, C1-4 alkyl and C1-4 alkanoyl.
3. Ambroxol derivative or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: and R is selected from H, methyl, ethyl or acetyl.
4. ambroxol derivative or a pharmaceutically acceptable salt thereof according to any of claims 1-3, characterized in that said pharmaceutically acceptable salt is selected from inorganic or organic salts.
5. the method of claim 2, wherein,
The inorganic salt is selected from hydrochloride, hydrobromide, phosphate or sulfate;
The organic salt is selected from acetate, trifluoroacetate, methanesulfonate, p-toluenesulfonate, lycinate, maleate, tartrate, fumarate, citrate or lactate.
6. A process for the preparation of ambroxol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that it comprises the following steps:
1) Taking the compound 2 as a starting material, and protecting aldehyde groups by using a carbonyl protection reagent to obtain a compound 3;
2) Reacting the compound 3 with a compound 6, and removing a protecting group by using a deprotection agent to obtain a compound 4;
3) Reacting the compound 4 with trans-4-aminocyclohexanol to obtain a Schiff base compound 5;
4) Reducing the compound 5 by a reducing agent to obtain a compound I;
Wherein PG is a carbonyl protecting group;
r' is C1-6 straight chain or branched chain alkyl, C1-6 straight chain or branched chain alkanoyl;
R is as defined in any one of claims 1 to 5.
7. The method of claim 6, wherein: the carbonyl protecting reagent in the step 1) is selected from: methanol, ethanol, isopropanol, 1, 2-ethanediol and 1, 3-propanediol.
8. The method of claim 6, wherein: the deprotection agent in the step 2) is selected from: trifluoroacetic acid, glacial acetic acid, acetic acid aqueous solution, hydrochloric acid aqueous solution and sulfuric acid aqueous solution.
9. The method of claim 6, wherein: the reducing agent in the step 4) is selected from: sodium borohydride, potassium borohydride, sodium triacetoxyborohydride.
10. a pharmaceutical composition comprising the ambroxol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 as an active ingredient and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, oral suspension, or injection.
12. Use of an ambroxol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for the manufacture of a medicament for the elimination of phlegm.
13. Use of an ambroxol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for the preparation of a medicament for the prevention, treatment, or amelioration of a respiratory disease.
14. The use according to claim 13, wherein said respiratory disorder is selected from the group consisting of acute and chronic pulmonary disorders with sputum excretion dysfunction, acute and chronic bronchitis with abnormal secretion from the respiratory tract, bronchial asthma, post-operative pulmonary complications, infant respiratory distress syndrome in premature and newborn infants.
CN201810584093.5A 2018-06-08 2018-06-08 Ambroxol derivative, and preparation method, pharmaceutical composition and application thereof Pending CN110577475A (en)

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Application publication date: 20191217