CN109608357B - A kind of medical compounds that treating stomatitis and composition and preparation method thereof - Google Patents

A kind of medical compounds that treating stomatitis and composition and preparation method thereof Download PDF

Info

Publication number
CN109608357B
CN109608357B CN201910014817.7A CN201910014817A CN109608357B CN 109608357 B CN109608357 B CN 109608357B CN 201910014817 A CN201910014817 A CN 201910014817A CN 109608357 B CN109608357 B CN 109608357B
Authority
CN
China
Prior art keywords
acid
acid derivative
rosin acid
added
dehydrogenated rosin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201910014817.7A
Other languages
Chinese (zh)
Other versions
CN109608357A (en
Inventor
吴婷
金红
聂元文
张诗扬
王禹锟
张欣
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mudanjiang Medical University
Original Assignee
Mudanjiang Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mudanjiang Medical University filed Critical Mudanjiang Medical University
Priority to CN201910014817.7A priority Critical patent/CN109608357B/en
Publication of CN109608357A publication Critical patent/CN109608357A/en
Application granted granted Critical
Publication of CN109608357B publication Critical patent/CN109608357B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (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)

Abstract

The present invention relates to a kind of medical compounds for treating stomatitis and compositions and preparation method thereof, more particularly to the dehydrogenated rosin acid derivative of the high treatment stomatitis of, bioavilability good with therapeutic effect, pharmaceutical composition comprising dehydrogenated rosin acid derivative, the preparation method of dehydrogenated rosin acid derivative, the preparation method of pharmaceutical composition comprising dehydrogenated rosin acid derivative and dehydrogenated rosin acid derivative are used to treat the purposes of stomatitis.

Description

A kind of medical compounds that treating stomatitis and composition and preparation method thereof
Technical field
It is specifically a kind of de- the present invention relates to a kind of medical compounds for treating stomatitis and composition and preparation method thereof The pharmaceutical composition of hydrogen rosin acid derivative and the acid derivative containing dehydrogenated rosin.
Background technique
Stomatitis refers to buccal, tongue side, and ulcer occurs for maxilla gums etc., and surrounding redness is had a pain, and ulcer surface has rotten to the corn Phenomenon.Stomatitis is easy recurrent exerbation and forms recurrent oral ulceration, and the recurrent oral ulceration cause of disease is complicated, recurrent exerbation, It is touching refractory, and disease incidence in recent years increases year by year.Especially suffer from the patient of systemic disease such as cancer or diabetes In, it has been observed that about 95% in them shows the stomatitis of certain menace level, to significantly affect quality of life. On the other hand, stomatitis is inflammatory disease, can slacken oral mucosa, is typically shown as erythema and pain in mouth is exedens It damages and in the case where mucous membrane of oropharynx inflammation, can also invade throat and esophagus.It is in the anticancer comprising radiotherapy and/or chemotherapy Common complication in treating and its can occur in up to 60% patient for receiving this treatment.When stomatitis is serious, Lead to the daily and traditional performance to patient's mouth including has significant negative effect in terms of exchanging and feeding.For receiving brain With the Most patients of neck cancer radiotherapy, stomatitis causes not feeding via oral cavity due to mucous membrane pain, and patient is instructed Via gastrostomy tube or intravenous injection feed.
Dehydrogenated rosin acid derivative is found to have preferable antibacterial effect, such as sulfonic acid dehydroabietic acid is shown to stomach Acid secretion or the secretion of position protease etc. have inhibitory activity, can be used as the prevention of gastric ulcer, duodenal ulcer or gastritis or control It treats drug (JP58-77814A, JP63-165361A), it has been found that also can treat or prevent oral cavity, inflammatory in pharynx or larynx mucous membrane The novel agent (WO2002/085347A1) of disease.
Due to derivative convenient on phenyl ring, current research focuses primarily upon the derivative of aromatic ring, yet there are no for other Site carries out the compound of derivative dehydroabietic acid.
Summary of the invention
The treatment stomatitis that the main purpose of the present invention is to provide a kind of is good with therapeutic effect, bioavilability is high Dehydrogenated rosin acid derivative, the pharmaceutical composition comprising dehydrogenated rosin acid derivative, the preparation method of dehydrogenated rosin acid derivative, The preparation method of pharmaceutical composition comprising dehydrogenated rosin acid derivative and dehydrogenated rosin acid derivative are for treating stomatitis Purposes.
Shown in the structure such as formula (I) of the dehydrogenated rosin acid derivative:
Wherein, X1 is H, O or NH；
R1 is substituted or unsubstituted native amino acid residues；
R2 is H, COOH or COR4；
R3 is H, CN, NO2, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy；
N is 0-3；
R4 is substituted or unsubstituted native amino acid residues；
The natural amino acid is glycine, l-Alanine, Valine, L-Leu, l-Isoleucine, L- phenylpropyl alcohol ammonia Acid, L-PROLINE, L-Trp, Serine, l-tyrosine, L-cysteine, L-Methionine, altheine, L- paddy ammonia Amide, L-threonine, L-Aspartic acid, Pidolidone, L-lysine, L-arginine and L-Histidine.
Further, formula (I) compound is preferably formula (II) compound:
R1, R2, R3 such as formula (I) are defined.
Further, formula (I) compound is preferably formula (III) compound:
Further, formula (I) compound is preferably formula (III) compound:
It is further:
The preferred NH of X1；
R1 is preferably following groups (* is connection site):
R2 preferred H or COR4；
The preferred H of R3, halogen, substituted or unsubstituted alkyl；
N preferably 1 or 2；
The preferred following groups of R4 (* is connection site):
When group is substituted, the preferred halogen of the substituent group, alkyl, alkoxy；
The preferred C1-6 alkyl of alkyl specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary fourth Base, amyl, isopentyl, hexyl etc.；
The alkoxy is preferably C1-6 alkoxy, specifically includes methoxyl group, ethyoxyl, propoxyl group, isopropoxy, fourth oxygen Base, isobutoxy, tert-butoxy, amyl oxygroup, isopentyl oxygroup and hexyl oxygroup etc..
Described halogen preferred F, Cl or Br, further preferred F or Cl.
Further, R1 is preferably following groups (* is connection site):
R4 is preferably following groups (* is connection site):
On the other hand, the present invention provide above compound with acid or alkali be formed by medically acceptable salt.
It can be organic acid, inorganic acid, organic base or inorganic base at the acid or alkali of salt, such as: with hydrochloric acid, hydrobromic acid, hydrogen The salt of the inorganic acids such as acid iodide, sulfuric acid, nitric acid, phosphoric acid, carbonic acid；With formic acid, acetic acid, propionic acid, trifluoroacetic acid, phthalic acid, grass Acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid, second sulphur The salt of the organic acids such as acid, benzene sulfonic acid, p-methyl benzenesulfonic acid；With the amino such as lysine, arginine, ornithine, glutamic acid, aspartic acid The salt of acid；With the salt of the alkali metal such as sodium, potassium, lithium；With the salt of the alkaline-earth metal such as calcium, magnesium；With the salt of the metals such as aluminium, zinc, iron；With first Amine, ethamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, piperidines, piperazine, pyridine, picoline, ethanol amine, diethanol amine, Triethanolamine, cyclohexylamine, dicyclohexyl amine, N-METHYL-ALPHA-L-GLUCOSAMINE, N, the salt of the organic bases such as N '-dibenzyl-ethylenediamin；Ammonium salt etc..
On the other hand, the compounds of this invention or its medically acceptable salt can according to need conversion solvate. It as such solvent, can enumerate: water, methanol, ethyl alcohol, 1- propyl alcohol, 2- propyl alcohol, butanol, the tert-butyl alcohol, acetonitrile, acetone, methyl Ethyl ketone, chloroform, ethyl acetate, diethyl ether, t-butyl methyl ether, benzene, toluene, N,N-dimethylformamide (DMF), dimethyl Sulfoxide (DMSO) etc..Can especially enumerate: water, methanol, ethyl alcohol, 1- propyl alcohol, 2- propyl alcohol, acetonitrile, acetone, methyl ethyl ketone and Ethyl acetate is as preferred solvent.
Further, the preferred following compounds of formula (I) compound:
Further, the preferred following compounds of formula (I) compound:
On the other hand, the present invention provides the preparation method of formula (I) compound.
The carboxylic acid of formula (II) and the carboxylate of natural amino acid, preferably carboxylate methyl ester, carboxylic acid, ethyl ester, in condensing agent DCC (two Carbodicyclo hexylimide) and catalyst DMAP (4-dimethylaminopyridine) in the presence of be condensed in organic solvent, then In the presence of base, the compound for generating formula (III) is hydrolyzed at room temperature, wherein each group is as defined in formula (1).
The hydroxyl dehydrogenated rosin acid derivative or amino dehydrogenated rosin acid derivative of formula (IV) and boc-protected native amino Acid is condensed, then in the presence of acid, in room in organic solvent in the presence of condensing agent DCC and catalyst DMAP The compound that Boc protecting group generates formula (I) is sloughed under temperature, wherein each group is as defined in formula (1).
The preferred methylene chloride of organic solvent, acetonitrile, tetrahydrofuran, n,N-Dimethylformamide (DMF), N, N- diethyl first Amide (DEF), dimethyl sulfoxide (DMSO) etc..
Alkali preferred NaOH, KOH, K2CO3；
The preferred hydrochloric acid of acid, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid；
The preferred anhydrous solvent of solvent；
Reaction preferably carries out under nitrogen protection；
On the other hand, the present invention provides a kind of comprising on formula (I) compound or its medically acceptable salt and pharmaceutics The pharmaceutical composition of acceptable carrier or excipient.
On the other hand, the present invention provides a kind of formula (I) compound as preventing or the purposes for the treatment of stomatitis.
The formula (I) or compound of inventive compound or its medically acceptable salt can be with direct with oral mucosa The dosage form of contact is administered, and can long term administration.These known preparations such as collutory, liniment (such as ointment, creme, Granule, fine grained agent, powder), patch (e.g., emplastrum, patch), spray, tablet (e.g., pastille, Buccal administration, release mouth Cavity preparations, sustained release oral preparation) etc..
The reagent that the present invention is used to prevent or treat oral inflammation is preferably carried out with administration route as mentioned above and preparation Administration.Above-mentioned preparation may include acceptable carrier or excipient in a kind of pharmaceutics.
Collutory can be solution or suspension.Pharmaceutical acceptable carrier or excipient for collutory include, such as water-bearing media (such as water), suspension (such as Arabic gum, gelatin, methylcellulose, sodium carboxymethylcellulose, hydroxymethyl cellulose, aluminum stearate Gel), surfactant (e.g., lecithin, dehydration water pears alcohol monoleate, glyceryl monostearate), nonaqueous carrier is (such as sweet Oil, propylene glycol, vegetable oil) etc..Collutory may include fragrance and/or colorant.The particle that is prepared by conventional methods, fine grained or Powder may be dissolved or suspended in water before being administered or being used as collutory use.
Conventional substrate preparation can be used in ointment, such as plastic substrate, albolene, paraffin, polyethylene glycol (PEG), poly- third Glycol (PG), stearyl alcohol, stearic acid, beeswax etc..
Conventional method can be used and prepare tablet using well known excipient or carrier, such as pastille, Buccal administration, release oral cavity Preparation or sustained release oral preparation, the excipient or carrier for example: (such as Arabic gum, gelatin, dextrin, hydroxypropyl are fine for adhesive Tie up element, methylcellulose, polyvinylpyrrolidone), diluent (such as lactose, sucrose, mannitol, cornstarch, potato Starch, calcium phosphate, calcium citrate, avicel cellulose), lubricant (such as magnesium stearate, calcium stearate, stearic acid, talcum, anhydrous Silicic acid), disintegrating agent (such as cornstarch, potato starch, carboxymethyl cellulose, calcium carboxymethylcellulose, alginic acid), wetting agent (such as lauryl sodium sulfate).
Known conventional method can be used, prepare other preparations using known excipient etc..
The dosage of formula (I) compound of active constituent as reagent of the present invention or itself or its medically acceptable salt takes Certainly in administration route, the age of patient, the severity of disease in need for the treatment of, but for adult, daily dose is usually About 10-300mg/kg, preferably from about 20-300mg/kg, especially 50-200mg/kg.
Specific embodiment
Embodiments of the present invention are described in detail by the following examples, however, the present invention is not limited thereto.
Embodiment 1
3.0g (10mmol) dehydroabietic acid is weighed in 100mL round-bottomed bottle, 50mL anhydrous methylene chloride is added, is being added 2.3g (11mmol) DCC and 0.12g (1mmol) DMAP, is stirred to react 1h at room temperature.Then 1.1g (11mmol) L- third is added Propylhomoserin methyl esters TLC monitors fully reacting.After reaction, vacuum revolving removes solvent, and 50mL acetonitrile solvent is added, is then added 2g sodium hydroxide is heated to reflux stirring 4h, and being acidified to pH with hydrochloric acid is 2-3, is extracted with dichloromethane, and obtains after column chromatography for separation white Color solid 2.9g (7.8mmol), yield 78.2%.
1H-NMR (300MHz, CDCl3) δ 1.29 (d, 6H), 1.34 (s, 3H), 1.42-1.45 (m, 4H), 1.46 (s, 3H), 1.56 (m, 3H), 1.64-1.69 (m, 6H), 1.78 (s, 1H), 3.12 (m, 1H), 4.64 (m, 1H), 6.88 (s, 1H), 6.80-6.85 (d, 2H), 8.0 (s, 1H), 11.0 (bs, 1H)；13C-NMR (75MHz, CDCl3) δ 16.3,16.8,18.8, 24.4,24.5,24.6,28.2,28.6,30.1,31.8,32.0,37.5,38.8,52.9,54.6,123.2,125.8, 126.2,137.3,141.8,145.7,177.0,178.5；ESI-HRMSm/z 372.2505[M+H]+(calcd for C23H33NO3,371.2505)。
Embodiment 2
3.0g (10mmol) dehydroabietic acid is weighed in 100mL round-bottomed bottle, 50mL anhydrous methylene chloride is added, is being added 2.5g (12mmol) DCC and 0.12g (1mmol) DMAP, is stirred to react 1h at room temperature.Then 1.4g (11mmol) L- figured silk fabrics is added Propylhomoserin methyl esters TLC monitors fully reacting.After reaction, vacuum revolving removes solvent, and 50mL acetonitrile solvent is added, is then added 2g sodium hydroxide is heated to reflux stirring 5h, and being acidified to pH with hydrochloric acid is 2-3, is extracted with dichloromethane, and obtains after column chromatography for separation white Color solid 3.5g (8.8mmol), yield 87.7%.
1H-NMR (300MHz, CDCl3) δ 1.01 (d, 6H), 1.29 (d, 6H), 1.34 (s, 3H), 1.42-1.45 (m, 4H), 1.46 (s, 3H), 1.56 (m, 1H), 1.64-1.69 (m, 6H), 1.78 (s, 1H), 3.11 (m, 1H), 4.45 (d, 1H), 6.88 (s, 1H), 6.81-6.86 (d, 2H), 8.0 (s, 1H), 11.2 (bs, 1H)；13C-NMR(75MHz,CDCl3)δ16.3, 16.6,16.8,18.8,24.4,24.5,24.6,28.2,28.6,30.1,31.8,32.0,37.5,38.8,52.9,54.6, 64.9,123.2,125.8,126.2,137.3,141.8,145.7,177.0,178.5；ESI-HRMSm/z,400.2831[M+ H]+(calcd for C25H37NO3,399.2831)。
Embodiment 3
Take 2.7g (10mmol) dehydrogenation decarboxylation rosin acid -2- alcohol(bibliography: The Journal Chemistry, Vol.35, No.2,1970 years Septembers of of Organic, the 478-483 pages) in 100mL round-bottomed bottle, it is added 50mL anhydrous acetonitrile is being added 2.3g (11mmol) DCC and 0.15g (1.25mmol) DMAP, is being stirred to react 1h at room temperature.So 2.4g (11mmol) L-Boc proline is added afterwards, TLC monitors fully reacting.After reaction, vacuum revolving removes solvent, adds Enter 50mL tetrahydrofuran solvent, it is 36% (quality) hydrochloric acid that 5mL concentration, which is then added, stirs 3h, is neutralized to pH with sodium hydroxide It for 9-10, is extracted with dichloromethane, obtains white solid 3.1g (8.4mmol) after column chromatography for separation, yield 84.0%.
1H-NMR (300MHz, CDCl3) δ 1.06 (d, 3H), 1.29 (d, 6H), 1.44 (s, 3H), 1.56 (s, 1H), 1.59 (m, 2H), 1.68-1.8 (m, 6H), 2.0 (m, 2H), 2.19 (m, 1H), 2.78 (m, 2H), 2.85 (m, 2H), 3.12 (m, 1H), 3.58 (m, 1H), 3.90 (m, 1H), 4.1 (s, 1H), 6.8-7.0 (m, 3H)；13C-NMR (75MHz, CDCl3), 12.2,22.9, 24.1,24.4,24.5,25.5,24.9,27.8,30.5,31.4,31.8,31.9,32.0,44.3,45.5,65.0,75.4, 123.2,125.8,126.2,137.3,141.8,145.7,172.0；ESI-HRMSm/z,370.2712[M+H]+(calcd for C24H35NO2,369.2712)。
Embodiment 4
It takes 2.7g (10mmol) dehydrogenation decarboxylation rosin acid -2- alcohol in 100mL round-bottomed bottle, 50mL anhydrous acetonitrile is added, 2.5g (12mmol) DCC and 0.15g (1.25mmol) DMAP is being added, is being stirred to react 1h at room temperature.Then 2.6g is added (12mmol) L-Boc valine, TLC monitor fully reacting.After reaction, vacuum revolving removes solvent, and 50mL tetrahydro is added THF solvent, it is 36% (quality) hydrochloric acid that 5mL concentration, which is then added, stirs 3h, being neutralized to pH with sodium hydroxide is 9-10, with two Chloromethanes extracts, and obtains white solid 2.8g (7.3mmol) after column chromatography for separation, yield 72.7%.
1H-NMR (300MHz, CDCl3) δ 1.01 (d, 6H), 1.06 (d, 3H), 1.29 (d, 6H), 1.46 (s, 3H), 1.56 (m, 2H), 1.62 (s, 1H), 1.68-1.69 (m, 4H), 2.19 (m, 1H), 2.70 (m, 1H), 2.85 (m, 2H), 3.12 (m, 1H), 3.44 (m, 1H), 3.90 (m, 1H), 4.2 (s, 2H), 6.88 (s, 1H), 6.81-6.93 (m, 2H)；13C-NMR(75MHz, CDCl3) 12.2 δ, 16.5,16.6,24.4,24.5,24.1,24.9,27.8,30.1,30.5,31.4,31.8,31.9,32.0, 45.5,46.7,65.3,123.2,125.8,126.2,137.3,141.8,145.7,172.0；ESI-HRMSm/z, 372.2845 [M+H]+(calcd for C24H37NO2,371.2845)。
Embodiment 5
It takes 2.7g (10mmol) dehydrogenation decarboxylation rosin acid -2- alcohol in 100mL round-bottomed bottle, 50mL anhydrous acetonitrile is added, 2.85g (15mmol) TsCl (paratoluensulfonyl chloride) reacts at room temperature 6h.Reaction terminates, methylene chloride extraction, successively uses water and satisfies And brine It, anhydrous sodium sulfate is dry, is spin-dried for obtaining white solid.Above-mentioned solid is dissolved in 50mlN, N- dimethyl formyl In amine, it is carefully added into 1.2g sodium azide, 50 DEG C of reaction 18h, nitrogen protection.Reaction terminates, and reaction solution is poured into water, pH tune To 9-10, water and saturated common salt water washing are successively used in ethyl acetate extraction, and anhydrous sodium sulfate is dry, is threaded to solid.It will be above-mentioned solid Body is added in reaction flask, and 3.87g triphenylphosphine (15mmol), water (5ml), tetrahydrofuran (50ml), back flow reaction 12h is added. Reaction terminates, and is spin-dried for reaction solution, and column chromatographs to obtain white solid 1.8g, yield 66.7%.
1H-NMR (300MHz, CDCl3) δ 1.06 (d, 3H), 1.29 (d, 6H), 1.44 (s, 3H), 1.56 (m, 1H), 1.64-1.69 (m, 6H), 1.78 (s, 1H), 2.56 (m, 1H), 2.85 (m, 2H), 3.11 (m, 1H), 4.45 (s, 2H), 6.88 (s, 1H), 6.81-6.86 (d, 2H)；13C-NMR (75MHz, CDCl3) δ 13.1,24.4,24.5,24.9,28.6,30.5, 31.4,31.8,32.0,32.3,32.8,46.4,51.0,123.2,125.8,126.2,137.3,141.8,145.7；ESI- HRMSm/z, 272.4412 [M+H]+(calcd for C19H29N, 271.4412).
Embodiment 6
The dehydrogenation decarboxylation rosin acid -2- amine for taking 2.7g (10mmol) embodiment 5 to prepare is added in 100mL round-bottomed bottle 50mL anhydrous tetrahydro furan is being added 2.5g (12mmol) DCC and 0.15g (1.25mmol) DMAP, is being stirred to react at room temperature 1h.Then 2.2g (12mmol) L-Boc alanine is added, TLC monitors fully reacting.After reaction, 5mL concentration is added is 36% (quality) hydrochloric acid stirs 3h, and being neutralized to pH with sodium hydroxide is 9-10, is extracted with dichloromethane, after column chromatography for separation White solid 2.8g (8.2mmol), yield 82.3%.
1H-NMR (300MHz, CDCl3) δ 1.06 (d, 3H), 1.26 (d, 3H), 1.29 (d, 6H), 1.44 (s, 3H), 1.56 (m, 1H), 1.64-1.69 (m, 6H), 2.22 (s, 1H), 2.85 (m, 2H), 3.12 (m, 1H), 3.53 (m, 1H), 3.74 (m, 1H), 4.45 (s, 2H), 6.88 (s, 1H), 6.81-6.86 (d, 2H), 8.0 (s, 1H)；13C-NMR(75MHz,CDCl3)δ 13.1,19.9,24.4,24.5,24.9,25.9,29.6,30.5,31.4,31.8,32.0,32.8,46.4,48.1,55.7, 123.2,125.8,126.2,137.3,141.8,145.7,175.1；ESI-HRMSm/z,343.5211[M+H]+(calcd for C22H34N2O,342.5211)。
Embodiment 7
The dehydrogenation decarboxylation rosin acid -2- amine for taking 2.7g (10mmol) embodiment 5 to prepare is added in 100mL round-bottomed bottle 50mL anhydrous acetonitrile is being added 2.5g (12mmol) DCC and 0.15g (1.25mmol) DMAP, is being stirred to react 1h at room temperature.So 2.4g (11mmol) L-Boc proline is added afterwards, TLC monitors fully reacting.After reaction, vacuum revolving removes solvent, adds Enter 50mL tetrahydrofuran solvent, it is 36% (quality) hydrochloric acid that 5mL concentration, which is then added, stirs 3h, is neutralized to pH with sodium hydroxide It for 9-10, is extracted with dichloromethane, obtains white solid 3.3g (9.0mmol) after column chromatography for separation, yield 89.7%.
1H-NMR (300MHz, CDCl3) δ 1.01 (d, 3H), 1.29 (d, 6H), 1.44 (s, 3H), 1.56 (m, 1H), 1.59 (m, 2H), 1.64-1.69 (m, 6H), 1.83 (m, 2H), 2.22 (m, 1H), 2.75 (m, 2H), 2.85 (m, 2H), 3.11 (m, 1H), 3.53 (m, 1H), 3.69 (m, 1H), 4.45 (s, 1H), 6.89 (s, 1H), 6.81-6.86 (d, 2H), 8.0 (s, 1H)； 13C-NMR (75MHz, CDCl3) δ 13.1,22.5,24.4,24.5,24.9,25.9,26.1,29.6,30.5,31.4,31.8, 32.0,32.8,43.9,46.4,48.1,63.7,123.2,125.8,126.2,137.3,141.8,145.7,174.4；ESI- HRMSm/z,369.5624[M+H]+(calcd for C24H36N2O,368.5624)。
Embodiment 8
The dehydrogenation decarboxylation rosin acid -2- amine for taking 2.7g (10mmol) embodiment 5 to prepare is added in 100mL round-bottomed bottle 50mL anhydrous acetonitrile is being added 2.3g (11mmol) DCC and 0.15g (1.25mmol) DMAP, is being stirred to react 1h at room temperature.So 2.6g (11mmol) L-Boc leucine is added afterwards, TLC monitors fully reacting.After reaction, vacuum revolving removes solvent, adds Enter 50mL tetrahydrofuran solvent, it is 36% (quality) hydrochloric acid that 5mL concentration, which is then added, stirs 3h, is neutralized to pH with sodium hydroxide It for 9-10, is extracted with dichloromethane, obtains white solid 3.3g (8.6mmol) after column chromatography for separation, yield 85.9%.
1H-NMR (300MHz, CDCl3) δ 1.01 (d, 6H), 1.06 (d, 3H), 1.29 (d, 6H), 1.44 (s, 3H), 1.56 (s, 1H), 1.65-1.69 (m, 6H), 1.75 (m, 2H), 1.83 (m, 1H), 2.22 (m, 1H), 2.85 (m, 2H), 3.53 (m, 1H), 3.56 (m, 1H), 3.12 (m, 1H), 4.45 (s, 2H), 6.88 (s, 1H), 6.81-6.86 (d, 2H), 8.0 (s, 1H)； 13C-NMR (75MHz, CDCl3) δ 13.1,21.6,21.7,22.4,24.4,24.5,24.9,25.9,29.6,30.5,31.4, 31.8,32.0,32.8,43.9,46.4,48.1,56.4,123.2,125.8,126.2,137.3,141.8,145.7,174.4； ESI-HRMSm/z,385.6015[M+H]+(calcd for C25H40N2O,384.6015)。
9 canker sore pharmacodynamic test of embodiment
(1) test model is established
Experiment every time, takes mature healthy rabbits 32 that weight size is essentially identical, is divided to two groups at random, i.e., model group and gives Medicine group.With an internal diameter 0.6cm, the glass tube of long 3cm is perpendicularly fixed at rabbit oral mucosal surface, the injected slurry volume score into pipe To dip in out glacial acetic acid with cotton swab after 30% glacial acetic acid 0.2ml, 30s.After for 24 hours, measurement is without oedema mucous membrane area and observation inflammation Congested situation, and be classified, grade scale: 0 grade: without blush, no oedema around ulcer；1 grade: slightly blush around ulcer；2 Grade: there are blush, no oedema around ulcer；3 grades: having blush around ulcer, there is oedema.Administration group gives drug of the present invention totally 2 days, Third day takes rabbit observation inflammatory congestion situation and measures ulcer area, and taking mucous membrane tissue volume fraction at ulcer is 10% Formalin is fixed, and pathologic diagnosis is carried out.
(2) experimental result
2.1 canker sore mucous membranes are congested and ulcer area changes
Influence of the drug of the present invention of table 1 to rabbit stomatocace inflammatory congestion
Influence of the drug of the present invention of table 2 to rabbit stomatocace area
Group Drug (mm before medication2) (mm after medication2)
Model group Nothing 35.6±3.2 25.8±1.9
Administration group Compound 1 37.1±2.4 16.2±3.2
Administration group Compound 2 36.5±3.5 15.8±1.8
Administration group Compound 3 35.8±2.9 12.1±1.7
Administration group Compound 4 36.9±2.5 11.5±1.5
Administration group Compound 5 34.9±2.0 3.5±1.0
Administration group Compound 6 36.3±3.1 2.6±1.1
Administration group Compound 7 35.7±2.3 3.1±1.1
Administration group Sulfonic acid dehydroabietic acid 36.8±3.0 17.8±1.7
2.2 histopathologic examination's results
Model group visually observes mucous membrane face and almost sees there is pitting defect: there are more canescence or lark inflammatory in surface Sphacelus；Obvious ulcer is seen under mirror, range is larger, and skin surface scaly epithelium necrosis falls off and has more necrotic tissue and inflammation Property exudate；Connective tissue, which is also shown in, under ulcer obvious necrosis；The inflammatory infiltrations such as a large amount of neutrality inflammatory cells, as deep as submucosa.
There is the visible recess of naked eyes after administration group, compound 1-4 and dehydroabietic acid administration, sees necrosis group at former ulcer under mirror It knits and inflammatory oozes out, surface granulation tissue and proliferation of fibrous tissue are less；It is visible by naked eyes substantially after compound 5-7 administration recessed It falls into, necrotic tissue at former ulcer is seen under mirror and inflammatory exudation is relatively light or nothing, surface covering thin layer scaly epithelium are upper subcutaneous a small amount of scorching Property cellular infiltration, and see that granulation tissue and proliferation of fibrous tissue are more.
2.3 interpretation of result
It is seen from the above data that the compounds of this invention 1-7, especially compound 5-7 have good treatment oral cavity The effect of ulcer, can significantly mitigate the inflammatory congestion reaction of mucous membrane, and can reduce canker sore area.Histopathology result Show that the oral cavity mucous membrane tissue of the compounds of this invention treatment group improves significantly.Therefore, the compounds of this invention can be used as mouth Chamber inflammation drug is for treating stomatitis.

Claims (7)

1. a kind of dehydrogenated rosin acid derivative or its medically acceptable salt, it is characterised in that its structure is formula (II) or formula (III) structure shown in:
Wherein, R1 is following groups, and * is connection site:
R2 is H or COR4；
R3 is H or halogen；
N is 0-3；
R4 is following groups, and * is connection site:
2. dehydrogenated rosin acid derivative according to claim 1 or its medically acceptable salt, it is characterised in that:
R1 is following groups, and * is connection site:
R4 is following groups, and * is connection site:
3. dehydrogenated rosin acid derivative according to claim 1 or its medically acceptable salt, it is characterised in that be selected from Following compounds:
4. dehydrogenated rosin acid derivative according to claim 1 or its medically acceptable salt, it is characterised in that be selected from Following compounds:
5. dehydrogenated rosin acid derivative or its medically acceptable salt comprising any one of claim 1-4 and can medically connect The pharmaceutical composition for the carrier received.
6. the dehydrogenated rosin acid derivative of any one of claim 1-4 a kind of or its medically acceptable salt treat mouth in preparation Purposes in the drug of chamber inflammation.
7. purposes according to claim 6, it is characterised in that stomatitis is canker sore.
CN201910014817.7A 2019-01-08 2019-01-08 A kind of medical compounds that treating stomatitis and composition and preparation method thereof Active CN109608357B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910014817.7A CN109608357B (en) 2019-01-08 2019-01-08 A kind of medical compounds that treating stomatitis and composition and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910014817.7A CN109608357B (en) 2019-01-08 2019-01-08 A kind of medical compounds that treating stomatitis and composition and preparation method thereof

Publications (2)

Publication Number Publication Date
CN109608357A CN109608357A (en) 2019-04-12
CN109608357B true CN109608357B (en) 2019-10-29

Family

ID=66016863

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910014817.7A Active CN109608357B (en) 2019-01-08 2019-01-08 A kind of medical compounds that treating stomatitis and composition and preparation method thereof

Country Status (1)

Country Link
CN (1) CN109608357B (en)

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61212547A (en) * 1985-03-18 1986-09-20 Harima Kasei Kogyo Kk Dehydroabiethylamino acid, salt thereof, and production thereof
JPS63170328A (en) * 1987-01-06 1988-07-14 Arakawa Chem Ind Co Ltd Dehydroabietic acid derivative and antiulcer agent comprising said derivative as active ingredient
EP1380294A1 (en) * 2001-04-17 2004-01-14 Tanabe Seiyaku Co., Ltd. Preventive/remedial agent for inflammatory disease in oral-cavity mucosa and the like
CA2460167A1 (en) * 2001-09-27 2003-04-10 Tanabe Seiyaku Co., Ltd. Aqueous ecabet sodium solution preparation
JP2005132768A (en) * 2003-10-30 2005-05-26 Sunstar Inc Composition for oral cavity
CN102702026A (en) * 2012-06-20 2012-10-03 上海大学 7-acyl hydrazone base dehydroabietic acid derivative and synthesis method of 7-acyl hydrazone base dehydroabietic acid derivative
CN102702024A (en) * 2012-06-20 2012-10-03 上海大学 Oximido dehydroabietic acid compound and synthesis method thereof
EP3200781A1 (en) * 2014-10-02 2017-08-09 University of Helsinki Abietane-type diterpenoids

Also Published As

Publication number Publication date
CN109608357A (en) 2019-04-12

Similar Documents

Publication Publication Date Title
CN115960088B (en) Novel coronavirus main protease inhibitor and preparation method and application thereof
KR101411422B1 (en) Deuterated catecholamine derivatives and medicaments comprising said compounds
EP0049658B1 (en) Substituted imino diacids, their preparation and pharmaceutical preparations containing them
CN107033087B (en) 1H-indazole-4-amine compounds and use thereof as IDO inhibitors
FR2487829A2 (en) NOVEL SUBSTITUTED IMINO ACIDS, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS AN ENZYME INHIBITOR
CN106458881B (en) Carotenoid derivatives, its pharmaceutically acceptable salt or its pharmaceutically acceptable esters or amides
US20170240558A1 (en) Sanguinarine analog pp2c inhibitors for cancer treatment
EP0315574A2 (en) Renin inhibitors
US9499484B2 (en) Indole, indoline derivatives, compositions comprising them and uses thereof
CN103003264A (en) Novel pyrimidine derivatives
JPH02193997A (en) Beta-aminoboron acid derivative
CN101817769B (en) Carbamido peptide aminopeptidase N inhibitor and application thereof
CN101822841A (en) Application of organic amine derivatives as brain-targeting modification group of small-molecule drug
CN109608357B (en) A kind of medical compounds that treating stomatitis and composition and preparation method thereof
JPH03101648A (en) Renin inhibitor of peptidilaminodiols
JPH09505317A (en) Novel amino acid derivative, process for producing them and pharmaceutical composition containing these compounds
WO2017024953A9 (en) Nimodipine water-soluble derivative, and preparation method and use thereof
EP0410278B1 (en) Renin inhibiting aminooligohydroxy-derivatives
CN103288916B (en) The derivative of tanshinone compound and synthetic method and purposes
TW200940530A (en) 3,8-diaminotetrahydroquinoline derivative
JP5271904B2 (en) Aminoisoquinoline thrombin inhibitors with improved bioavailability
CN109134295B (en) Anthracene diketone derivative and preparation method and application thereof
CN115160204B (en) Fibroblast activation protein inhibitor and preparation method and application thereof
CN118125936A (en) N-acyl ethanolamide derivative, preparation method and application thereof
CN118108786A (en) 10-Amino camptothecine compound cleaved by connective tissue proteinase B and its synthesis and application

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant