CN102060809B - Rhein derivatives and preparation and application thereof - Google Patents

Rhein derivatives and preparation and application thereof Download PDF

Info

Publication number
CN102060809B
CN102060809B CN200910027419.5A CN200910027419A CN102060809B CN 102060809 B CN102060809 B CN 102060809B CN 200910027419 A CN200910027419 A CN 200910027419A CN 102060809 B CN102060809 B CN 102060809B
Authority
CN
China
Prior art keywords
acid
medicine
preparation
piperazine
drug
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
CN200910027419.5A
Other languages
Chinese (zh)
Other versions
CN102060809A (en
Inventor
顾书华
曹贺
孙伟新
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.)
CHANGZHOU HIGH-TECH INDUSTRIAL DEVELOPMENT ZONE SANWEI INDUSTRY TECHNOLOGY RESEARCH Co Ltd
Original Assignee
CHANGZHOU HIGH-TECH INDUSTRIAL DEVELOPMENT ZONE SANWEI INDUSTRY TECHNOLOGY RESEARCH Co Ltd
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 CHANGZHOU HIGH-TECH INDUSTRIAL DEVELOPMENT ZONE SANWEI INDUSTRY TECHNOLOGY RESEARCH Co Ltd filed Critical CHANGZHOU HIGH-TECH INDUSTRIAL DEVELOPMENT ZONE SANWEI INDUSTRY TECHNOLOGY RESEARCH Co Ltd
Priority to CN200910027419.5A priority Critical patent/CN102060809B/en
Priority to PCT/CN2010/000517 priority patent/WO2010124521A1/en
Publication of CN102060809A publication Critical patent/CN102060809A/en
Application granted granted Critical
Publication of CN102060809B publication Critical patent/CN102060809B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • 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
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon 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
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
    • C07C309/15—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton the nitrogen atom of at least one of the amino groups being part of any of the groups, X being a hetero atom, Y being any atom
    • 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
    • C07D207/06—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 radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
    • 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
    • C07C2603/24—Anthracenes; Hydrogenated anthracenes

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Child & Adolescent Psychology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides rhein derivatives with a structural general formula (I), a preparation method and application thereof in preparation of medicaments for treating metabolic diseases.

Description

A kind of Rhein derivatives and preparation thereof and purposes
Technical field
The present invention relates generally to Rhein derivatives and preparation method thereof and the application in the medicine for the preparation for the treatment of metabolism class disease.
Technical background
Rhubarb yellow is that extraction and isolation is refined or obtained through the preparation of suitable chemical reaction from the Chinese medicines such as plant rheum officinale, Tuber Fleeceflower Root, giant knotweed, sennae, aloe, there are hypoglycemic, anti-inflammatory, the effect (Guo Meizi etc. such as antibacterial, antiviral, foreign medical science traditional Chinese medicine fascicle, 2002,24 (3): 139-143; Liu Kai etc., Chinese materia medica academic periodical, 2004,22 (9): 1732-1734).Rhubarb yellow is used for the treatment of diabetic nephropathy also has report, and Chinese patent CN1178669A discloses a kind of using rhubarb yellow and rheum officinale hydrochlorate as the medicine for the treatment of diabetic nephropathy; Chinese patent CN1748675A discloses complex therapies diabetes and the diabetic nephropathy of rhein compound.
But rhubarb yellow has following defect, such as carinogenicity, bioavailability are low etc., therefore need further to study it.
Summary of the invention
The present invention has carried out structure of modification to rhubarb yellow, and its toxicity is reduced, and bioavailability improves.
One of feature of the present invention is to provide new Rhein derivatives of a class and preparation method thereof;
Two of feature of the present invention is to provide a class Rhein derivatives and pharmaceutically acceptable salt is used for preparing the medicine for the treatment of the various diseases such as diabetic complication and tumour, osteoporosis, bacteriological infection, icterohepatitis, metabolic disease such as diabetes, diabetic nephropathy, cardiovascular pathological changes, renal failure, retinopathy and nervous system disorders;
Three of feature of the present invention is to provide a kind of drug regimen, and it contains Rhein derivatives of the present invention or its pharmaceutically acceptable salt and antidiabetic medicine, the medicine for the treatment of diabetic complication, anti-obesity medicine, antihypertensive drug, osteosporosis resistant medicament, antiplatelet drug, Antiatherosclerosis medicine/or blood lipid-lowering medicine, antitumor drug.
Detailed Description Of The Invention
The present invention relates to formula (I) Rhein derivatives and pharmaceutically acceptable salt thereof or ester, or its isomer or prodrug:
Wherein R is amino acid group; Nitrogenous organic base pharmaceutical group; Optionally by the nitrogen heterocyclic ring group of following substituting group replacement: amino, hydroxyl, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino, nitro, itrile group, above-mentioned group is connected by nitrogen-atoms.
Amino acid in the present invention comprises the amino acid of needed by human and non-human essential amino acid, and it is to contain the saturated or undersaturated alkyl or cycloalkyl of one or more amino and carboxyl substituted for feature simultaneously in structure.
The amino acid forming amino acid group in the present invention is selected from: Gelucystine, glycine, L-Ala, Beta-alanine, α-amino-isovaleric acid, leucine, Isoleucine, phenylalanine, proline(Pro), tryptophane, tyrosine, Serine, halfcystine, methionine(Met), l-asparagine, glutamine, Threonine, aspartic acid, L-glutamic acid, Methionin, arginine, Histidine and methionine(Met), and enantiomer or its DL body.
The medicine of organic bases pharmaceutical group nitrogenous in the present invention comprises and has certain active raw material, intermediate or preparation containing primary amine or secondary amine.
The medicine of organic bases pharmaceutical group nitrogenous in the present invention is selected from: meglumine, glucosamine, enalapril, timolol, taurine, ubenimex, levodopa, salbutamol, atenolol USP 23, metaraminol, N1,N1-Dimethylbiguanide, methoxamedrine, Dopamine HCL, dobutamine, suprarenin, tocainide, guanamprazine, mexiletine, betahistine, ephedrine, clorprenaline, ketamine, Propafenone, Proprasylyte, amrinone, dapsone, amphetamine, White streptocide, sulfasalazine, mafenide, Sulfadiazine Silver, sulphamethazine, sulphasomidine, SIZ (SIZ), sulfaphenazole, sulfamonomethoxine, iodine amine is to Sulfamonomethoxine, how pungent iodine amine is, sulfanilylguanidine, Sulphadiazine Sodium (SD), sulfamethoxazole, Sulf-10, zinc sulfadiazine, Sulfametopyrazine, Sulfamethoxazole Compound, compound sulfadiazine, succinylsulfathiazole, Sulfametoxydiazine, sodium sulfadimidine injection liquid, sulphafurazole, sulfamethoxazole, sulfadiazine and trimethoprim, phthalylsulfathiazole, ergotocine, Benorilate, diclofenac (sodium), proglumide, Protionamide, propylthiouracil, selagine, bumetanide, primidone, Carbamzepine, carmustine, carmofur, mebendazole, tolbutamide, trimethoprim, metoclopramide, methyldopa.
The medicine forming nitrogenous organic base pharmaceutical group in the present invention is preferred: meglumine, glucosamine, enalapril, timolol, taurine, ubenimex, levodopa, salbutamol, atenolol USP 23, metaraminol, N1,N1-Dimethylbiguanide, methoxamedrine, Dopamine HCL, dobutamine, suprarenin, tocainide, guanamprazine, mexiletine, betahistine, ephedrine, clorprenaline, ketamine, Propafenone, Proprasylyte, amrinone, dapsone and amphetamine.
The nitrogen heterocyclic ring of the nitrogen heterocyclic ring group replaced arbitrarily in the present invention comprise replace arbitrarily nitrogenous ternary, quaternary, five yuan, hexa-atomic, seven yuan of saturated or unsaturated heterocycles.Wherein replace arbitrarily the ring comprising the 3-7 unit that the hydrogen, the alkyl of replacement, the carbocylic radical of the 3-7 unit of replacement, the heterocyclic radical of replacement, the aryl of replacement or carbon, oxygen, sulphur or the nitrogen-atoms cyclization that replace arbitrarily become can be substituted arbitrarily; Wherein nitrogen-containing hetero nuclear nitrogen is secondary amine (nitrogen connects a hydrogen).
The alkyl wherein replaced arbitrarily comprises CH 3, CH (CH 2cH 3) 2, CH 2(CH 2) mcH 3, C 1-C 4alkoxy C H 2o (CH 2) mcH 3, C 1-C 4alkane sulfydryl CH 2s (CH 2) mcH 3, (CH 2) mcX 3, (CH 2) mcN, (CH 2) mcOOH, C 1-C 4alkyloyl (CH 2) mcOOR 1, (CH 2) moH, (CH 2) mx, SO 2(CH 2) mcH 3, (CH 2) msO 2r 1, C 1-C 4thiazolinyl, C 1-C 4alkynyl, C 1-C 4alkylamino.
The 3-7 unit carbocylic radical wherein replaced arbitrarily comprises CH (CH 2) n, CHCnH2 n-aX a, CHC nh 2n-a(OH) a, CHC nh 2n-a(CH 3) a, CHC nh 2n-a(COOH) a, CHC nh 2n-a(CH 2oH) a, valiolamine, bicyclic alkyl, three cyclic groups and cycloalkenyl group.
The nitrogen heterocycle of any replacement comprises piperidyl, morpholinyl, furyl, piperazinyl, thienyl, thiazolyl, imidazolyl, pyridyl, pyrryl, quinolyl, indyl, pyrazinyl, pyridazinyl, pyrimidyl, isoquinolyl, purine radicals, acridyl, pentose base, hexose-based, amino glycosyl.
The aryl of any replacement or use as a part for another group, comprise phenyl, naphthyl, heteroaryl, thick and carbocyclic ring or other the ring of 1-3 of heterocycle, and to be replaced by 1-3 optional halogen, low alkyl group, lower alkoxy, lower alkyl amino, low-grade alkenyl, alkynyl of low-grade chain, cyclic group and heterocyclic radical, arylamino by available carbon atom.
The ring of the 3-7 unit that carbon, oxygen, sulphur or nitrogen-atoms cyclization become can be substituted arbitrarily comprises Pyrrolidine, pyrrolin, piperidines, morpholine, hexahydropyridine, dihydropyridine, piperazine, furans, thiophene, thiazole, imidazoles, oxazole, pyridine, pyrroles, quinoline, indoles, pyrazine, pyridazine, pyrimidine, isoquinoline 99.9, purine, acridine.
In the present invention, the heterocyclic radical of the optional nitrogen heterocyclic ring group replaced is preferred: morpholinyl, piperidyl, piperazinyl, Pyrrolidine base, imidazolyl, pyrazolyl, indyl, indoline base.
The piperazine of the piperazinyl replaced arbitrarily in the present invention includes but not limited to 4-methylpiperazine, cinnamyl piperazine, benzyl diethylenediamine, phenylpiperazine, trimetazidine, Ciprofloxacin, enoxacin, norfloxicin, clonidine, 2-oxypiperazin acetic acid, piperidines piperazine, benzhydryl piperazidine, 1-(2-p-methoxy-phenyl) piperazine, 1-(2-fluorophenyl) piperazine, 1-(2,3-3,5-dimethylphenyl) piperazine, 1-(2,4-3,5-dimethylphenyl) piperazine, 1-(3,4-3,5-dimethylphenyl) piperazine, N-hydroxyethyl piperazine, 1-(5-methyl-2-pyridyl) piperazine, 2,5-lupetazin, 2,6-dimethyl-piperizine, 2-methylpiperazine, 1-(2,4 difluorobenzene base) piperazine, 1-(2,3-dichlorophenyl) piperazine, ethoxycarbonylpiperazine, 4-tertbutyloxycarbonyl-2-thyl-piperazin, 2-methyl-tert-butoxycarbonyl-piperazine, 2-carboxypiperazin, 4-N-tert-butoxycarbonyl-piperazine-2-carboxylic acid, 1-(2-chloro-phenyl-) piperazine, 1-[2-(2-hydroxyl-oxethyl) ethyl] piperazine, 1-(2-methoxy ethyl) piperazine, 1-sec.-propyl piperazine, N-Acetylpiperazine, 2-ethyl piperazidine, N-tert-butoxycarbonyl-piperazine, 4-N-tertbutyloxycarbonyl-2-methylpiperazine, 4-tbutyloxycarbonyl-piperazin t-butyl carboxamide, 1-(the fluoro-4-nitrophenyl of 2-) piperazine, 1-(3-trifluoromethyl) phenylpiperazine, 4-tert-butoxycarbonyl-piperazine-2-carboxylic acid, 1-(2-aminomethyl phenyl) piperazine, 1-[3,5-bis-(trifluoromethyl) phenyl] piperazine, N-tertbutyloxycarbonyl-2-methylpiperazine, 1-cyclohexylpiperazin, 1-(thiazol-2-yl) piperazine, 1-(2-pyrimidyl) piperazine, 1-cyclopentyl-based piperazine, N-propylpiperazine, 1-(4-fluorophenyl) piperazine, 2-oxo-1-piperazine acetic acid, 4-benzyl-2-(benzyloxymethyl) piperazine, 4,4 '-difluoro phenmetrazine, formyl homopiperazine, 1-(2-methyl) benzyl diethylenediamine, 1-(4-chlorobenzhydryl) piperazine, benzyl-1-piperazine carbonic ether, 1-(3-bromophenyl) piperazine, N-1-benzyl-3-ethyl piperazidine, N-1-benzyl-3-methylpiperazine, piperidines piperazine, N-1-benzyl-3-sec.-propyl piperazine, N-tertbutyloxycarbonyl-2-ethyl piperazidine, 1-(pyridin-3-yl methyl) piperazine, 1-(2-pyridyl) piperazine, 1-(2-p-methoxy-phenyl) piperazine, 1-(4-p-methoxy-phenyl) piperazine, 1-(4-chloro-phenyl-) piperazine, t-butylpiperazine, 1-tertbutyloxycarbonyl-2-ethyl piperazidine, 1-(2-chloro-phenyl-) piperazine, 1-(2-aminomethyl phenyl) piperazine, 1-(2-furancarbonyl) piperazine, 1-(3,4-dichlorophenyl) piperazine, 1-(thiazol-2-yl) piperazine, 1-tertbutyloxycarbonyl-3-ethyl piperazidine, 2-methylpiperazine-1-benzyl formate, N4-benzyl-2-isobutyl piperazine, 4-phenmethyl-2-piperazine ethanol, N-tertbutyloxycarbonyl-2-benzyl diethylenediamine, N-tertbutyloxycarbonyl-3-phenylpiperazine, N-tertbutyloxycarbonyl-3-benzyl diethylenediamine, 2-phenylpiperazine, MPP, N-(2,6-3,5-dimethylphenyl)-1-piperazineacetamide, NEP, N-isobutyl piperazine, N-butyl piperazine, N-1-benzyl-3-phenylpiperazine, N-1-benzyl-2-phenylpiperazine, 2-piperazinones, 1-(6-chlorine pyridazine-3-base) piperazine, 1-(2-nitrophenyl) piperazine, N-ethyl dioxygen ethylene imine, between hydroxy phenyl piperazine, 2-piperazinyl-4-amido-6,7-dimethoxy quinazoline, 1-(2-furancarbonyl) piperazine, 1-(4-nitrophenyl) piperazine, tetrahydrochysene furoyl piperazine, 1-(4-fluorophenyl) piperazine, 1-(2-chloro-phenyl-) piperazine, N-tertbutyloxycarbonyl-2-sec.-propyl piperazine, N-tertbutyloxycarbonyl-2-isobutyl piperazine, 4-piperazine-1-base cyanobenzene, 4-(1-benzyl diethylenediamine-4-base) piperidines, Isosorbide-5-Nitrae-benzdioxan-2-carbonyl piperazine, 1-[2-(4-fluorophenyl) ethyl] piperazine, 5-chloro-2-methyl phenylpiperazine, N-formyl piperazine, 1-(5-nitropyridine-2-base) piperazine, 1-benzhydryl piperazidine, 2-benzyl diethylenediamine, N-1-tertbutyloxycarbonyl-2-phenylpiperazine, 1-(3-nitropyridine-2-base) piperazine, 1,2-benzisothiazole-3-piperazine, 1-(2-trifluoromethyl benzyl) piperazine etc.
Nitrogen-containing heterocycle compound that in the present invention, other replaces arbitrarily except piperazine can replace with reference to as above piperazines substituted radical.
The pharmacologically acceptable salt of the compounds of this invention can be synthesized by the compound of the present invention comprising alkalescence or acidic moiety with conventional chemical processes.Generally speaking, basic cpd salt by ion-exchange chromatography or by by free alkali and stoichiometric or excessive needed for the mineral acid of salify or organic acid carry out reacting in the various combinations of suitable solvent or solvent and be prepared.Similarly, the salt of acidic cpd is by carrying out reacting being formed with suitable inorganic or organic bases.
The pharmacologically acceptable salt of the compounds of this invention comprises by by the compounds of this invention of alkalescence and inorganic or organic acid reaction and the conventional non-toxic salts of the compounds of this invention formed.Such as, conventional non-toxic salts comprise derive from mineral acid and organic acid those, described mineral acid is such as hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, sulfonic acid, phosphoric acid, nitric acid etc., described organic acid is such as acetic acid, propionic acid, succsinic acid, oxyacetic acid, stearic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, flutter acid, Citric Acid, toxilic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, Sulphanilic Acid, 2-acetoxy-benzoic, fumaric acid, toluenesulphonic acids, methylsulfonic acid, ethane disulfonic acid, oxalic acid, hydroxyethylsulfonic acid, trifluoroacetic acid etc.
In the pharmacologically acceptable salt of the compounds of this invention, preferred acid comprises acetic acid, hydrochloric acid, sulfuric acid, sulfonic acid, phosphoric acid, succsinic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, Citric Acid, toxilic acid, oxalic acid, fumaric acid, methylsulfonic acid.
In the pharmacologically acceptable salt of the compounds of this invention, most preferred acid comprises acetic acid, succsinic acid, tartrate, Citric Acid, toxilic acid, oxalic acid, hydrochloric acid, sulfuric acid, phosphoric acid.
When the compounds of this invention is acidity, suitable " pharmacologically acceptable salt " refers to the salt obtained by pharmaceutically acceptable mineral alkali and organic bases.The salt deriving from mineral alkali comprises aluminium salt, ammonium salt, calcium salt, mantoquita, trivalent iron salt, divalent iron salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt etc.Ammonium salt, calcium salt, magnesium salts, sylvite and sodium salt are particularly preferred.The salt deriving from pharmaceutically acceptable non-toxic organic alkali comprises the salt of following alkali: primary amine, secondary amine and tertiary amine, the amine replaced, comprise the amine of natural replacement, cyclammonium and deacidite, such as arginine, trimethyl-glycine, caffeine, choline, N, N1-dibenzyl-ethylenediamin, diethylamine, 2-DEAE diethylaminoethanol, DMAE, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, berberine, glucosamine, Histidine, breathe out amine (hydrabamine), isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol etc.When the compounds of this invention is acid, term " free form " refers to the compound of its salt-independent shape, and such acidic functionality remains protonated.
In the pharmacologically acceptable salt of the compounds of this invention, preferred alkali comprises trimethyl-glycine, caffeine, Theobromine, glucosamine, methylglucosamine, triethylamine, PROCAINE HCL, PHARMA GRADE, quaternary ammonium, potassium hydroxide, sodium hydroxide.
In the pharmacologically acceptable salt of the compounds of this invention, most preferred alkali comprises glucosamine, methylglucosamine, triethylamine, potassium hydroxide, sodium hydroxide.
The preparation of above-mentioned pharmacologically acceptable salt and other common pharmacologically acceptable salt, by people such as Berg, is described in more detail in " Pharmaceutical Salts, " J.Pharm.Sci., 1977:66:1-19.
Rhein derivatives of the present invention (I) or its pharmacy acceptable salt comprise its molecule inner salt or its salt containing crystal water.
The inner salt of the compounds of this invention or zwitter-ion, in physiological conditions, deprotonated acidic moiety in compound such as carboxyl can be negatively charged ion, and this electric charge can by the cationic charge of protonated or alkylating basic moiety such as quaternary nitrogen atoms in internal balance.There is internal balance electric charge, and the compound be separated therefore do not associated with intermolecular counter ion also can be considered as the compound of " free form ".
The preferred compound of this analog derivative has rhubarb yellow pyrrolidine, rhubarb yellow piperazine amide, rhubarb yellow piperidine amides, rhubarb yellow 3-methyl piperidine acid amides, rhubarb yellow N methyl piperazine acid amides, rhubarb yellow trimetazidine acid amides, rhubarb yellow atenolol USP 23 acid amides, rhubarb yellow taurine acid amides, rhubarb yellow glucosamine acid amides, rhubarb yellow 3-hydroxymethyl piperidine acid amides, rhubarb yellow morpholino amide, rhubarb yellow benzyl diethylenediamine acid amides, rhubarb yellow phenylpiperazine acid amides, rhubarb yellow piperidines piperazine amide, rhubarb yellow benzhydryl piperazidine acid amides, rhubarb yellow prolinamide, rhubarb yellow Glycine amide, rhubarb yellow Beta-alanine acid amides.
In addition, present invention also offers a kind of pharmaceutical composition containing Rhein derivatives or its change steric isomer or its pharmaceutically acceptable carrier.
Present invention also offers the preparation method of the pharmaceutical composition containing Rhein derivatives or its change steric isomer or its pharmaceutically acceptable carrier, this method comprises and Rhein derivatives or its tautomer or its pharmaceutically acceptable solvate to be mixed mutually with pharmaceutically acceptable carrier or dissolve.
Term " pharmaceutically acceptable " comprises people's use and compound, composition and component for animals herein.
If needed, composition can be packed, and with the operation instruction of writing or print.
Pharmaceutical composition of the present invention, is prepared into various pharmaceutical preparation, and said preparation is oral Preparation, injecting and administering preparations or local administration preparation, wherein:
(1) oral Preparation comprises ordinary tablet, slow releasing tablet, granule, hard or soft capsule, syrup, solution, emulsion; The carrier of oral Preparation comprises weighting agent, disintegrating agent, tackiness agent, lubricant, tinting material, correctives or other conventional additives, specifically comprises starch, lactose, Microcrystalline Cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone, hypromellose, Magnesium Stearate, silicon-dioxide and poly-sorb fat-80, sodium lauryl sulphate;
(2) injecting and administering preparations comprises the aqueous solution, the oil-in-water microemulsion of aseptic injection, the injectable sterile powder of aseptic injection; The carrier of injecting and administering preparations comprises solvent for injection, injection additives, and concrete injection solvent comprises water for injection, oil for injection as soybean oil, and injection solubilizing agent is as ethanol, propylene glycol, polyoxyethylene glycol, glycerine, and isotonic material is as sodium-chlor, glucose;
(3) local administration preparation is patch, suppository, creme, paste, gelifying agent, solution, targeting preparation or suspension, and wherein targeting preparation comprises liposome, microspheres agent, nanoparticle, inclusion, monoclonal antibody coupling matter; The carrier of local administration preparation comprises pharmaceutically for the conventional carrier of topical.
Pharmaceutical preparation form of medication comprises: vein, intramuscular, peritonaeum, subcutaneous, oral, rectal suppository interpolation, vaginal suppository interpolation, target administration, inhaling type, gavage formula, nasal feeding formula, sublingual administration, dripping method, the administration of micropin formula, successive administration system and topical, topical modes is as lagging preparation, or implanted successive administration release system, wherein lagging preparations carrier comprises framework material as hydrophobic polysiloxane and hydrophilic polyvinyl alcohol etc., release-controlled film material is as polysiloxane and ethylene-vinyl acetate copolymer etc., pressure sensitive adhesive is as polyisobutene, polysiloxane and polyacrylic ester, activeconstituents General Decentralized is in pressure sensitive adhesive, macromolecular material wherein selected by implanted successive administration release system comprises poly(lactic acid) one ethanol copolymer, PEG6000-PLA, polylactic acid and caprolactone, poly-[carbonic acid (Aden ester-co-6-caprolactone) ester], poly-butyrolactone valerolactone, poly-dioxanone (PDS), poly-3-hydroxybutyrate ester (PHB), PLLA (PLLA), polyglycolic acid (PGA), poly-epsilon-caprolactone (PCL), polycaprolactone/poly (glycolide-co-lactide) (PCL/PLGA), hydroxyethyl methylacrylate (HEMA).
Pharmaceutical composition of the present invention is made generally in unit formulation, the dosage that unit formulation contains activeconstituents is according to route of administration, patient age body weight and the state of an illness or be treated the severity of disease and change, usual dosage is at 0.001-100mg/kg/ days, be preferably 0.01-50mg/kg/ days, be more preferably 0.05-5mg/kg/ days.
The preparation of the activeconstituents of pharmaceutical composition above-mentioned in the present invention comprise following characteristics or its one of.
(1) compound in the compounds of this invention (I):
Be prepared under alkaline anhydrous condition by beginning compound (II) and corresponding amino acid, nitrogenous organic bases, any nitrogen heterocyclic ring replaced:
Wherein the nitrogen heterocyclic ring of amino acid, nitrogenous organic bases, replacement is arbitrarily compound as defined above.
Solvent can be the Conventional solvents of any not disturbance reponse, such as ester (such as ethyl acetate), halohydrocarbon (such as methylene dichloride), amides (such as dimethyl formamide), ethers (such as tetrahydrofuran (THF)), nitrile (acetonitrile) etc. or its mixture.
This reaction can be carried out under normal temperature to Heating temperature, and preferable temperature is 20 DEG C to 150 DEG C, particularly preferably 40 DEG C to 120 DEG C.
The alkaline condition of reaction can be the aprotic such as pyridine, triethylamine organic bases.
(2) compound in the compounds of this invention (II):
Be prepared in anhydrous conditions by beginning compound (III) and chlorizating agent:
Solvent can be the Conventional solvents of any not disturbance reponse, such as ester (such as ethyl acetate), halohydrocarbon (such as methylene dichloride), amides (such as dimethyl formamide), ethers (such as tetrahydrofuran (THF)), nitrile (acetonitrile) etc. or its mixture.
This reaction can be carried out under normal temperature to Heating temperature, and preferable temperature is 20 DEG C to 150 DEG C, particularly preferably 40 DEG C to 120 DEG C.
Chlorizating agent can be sulfur oxychloride, oxalyl chloride.
The compounds of this invention is used for preparing treatment diabetes, diabetic nephropathy and the diabetes fat, the protein metabolism disturbance that cause, and the application in the medicine of the diabetic complications such as the blood level of the rising of the cardiovascular pathological changes caused thus, renal failure, retinopathy, delay wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndromes, atherosclerosis, hypertension and nervous system disorders.
The compounds of this invention can be used to preparation treatment metabolic disease and comprises water and eletrolytes metabolism disorder, acid base imbalance, diabetes, lactic acidosis, hypoglycemia, glycogen storage disease, blood lipoprotein disorder, porphyria, hyper aminoaciduria, vitiligoidea, hemochromatosis, mucopolysaccharidosis, fructose intolerance, galactosemia, other purine and pyrimidine metabolic disease.
The compounds of this invention is used for preparing the application in the medicines such as treatment tumour, osteoporosis, jaundice, immunity degradation.
The compounds of this invention is used for preparing tumor, and wherein tumour comprises the kinds of tumors such as acute myeloblastic leukemia, the kidney transparency cancer, mammary cancer, Lymphocytic leukemia, prostate cancer, liver cancer, lymphoma, lung cancer, cancer of the stomach, esophagus cancer, colorectal carcinoma.
In addition, according to the present invention, there is provided a kind for the treatment of as the method in the diabetes defined before this and after this and relative disease, the compound of structure (I) and the pharmaceutical composition of the antidiabetic medicine of other type and/or the therapeutical agent of other type of wherein treating significant quantity are given the patient needing to treat.
The application in the medicine of the following disease of preparation treatment of compound of the present invention or pharmaceutical composition:
Increase the level of high-density lipoprotein (HDL), memory, improve learning capacity, old and feeble, metabolism class disease, diabetes, diabetic nephropathy, diabetic foot, diabetic retinopathy, diabetic neuropathy, diabetic complication, postpone wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, the level of lipid acid or glycerine raises, hyperlipidaemia, obesity, hypertriglyceridemia, atherosclerosis, hypertension, metabolic syndrome (X syndromes), anaemia (as sickle cell anemia), acne, tumour, rheumatic arthritis, sacroiliitis, enteritis, psoriatic, multiple sclerosis, neurodegenerative disorders, congestive heart failure, apoplexy, aortic stenosis, ephritis, renal failure, gout, lupus erythematosus, IgA nephropathy, ecphyaditis, pancreatitis, transformation reactions is (as rhinitis, sinusitis paranasal sinusitis), cystic fibrosis, osteopathy, osteoporosis, cardiovascular disorder is (as irregular pulse, cardiovascular shock, stenocardia), radiotherapy and Chemotherapy Complications, hepatopathy (as hepatitis), disorder of gastrointestinal tract (as gastritis and gastro-enteritis), conjunctivitis, Si Yegelun (Sjogren ' s) syndromes, tuberculosis, ephrosis (as multicystic kidney disease), dermatitis, HIV associated conditions, malaria (as brain malaria), ankylosing spondylitis, leprosy, immunological disease, dysthymia disorders, senile dementia, oedema, ulcer, schizophrenia, mental disorder disease, anaphylactic shock, diabetes insipidus, asthma, glaucoma, mitochondrial disease, Parkinson, , the glycosylation end product that pathology is aging, abnormal energy metabolism, matrix metalloproteinase pathological conditions.
The prodrug of the said compound of the present invention (I) includes but not limited to that one or more alcoholic extract hydroxyl groups of compound (I) and/or phenolic hydroxyl group acylate are as acetyl, propionyl, butyryl product and one or more alcoholic extract hydroxyl groups and/or phenolic hydroxyl group benzyl, methyl, ethyl product etc.
The glycosylation end product relative disease that the said pathology of the present invention is aging include but not limited in the disease such as diabetes, senile dementia, atherosclerosis, ephrosis, osteoarthritis, osteoporosis, aging one or more.
The said matrix metalloproteinase pathological conditions of the present invention includes but not limited to atherosclerosis, inflammation of the central nervous system, Alzheimer (family name) is sick, asthma, skin aging, rheumatoid arthritis, osteoarthritis, osteoporosis, septic arthritis, endometriosis, keratohelcosis adhesion, osteopathy, proteinuria, abdominal aortic aneurysm, degenerative cartilage loss, hyperactivity sclerosis, the consume of myelin nerve, hepatic fibrosis, nephroglomerular is sick, germinal membrane rupture, enteritis, periodontopathy, age-related macular degeneration, Diabetic retinopathy, retina vitreum hyperplasia, retinal dysplasia, ophthalmia, keratohelcosis, sjogren ' s complication, the near-sighted knurl of eye, one or more in metastases.
The said mitochondrial disease of the present invention includes but not limited to ophthalmoplegia, muscle changes, ataxia, epileptic seizures, myoclonus, apoplexy, optic neuropathy, sensorineural deafness, dull-witted, peripheral neuropathy, myodystonia, myeleterosis, myocardosis, cataract, pigmentary retinopathy becomes, metabolic acidosis, feel sick, vomiting, hepatopathy, ephrosis, intestinal pseudo obstruction, sideroblastic anemia, diabetes, one or more in exocrine pancreatic function obstacle and hypoparathyroidism disease.
The said abnormal energy metabolism disease of the present invention includes but not limited to wound, the disease that reperfusion iujurt causes, as the wound caused by various Acute Chemical physical factor, poisoning, shock, altitude sickness, radiation syndrome, pneumoconiosis, electric burn, motion sickness, acute and chronic cardiac insufficiency, irregular pulse, cardiac conduction disturbances, cardiac pacing, cardiovascular interventional therapy, valvular heart disease, atherosclerosis, coronary heart disease, (comprising sudden death), congenital heart disease, hypertension, infective endocarditis, cor pulmonale, pericarditis, myocardosis, peripheral vascular disease (comprises multiple takayasu arteritis, Raynaud syndrome, thromboangiitis obliterans, atherosclerosis obliterans etc.), heart transplant operation, neurodynia, neuritis, various peripheral neuropathy, various diseases of spinal cord, acute cerebrovascular disease (comprises cerebral infarction, cerebral embolism, hematencephalon, subarachnoid hemorrhage etc.), intracranial tumors, central nervous system infection (comprises virus and bacterial encephalitis, meningitis etc.), dyskinetic disorder (Parkinson's disease, tarantism, hepatolenticular degeneration, myodystonia, twitch and chatter) paroxysmal disease (comprises epilepsy, migraine, narcolepsy and cataplexy etc.), demyelinating disease (comprises multiple sclerosis, optic neuromyelitis, leukodystrophy), skeletal muscle disease (comprises muscular dystrophy, tatanic myopathy, myasthenia gravis, inflammatory myositis, metabolic myopathy, periodic paralysis), autonomic nerve disease (comprises raynaud's disease, erythromelalgia, diencephalon syndromes), disseminated inravascular coagulation etc., the disease that the factor such as insulin resistant and internal secretion causes, as obesity, hypoglycemia caused by a variety of causes, insuline resistance syndrome, metabolic syndrome, it is malnutritive that (dystrophic is skinny and wizened, kwashiorkor, Secondary cases energy-protein malnutrition), enteral nutrition, parenteral nutrition, water-electrolyte metabolism is disorderly, acid base imbalance, diabetes, diabetes and cardiovascular disease, diabetic peripheral neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic foot, gestation and diabetes, diabetes complicated infection, Diabetic Acute Metabolic complication, lactic acidosis, various glycogen storage disease, blood lipoprotein is disorderly, hyper aminoaciduria, vitiligoidea, mucopolysaccharidosis, fructose intolerance, galactosemia, other purine and pyrimidine metabolic disease, nutrition and the dermotosis of metabolism disturbance (vitamin deficiency, acrodermatitis enteropathica, primary cutaneous amyloidosis, skin porphyria, xanthomatosis), Diabetic retinopathy, growth hormone deficiency dwarfism, grownup's adenohypophysis hypofunction, suprarenalopathy, thyropathy, parathyropathy, ovariopathy, sexual prematurity, islet endocrine tumour, the diseases such as MEA, the diseases such as tumour, as various tumour, cancer, sarcoma, leukemia, acute and chronic white corpuscle and myelocytic leukemia, anaemia caused by a variety of causes (comprises myeloide anaemia, aplastic anemia, meniscocytosis), lymphocyte is sick, autoimmune disorder, primary and secondary immunodeficiency disease, lung tumors, lung sarcoma, peptide ulceration, esophagus cancer, cancer of the stomach, gastric tumor, large bowel cancer, tumor of kidney, mouth neoplasm, primary and secondary liver cancer, tumor of bile duct, acquired immune deficiency syndrome (AIDS), various skin carcinoma, the diseases such as myeloid tumor, inflammation, the disease that severe infections and immune response cause, as septic shock, MOFE, high temperature, low temperature syndromes, infectious diseases (respiratory tract infection, asthma, SARS (Severe Acute Respiratory Syndrome), viral hepatitis, mumps, epidemic encephalitis type B, rabies, poliomyelitis, measles, rubella, smallpox, varicella, herpes simplex, zoster, epidemic hemorrhagic fever, yellow jack, each system infections caused by enterovirus, infectious monocytosis, cytomegalovirus infection, acquired immune deficiency syndrome (AIDS), rickettsiosis, choamydiae infection, mycoplasma infection, bacteriosis (comprises Tuberculous disease anaerobic infection, septicemia, tetanus etc.), fungal disease, spirochetosis, parasitosis, the infectious diarrhea that a variety of causes causes, acute hemorrhagic necrotic enteritis, ulcerative colitis, intestinal obstruction, gastric motility and functional disease, acute peritonitis, acute pancreatitis, a variety of causes causes liver cirrhosis, fatty liver, jaundice, diarrhoea, digestive tract hemorrhage, reflux esophagitis, explosive liver failure, hepatogenic encephalopathy, chololithiasis, cholecystitis, acute or chronic renal failure, blood purification therapy, acute and chronic respiratory insufficiency, chronic obstructive pulmonary disease, bronchial asthma, bronchiectasis, the pneumonia that a variety of causes causes, pulmonary abscess, pulmonary edema, pulmonary infarction, pulmonary vein fistula, pulmonary tuberculosis, congenital aplasia of lung, Obstructive Sleep Apnea, respiratory insufficiency, adult respiratory distress syndrome, acute and chronic nephritis, nephrotic syndrome, minimal change ephrosis, membranous nephropathy, FGS, Pathology of Mesangial Proliferative Glomerulonephritis, mesentery blood capillary proliferation ephritis, secondary glomerulopathy, hereditary nephritis, urinary tract infection, interstitial nephritis, renal tubular disease, nephrolithiasis, periodontal abscess, viral dermatosis, bacterial skin disorders, dermatomycosis, urticaria class tetter, become deaf, Meniere's syndrome, acute and chronic otitis media, conjunctiva is sick, keratopathy, cataract, glaucoma, uvea disease, retinopathy, optic neuropathy, acute and chronic tonsillitis, tonsillar abscess, osteoarthritis, metabolic osteopathy, osteoporosis, gout and hyperuricemia, sarcoidosis, amyloidosis, Kaschin-Beck disease, pigmented dermatosis (vitiligo, chloasma, freckle, melanosis, epidermolysis bullosa hereditaria's disease, ichthyosis, keratosis pilaris, familial benign pemphigus, solar lentigines tetter, pernio, radioactive skin is sick, acne, seborrheic dermatitis, alopecia areata, androgenetic alopecia, rheumatic fever, systematicness erythema capsule sore, rheumatoid arthritis, SpA, polymyositis and dermatomyositis, scleroderma and systemic sclerosis, anaphylactic disease etc., the degeneration that mitochondria dysfunction caused by a variety of causes causes and neuropsychiatric disease, as aging, alzheimer disease, the mitochondrial disease that a variety of causes causes, as Heng Tingdunshi disease, Parkinson's disease (PD), amyotrophic lateral sclerosis, mitochondrial encephalomyopathy companion's lactic acidosis and apoplexy sample outbreak syndrome (MELAS), lafora's disease companion's ragged-red fiber disease (MERRF), Leber hereditary optic neuropathy (LHON), plastosome myocardosis, myopathy, dull-witted, out of contior Muscle contraction (myoclonic epilepsy) of burst, mental disorder comprises organic mental disorders (dementia, delirium syndromes, amnesia syndrome, acquired immune deficiency syndrome (AIDS) caused by mental disorder), psychoactive drug substance caused by mental disorder (alcoholism and alcohol dependence, pharmacological dependence), schizophrenia, affective disorder, neurosis disorder (phobia, anxiety disorder, obsession, neurasthenia, hysteria, hypochondriasis), eating disorder, somnopathy, pervasive developmental disorders, mental retardation, many dynamic obstacles, tic disorder, the disease acute and chronic ischemics such as male sexual disorder, wound, severe infections, diabetes and tumour etc.
The said diabetic complication of the present invention includes but not limited to the microvascular disease that diabetic nephropathy, diabetic foot, diabetic retinopathy, diabetic neuropathy etc. are relevant to diabetes.
Being referred to as the illness of " X syndromes " (being also called metabolic syndrome), disease and illness is take central obesity as core, merge blood pressure, blood sugar, triglyceride level raises and/or HDL-C reduces, the sugar caused by insulin resistant, to merge, disorders of lipid metabolism, occurs that one group that multiple metabolic disease is clinical characters has a strong impact on healthy syndrome.Be specified in Johannsson J.Clin.Endocrinol.Metab., in 82,727-34 (1997).
Term " therapeutical agent of other type " used herein comprises the medicine for the treatment of diabetic complication, anti-obesity medicine, antihypertensive drug, antiplatelet drug, Antiatherosclerosis medicine/or blood lipid-lowering medicine, antioxidant, carnitine (especially L-carnitine) and relevant salt thereof, (especially L-carnitine derivative is as acetylcarnitine for carnitine derivative, propionyl carnitine), Carnitine palmitoyltransferase inhibitor, carnitine capryloyl transferase inhibitor, acetylcarnitine stimulant, antitumor drug, anti-gout drugs, treatment medicine for treating osteoporosis, anti-depression drug, treatment anaemia medicine, treatment senile dementia, anti-inflammatory drug, one or more in immunogenic pharmaceutical and phlorizin extract.
As the compound of the structure (I) of the treatment significant quantity of the first activeconstituents be 1: 0.0001-1: 0.01 as the ratio of the therapeutical agent of one or more other types of the second activeconstituents in pharmaceutical composition of the present invention.
Pharmaceutical composition in the present invention, wherein activeconstituents accounts for the 0.1-99.9% of composition weight.
Pharmaceutical composition in the present invention, optimum composition makes unit formulation, and unit formulation contains the dosage of activeconstituents usually according to route of administration, patient age body weight and the state of an illness, or is treated the severity of disease and changes.Coming-of-Age Day, dosage was 1/6 of rat by per kilogram of body weight consumption, and (dose,equivalent in pharmacological testing between animal and between animals and human beings body converts, Chinese Clinical pharmacology and therapeutics, 2004 Sep to be that 1/12 of mouse calculates; 9 (9): 1069-1072).Usually for oral administration, dosage, at 0.05-100mg/kg/ days, is preferably 0.1-50mg/kg/ days, is more preferably 0.5-50mg/kg/ days.For gastrointestinal administration, dosage, at 0.005-100mg/kg/ days, is preferably 0.01-50mg/kg/ days, is more preferably 0.05-5mg/kg/ days.
Term " therapeutical agent of other type " used herein refer to one or more antidiabetic medicine, one or more anti-obesity medicine, antihypertensive drug, antiplatelet drug, Antiatherosclerosis medicine and/or one or more blood lipid-lowering medicines (comprising Antiatherosclerosis medicine), anti-inflammatory drug, antitumor drug.
Can optionally formula (I) compound to combine in the antidiabetic medicine giving other type 1,2,3 kind or more plant antidiabetic medicine or hyperglycemia medicine, comprise Regular Insulin, secretogogue or euglycemic agent and other antidiabetic medicine.Preferably include biguanide class, sulfonylurea, alpha-glucosidase inhibitors, PPAR gamma agonist as thiazolidinedione, aP2 inhibitor, PPAR α/γ dual agonists, DPP IV (DP4) inhibitor and/or meglitinide, and Regular Insulin, hyperglycemic-glycogenolytic factor-sample peptide-1 (GLP-1), PTP1B inhibitor, glycogen phosphorylase inhibitors and/or Robison ester enzyme inhibitors.
Anti-obesity medicine, antihypertensive drug, antiplatelet drug, Antiatherosclerosis medicine and/or hypolipemic preparation can be comprised for therapeutical agent optionally for combining other type given with formula (I) compound.
Structure (I) compound and 1,2,3 or more plant hyperglycemia effect that other antidiabetic medicine conbined usage produces be greater than each that be used alone these medicines can obtainable effect, and be greater than the associating that these medicines produce add and hyperglycemia effect.
Other antidiabetic medicine can be oral reducing hyperglycaemia medicine, and preferred biguanides is as N1,N1-Dimethylbiguanide or phenformin and salt, most preferably Metformin.
Other oral antidiabetic medicine also can preferably sulfonylurea as Glyburide, Glipizide, glimepiride, gliclazide, P-607 etc., most preferably Glyburide and Glipizide.
Other oral antidiabetic medicine also can preferably alpha-glucosidase inhibitors as acarbose, voglibose, miglitol.
Other oral antidiabetic medicine also can preferably thiazolidinedione as rosiglitazone, pioglitazone, englitazone, darglitazone etc., most preferably rosiglitazone and pioglitazone.
Other oral antidiabetic medicine also can preferably glucagon-sample peptide-1 (GLP-1) if GLP-1 (1-36) acid amides, GLP-1 (7-36) acid amides, GLP-1 (1-36) acid amides, GLP-1 (7-37) acid amides, GLP-1 (S3-20-32), GLP-1 (S3-11-14), GLP-1 (S6-14), GLP-1 (S8) are (as the United States Patent (USP) 5614492 at Habener, the Chinese publication 1884278 of Shanghai Pharmaceutical Inst., Chinese Academy of Sciences), and AC2993 (Amylen) and LY-315902 (Lilly).
The preferred repaglinide of meglitinide, the nateglinide of optional formula (I) compound conbined usage.
Other oral antidiabetic medicine also can be that PPAR α/γ dual agonists is as AR-HO39242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (KyorinMerck) and " serving as the new euglycemic agent of the α acceptor (PPRA α) of peroxisome proliferation-activation and the common part (coligand) of PPRA γ by Murakami etc.PPRA α is activated in the liver of Zucker obese rat to the effect of Abnormal Lipid Metabolism ", Diabetes, 47,1841-1847 (1998).
Other oral antidiabetic medicine can also be DP4 inhibitor, as patent WO99/38501, WO99/46272, WO99/67279, by Hughes etc., Biochemistry, 38 (36), 11597-11603, NVP-DPP728A (Novartis) etc. disclosed in 1999.
Formula (I) compound can with the weight ratio about 0.01: 1 of meglitinide, PPRA gamma agonist, PPAR α/γ dual agonists, DP4 inhibitor to about 100: 1, preferably about 0.2: 1 to about 10: 1.
Optionally can comprise 1 with the hypolipidemic of formula of the present invention (I) compound conbined usage or lipid lowering agent, 2,3 kind or more shellfish butyric acid class, HMG-CoA reductase inhibitor, inhibitor for squalene synthetic enzyme, nicotinic acid derivates, the rise thing of ldl receptor activity, lipoxygenase inhibitor, ACAT inhibitor, cholesterol absorption inhibitor, ileum sodium+/ bile acid cotransporter inhibitor, cholic acid chelating agent.
Blood lipid-lowering medicine can be shellfish butyric acid class, includes but not limited to clofibrate, bezafibrate, fenofibrate, gemfibrozil, Win-35833, S-8527, probucol.
Blood lipid-lowering medicine can be HMG-CoA reductase inhibitor, includes but not limited to mevastatin, lovastatin, Pravastatin, Simvastatin, fluvastatin, atorvastatin etc.
Blood lipid-lowering medicine can be inhibitor for squalene synthetic enzyme, includes but not limited to the α-phosphono-sulphonate in United States Patent (USP) 5712396, by Biller etc., J.Med.Chem., the 1988,31st volume, 10 phases, compound disclosed in 1869-1871.
Other hypolipemic preparation includes but not limited to that the agent of cholic acid chelating is as Colestyramine, colestipol, and cholesterol absorption inhibitor is as Zetia, and nicotinic acid class is if nicotinic acid, acipimox and other medicines are as probucol, Pantethine etc.
Optionally can comprise 1 with the anti-obesity medicine of formula of the present invention (I) compound conbined usage, 2,3 kind or more 'beta '3 adrenergic agonists, lipase inhibitor, thrombotonin (and Dopamine HCL) reuptake inhibitor, thyroid receptor beta medicine, anoretics, NPY antagonist, MC4 agonist.
Anti-obesity medicine can be 'beta '3 adrenergic agonists, includes but not limited to the 'beta '3 adrenergic agonists in AJ9677 (Takeda/Dainippon), L750355 (Merck) and US5541204, US5770615, US5491134, US5776983 and US5488064.
Anti-obesity medicine can be lipase inhibitor, includes but not limited to orlistat, Alizyme.
Anti-obesity medicine can be that thrombotonin (and Dopamine HCL) reuptake inhibitor includes but not limited to sibutramine, topiramate, axokine.
Other antiadipositas drug includes but not limited to that anoretics is as Dextrofenfluramine, phentermine, Phenylpropanolamine, Mazindol.
Optionally can comprise ReoPro, ticlopidine, Dipyridmole, acetylsalicylic acid, anagrelide, tirofiban, eptifibatide, clopidogrel with the antiplatelet drug of formula of the present invention (I) compound conbined usage.
Optionally can comprise ACE inhibitor as enalapril with the antihypertensive drug of formula of the present invention (I) compound conbined usage, captopril, quinapril, benazepril, perindopril, calcium antagonist is as amlodipine, nifedipine, nitrendipine, nimodipine, Odizem, verapamil, alpha block agent comprises terazosin, Doxazosin, Prazosin, diuretic(s) comprises hydrochlorothiazide, Katlex, spironolactone, indapamide, cental system agent comprises serpentine, clonidine, guanfacine, angiotensin-ii antagonist comprises losartan, valsartan, telmisartan, beta blocker comprises meter Tuo Luoer, Proprasylyte, atenolol USP 23, carvedilol, sotalol, blood vessel tire enzyme inhibitors comprises omapatrilat, gemopatrilat.
Optionally can include but not limited to acetylsalicylic acid with the anti-inflammatory drug of formula of the present invention (I) compound conbined usage, Phenylbutazone, Naproxen Base, fenbufen, Ibuprofen BP/EP, indomethacin, naphthalene butanone, diflunisal, paracetamol, Benorilate, Whitfield's ointment, etofenamate, R-ETODOLAC, Ketoprofen, diclofenac, Trolovol, celecoxib, nimesulide, meloxicam, loxoprofen, leflunomide, Zentinic, benzo oxanamide, oxaprozin, sulindac, quinizine, auranofin, piroxicam, imidazate, Tolmetin, meclofenamic acid, acemetacin.
Optionally can include but not limited to alkylating agent, antitumor antibiotics, dihydrofolate reductase inhibitor, purines, miazines, topoisomerase enzyme inhibitor, tumor angiogenesis inhibitor, natural drug etc. with the antitumor drug of formula of the present invention (I) compound conbined usage.
Alkylating agent includes but not limited to that endoxan, mustargen, thiophene reach platinum, oxaliplatin, melphalan, n-formyl sarcolysine, carmustine, lomustine, semustine, nimustine, ranomustine, special Muzolimine, rice holder azoles enzyme amine, teroxirone, busulphan for group, naphthalene.
Antitumor antibiotics includes but not limited to Zorubicin, mitomycin, bleomycin, zhengdingmeisu, epirubicin, mitomycin, daunorubicin, aclacinomycin, carminomycin, mitoxantrone, soft than star, pirarubicin, penta soft pyrrole star according to reaching.
Dihydrofolate reductase inhibitor includes but not limited to methotrexate, altretamine.
Purine medicaments includes but not limited to mercaptopurine.
Miazines medicine includes but not limited to Fluracil, carmofur.
Antitumor natural drug includes but not limited to camptothecine, vincristine(VCR), taxol, colchicine, euonymus mupinesis, compound gossypol acetate, KANGLAITE (Semen Coicis extract), Elemenum (zedoary turmeric oil extract), harringtonine, polyporusum bellatus, Pachymose, lentinan, panaxan, tremella polysaccharide, krestin, Dihuang polysaccharide, lycium barbarum polysaccharide, Kiwifruit polysaccharide, astragalus polysaccharides, Radix Angelicae Sinensis polysaccharide, gynostemma pentaphylla polysaccharide, dictyophora fungus polysaccharide, Radix Et Caulis Acanthopanacis Senticosi polysaccharide, Achyranthan etc.
Topoisomerase enzyme inhibitor includes but not limited to that irinotecan, topotecan, reed are than replacing bank.
Tumor angiogenesis inhibitor includes but not limited to angiostatin, endostatin, suramin, Thalidomide, Fumngillin, monoclonal antibody, Batimastat, Marimastat, genistein.
Optionally can include but not limited to prednisone, Ultracortene-H, dexamethasone, hydrocortisone, danazol, endoxan, cyclosporin A, mycophenlate mofetil, leflunomide, trypterygine with the immunosuppressive drug of formula of the present invention (I) compound conbined usage, azathioprine, heparin-warfarin, Dipyridmole, tacrolimus, sirolimus, Kanglemycin C, mizoribine, immunoglobulin (Ig), timnodonic acid, docosahexenoic acid (DHA), benefit match general, Dacliximab, Rituximab, infliximab, Interferon, rabbit.
Optionally can include but not limited to colchicine, INDOMETHACIN, Ibuprofen BP/EP, Naproxen Base, Phenylbutazone, diclofenac, piroxicam, Western music flower, meloxicam, Zyloric, Potassium Citrate, sodium bicarbonate, probenecid, benzbromarone, Zynol, sulphonyl pyrazoles, narcaricin etc. with the gout medicine of formula of the present invention (I) compound conbined usage.
The anti-depression drug of formula of the present invention (I) compound conbined usage is tricyclic antidepressants, oxidase inhibitor, serotonin reuptake inhibitor, vagusstoff reuptake inhibitor etc.
Anti-depression drug can be tricyclic drugs, includes but not limited to imipramine, chlorimipramine, amitriptyline, P-3693A, desmethylimipramine, nortriptyline.
Anti-depression drug can be four lopps medicines, includes but not limited to mianserin, maprotiline.
Anti-depression drug can be oxidase inhibitor, includes but not limited to Phenelzine, super tranylcypromine, moclobemide.
Anti-depression drug can be selectivity 5-HT reuptake inhibitor, includes but not limited to that fluoxetine, Paro west is fixed, Sertraline, citalopram, volt fluorine sand are bright.
Anti-depression drug can be 5-HT and NE reuptake inhibitor, includes but not limited to Venlafaxine, venlafaxin.
Anti-depression drug can also be other medicines, and it pricks flat, Lu Youtai, Diethylpropion to include but not limited to the general product of Reboxetine, cloth, trazodone, nefazodone, rice.
The treatment dementia medicine of formula of the present invention (I) compound conbined usage includes but not limited to tetrahydroaminoacridine (tacrine), four hydroxylamino acridines, Physostigmine, heptene Physostigmine, lycoremine, U.S. bent phosphatide (Trichlorphon), E 2020, selagine, liquor epinephrinae bitartratis ophthalmicus Kalarba spit of fland, xanomeline, risperidone, moclobemide, lazabemide, Sabeluzole, heptylstigmine, selegiline, propentofylline, new Qu Feisi, An Palaisi, nefiracetam, linopirdine, Montirelin, Azetirelin, olanzapine, ZT-1, pramiracetam, bifemelane, exifone, Noin, meclofenoxate, piracetam, pyritinol, aceglutamide, antiradon, citicoline, aniracetam, nimodipine, acetyl-L-camitine, L-BETAIN, nicergoline, profit cuts down department for bright, Sabcomedine hydrochloricde, , Milameline, Talsaclidine.
The treatment medicine for treating osteoporosis of formula of the present invention (I) compound conbined usage is bone resorption inhibitor, bone formation-promoter, bone mineralized material and other treatment medicine for treating osteoporosis.
Bone resorption inhibitor includes but not limited to diphosphonate, oestrogenic hormon, thyrocalcitonin, progestogen, isoflavones, strontium salt.
Diphosphonate includes but not limited to etidronate, clodronate, Tiludronate, pamldronate, Alendronate, risedronate, incadronate, zoledronate, dtidronate, ibandronate.
Oestrogenic hormon includes but not limited to raloxifene, clo rice sweet smell (relaxing muscles and tendons is fragrant), tamoxifen, droloxifene, noforxidine, idoxifene, WAY 140424, Lasofoxifene, tibolone, nilestriol.
Thyrocalcitonin includes but not limited to Thyrocalcitonin, elcatonin, salcatonin.
Bone formation-promoter includes but not limited to fluorochemical (Tridin), Rat parathyroid hormone 1-34 (PTH), assimilation steroid medicine, human normal immunoglobulin (IGF).
Other treats osteoporotic medicine can also be Statins, alanylhistidine zinc (AHZ), cathepsin K inhibitor, endothelium integrin receptor blocker, neuropeptide, somatomedin (rhIGF-1, transforming growth factor, Delicious peptide), osteoprotegerin (osteoprotegerin OPG).
Specific embodiment
The present invention will be further described in conjunction with the embodiments.
Help understand the present invention further by embodiment.Concrete material, species and condition used are all in order to demonstrate the invention, instead of limit zone of reasonableness of the present invention.There is steric isomer in what molecular structure of the present invention had, they are split by chiral reagent controlled syntheses or molecule or purified post obtains simple steric isomer, and these steric isomers all do not illustrate in the present embodiment but do not limit the present invention.
The preparation of embodiment 1 rhubarb yellow trimetazidine acid amides
(1) preparation of rhubarb yellow acyl chlorides
Take rhubarb yellow 2.1g, put in 500ml round-bottomed flask, add methylene dichloride 200ml, sulfur oxychloride 100ml, put 50 DEG C of oil bath pans and be heated to backflow, after stirring reaction 5h, solution becomes clear from muddiness, and recycling design obtains yellow solid powder.
(2) preparation of rhubarb yellow trimetazidine acid amides
Pressed powder 300ml toluene obtained for upper step is dissolved, puts in 70 DEG C of oil baths and stir, take a small amount of methylene dichloride of 1.9g Trimetazidine Hydrochloride and dissolve, slowly be added drop-wise in reaction solution, regulate pH to alkalescence with triethylamine, solution becomes red-brown, reacts stopping in 2 hours.
(3) recrystallization
Wash above-mentioned reaction solution to water layer with water substantially colourless, reaction solution to 50 DEG C is revolved steaming evaporate to dryness, solid obtains red brown solid powder 3.6g through re crystallization from toluene.
Molecular weight: 532, molecular formula is: C 29h 28n 2o 8.
Element Analyzing：C 65.41％，H 5.30％，N 5.26％，O 24.03％；
ESI-MS(m/s)：533[M+1] +，531[M-1] +；
1H-NMR(CDCl 3)δ：12.11(1H，brs)，12.00(1H，brs)，7.86(1H，dd，J＝7.4，1.0Hz)，7.81(1H，d，J＝1.5Hz)，7.72(1H，t，J＝8.4，7.4Hz)，7.33(1H，dd，J＝8.4，1.0Hz)，7.30(1H，d，J＝1.5Hz)，6.97(1H，d，J＝8.5Hz)，6.64(1H，d，J＝8.5Hz)，3.89(3H，s)，3.88(3H，s)，3.86(3H，s)，3.80(2H，brs)，3.52(2H，s)，3.40(2H，brs)，2.58(2H，brs)，2.44(2H，brs)；
13C-NMR(CDCl 3)δ：192.6，181.1，167.2，162.7，162.6，153.2，152.7，144.7，142.4，137.6，134.1，133.5，125.1，125.0，123.2，122.5，120.3，118.1，116.2，115.8，107.0，61.2，60.8，56.4，56.0，53.1，52.4，47.7，42.3。
The preparation of embodiment 2 rhubarb yellow pyrrolidine
Rhubarb yellow: tetramethyleneimine=1: 1 (mol ratio) feeds intake, and prepares rhubarb yellow pyrrolidine according to the working method of embodiment 1, obtains yellow pressed powder 2.4g.
Molecular weight: 337, molecular formula is: C 19h 15nO 5.
Element Analyzing：C 67.65％，H 4.48％，N 4.15％，O 23.72％；
ESI-MS(m/s)：338[M+1] +，336[M-1] +；
1H-NMR(CDCl3)δ：12.07(1H，s)，12.00(1H，s)，7.92(1H，d，J＝1.5Hz)，7.84(1H，dd，J＝7.6，1.1Hz)，7.71(1H，t，J＝8.4，7.6Hz)，7.41(1H，d，J＝1.5Hz)，7.32(1H，dd，J＝8.4，1.1Hz)，3.67(2H，t，J＝6.8Hz)，3.43(2H，t，J＝6.6Hz)，2.00(2H，q，J＝6.8，5.6Hz)，1.94(2H，q，J＝6.6，5.6Hz)；
13C-NMR(CDCl3)δ：192.6，181.1，166.8，162.7，162.6，145.7，137.5，133.9，133.5，124.9，122.7，120.3，118.2，116.3，115.8，49.2，46.3，26.4，24.4。
The preparation of embodiment 3 rhubarb yellow morpholino amide
Rhubarb yellow: morpholine=1: 1 (mol ratio) feeds intake, and prepares rhubarb yellow morpholino amide according to the working method of embodiment 1, obtains yellow pressed powder 2.7g.
Molecular weight: 353, molecular formula is: C 19h 15nO 6.
Element Analyzing：C 64.59％，H 4.28％，N 3.96％，O 27.17％；
ESI-MS(m/s)：338[M+1] +，336[M-1] +；
1H-NMR(CDCl3)δ：12.12(1H，s)，11.99(1H，s)，7.86(1H，dd，J＝7.5，1.1Hz)，7.82(1H，d，J＝1.5Hz)，7.73(1H，t，J＝8.4Hz)，7.35(1H，dd，J＝8.4，1.1Hz)，7.33(1H，d，J＝1.6Hz)，3.83(4H，s)，3.67(2H，s)，3.45(2H，s)；
13C-NMR(CDCl3)δ：192.6，180.9，167.4，162.8，162.7，144，137.6，134.1，133.4，125.0，122.6，120.4，117.9，116.4，115.7，66.8(×2)，48.0，42.5。
The preparation of embodiment 4 rhubarb yellow 3-methyl piperidine acid amides
Rhubarb yellow: 3-methyl piperidine=1: 1 (mol ratio) feeds intake, prepares rhubarb yellow 3-methyl piperidine acid amides according to the working method of embodiment 1, obtains yellow pressed powder 3.6g.
Molecular weight: 365, molecular formula is: C 21h 19nO 5.
Element Analyzing：C 69.03％，H 5.24％，N 3.83％，O 21.89％；
ESI-MS(m/s)：366[M+1] +，364[M-1] +；
1H-NMR(CDCl3)δ：12.12(1H，s)，11.99(1H，s)，7.88(1H，dd，J＝7.5，1.1Hz)，7.83(1H，d，J＝1.5Hz)，7.87(1H，t，J＝8.4Hz)，7.06(1H，dd，J＝8.4，1.1Hz)，7.39(1H，d，J＝1.6Hz)，3.43(1H，d，J＝6.4Hz)，3.34(2H，t，J＝5.8Hz)，3.18(1H，J＝5.6Hz)，1.34-1.59(5H，m)，0.96(3H，d，J＝6.6Hz)；
13C-NMR(CDCl3)δ：188.0，182.1，172.5，161.9，160.0，140.0，136.2，133.1，131.4，124.1，119.8，119.4，117.3，116.3(×2)，51.2，45.5，32.2，28.7，22.9，18.1。
The preparation of embodiment 5 rhubarb yellow piperazine amide
Rhubarb yellow: piperazine=1: 1 (mol ratio) feeds intake, and prepares rhubarb yellow piperazine amide according to the working method of embodiment 1, obtains yellow pressed powder 3.6g.
Molecular weight: 352, molecular formula is: C 19h 16n 2o 5.
Element Analyzing：C 64.77％，H 4.58％，N 7.95％，O 22.7％；
ESI-MS(m/s)：353[M+1] +，351[M-1] +；
1H-NMR(CDCl3)δ：12.12(1H，s)，11.99(1H，s)，7.88(1H，dd，J＝7.5，1.1Hz)，7.83(1H，d，J＝1.5Hz)，7.87(1H，t，J＝8.4Hz)，7.06(1H，dd，J＝8.4，1.1Hz)，7.39(1H，d，J＝1.6Hz)，3.46(4H，t，J＝6.4Hz)，2.85(4H，t，J＝6.4Hz)，2.0(1H，brs)；
13C-NMR(CDCl3)δ：188.0，182.1，168.9，161.9，160.0，140.0，136.2，133.1，131.4，124.1，119.8，119.4，117.3，116.3(×2)，50.1(×2)，47.2(×2)。
The preparation of embodiment 6 rhubarb yellow N methyl piperazine acid amides
Rhubarb yellow: N methyl piperazine=1: 1 (mol ratio) feeds intake, prepares rhubarb yellow N methyl piperazine acid amides according to the working method of embodiment 1, obtains yellow pressed powder 3.1g.
Molecular weight: 366, molecular formula is: C 20h 18n 2o 5.
Element Analyzing：C 65.57％，H 4.95％，N 7.65％，O 21.84％；
ESI-MS(m/s)：367[M+1] +，365[M-1] +；
1H-NMR(CDCl3)δ：12.12(1H，s)，11.99(1H，s)，7.88(1H，dd，J＝7.5，1.1Hz)，7.83(1H，d，J＝1.5Hz)，7.87(1H，t，J＝8.4Hz)，7.06(1H，dd，J＝8.4，1.1Hz)，7.39(1H，d，J＝1.6Hz)，3.44(4H，t，J＝6.4Hz)，2.31(4H，t，J＝6.4Hz)，2.30(3H，s)；
13C-NMR(CDCl3)δ：188.0，182.1，168.9，161.9，160.0，140.0，136.2，133.1，131.4，124.1，119.8，119.4，117.3，116.3(×2)，49.0(×2)，47.6(×2)，45.5。
The preparation of embodiment 7 rhubarb yellow Valinamide
(1) preparation of rhubarb yellow acyl chlorides
Take rhubarb yellow 2.1g, put in 500ml round-bottomed flask, add methylene dichloride 200ml, sulfur oxychloride 100ml, put 50 DEG C of oil bath pans and be heated to backflow, after stirring reaction 15h, solution becomes clear from muddiness, and recycling design obtains yellow solid powder.
(2) preparation of rhubarb yellow and Valinamide
The yellow solid powder 30ml dioxane that upper step obtained slowly is added drop-wise to after dissolving and is dissolved with in the sodium hydroxide buck of 2g α-amino-isovaleric acid, controls pH value more than 8, and below 40 DEG C after stirring reaction 3-4 hour tlc analysis to substantially without rhubarb yellow.
(3) refining
After reclaiming reaction solvent, obtain dichloromethane extraction layer recycling design with carrying out extraction with methylene dichloride after water ultrasonic dissolution and obtain yellow-brown solid powder 2.5g with methylene dichloride recrystallization.
Molecular weight: 369, molecular formula is: C 19h 15nO 7.
Element Analyzing：C 61.79％，H 4.09％，N 3.79％，O 30.32％；
ESI-MS(m/s)：370[M+1] +，368[M-1] +；
1H-NMR(CDCl3)δ：12.34(1H，s)，11.99(1H，s)，11.85(1H，s)，8.44(1H，s)，7.88(1H，dd，J＝7.5，1.1Hz)，7.83(1H，d，J＝1.5Hz)，7.87(1H，t，J＝8.4Hz)，7.06(1H，dd，J＝8.4，1.1Hz)，7.39(1H，d，J＝1.6Hz)，1.56(6H，s)；
13C-NMR(CDCl3)δ：188.0，182.1，178.6，167.2，161.9，160.3，139.0，136.2，133.1，131.7，124.1，120.1，119.7，119.4，116.6，116.3，59.0，24.1(×2)。
The preparation of embodiment 8 rhubarb yellow Beta-alanine acid amides
Rhubarb yellow: Beta-alanine=1: 1 (mol ratio) feeds intake, prepares rhubarb yellow Beta-alanine acid amides according to the working method of embodiment 6, obtains yellow solid powder 3.5g.
Molecular weight: 355, molecular formula is: C 18h 13nO 7.
Element Analyzing：C 60.85％，H 3.69％，N 3.94％，O 31.52％；
ESI-MS(m/s)：356[M+1] +，354[M-1] +；
1H-NMR(CDCl3)δ：12.18(1H，s)，11.99(1H，s)，11.85(1H，s)，8.56(1H，s)，7.88(1H，dd，J＝7.5，1.1Hz)，7.83(1H，d，J＝1.5Hz)，7.87(1H，t，J＝8.4Hz)，7.06(1H，dd，J＝8.4，1.1Hz)，7.39(1H，d，J＝1.6Hz)，3.67(2H，t，J＝5.6Hz)，2.53(2H，t，J＝5.6Hz)；
13C-NMR(CDCl3)δ：188.0，182.1，175.5，167.5，161.9，160.3，139.0，136.2，133.1，131.7，124.1，120.1，119.7，119.4，116.6，116.3，36.4，34.7。
The preparation of embodiment 9 rhubarb yellow sarkosine acid amides
Rhubarb yellow: sarkosine=1: 1 (mol ratio) feeds intake, prepares rhubarb yellow sarkosine acid amides according to the working method of embodiment 6, obtains yellow solid powder 3.7g.
Molecular weight: 355, molecular formula is: C 18h 13nO 7.
Element Analyzing：C 60.85％，H 3.69％，N 3.94％，O 31.52％；
ESI-MS(m/s)：356[M+1] +，354[M-1] +；
1H-NMR(CDCl3)δ：13.03(1H，s)，11.99(1H，s)，11.85(1H，s)，7.88(1H，dd，J＝7.5，1.1Hz)，7.83(1H，d，J＝1.5Hz)，7.87(1H，t，J＝8.4Hz)，7.06(1H，dd，J＝8.4，1.1Hz)，7.39(1H，d，J＝1.6Hz)，3.90(2H，t，s)，3.47(3H，s)；
13C-NMR(CDCl3)δ：188.0，182.1，173.1，169.5，161.9，160.0，140.0，136.2，133.1，131.4，124.1，119.8，119.4，117.3，116.3(×2)，53.4，34.8。
The preparation of embodiment 10 rhubarb yellow aspartic acid acid amides
Rhubarb yellow: aspartic acid=1: 1 (mol ratio) feeds intake, prepares rhubarb yellow aspartic acid acid amides according to the working method of embodiment 6, obtains yellow solid powder 3.7g.
Molecular weight: 399, molecular formula is: C 19h 13nO 9.
Element Analyzing：C 57.15％，H 3.28％，N 3.51％，O 36.06％；
ESI-MS(m/s)：400[M+1] +，398[M-1] +；
1H-NMR(CDCl3)δ：12.57(2H，s)，11.99(1H，s)，11.85(1H，s)，8.88(1H，s)，7.88(1H，dd，J＝7.5，1.1Hz)，7.83(1H，d，J＝1.5Hz)，7.87(1H，t，J＝8.4Hz)，7.06(1H，dd，J＝8.4，1.1Hz)，7.39(1H，d，J＝1.6Hz)，4.76(1H，t，J＝7.8，5.4Hz)，2.84(2H，dd，J＝11.6，5.4Hz)；
13C-NMR(CDCl3)δ：188.0，182.1，173.2，172.3，167.5，161.9，160.3，139.0，136.2，133.1，131.7，124.1，120.1，119.7，119.4，116.6，116.3，50.9，35.9。
The preparation of embodiment 11 rhubarb yellow lysine amide
Rhubarb yellow: Methionin=2: 1 (mol ratio) feeds intake, and prepares rhubarb yellow lysine amide according to the working method of embodiment 6, obtains yellow solid powder 3.7g.
Molecular weight: 678, molecular formula is: C 36h 26n 2o 12.
Element Analyzing：C 63.72％，H 3.86％，N 4.13％，028.29％；
ESI-MS(m/s)：679[M+1] +，677[M-1] +；
1H-NMR(CDCl3)δ：12.57(1H，s)，11.99(2H，s)，11.85(2H，s)，8.88(1H，s)，8.44(1H，s)，7.88(2H，dd，J＝7.5，1.1Hz)，7.83(2H，d，J＝1.5Hz)，7.87(2H，t，J＝8.4，7.5Hz)，7.06(2H，dd，J＝8.4，1.1Hz)，7.39(2H，d，J＝1.6Hz)，4.55(1H，t，J＝4.5Hz)，3.30(2H，t，J＝4.8Hz)，1.25-1.82(6H，m)；
13C-NMR(CDC13)δ：188.0(×2)，182.1(×2)，180.1，167.5(×2)，161.9(×2)，160.3(×2)，139.0(×2)，136.2(×2)，133.1(×2)，131.7(×2)，124.1(×2)，120.1(×2)，119.7(×2)，119.4(×2)，116.6(×2)，116.3(×2)，55.5，39.7，30.6，29.7，22.7。
The preparation of embodiment 12 rhubarb yellow taurine acid amides
Rhubarb yellow: taurine=1: 1 (mol ratio) feeds intake, prepares rhubarb yellow taurine acid amides according to the working method of embodiment 6, obtains yellow solid powder 3.3g.
Molecular weight: 391, molecular formula is: C 17h 13nO 8s.
Element Analyzing：C 52.17％，H 3.35％，N 3.58％，O 32.71％，S 8.19％
ESI-MS(m/s)：392[M+1] +，390[M-1] +；
1H-NMR(CDCl3)δ：11.99(1H，s)，11.85(1H，s)，8.56(1H，s)，7.88(1H，dd，J＝7.5，1.1Hz)，7.83(1H，d，J＝1.5Hz)，7.87(1H，t，J＝8.4，7.5Hz)，7.06(1H，dd，J＝8.4，1.1Hz)，7.39(1H，d，J＝1.6Hz)，3.76(2H，t，J＝5.6Hz)，3.71(2H，t，J＝5.6Hz)；
13C-NMR(CDCl3)δ：188.0，182.1，167.5，161.9，160.3，139.0，136.2，133.1，131.7，124.1，120.1，119.7，119.4，116.6，116.3，47.8，37.9。
The preparation of embodiment 13 rhubarb yellow atenolol USP 23 acid amides
Rhubarb yellow: atenolol USP 23=2: 1 (mol ratio) feeds intake, prepares rhubarb yellow atenolol USP 23 acid amides according to the working method of embodiment 6, obtains yellow solid powder 3.1g.
The preparation of embodiment 14 rhubarb yellow glucosamine acid amides
Rhubarb yellow: glucosamine=2: 1 (mol ratio) feeds intake, prepares rhubarb yellow glucosamine acid amides according to the working method of embodiment 6, obtains yellow solid powder 2.4g.
Embodiment 15 Rhein derivatives In Vitro Anti diabetic nephropathy screening active ingredients laboratory report
(1) Rhein derivatives trial drug: RD1=rhubarb yellow Glycine amide; RD2=rhubarb yellow lysine amide; RD3=rhubarb yellow taurine acid amides; RD4=rhubarb yellow atenolol USP 23 acid amides; RD5=rhubarb yellow cinepazide acid amides; RD6=rhubarb yellow trimetazidine acid amides; RD7=rhubarb yellow Valinamide; RD8=rhubarb yellow piperazine amide; RD9=rhubarb yellow glucosamine acid amides; RD10=rhubarb yellow β-Beta Alanine acid amides
(2) pharmacodynamic observation index: transforming growth factor (TGF-β) and fibronectin (FN)
TGF-β and FN is the important cytokine in diabetic nephropathy (DN) pathogenic process.TGF-β known causes the strongest cytokine of sclerization in diabetic nephropathy, in vitro or in experiment in vivo, short-term blocks the increase of TGF-'beta ' activity energy T suppression cell epimatrix and alleviates renal fibrosis; FN is mainly distributed in extracellular matrix, form one of main non-collagen sugar albumen of ECM (basilar membrane) two kinds, just because of the excessive buildup of the normal ECM composition such as renal glomerulus ColIV, FN, LN during DN, just cause GBM to thicken and mesentery expansion, become the basis occurring degradation clinical symptom under proteinuria, renal function Progressive symmetric erythrokeratodermia.
(3) experimental technique:
This vitro Drug shaker test, select TGF-β and FN as target index, mesangial cell under low sugar (simulation Normal group) and height sugar (simulation diabetic nephropathy model group) are cultivated, after the process of trial drug, the method for real-time fluorescence quantitative PCR is utilized to observe the expression of TGF-β and FN culture condition in vitro.In cultivating with high sugar in experiment, TGF-β's and FN is expressed as 1, the xx value drawn is compared with it in the expression of Normal group (low sugar cultivation) and trial drug group, < 1 has restraining effect for this drugs on cytokine, indicates that in vitro tests has good anti-DN active; > represents that In Vitro Anti DN activity is more weak to this cytokine unrestraint effect.In the expression experiment of cytokine, often kind of medicine carries out three groups of repeated samplings, and carries out statistical procedures.
(4) result (see table 1)
1. the inhibit activities of candidate drug to TGF-b is followed successively by RD6 > RD3 > RD5 > RD2 > RD10; RD7, RD1, RD4, RD8, RD9 then unrestraint are active.
2. the inhibit activities of candidate drug to FN is followed successively by: RD2 > RD10 > RD4 > RD6 > RD5 > RD7; RD1, RD3, RD8 and RD9 then unrestraint are active.

Claims (9)

1. the Rhein derivatives of following formula or its pharmaceutically acceptable salt:
2. the compound of claim 1, wherein said pharmacy acceptable salt is: when compound is alkalescence, itself and following organic acid or inorganic acids, described organic acid or mineral acid are selected from acetic acid, succsinic acid, tartrate, Citric Acid, toxilic acid, oxalic acid, hydrochloric acid, sulfuric acid and phosphoric acid; When compound is acidity, itself and following organic bases or mineral alkali salify, described organic bases or mineral alkali are selected from: glucosamine, methylglucosamine, triethylamine, potassium hydroxide, sodium hydroxide.
3. a pharmaceutical composition, it contains compound described in any one of claim 1-2 and pharmaceutical carrier.
4. a pharmaceutical composition, its compound containing any one of claim 1-3 is selected from following medicine as the second activeconstituents as the first activeconstituents and one or more: antidiabetic medicine, the medicine for the treatment of diabetic complication, anti-obesity medicine, antihypertensive drug, antiplatelet drug, Antiatherosclerosis medicine/or blood lipid-lowering medicine, antioxidant, carnitine, carnitine derivative, Carnitine palmitoyltransferase inhibitor, carnitine capryloyl transferase inhibitor, acetylcarnitine stimulant, antitumor drug, anti-gout drugs, treatment medicine for treating osteoporosis, anti-depression drug, treatment anaemia medicine, treatment senile dementia, anti-inflammatory drug and immunogenic pharmaceutical.
5. the pharmaceutical composition of claim 4, the second wherein said activeconstituents is selected from: antidiabetic medicine, the medicine for the treatment of diabetic complication, anti-obesity medicine, antihypertensive drug, Antiatherosclerosis medicine/or blood lipid-lowering medicine, L-carnitine, L-carnitine derivative, antitumor drug, anti-inflammatory drug and immunogenic pharmaceutical.
6. the pharmaceutical composition of claim 5, is characterized in that the ratio of wherein said first activeconstituents and described second activeconstituents is 1: 0.0001-1: 0.01.
7. the pharmaceutical composition of claim 4 or 5, wherein activeconstituents accounts for the 0.1-99.9% of composition weight.
8. the pharmaceutical composition of claim 4 or 5, is characterized in that this pharmaceutical composition is a kind of oral Preparation, injecting and administering preparations or local administration preparation, wherein:
(1) described oral Preparation is selected from ordinary tablet, slow releasing tablet, granule, hard or soft capsule, syrup, solution, emulsion;
(2) described injecting and administering preparations is selected from the aqueous solution, the oil-in-water microemulsion of aseptic injection, the injectable sterile powder of aseptic injection;
(3) described local administration preparation is patch, suppository, creme, paste, gelifying agent, solution, suspension or targeting preparation, and described targeting preparation is selected from liposome, microspheres agent, nanoparticle, inclusion, monoclonal antibody coupling matter.
9. composition described in the compound described in claim 1 or 2 or claim 3 or the application of composition according to claim 4 in preparation treatment medicine for treating diabetic nephropathy.
CN200910027419.5A 2009-05-01 2009-05-01 Rhein derivatives and preparation and application thereof Active CN102060809B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN200910027419.5A CN102060809B (en) 2009-05-01 2009-05-01 Rhein derivatives and preparation and application thereof
PCT/CN2010/000517 WO2010124521A1 (en) 2009-05-01 2010-04-16 Derivatives of rhein, preparation methods and uses thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN200910027419.5A CN102060809B (en) 2009-05-01 2009-05-01 Rhein derivatives and preparation and application thereof

Publications (2)

Publication Number Publication Date
CN102060809A CN102060809A (en) 2011-05-18
CN102060809B true CN102060809B (en) 2015-05-20

Family

ID=43031715

Family Applications (1)

Application Number Title Priority Date Filing Date
CN200910027419.5A Active CN102060809B (en) 2009-05-01 2009-05-01 Rhein derivatives and preparation and application thereof

Country Status (2)

Country Link
CN (1) CN102060809B (en)
WO (1) WO2010124521A1 (en)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102478503A (en) * 2010-11-25 2012-05-30 苏州卫生职业技术学院 Method for detecting action mechanism of ursolic acid in inhibiting AGEs (advanced glycation end products)
CN102526013B (en) * 2010-12-31 2016-05-18 常州高新技术产业开发区三维工业技术研究所有限公司 A kind of pharmaceutical composition and application thereof
CN102225913B (en) * 2011-04-07 2013-09-04 栗进才 Rheinic acid derivatives and treatment application thereof
CN102697762A (en) * 2012-06-14 2012-10-03 中国科学院上海药物研究所 Application of parietic acid or parietic acid compound in preparing drug for treating disease taking FTO (Fat mass and obesity-associated) as target point
CN102871967B (en) * 2012-09-18 2013-09-25 刘晓忠 Preparation of salified medicinal particles of levosalbutamol and traditional Chinese medicine monomer and preparation of particle inhalable aerosol
CN103524555B (en) * 2013-10-12 2016-01-20 广西师范大学 Rhubarb yellow aminophosphonate ester derivatives and synthetic method thereof and application
CN103709052B (en) * 2014-01-12 2016-01-27 何黎琴 A kind of rhubarb yellow amido alkoxide compound, its preparation method and medicinal use
CN103864658B (en) * 2014-03-06 2016-06-15 南京工业大学 Aza cyclo-butanone derivatives and preparation method thereof and application
SG11201708030XA (en) * 2015-04-06 2017-10-30 Shenzhen Hightide Biopharmaceutical Ltd Conjugate compounds of ursodeoxycholic, berberine or l-carnitine, and compositions and methods thereof
EP3337782A4 (en) * 2015-08-17 2019-04-03 TWI Biotechnology, Inc. Diacerein or its analogs for inhibiting expression of asc, nlrp3, and/or formation of nlrp3 inflammasome complex
CN105832724B (en) * 2015-10-16 2018-07-03 北京冠瑞金生物科技有限公司 Purposes of the indanol in anti-depression drug is prepared
CN105884645B (en) * 2016-05-06 2018-06-26 上海市伤骨科研究所 A kind of rhein compound and application thereof
CN107298648B (en) * 2017-06-06 2019-01-25 上海市伤骨科研究所 A kind of Rhein thioamide analog compound, preparation method and the usage
CN110179865A (en) * 2019-06-26 2019-08-30 广州中医药大学(广州中医药研究院) A kind of preparation method and applications of rhubarb anthraquinones component
WO2021110177A1 (en) * 2019-12-05 2021-06-10 中检科医药科技(北京)集团有限公司 Rhein derivative and antiviral use thereof
CN111388739B (en) * 2020-01-06 2021-11-16 太原理工大学 Nano silicon dioxide/decomposition enzyme/polycaprolactone composite microsphere and preparation method and application thereof
CN111592479B (en) * 2020-05-29 2021-10-19 四川大学华西医院 Aloe-emodin nitrogen heterocyclic derivative and preparation method and application thereof
CN112641769A (en) * 2020-12-23 2021-04-13 上海中医药大学附属岳阳中西医结合医院 Application of rhein in preparation of medicine for promoting diabetic ulcer wound healing

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5451606A (en) * 1991-03-12 1995-09-19 Istituto Gentili S.P.A. Anthraquinone compounds useful to treat osteoarticular conditions, pharmaceutical compositions and method of treatment
US6600057B2 (en) * 2000-12-29 2003-07-29 Kimberly-Clark Worldwide, Inc. Matrix metalloproteinase inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5451606A (en) * 1991-03-12 1995-09-19 Istituto Gentili S.P.A. Anthraquinone compounds useful to treat osteoarticular conditions, pharmaceutical compositions and method of treatment
US6600057B2 (en) * 2000-12-29 2003-07-29 Kimberly-Clark Worldwide, Inc. Matrix metalloproteinase inhibitors

Also Published As

Publication number Publication date
WO2010124521A1 (en) 2010-11-04
CN102060809A (en) 2011-05-18

Similar Documents

Publication Publication Date Title
CN102060809B (en) Rhein derivatives and preparation and application thereof
CN101638423B (en) Phloridzin derivative as well as preparation method and application thereof
CN101959404B (en) AMP activated protein kinase regulator
CA2723233C (en) Specific inhibitors for vascular endothelial growth factor receptors
CN104395319B (en) The Thienopyridinone derivatives of activator as AMPK
WO2011007819A1 (en) Pharmaceutical product containing lactam or benzene sulfonamide compound
AU2017242027A1 (en) Estrogen receptor modulators
CN105727298A (en) Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof
CN104718200B (en) Thiophene derivant for treating diabetes
US10717727B2 (en) Pyridinium compounds
WO2018130124A1 (en) Tricyclic compound as selective estrogen receptor down-regulator and use thereof
CN102365270A (en) Novel hydroxamate derivative, a production method for the same, and a pharmaceutical composition comprising the same
CN102924443B (en) 5-hydroxy indole derivative contain heterocyclic ring and applications thereof
CN102256944A (en) Sphingosine-1-phosphate receptor antagonists
CN109415343A (en) For treating substituted 2,4- diamino-quinoline of proliferative diseases
CN102268000A (en) Novel spiroheterocyclic compound and application of same serving as therapeutic agent
CN104995188B (en) 2- ((1R, 4R) -4- (4- (5- (benzoxazole -2- bases amino) pyridine -2- bases) phenyl) cyclohexyl) acetic acid meglumine salt form and their purposes as DGAT1 inhibitor
WO2012139524A1 (en) Cb1 receptor inhibitor with low toxicity and optical activity and preparation method and use thereof
CN107089955A (en) Sulfonic acid amide derivatives and its production and use
CA2887420C (en) Matrix metalloproteinase inhibitors and methods for the treatment of pain and other diseases
IL293932A (en) Selective cdk4/6 inhibitor cancer therapeutics
WO2010083649A1 (en) Bisarylurea derivatives and their use
AU2015201306B2 (en) Small molecule inhibitors of the pleckstrin homology domain and methods for using same
US10406157B2 (en) Tetrahydropyridopyrazine modulators of GPR6
CN108218946A (en) A kind of deoxycholic aicd class compound, preparation method and application

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant