WO2010124521A1 - Derivatives of rhein, preparation methods and uses thereof - Google Patents

Derivatives of rhein, preparation methods and uses thereof Download PDF

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WO2010124521A1
WO2010124521A1 PCT/CN2010/000517 CN2010000517W WO2010124521A1 WO 2010124521 A1 WO2010124521 A1 WO 2010124521A1 CN 2010000517 W CN2010000517 W CN 2010000517W WO 2010124521 A1 WO2010124521 A1 WO 2010124521A1
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acid
drug
group
compound
disease
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Chinese (zh)
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顾书华
曹贺
孙伟新
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常州高新技术产业开发区三维工业技术研究所有限公司
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    • 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
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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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

Definitions

  • the present invention relates generally to rhein derivatives, processes for their preparation, and their use in the manufacture of a medicament for the treatment of metabolic diseases.
  • BACKGROUND OF THE INVENTION Rhein is obtained by extracting and purifying traditional Chinese medicines such as rhubarb, Polygonum multiflorum, Polygonum cuspidatum, Radix scutellariae, and Aloe vera or by appropriate chemical reaction, and has the functions of lowering blood sugar, anti-inflammatory, antibacterial and anti-viral (Guo Meizi et al.
  • the use of rhein for the treatment of diabetic nephropathy has also been reported.
  • Chinese patent CN1178669 A discloses a drug for treating diabetic nephropathy with rhein and rhein;
  • Chinese patent CN1748675A discloses a complex of rhein compound for treating diabetes and diabetic nephropathy.
  • rhein has the following drawbacks, such as carcinogenicity, low bioavailability, etc., and further research is needed.
  • SUMMARY OF THE INVENTION The present invention structurally reforms rhein to reduce toxicity and improve bioavailability.
  • One of the features of the present invention is to provide a novel class of rhein derivatives and a process for the preparation thereof;
  • a second feature of the present invention is to provide a class of rhein derivatives and pharmaceutically acceptable salts thereof for the preparation of diabetic complications such as diabetes, diabetic nephropathy, cardiovascular disease, renal failure, retinopathy and neurological disorders.
  • Drugs for various diseases such as tumors, osteoporosis, bacterial infections, jaundice hepatitis, and metabolic diseases;
  • a third feature of the present invention is to provide a pharmaceutical composition comprising the rhein derivative of the present invention or a pharmaceutically acceptable salt thereof and an antidiabetic agent, a medicament for treating diabetic complications, an antiobesity drug, and an antihypertensive Drugs, anti-osteoporosis drugs, anti-platelet drugs, anti-atherosclerotic drugs / or hypolipidemic drugs, anti-tumor drugs.
  • the present invention relates to a formula (I) of a rhein derivative and a pharmaceutically acceptable salt or ester thereof, or an isomer thereof Description
  • R is an amino group; a nitrogen-containing salty drug group; a nitrogen-containing heterocyclic group optionally substituted by the following substituent: amino group, hydroxyl group, C1-6 alkyl group, C1-6 alkoxy group, C1-6 An alkylamino group, a nitro group, a nitrile group, and the above groups are bonded through a nitrogen atom.
  • amino acids in the present invention include essential amino acids and non-essential amino acids, which are characterized by a saturated or unsaturated alkyl or cycloalkyl group having one or more amino and carboxyl groups substituted in the structure.
  • the amino acid forming an acid group in the present invention is selected from the group consisting of: cystine, glycine, alanine, ⁇ -alanine, valine, leucine, isoleucine, phenylalanine, valine, Tryptophan, tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine and Methionine, its enantiomer or its hybrid.
  • the drug containing a nitrogen-containing organic base drug group in the present invention includes a certain active material, an intermediate or a preparation containing a primary or secondary amine.
  • the nitrogen-containing drug having the drug group in the present invention is selected from the group consisting of: glucosamine, glucosamine, enalapril, timolol, taurine, umbrel, levodopa, salbutamol, Tirolol, m-hydroxylamine, diterpene, oxime, dopamine, dobutamine, adrenaline, tonicani, amiloride, mexiletine, betahistine, ephedrine, clonidine Lin, ketamine, propafenone, propranolol, amrinone, dapsone, amphetamine, sulfonamide, sulfasalazine, sulfametholone, silver sulfadiazine, sulfamethazine, trace amine Pyrimidine, iodosylisoxazole (SIZ), sulfaphenazole, sulfamonomethoxine, io
  • a drug containing a nitrogen-containing drug group is preferably: meglumine, glucosamine, enalapril, timolol, taurine, umbrel, levodopa, salbutamol, alte Lol, m-hydroxylamine, diterpene, oxime, dopamine, dobutamine, adrenaline, tonicani, amiloride, mexiletine, betahistine, ephedrine, clonidine , ketamine, propafenone, propranolol, amrinone, dapsone and amphetamine.
  • the nitrogen-containing heterocyclic ring of the optionally substituted nitrogen-containing heterocyclic group in the present invention includes an optionally substituted nitrogen-containing ternary, quaternary, five-membered, six-membered, seven-membered saturated or unsaturated heterocyclic ring. Any of the substitutions including optionally substituted hydrogen, substituted alkyl, substituted 3-7 membered carbocyclic group, substituted heterocyclic group, substituted aryl group, or carbon, oxygen, sulfur or nitrogen atom can be optionally synthesized. a substituted 3-7 membered ring; wherein the nitrogen in the nitrogen-containing heterocycle is a secondary amine (a hydrogen is attached to the nitrogen).
  • Any optionally substituted alkyl group includes CH 3 , CH (CH 2 CH 3 ) 2 , CH 2 (CH 2 ) n CH 3 , d_C 4 alkoxy CH 2 0 (CH 2 ) m CH 3 , dC 4 alkanoyl CH 2 S (CH 2 ) ra CH 3 , (CH 2 ) m CX 3 , (CH 2 ) ra CN, (CH 2 ) m C00H, C -C 4 alkanoyl (CIU OOR, (CH 2 ) m 0H, ( CH 2 ) J, S0 2 (CH 2 ) m CH 3 , C "C 4 alkenyl, C -C 4 alkynyl, dC 4 alkylamino.
  • the optionally substituted 3-7 membered carbocyclic group includes CH(CH 2 ) n , CHCnH2 n - aX a , CHC n H 2n — a (OH) a , CHC n H 2n - a (CH 3 ) a , CHC n H 2n — a (C00H) a , CHC n H 2n — a (CH 2 0H) a , jingtanolamine, bicycloalkyl, tricyclo and cycloalkenyl.
  • Optionally substituted nitrogen-containing heterocyclic groups include piperidinyl, morpholinyl, furanyl, piperazinyl, thienyl, oxazolyl, imidazolyl, pyrazolyl 11 set, pyrrolyl, quinolinyl leaching yl, indazol taste, pyrazolyl.
  • Qin Ji . Sigma -methyl, pyrimidin, isoquinolyl, decyl, acridinyl, pentose, hexosyl, aminoglycosyl.
  • any optionally substituted aryl or used as part of another group including phenyl, naphthyl, heteroaryl, fused carbocyclic or heterocyclic, 1-3 other rings, and through available carbon atoms Substituted by 1-3 optional halogen, lower alkyl, lower alkoxy, lower alkylamino, lower alkenyl, lower alkynyl, cyclic and heterocyclic, arylamino.
  • the optionally substituted 3-7 membered ring includes tetrahydropyrrole, dihydropyrrole, piperidine, chlorin, hexahydropyridine, dihydropyridine, piperazine, furan, thiophene. , thiazole, imidazole, oxazole, pyrazole set 1, pyrazole 17 each, gold leaching, taste indole, pyrazole, "Qin, up, ethyl, set, will be different leaching, purine, acridine 1 set.
  • the optionally substituted nitrogen-containing heterocyclic group-containing heterocyclic group in the present invention is preferably: morpholinyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, imidazolyl, pyrazolyl, fluorenyl, porphyrin base.
  • Piperazines of any of the substituted piperazinyl groups in the present invention include, but are not limited to, 4-mercaptopiperazine, cinnamylpiperazine, Instruction manual
  • 2-oxopiperazineacetic acid piperidazine piperazine, diphenylhydrazine piperazine, 1-(2-methoxyphenyl) piperazine, 1-(2-fluorophenyl) piperazine, 1-( 2,3-Dimercaptophenyl)piperazine, 1-(2,4-dimercaptophenyl)piperazine, 1-(3,4-didecylphenyl)piperazine, N-hydroxyethyl Piperazine, 1-(5-fluorenyl-2-pyridyl)piperazine, 2,5-dimercaptopiperazine, 2,6-dimercaptopiperazine, 2-mercaptopiperazine, 1- (2 , 4-difluorophenyl)piperazine, 1-(2,3-dichlorophenyl)piperazine, ethoxycarbonylpyrazine, 4 butoxycarbonyl-2-methyl-piperazine, 2-indenyl " ⁇ -butoxycarbonylpiperazine
  • N-decanoyl piperazine 1-(5-nitropyridin-2-yl)piperazine, 1-diphenylmethylpiperazine, 2-benzylpiperazine, N-1-tert-butoxycarbonyl-2- Phenylpiperazine, 1-(3-nitropyridine-2-yl)piperazine, 1,2-benzisothiazol-3-piperazine, 1-(2-trifluorodecylbenzyl)piperazine, etc. .
  • an optionally substituted nitrogen-containing heterocyclic compound other than piperazine may be substituted with reference to the above piperazine-based substituent.
  • the pharmaceutically acceptable salts of the compounds of the present invention can be synthesized from the compounds of the present invention containing a basic or acidic moiety by conventional chemical methods.
  • the salt of the basic compound is reacted by ion exchange chromatography or by various combinations of the free base with a stoichiometric or excess amount of the desired salt-forming mineral or organic acid in a suitable solvent or solvent.
  • salts of acidic compounds are formed by reaction with a suitable inorganic or organic product.
  • compositions of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by reacting a basic compound of the invention with an inorganic or organic acid.
  • conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, sulfonic acid, phosphoric acid, nitric acid, etc., and organic acids such as acetic acid.
  • propionic acid succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, citric acid, citric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzene Capric acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, terephthalic acid, sulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, three Fluoroacetic acid, etc.
  • Preferred acids in the pharmaceutically acceptable salts of the compounds of the invention include acetic acid, hydrochloric acid, sulfuric acid, sulfonic acid, phosphoric acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, citric acid, maleic acid, oxalic acid, fumaric acid. , sulfonic acid.
  • the most preferred acids among the pharmaceutically acceptable salts of the compounds of the present invention include acetic acid, succinic acid, tartaric acid, citric acid, maleic acid, oxalic acid, hydrochloric acid, sulfuric acid, phosphoric acid.
  • suitable “pharmaceutically acceptable salts” refer to salts prepared from pharmaceutically acceptable inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, divalent iron salts, lithium salts, magnesium salts, manganese salts, divalent manganese salts, potassium salts, sodium salts, zinc salts. Salt and so on. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred.
  • Salts derived from pharmaceutically acceptable non-toxic organic bases include the salts of the following bases: primary, secondary and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines and basic ion exchange resins such as arginine, Betaine, caffeine, choline, N,N1-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-didecylaminoethanol, ethanolamine, ethylenediamine, N-ethyl Morpholine, N-ethylpiperidine, glucosamine, berberine, glucosamine, histidine, hydrabamine, isopropylamine, lysine Description
  • Preferred bases in the pharmaceutically acceptable salts of the compounds of the invention include betaines, caffeine, theobromine, glucosamine, decyl glucosamine, triethylamine, procaine, quaternary ammonium, potassium hydroxide, hydroxide sodium.
  • the most preferred bases among the pharmaceutically acceptable salts of the compounds of the present invention include glucosamine, methyl glucosamine, triethylamine, potassium hydroxide, sodium hydroxide.
  • the rhein derivative (I) of the present invention or a pharmaceutically acceptable salt thereof includes an intramolecular salt thereof or a salt thereof containing crystal water.
  • An internal salt or a zwitterion of a compound of the invention under physiological conditions, a deprotonated acidic moiety such as a carboxyl group in the compound may be an anion, and the charge may be a protonated or alkylated basic moiety such as a cationic charge of a quaternary nitrogen atom Balanced internally.
  • a deprotonated acidic moiety such as a carboxyl group in the compound
  • the charge may be a protonated or alkylated basic moiety such as a cationic charge of a quaternary nitrogen atom Balanced internally.
  • An isolated compound having an internal equilibrium charge and thus not associated with an intermolecular counterion can also be considered a "free form" compound.
  • Preferred derivatives of such derivatives are pyrrolizyl rhein, piperazine amide, piperidamide of rhein, 3-methylpiperidinamide of rhein, N-mercapto piperazine amide, and rhein Oxazinamide, altolinamide of rhein, leucovoramide of rhein, glucosamine amide of rhein, 3-hydroxymethyl piperidamide of rhein, morpholinamide of rhein, benzyl piperazamide of rhein, Phenyl piperazine amide, piperidazine piperazine amide, diphenyl hydrazino piperazine amide, rhein glutamic acid amide, rhein glycine amide, rhein ⁇ -alanine amide.
  • the present invention provides a pharmaceutical composition comprising a rhein derivative or a tautomeric stereoisomer thereof or a pharmaceutically acceptable carrier thereof.
  • a method of preparing a pharmaceutical composition of a carrier which comprises mixing or dissolving a rhein derivative or a tautomer thereof, or a pharmaceutically acceptable solvate thereof, with a pharmaceutically acceptable carrier.
  • compositions and components include both human and veterinary compounds, compositions and components. If desired, the composition can be packaged with instructions for writing or printing.
  • composition of the present invention is prepared into various pharmaceutical preparations, which are oral administration preparations, injection administration preparations or topical administration preparations, wherein: Instruction manual
  • Oral administration preparations include ordinary tablets, sustained release tablets, granules, hard or soft capsules, syrups, solutions, emulsions; carriers for oral administration include fillers, disintegrators, binders, Lubricants, colorants, flavors or other conventional additives, including starch, lactose, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, polyvinylpyrrolidone, hypromellose, stearic acid Magnesium, silica and polysorbate-80, dodecyl ⁇ sodium;
  • the preparation for administration by injection includes a sterile injectable aqueous solution, a sterile injectable oil-in-water microemulsion, a sterile powder for injection; a carrier for injecting the preparation for injection includes a solvent for injection, an additional agent for injection, and the specific injection solvent includes Water for injection, oil for injection such as soybean oil, solubilizer for injection such as ethanol, propylene glycol, polyethylene glycol, glycerin, isotonic materials such as sodium chloride, glucose;
  • the topical preparation is a patch, a suppository, a cream, a cream, a gel, a solution, a targeted preparation or a suspension, wherein the targeted preparation comprises a liposome, a microsphere, a nanoparticle, an inclusion.
  • monoclonal antibody conjugates; carriers for topical formulations include conventional carriers for pharmaceutically acceptable topical administration.
  • the pharmaceutical preparation forms include: intravenous, intramuscular, peritoneal, subcutaneous, oral, rectal suppository insertion, vaginal suppository insertion, targeted administration, inhalation, gavage, nasal feeding, sublingual administration, drip Method, microneedle administration, continuous administration system and topical administration, topical administration such as a skin preparation, or an implantable continuous administration release system, wherein the skin preparation carrier comprises a skeleton material such as hydrophobic silicone Alkane and hydrophilic polyvinyl alcohol, etc., controlled release membrane materials such as polysiloxane and ethylene-vinyl acetate copolymer, pressure sensitive adhesives such as polyisobutylene, polysiloxane and polyacrylate, the active ingredients are generally dispersed in pressure In the sensitive gel; the polymer materials selected for the implantable continuous drug delivery system include polylactic acid-glycolic acid copolymer, polyethylene glycol polylactic acid copolymer, polylactic acid/polycaprolactone, poly [carbonic acid (
  • the dosage of the pharmaceutical composition of the present invention is generally in the form of a unit preparation, the dosage of the active ingredient in the unit preparation according to the route of administration, the patient's age and weight, or the severity of the disease to be treated, usually at a dose of 0.001-100 mg / kg 05-5mg/ ⁇ / ⁇ More preferably 0. 01-5 50mg / kg / day, more preferably 0. 05-5mg / kg / day.
  • the preparation of the active ingredient of the above pharmaceutical composition in the present invention includes the following features or one of them.
  • the amino acid, the nitrogen-containing organic base, and the optionally substituted nitrogen-containing heterocyclic ring are compounds as defined above.
  • the solvent may be any conventional solvent that does not interfere with the reaction, such as an ester (e.g., ethyl acetate), a halogenated hydrocarbon.
  • the reaction can be carried out at a normal temperature to a heating temperature, preferably at a temperature of from 20 ° C to 150 ° C, particularly preferably from 40 ° C to 120 ° C.
  • the basic condition of the reaction may be an aprotic organic base such as pyridine or triethylamine.
  • the solvent may be any conventional solvent which does not interfere with the reaction, such as an ester (e.g., ethyl acetate), a halogenated hydrocarbon (e.g., dichloromethane), an amide (e.g., dimethylformamide), an ether (e.g., tetrahydrofuran), a nitrile. Class (acetonitrile), etc. or a mixture thereof.
  • an ester e.g., ethyl acetate
  • a halogenated hydrocarbon e.g., dichloromethane
  • an amide e.g., dimethylformamide
  • an ether e.g., tetrahydrofuran
  • nitrile e.g., tetrahydrofuran
  • Class acetonitrile
  • the reaction can be carried out at a normal temperature to a heating temperature, preferably at a temperature of from 20 Torr to 15 (TC, particularly preferably from 40 to 120 °C.
  • the chlorinating agent may be thionyl chloride or oxalyl chloride.
  • the compound of the invention is used for preparing diabetes, diabetic nephropathy and diabetes caused by fat, protein metabolism disorder, and thereby causing cardiovascular disease, renal failure, retinopathy, delayed wound healing, insulin resistance, hyperglycemia, high insulin Hyperglycemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, atherosclerosis, hypertension, and neurological disorders such as diabetes complications Applications.
  • the compounds of the present invention can be used for the preparation of therapeutic metabolic diseases including water and electrolyte metabolism disorders, acid-base balance disorders, diabetes, lactic acidosis, hypoglycemia, glycogen accumulation diseases, dyslipoprotein disorders, porphyria diseases, high amino aciduria , xanthoma, hemochromatosis, mucopolysaccharidosis, fructose intolerance, galactosemia, other sputum and pyrimidine metabolic diseases.
  • therapeutic metabolic diseases including water and electrolyte metabolism disorders, acid-base balance disorders, diabetes, lactic acidosis, hypoglycemia, glycogen accumulation diseases, dyslipoprotein disorders, porphyria diseases, high amino aciduria , xanthoma, hemochromatosis, mucopolysaccharidosis, fructose intolerance, galactosemia, other sputum and pyrimidine metabolic diseases.
  • the compounds of the present invention are useful for the preparation of a medicament for the treatment of tumors, osteoporosis, jaundice, and decreased immunity.
  • the compound of the invention is used for preparing a medicament for treating tumor, wherein the tumor comprises acute myeloid leukemia, renal transparent cancer, breast cancer, lymphocytic leukemia, prostate cancer, liver cancer, lymphoma, lung cancer, gastric cancer, esophageal cancer, colon cancer and the like. Tumors.
  • a method of treating diabetes and related diseases as defined hereinbefore and hereinafter wherein a therapeutically effective amount of a compound of structure (I) with other types of anti-diabetic agents and/or other types of therapeutic agents
  • the pharmaceutical composition is administered to a patient in need of treatment.
  • the prodrug of the compound (I) according to the present invention includes, but is not limited to, one or more alcoholic hydroxyl groups and/or phenolic hydroxyl acylates of the compound (I) such as acetyl, propionyl, butyryl product and one or more Alcoholic hydroxyl and/or phenolic hydroxybenzyl, methyl, ethyl, and the like.
  • the pathologically aged glycosylation end product related diseases of the present invention include, but are not limited to, one or more of diabetes, Alzheimer's disease, atherosclerosis, kidney disease, osteoarthritis, osteoporosis, aging and the like. .
  • the matrix metalloproteinase pathological diseases of the present invention include, but are not limited to, atherosclerosis,: central nervous system inflammation, Alzheimer's disease, asthma, skin aging, rheumatoid arthritis, osteoarthritis , osteoporosis, septic arthritis, endometriosis, corneal ulcer adhesion, bone disease, proteinuria, abdominal aortic aneurysm, degenerative cartilage loss, hyperactivity sclerosis, myelin nerve loss, liver fibrosis , nephroglomerular disease, rupture of the blastum, enteritis, periodontal disease, age-related macular degeneration, diabetic retinopathy, retinal vitreous hyperplasia, retinal dysplasia, ophthalmia, corneal ulcer, S jogren's complications, witness myopia, tumor One or more of the transitions.
  • the mitochondrial diseases of the present invention include, but are not limited to, ophthalmoplegia, muscle lesions, movement disorders, seizures, myoclonus, stroke, optic neuropathy, sensorineural hearing loss, dementia, peripheral neuropathy, dystonia, spinal cord lesions. , cardiomyopathy, cataract, pigmented retinopathy, metabolic acidosis, nausea, vomiting, liver disease, kidney disease, pseudo-intestinal obstruction, iron granulocyte anemia, diabetes, pancreatic exocrine dysfunction and hypoparathyroidism One or more.
  • the abnormal energy metabolism diseases include, but are not limited to, diseases caused by trauma, ischemia and reperfusion injury, such as trauma, poisoning, shock, altitude sickness, radiation sickness, pneumoconiosis, electric shock caused by various acute chemical and physical factors. , motion sickness, acute and chronic cardiac insufficiency, arrhythmia, abnormal cardiac conduction, artificial cardiac pacing, cardiovascular interventional therapy, valvular disease, atherosclerosis, coronary heart disease, (including sudden death), Instruction manual
  • Cytomegalox cytomegalovirus infection, AIDS, rickettsial disease, chlamydia infection, mycoplasma infection, bacterial disease (including tuberculosis anaerobic infection, sepsis, tetanus, etc.), fungal diseases, spirochetes, Parasitic diseases, infectious diarrhea caused by various causes, acute hemorrhagic necrotizing enterocolitis, ulcerative colitis, intestinal obstruction, gastric motility and functional diseases, acute peritonitis, acute pancreatitis, cirrhosis caused by various causes, Fatty liver, jaundice, diarrhea, gastrointestinal bleeding, reflux esophagitis, fulminant hepatic failure, hepatic encephalopathy, cholelithiasis, cholestasis, acute and chronic renal failure, blood purification therapy, acute and chronic respiratory insufficiency, chronic Obstructive pulmonary disease, bronchial asthma, bronchiectasis, pneumonia caused
  • the diabetic complications referred to in the present invention include, but are not limited to, diabetic nephropathy, diabetic foot disease, diabetic retinopathy, diabetic neuropathy, and the like.
  • X Syndrome also known as metabolic syndrome
  • X Syndrome also known as metabolic syndrome
  • Insulin resistance caused by sugar, lipid metabolism disorder combined with the emergence of a variety of metabolic diseases as a clinical feature of a group of severely affected health syndrome. Details are described in Johannsson J. Cl in. Endocr inol. Metab., 82, 727-34 (1997).
  • other types of therapeutic agents includes drugs for treating diabetic complications, anti-obesity drugs, antihypertensive drugs, antiplatelet drugs, antiatherogenic drugs or hypolipidemic drugs, antioxidants, meat.
  • Alkali especially L-carnitine
  • carnitine derivatives especially L-carnitine derivatives such as acetylcarnitine, propionylcarnitine
  • carnitine palmitoyltransferase inhibitors carnitine octanoyl Transferase inhibitors
  • acetylcarnitine stimulants antitumor drugs, anti-gout drugs, osteoporosis drugs, antidepressants, anemia drugs, Alzheimer's drugs, anti-inflammatory drugs, immunological drugs and root bark
  • One or more of the glycoside extracts One or more of the glycoside extracts.
  • the ratio of the therapeutically effective amount of the compound of the structure (I) as the first active ingredient in the pharmaceutical composition of the present invention to one or more other types of therapeutic agents as the second active ingredient is 1: 0001-1: 0. 01.
  • the most suitable composition is a unit preparation, and the unit preparation usually contains the active ingredient in a dose depending on the route of administration, the age and condition of the patient, or the severity of the disease to be treated.
  • the dosage of adult daily dose is 1/6 of that of rats per kilogram of body weight, which is calculated from 1-8 of mice. (Equivalent dose conversion between animals and animals and human body in pharmacological test, Chinese clinical pharmacology and therapeutics , 2004 Sep ; 9 (9) : 1069-1072 ). 5-50mg/ ⁇ / ⁇
  • the dosage is usually 0. 05-100mg / kg / day, preferably 0. 1- 50mg / kg / day, more preferably 0. 5- 50mg / kg / day.
  • the dose is 0. 005-100mg / k g / day, preferably 0. 01- 50mg / kg / day, more preferably 0. 05-5mg / kg / day.
  • other types of therapeutic agents refers to one or more anti-diabetic agents, one or more anti-obesity drugs, antihypertensive drugs, anti-platelet drugs, anti-atherosclerosis. Drugs and / or one or more hypolipidemic drugs (including anti-atherosclerotic drugs), anti-inflammatory Description
  • the compound of formula (I) may optionally be administered in combination with 1, 2, 3 or more anti-diabetic or anti-hyperglycemic agents, including insulin, secretagogue or insulin sensitizer, and other anti-diabetic agents in other types of anti-diabetic drugs.
  • Diabetes medication Preferably, it includes a bifloconazole, a sulfonylurea, a glucosidase inhibitor, a PPAR gamma agonist such as a thiazolidinedione, an aP2 inhibitor, a PPAR ⁇ I ⁇ dual agonist, and a dipeptidyl peptidase IV (DP4 ) inhibition.
  • DP4 dipeptidyl peptidase IV
  • meglitinide, and insulin glucagon-like peptide-1 (GLP-1), PTP1B inhibitor, glycogen phosphorylase inhibitor and/or glucose-6-phosphatase inhibitor .
  • therapeutic agents that may optionally be administered in combination with a compound of formula (I) include anti-obesity agents, anti-hypertensive drugs, anti-platelet drugs, anti-atherosclerotic drugs, and/or hypocholesterolemic drugs.
  • the anti-hyperglycemic effect of the compound of structure (I) in combination with 1, 2, 3 or more other anti-diabetic drugs is greater than that which may be obtained by using each of these drugs alone, and is greater than the combined increase produced by these drugs. And anti-hyperglycemic effect.
  • antidiabetic agents may be oral hypoglycemic agents, preferably biguanides such as diterpene or phenformin and its salts, most preferably metformin hydrochloride.
  • oral antidiabetic agents may also be preferably sulfonylureas such as glibenclamide, glipizide, glimepiride, gliclazide, chlorpropamide, etc., most preferably glibenclamide and glipizide. .
  • oral anti-diabetic agents may also preferably be glucosidase inhibitors such as acarbose, voglibose, miglitol.
  • oral antidiabetic agents may also be preferably thiazolidinediones such as rosiglitazone, pioglitazone, engglitazone, daglitazone, etc., most preferably rosiglitazone and pioglitazone.
  • GLP-1 glucagon-like peptide-1
  • GLP-1 glucagon-like peptide-1
  • GLP-1 glucagon-like peptide-1
  • Other oral antidiabetic agents may also preferably be glucagon-like peptide-1 (GLP-1) such as GLP-1 (1-36) amide, GLP-1 (7-36) amide, GLP-1 (1-36).
  • GLP-1 glucagon-like peptide-1
  • GLP-1 (1-36) amide, GLP-1 (7-36) amide, GLP-1 (1-36).
  • amide, GLP-1 (7-37) amide, GLP-K S3-20-32), GLP-1 (S3- 11-14), GLP-1 (S6-14), GLP-1 (S8) for example, in US Patent 5,941,492 of Hamener, Chinese Open Patent 1884278 of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and AC2993 (Amylen) and LY-315902 (Li lly)
  • the meglitinic acid used in combination with the compound of the formula (I) of the present invention is preferably repaglinide or nateglinide.
  • anti-diabetic drugs may also be PPAR oc / ⁇ dual agonists such as AR-H039242 (As tra/Zeneca), GW-409544 (G 1 axo-We 11 come), KRP297 (yor in Merck), and Murakami et al. "acting as a peroxisome proliferator-activated alpha receptor (PPRA ot) Instruction manual
  • oral anti-diabetic agents may also be DP4 inhibitors, such as patents WO 99/38501, W099/46272, 9/67279, by Hughes et al, Biochemi s try, 38 (36), 11597-11603, NVP published in 1999. -DPP728A ( Novart is ) and so on.
  • the ratio of the compound of the formula (I) to the megdophenone, the PPRA y agonist, the PPAR ct / ⁇ dual agonist, and the DP4 inhibitor is from about 0.01:1 to about 100:1, preferably at about 0.2. 1 to about 10: 1.
  • a hypolipidemic or lipid lowering agent which may optionally be used in combination with a compound of formula (I) of the present invention includes 1, 2, 3 or more benbutyric acids, HMG-CoA reductase inhibitors, squalene synthetase Inhibitors, niacin 4 staining organisms, upregulation of LDL receptor activity, lipoxygenase inhibitors, ACAT inhibitors, cholesterol absorption inhibitors, ileal sodium +/cholic acid cotransporter inhibitors, bile acid sequestrants.
  • the hypolipidemic drug may be benbutin, including but not limited to, clofibrate, bezafibrate, fenofibrate, gemfibrozil, ciprofibrate, clebate, probucol.
  • the hypolipidemic drug can be an HMG-CoA reductase inhibitor including, but not limited to, mevastatin, lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, and the like.
  • the hypolipidemic drug may be a squalene synthetase inhibitor, including, but not limited to, the ot-phosphono-lipidate of U.S. Patent No. 5,712,396, by Biler et al, L Med. Chem., 1988, Vol. 31, 10 The compound disclosed in 1869-1871.
  • hypocholesterolemic drugs include, but are not limited to, cholic acid chelating agents such as cholestyramine, colestipol, cholesterol absorption inhibitors such as ezetimibe, niacins such as niacin, acipimox, and other drugs such as pro Clocoan, pantethine, etc.
  • Anti-obesity agents which may optionally be used in combination with a compound of formula (I) of the invention include 1, 2, 3 or more P 3 adrenergic agonists, lipase inhibitors, serotonin (and dopamine) reuptake inhibition Agent, thyroid P receptor drug, anorectic agent, NPY antagonist, MC4 agonist.
  • the anti-obesity agent may be a ⁇ 3 adrenergic agonist, including but not limited to AJ9677 (Takeda/Da ini pon), L750355 (Merck), and US 3,541,204, US 5,770, 615, US 5,491, 134, US 5,776, 983 and US 5, 486, 064. .
  • the anti-obesity agent can be a lipase inhibitor including, but not limited to, orlistat, Al izyme.
  • the anti-obesity agent may be a serotonin (and dopamine) reuptake inhibitor including, but not limited to, sibutramine, tol-p-ester, axokine.
  • anti-obesity agents include, but are not limited to, anorectic agents such as dextroamphetamine, phentermine, phenylpropanolamine, and horseshoe.
  • Antiplatelet agents which may optionally be used in combination with a compound of formula (I) of the invention include abciximab, ticlopidine, dimetamol, aspirin, anagrelide, ti rof iban, ept if ibat ide, chlorine Pigre.
  • Antihypertensive agents which may optionally be used in combination with a compound of formula (I) of the invention include ACE inhibitors such as enalapril, captopril, quinapril, benazepril, perindopril, calcium Antagonists such as amlodipine, nifedipine, nitrendipine, nimodipine, diltiazem, verapamil, alpha-blockers including terazosin, doxapazine, prazosin, diuretics including hydrochlorothiazide , furosemide, spironolactone, indapamide, central systemic agents including reserpine, clonidine, guanfacine, angiotensin II antagonists including losartan, valsartan, telmisartan, beta - Blockers include mitoxolol, propranolol, atenolol, carvedilol, so
  • Anti-inflammatory drugs which may optionally be used in combination with a compound of formula (I) of the present invention include, but are not limited to, aspirin, phenylbutazone, cilampan, fenbufen, ibuprofen, indomethacin, nabumetone, diflunis Willow, acetaminophen, benol ester, salicylic acid, etofenamate, etodolac, ketoprofen, diclofenac, penicillamine, celecoxib, nimesulide, meloxicam, lo Soprofen, leflunomide, non-Prazin, benzoxamide, oxaprozine, sulindac, antipyrine, auranofin, piroxicam, imidazoxil, tometetine, chlorpheniramine That acid, asimin.
  • Antitumor agents which may optionally be used in combination with a compound of formula (I) of the invention include, but are not limited to, alkylating agents, antitumor antibiotics, dihydrofolate reductase inhibitors, terpenoids, pyrimidines, topoisomerase inhibitors, Tumor neovascularization inhibitors, natural drugs, and the like.
  • Alkylating agents include, but are not limited to, cyclophosphamide, nitrogen mustard, thiotepa, nadropaplatin, oxaliplatin, melphalan, carbamazepine, carmustine, lomustine, semustine, nitrite Mustine, ramustine, temozolomide, mitoxazole amine, troxidone, mesamine.
  • Antitumor antibiotics include, but are not limited to, doxorubicin, mitomycin, bleomycin, gentamicin, epirubicin, mitomycin, daunorubicin, aclarithromycin, erythromycin, mito ⁇ , edarubicin, pirarubicin, pentopirin.
  • Dihydrofolate reductase inhibitors include, but are not limited to, methotrexate, hexamidine melamine.
  • Terpenoids include, but are not limited to, including but not limited to sputum.
  • Pyrimidine drugs include, but are not limited to, fluorouracil, carmofur. Instruction manual
  • Anti-tumor natural drugs include, but are not limited to, camptothecin, vincristine, paclitaxel, colchicine, green gluten, compound acetate gossypol, Kanglaite (barley extract), elemene (arthritis oil extract), Cedar gum base, Polyporus polysaccharide, Lycium barbarum polysaccharide, Lentinus edodes polysaccharide, Ginseng polysaccharide, Tremella polysaccharide, Yunzhi polysaccharide, Rehmannia polysaccharide, Lycium barbarum polysaccharide, Kiwi polysaccharide, Astragalus polysaccharide, Angelica polysaccharide, Gynostemma pentaphyllum polysaccharide, Radix polysaccharide, Prickly ash Add polysaccharides, Achyranthes polysaccharides, etc.
  • Topoisomerase inhibitors include, but are not limited to, irinotecan, topotecan, and rebitantan.
  • Tumor neovascularization inhibitors include, but are not limited to, angios tat in, endos tat in, suramin, thalidomide, fumagillin, monoclonal antibodies, bamastat, marimastat, geni s te in.
  • Immunosuppressive drugs which may optionally be used in combination with the compounds of the invention (I) include, but are not limited to, prednisone, prednisolone, dexamethasone, hydrocortisone, danazol, cyclophosphamide, cyclosporine , mycophenolate mofetil, leflunomide, tripterygium, azathioprine, heparin-warfarin, dimetamol, tacrolimus, sirolimus, kalemycin (imidazole, immunization) Globulin, eicosapentaenoic acid, docosahexaenoic acid (DHA), escital, daximab, rituximab, infliximab, interferon.
  • prednisone prednisolone
  • dexamethasone hydrocortisone
  • danazol danazol
  • cyclophosphamide cyclo
  • Gout drugs which may optionally be used in combination with the compounds of formula (I) of the present invention include, but are not limited to, colchicine, indomethacin, ibuprofen, naproxen, phenylbutazone, fustatin, inflammatory pain, xicola, Meloxicam, allopurinol, citric acid clock, sodium bicarbonate, probenecid, benzbromarone, thiazolone, sulfonylpyrazole, gout, etc.
  • the antidepressant drugs used in combination with the compound of the formula (I) of the present invention are tricyclics, monoamine oxidase inhibitors, serotonin reuptake inhibitors, acetylcholine reuptake inhibitors and the like.
  • the antidepressant drug can be a tricyclic drug, including but not limited to a propyl.
  • Qin clomipramine, amitriptyline, doxepin, imipramine, deferiline.
  • Antidepressant drugs can be tetracyclic drugs including, but not limited to, mianserin, maprotiline.
  • the antidepressant drug can be a monoamine oxidase inhibitor including, but not limited to, phenethyl hydrazine, benzophenone, and moclobemide.
  • the antidepressant may be a selective 5-HT reuptake inhibitor including, but not limited to, fluoxetine, paroxetine, sertraline, citalopram, and flufen samine.
  • Antidepressant drugs may be 5-HT and NE reuptake inhibitors including, but not limited to, venlafaxine, venlafaxine.
  • the antidepressant drug may also be other drugs including, but not limited to, reboxetine, buppe, trazodone, nefazodone, mtitapine, luteapine, amfepramone.
  • the medicament for treating dementia used in combination with the compound of the formula (I) of the present invention includes, but is not limited to, tetrahydroaminoacridine (tacrine), tetrahydroxyaminoacridine, physostigmine, heptene lenola, galantamine , koji lecithin (trichlorfon), donepezil hydrochloride, huperzine bismuth, carbaplatin heavy tartaric acid, nymeline, risperidone, moclobemide, lazabe, salbezole, ises Ming, Selegiline, Propofol, New Qufusi, Apelis, Nefiracetam, Linolididine, Montesporin, Nitrorelin, Olanzapine, ⁇ - ⁇ , Pu Racacetin, diphenylmethane, epoxone, oxazolidine, meclofenoxate, piracetam, pyrithi
  • the osteoporosis drugs used in combination with the compound of the formula (I) of the present invention are bone resorption inhibitors, bone formation accelerating agents, bone mineralizing substances and other osteoporosis drugs.
  • Bone resorption inhibitors include, but are not limited to, bisphosphonates, estrogens, cytokines, progestins, isoflavones, guanidinium salts.
  • Bisphosphonates include, but are not limited to, etidronate, clodronate, tiludronate, pamidronate, alendronate, risedronate, incadronate, zoledronate , dt idronate, ibandronate.
  • Estrogens include, but are not limited to, raloxifene, clomiphene citrate, tamoxifen, droloxifene, noforxidine, idoxifene, adoxifene, benzedoxifene, lasofoxifene, tibolone, nis Estriol.
  • Degradants include, but are not limited to, dense calcium, sulphate, and salcatonin.
  • Bone formation promoters include, but are not limited to, fluoride (telidine), parathyroid hormone (PTH), anabolic steroid drugs, human immunoglobulin (IGF).
  • Other drugs for the treatment of osteoporosis may also be statins, zinc alaninate (AHZ), cathepsin K inhibitors, endostein receptor blockers, neuropeptides, growth factors (insulin-like growth factors, Transforming growth factor, bone morphogenetic protein), osteoprotegerin (os teoproteger in 0PG).
  • statins zinc alaninate (AHZ)
  • cathepsin K inhibitors alaninate
  • endostein receptor blockers neuropeptides
  • growth factors insulin-like growth factors, Transforming growth factor, bone morphogenetic protein
  • osteoprotegerin osteoprotegerin (os teoproteger in 0PG).
  • the solid powder prepared in the previous step was dissolved in 300 ml of benzene, and stirred in an oil bath at 70 ° C, and 1.9 g of trimetazidine hydrochloride was dissolved in a small amount of dichlorosilane, and slowly added dropwise to the reaction solution.
  • the pH of the ethylamine was adjusted to be alkaline, the solution turned brownish red, and the reaction was stopped for 2 hours.
  • Morpholine amide gave 2.7 g of a yellow solid powder.
  • the yellow solid powder obtained in the previous step was dissolved in 30 ml of dioxane and slowly added dropwise to sodium hydroxide alkali water in which 2 g of proline was dissolved to control the pH value to be 8 or more, and the reaction was stirred at 40 ° C or lower. After 4 hours, the layers were analyzed until substantially free of rhein.
  • TGF- ⁇ transforming growth factor
  • FN fibronectin
  • TGF- ⁇ and FN are important cytokines in the pathogenesis of diabetic nephropathy (DN).
  • TGF- ⁇ is a known cytokine with the strongest sclerosis in diabetic nephropathy.
  • short-term blocking of TGF- ⁇ activity can inhibit the increase of extracellular matrix and reduce renal fibrosis;
  • mesangial matrix it is one of the two main non-collagen glycoproteins that constitute ECM (basement membrane).
  • DN is due to the excessive accumulation of normal ECM components such as glomerular Col IV, FN, LN, which leads to GBM. Thickening and mesangial expansion are the basis for clinical symptoms such as proteinuria and progressive decline in renal function.
  • TGF- ⁇ and FN were selected as target indicators, and mesangial cells cultured in low glucose (simulated normal control group) and high glucose (simulated diabetic nephropathy model group) were treated with test drugs.
  • Real-time quantitative PCR was used to observe the expression of TGF- ⁇ and FN in vitro.
  • the expression of TGF- ⁇ and FN in high glucose culture was 1, the expression of XX in the normal control group (low sugar culture) and the test drug group, ⁇ 1 is the inhibitory effect of the drug on cytokines. It indicates that the in vitro test- ⁇ has better anti-DN activity; >1 indicates no inhibition of the cytokine, and the anti-DN activity in vitro is weak. Cytokine expression experiments in each group of three repeated sampling, and into Explain the statistical processing of books.
  • the inhibitory activity of the candidate drug against TGF-b was RD6>RD3>RD5>RD2>RD10; RD7, RD1, RD4, RD8 and RD9 had no inhibitory activity.

Abstract

Provided are derivatives of rhein having the structure of general formula (I), their preparation methods and uses in the preparation of medicaments for treating metabolic diseases.

Description

说 明 书  Description
一种大黄酸衍生物及其制备和用途  Rarenic acid derivative and preparation and use thereof
技术领域 本发明主要涉及大黄酸衍生物及其制备方法和在用于制备治疗代谢类疾病 的药物中的应用。 技术背景 大黄酸是从植物大黄、 何首乌、 虎杖、 蕃泻叶、 芦荟等中药中提取分离精制 或经适当的化学反应制备而得， 具有降血糖、 抗炎、 抗菌、 抗病毒等作用 （郭 美姿等， 国外医学中医中药分册， 2002， 24 ( 3 ): 139-143; 刘凯等， 中医药学 刊， 2004， 22 ( 9 ): 1732-1734 )。 大黄酸用于治疗糖尿病肾病也有报道， 中国 专利 CN1178669 A公开了一种以大黄酸和大黄酸盐作为治疗糖尿病肾病的药物； 中国专利 CN1748675A公开了大黄酸类化合物的复合物治疗糖尿病及糖尿病肾 病。 TECHNICAL FIELD The present invention relates generally to rhein derivatives, processes for their preparation, and their use in the manufacture of a medicament for the treatment of metabolic diseases. BACKGROUND OF THE INVENTION Rhein is obtained by extracting and purifying traditional Chinese medicines such as rhubarb, Polygonum multiflorum, Polygonum cuspidatum, Radix scutellariae, and Aloe vera or by appropriate chemical reaction, and has the functions of lowering blood sugar, anti-inflammatory, antibacterial and anti-viral (Guo Meizi et al. , Chinese Medical Journal of Traditional Chinese Medicine, 2002, 24 ( 3 ): 139-143; Liu Kai et al., Journal of Traditional Chinese Medicine, 2004, 22 ( 9 ): 1732-1734 ). The use of rhein for the treatment of diabetic nephropathy has also been reported. Chinese patent CN1178669 A discloses a drug for treating diabetic nephropathy with rhein and rhein; Chinese patent CN1748675A discloses a complex of rhein compound for treating diabetes and diabetic nephropathy.
但是大黄酸有如下缺陷， 例如致癌性、 生物利用度低等， 因此需要对其进行 进一步的研究。 发明内容 本发明对大黄酸进行了结构改造， 使其毒性降低， 生物利用度提高。  However, rhein has the following drawbacks, such as carcinogenicity, low bioavailability, etc., and further research is needed. SUMMARY OF THE INVENTION The present invention structurally reforms rhein to reduce toxicity and improve bioavailability.
本发明的特征之一是提供一类新的大黄酸衍生物及其制备方法；  One of the features of the present invention is to provide a novel class of rhein derivatives and a process for the preparation thereof;
本发明的特征之二是提供一类大黄酸衍生物及其药物上可接受的盐用来制 备治疗糖尿病、 糖尿病肾病、 心血管病变、 肾功能衰竭、 视网膜病变以及神经 系统障碍等糖尿病并发症和肿瘤、 骨质疏松、 细菌感染、 黄疸肝炎、 代谢性疾 病等多种疾病的药物；  A second feature of the present invention is to provide a class of rhein derivatives and pharmaceutically acceptable salts thereof for the preparation of diabetic complications such as diabetes, diabetic nephropathy, cardiovascular disease, renal failure, retinopathy and neurological disorders. Drugs for various diseases such as tumors, osteoporosis, bacterial infections, jaundice hepatitis, and metabolic diseases;
本发明的特征之三是提供一种药物组合，其含有本发明的大黄酸衍生物或其 药物上可接受的盐和抗糖尿病药物、 治疗糖尿病并发症的药物、 抗肥胖症药物、 抗高血压药物、 抗骨质疏松药物、 抗血小板药物、 抗动脉粥样硬化药物 /或降血 脂药物、 抗肿瘤药物。  A third feature of the present invention is to provide a pharmaceutical composition comprising the rhein derivative of the present invention or a pharmaceutically acceptable salt thereof and an antidiabetic agent, a medicament for treating diabetic complications, an antiobesity drug, and an antihypertensive Drugs, anti-osteoporosis drugs, anti-platelet drugs, anti-atherosclerotic drugs / or hypolipidemic drugs, anti-tumor drugs.
发明详述 Detailed description of the invention
本发明涉及式（I ) 大黄酸衍生物及其药物上可接受的盐或酯， 或其异构体 说 明 书 The present invention relates to a formula (I) of a rhein derivative and a pharmaceutically acceptable salt or ester thereof, or an isomer thereof Description
或前药： Or prodrug:
Figure imgf000004_0001
Figure imgf000004_0001
其中 R为氨基 团；含氮有 咸药物基团； 任选被下列的取代基取代的含 氮杂环基团： 氨基 、 羟基、 C1-6烷基、 C1 - 6烷氧基、 C1- 6烷氨基、 硝基、 腈 基， 上述基团是通过氮原子连接。  Wherein R is an amino group; a nitrogen-containing salty drug group; a nitrogen-containing heterocyclic group optionally substituted by the following substituent: amino group, hydroxyl group, C1-6 alkyl group, C1-6 alkoxy group, C1-6 An alkylamino group, a nitro group, a nitrile group, and the above groups are bonded through a nitrogen atom.
本发明中的氨基酸包括人体必需的氨基酸和非人体必需的氨基酸，其以结 构中同时含一个或一个以上的氨基和羧基取代的饱和或不饱和的烷基或环烷基 为特征。  The amino acids in the present invention include essential amino acids and non-essential amino acids, which are characterized by a saturated or unsaturated alkyl or cycloalkyl group having one or more amino and carboxyl groups substituted in the structure.
本发明中形成 酸基团的氨基酸选自： 胱氨酸、 甘氨酸、 丙氨酸、 β -丙 氨酸、 缬氨酸、 亮氨酸、 异亮氨酸、 苯丙氨酸、 脯氨酸、 色氨酸、 酪氨酸、 丝 氨酸、 半胱氨酸、 蛋氨酸、 天冬酰胺、 谷氨酰胺、 苏氨酸、 天冬氨酸、 谷氨酸、 赖氨酸、 精氨酸、 组氨酸和曱硫氨酸， 及其对映异构体或其混旋体。  The amino acid forming an acid group in the present invention is selected from the group consisting of: cystine, glycine, alanine, β-alanine, valine, leucine, isoleucine, phenylalanine, valine, Tryptophan, tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine and Methionine, its enantiomer or its hybrid.
本发明中含氮的有机碱药物基团的药物包括含有伯胺或仲胺的具有一定活 性的原料、 中间体或制剂。  The drug containing a nitrogen-containing organic base drug group in the present invention includes a certain active material, an intermediate or a preparation containing a primary or secondary amine.
本发明中含氮的有 «^药物基团的药物选自： 葡曱胺、 氨基葡萄糖、 依那 普利、 噻吗洛尔、 牛磺酸、 乌苯美司、 左旋多巴、 沙丁胺醇、 阿替洛尔、 间羟 胺、 二曱双胍、 曱氧明、 多巴胺、 多巴酚丁胺、 肾上腺素、 妥卡尼、 阿米洛利、 美西律、 倍他司汀、 麻黄碱、 氯丙那林、 氯胺酮、 普罗帕酮、 普萘洛尔、 氨力 农、 氨苯砜、 苯丙胺、 氨苯磺胺、 柳氮磺吡啶、 磺胺米隆、 磺胺嘧啶银、 磺胺 二曱嘧啶、 蹟胺二曱异嘧啶、 碘胺异恶唑 （SIZ )、 磺胺苯吡唑 、 磺胺间甲氧 嘧啶、 碘胺对曱氧嘧啶、 碘胺多辛、 磺胺脒、 磺胺嘧啶（SD )、 磺胺甲恶唑、 磺 胺醋酰钠、 磺胺嘧啶辞、 磺胺林、 复方磺胺曱恶唑、 复方磺胺嘧啶、 琥珀磺胺 噻唑、 磺胺对曱氧嘧啶、 磺胺二曱嘧啶钠注射液、 横胺异恶唑、 联磺曱氧苄啶、 酞磺胺噻唑、 麦角新碱、 贝诺酯、 双氯芬酸（钠）、 丙谷胺、 丙硫异烟胺、 丙硫 氧嘧啶、 石杉碱曱、 布美他尼、 朴米酮、 卡马西平、 卡莫司汀、 卡莫氟、 曱苯 达唑、 曱苯磺丁脲、 曱氧苄啶、 甲氧氯普胺、 曱基多巴。 说 明 书 The nitrogen-containing drug having the drug group in the present invention is selected from the group consisting of: glucosamine, glucosamine, enalapril, timolol, taurine, umbrel, levodopa, salbutamol, Tirolol, m-hydroxylamine, diterpene, oxime, dopamine, dobutamine, adrenaline, tonicani, amiloride, mexiletine, betahistine, ephedrine, clonidine Lin, ketamine, propafenone, propranolol, amrinone, dapsone, amphetamine, sulfonamide, sulfasalazine, sulfametholone, silver sulfadiazine, sulfamethazine, trace amine Pyrimidine, iodosylisoxazole (SIZ), sulfaphenazole, sulfamonomethoxine, iodine to apoxine, iodine polyamine, sulfaguanidine, sulfadiazine (SD), sulfamethoxazole, sulfonamide Sodium sulfonate, sulfadiazine, sulfamethamine, compound sulfamethoxazole, compound sulfadiazine, amber sulfathiazole, sulfamethoxazole, sulfadiazine pyrimidine sodium injection, tromethamine, sulfoxime , sulfamethoxazole, ergometrine, N-ester, diclofenac (sodium), proglumide, prothionamide, propylthiouracil, huperzine, bumetanide, pumilone, carbamazepine, carmustine, camoforol, Indapazole, acesulfame, aziridine, metoclopramide, decidopa. Instruction manual
本发明中形成含氮有«<药物基团的药物优选： 葡甲胺、 氨基葡萄糖、 依 那普利、 噻吗洛尔、 牛磺酸、 乌苯美司、 左旋多巴、 沙丁胺醇、 阿替洛尔、 间 羟胺、 二曱双胍、 曱氧明、 多巴胺、 多巴酚丁胺、 肾上腺素、 妥卡尼、 阿米洛 利、 美西律、 倍他司汀、 麻黄碱、 氯丙那林、 氯胺酮、 普罗帕酮、 普萘洛尔、 氨力农、 氨苯砜和苯丙胺。  In the present invention, a drug containing a nitrogen-containing drug group is preferably: meglumine, glucosamine, enalapril, timolol, taurine, umbrel, levodopa, salbutamol, alte Lol, m-hydroxylamine, diterpene, oxime, dopamine, dobutamine, adrenaline, tonicani, amiloride, mexiletine, betahistine, ephedrine, clonidine , ketamine, propafenone, propranolol, amrinone, dapsone and amphetamine.
本发明中任意取代的含氮杂环基团的含氮杂环包括任意取代的含氮的三 元、 四元、 五元、 六元、 七元饱和或不饱和杂环。 其中任意取代包括任意取代 的氢、 取代的烷基、 取代的 3-7 元的碳环基、 取代的杂环基、 取代的芳基、 或 碳、 氧、 硫或氮原子环合成可任意被取代的 3-7 元的环； 其中含氮杂环中的氮 是仲胺（氮上连接一个氢） 。  The nitrogen-containing heterocyclic ring of the optionally substituted nitrogen-containing heterocyclic group in the present invention includes an optionally substituted nitrogen-containing ternary, quaternary, five-membered, six-membered, seven-membered saturated or unsaturated heterocyclic ring. Any of the substitutions including optionally substituted hydrogen, substituted alkyl, substituted 3-7 membered carbocyclic group, substituted heterocyclic group, substituted aryl group, or carbon, oxygen, sulfur or nitrogen atom can be optionally synthesized. a substituted 3-7 membered ring; wherein the nitrogen in the nitrogen-containing heterocycle is a secondary amine (a hydrogen is attached to the nitrogen).
其中任意取代的烷基包括 CH3、 CH (CH2CH3) 2、 CH2 (CH2) nCH3、 d_C4烷氧基 CH20 (CH2) mCH3、 d-C4烷巯基 CH2S (CH2) raCH3、 （CH2) mCX3、 （CH2) raCN、 （CH2) mC00H、 C -C4 烷酰基（CIU OOR, (CH2) m0H, (CH2) J、 S02 (CH2) mCH3、
Figure imgf000005_0001
C「C4烯基、 C -C4 炔基、 d-C4烷基氨基。 Any optionally substituted alkyl group includes CH 3 , CH (CH 2 CH 3 ) 2 , CH 2 (CH 2 ) n CH 3 , d_C 4 alkoxy CH 2 0 (CH 2 ) m CH 3 , dC 4 alkanoyl CH 2 S (CH 2 ) ra CH 3 , (CH 2 ) m CX 3 , (CH 2 ) ra CN, (CH 2 ) m C00H, C -C 4 alkanoyl (CIU OOR, (CH 2 ) m 0H, ( CH 2 ) J, S0 2 (CH 2 ) m CH 3 ,
Figure imgf000005_0001
C "C 4 alkenyl, C -C 4 alkynyl, dC 4 alkylamino.
其中任意取代的 3-7元碳环基包括 CH (CH2) n、 CHCnH2n- aXa、 CHCnH2n— a (OH) a、 CHCnH2n-a (CH3) a、 CHCnH2n— a (C00H) a、 CHCnH2n—a (CH20H) a、 井冈霉醇胺、 双环烷基、 三 环基和环烯基。 The optionally substituted 3-7 membered carbocyclic group includes CH(CH 2 ) n , CHCnH2 n - aX a , CHC n H 2n — a (OH) a , CHC n H 2n - a (CH 3 ) a , CHC n H 2n — a (C00H) a , CHC n H 2n — a (CH 2 0H) a , jingtanolamine, bicycloalkyl, tricyclo and cycloalkenyl.
任意取代的含氮杂环基包括哌啶基、 吗啉基、 呋喃基、 哌嗪基、 噻吩基、 唑基、 咪唑基、 吡11定基、 吡咯基、 喹淋基、 吲味基、 吡。秦基、 。达 σ秦基、 嘧 基、 异喹啉基、 嘌呤基、 吖啶基、 戊糖基、 己糖基、 氨基糖基。 Optionally substituted nitrogen-containing heterocyclic groups include piperidinyl, morpholinyl, furanyl, piperazinyl, thienyl, oxazolyl, imidazolyl, pyrazolyl 11 set, pyrrolyl, quinolinyl leaching yl, indazol taste, pyrazolyl. Qin Ji,. Sigma -methyl, pyrimidin, isoquinolyl, decyl, acridinyl, pentose, hexosyl, aminoglycosyl.
任意取代的芳基或作为另一基团的一部分使用， 包括苯基、 萘基、 杂芳基、 稠和的碳环或杂环的 1-3个其它的环， 并且通过可利用的碳原子由 1-3个任选 的卤素、 低级烷基、 低级烷氧基、 低级烷氨基、 低级链烯基、 低级链炔基、 环 基及杂环基、 芳基氨基取代。  Any optionally substituted aryl or used as part of another group, including phenyl, naphthyl, heteroaryl, fused carbocyclic or heterocyclic, 1-3 other rings, and through available carbon atoms Substituted by 1-3 optional halogen, lower alkyl, lower alkoxy, lower alkylamino, lower alkenyl, lower alkynyl, cyclic and heterocyclic, arylamino.
碳、 氧、 硫或氮原子环合成可任意被取代的 3-7 元的环包括四氢吡咯、 二 氢吡咯、 哌啶、 吗淋、 六氢吡啶、 二氢吡啶、 哌嗪、 呋喃、 噻吩、 噻唑、 咪唑、 噁唑、 吡1定、 吡17各、 金淋、 吲味、 吡 "秦、 达 、 嘧，定、 异会淋、 嘌呤、 吖1定。 Cyclic synthesis of carbon, oxygen, sulfur or nitrogen atoms The optionally substituted 3-7 membered ring includes tetrahydropyrrole, dihydropyrrole, piperidine, chlorin, hexahydropyridine, dihydropyridine, piperazine, furan, thiophene. , thiazole, imidazole, oxazole, pyrazole set 1, pyrazole 17 each, gold leaching, taste indole, pyrazole, "Qin, up, ethyl, set, will be different leaching, purine, acridine 1 set.
本发明中任选取代的含氮杂环基团的杂环基优选： 吗啉基、 哌啶基、 哌嗪 基、 四氢吡咯基、 咪唑基、 吡唑基、 吲哚基、 吲哚啉基。  The optionally substituted nitrogen-containing heterocyclic group-containing heterocyclic group in the present invention is preferably: morpholinyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, imidazolyl, pyrazolyl, fluorenyl, porphyrin base.
本发明中任意取代的哌嗪基的哌嗪包括但不限于 4-曱基哌嗪、肉桂基哌嗪、 说 明 书 Piperazines of any of the substituted piperazinyl groups in the present invention include, but are not limited to, 4-mercaptopiperazine, cinnamylpiperazine, Instruction manual
苄基哌嗪、 苯基派嗪、 曲美他嗪、 环丙沙星、 依诺沙星、 诺氟沙星、 可乐定、Benzylpiperazine, phenylpyrazine, trimetazidine, ciprofloxacin, enoxacin, norfloxacin, clonidine,
2-氧代哌嗪乙酸、 哌啶并哌嗪、 二苯曱基哌嗪、 1- (2-甲氧基苯基)哌嗪、 1- (2- 氟苯基)哌嗪、 1- (2， 3-二曱基苯基)哌嗪、 1- (2， 4-二曱基苯基)哌嗪、 1- (3，4 - 二曱基苯基）哌嗪、 N-羟乙基哌嗪、 1- (5-曱基- 2-吡啶基）哌嗪、 2， 5-二曱基哌 嗪、 2, 6-二曱基哌嗪、 2-曱基哌嗪、 1- (2， 4-二氟苯基)哌嗪、 1- (2, 3-二氯苯基） 哌嗪、 乙氧羰基派嗪、 4 又丁氧羰基 -2-甲基-哌嗪、 2-曱基"^又丁氧羰基哌嗪、 2-羧基哌嗪、 4- 丁氧羰基哌嗪 -2-羧酸、 1- (2-氯苯基)哌嗪、 1- [2- (2-羟基 乙氧基）乙基]哌嗪、 1- (2-曱氧基乙基)哌嗪、 1-异丙基哌嗪、 N-乙酰基哌嗪、 2 -乙基哌嗪、 又丁氧羰基哌嗪、 4- 又丁氧羰基- 2-甲基哌嗪、 4-^又丁氧羰基 -哌嗪叔丁酰胺、 1- (2-氟- 4-硝基苯基)哌嗪、 1- (3-三氟曱基）苯基哌嗪、 4-叔 丁氧羰基哌嗪 -2-羧酸、卜 (2-曱基苯基)哌嗪、 1- [3, 5-二 (三氟曱基)苯基]哌嗪、 又丁氧羰基- 2-曱基哌嗪、 1-环己基哌嗪、 1- (噻唑 -2-基）哌嗪、 1- (2-嘧啶基） 哌嗪、 1-环戊基哌嗪、 N-丙基哌嗪、 1- (4-氟苯基)哌嗪、 2-氧代- 1-哌嗪乙酸、 4-苄基 -2- (苄氧基甲基)哌"秦、 4， 4' -二氟苯曱哌嗪、 曱酰高哌嗪、 1- (2-曱基） 苄基哌嗪、 1- (4-氯二苯曱基)哌嗪、 苄基-卜哌嗪碳酸酯、 1- (3-溴苯基)哌嗪、 N-1-苄基- 3-乙基派。秦、 N- 1-苄基 -3-曱基哌嗪、 哌啶并哌嗪、 N-1-苄基- 3-异丙 基哌嗪、 N-叔丁氧羰基- 2-乙基哌嗪、 1- (吡啶 -3-基曱基）哌嗪、 1- (2-吡啶基） 哌嗪、 1— (2-曱氧基苯基)哌嗪、 1- (4-曱氧基苯基)哌嗪、 1- (4-氯苯基)哌嗪、 叔丁基派。秦、 1 又丁氧羰基- 2-乙基哌嗪、 1- (2-氯苯基)哌嗪、 1- (2-甲基苯基） 哌嗪、 1- (2-呋喃甲酰基)哌嗪、 1- (3， 4-二氯苯基）哌嗪、 1- (噻唑 -2-基)哌嗪、 1 又丁氧羰基- 3-乙基哌嗪、 2-甲基哌嗪- 1-曱酸苄酯、 N4-苄基- 2-异丁基哌嗪、 4-苯曱基 -2-哌嗪乙醇、 N-叔丁氧羰基 -2-苄基哌嗪、 氧羰基 -3-苯基哌嗪、 又丁氧羰基 -3-苄基哌嗪、 2-苯基哌嗪、 1-曱基- 3-苯基哌嗪、 N- (2，6-二甲基 苯基) -1-哌嗪乙酰胺、 N-乙基哌嗪、 N-异丁基哌嗪、 N-丁基哌嗪、 N- 1-苄基- 3- 苯基哌嗪、 N- 1-苄基- 2-苯基哌嗪、 2-哌嗪酮、 1- (6-氯哒嗪 -3-基)哌嗪、 1- (2- 硝基苯基)哌嗪、 N-乙基双氧哌嗪、 间羟基苯基哌嗪、 2-哌嗪基 -4-氨基 -6， 7 -二 甲氧基喹唑啉、 1- (2-呋喃曱酰基)哌嗪、 1- (4-硝基苯基)哌嗪、 四氢糠酰哌嗪、 卜 (4-氟苯基)派嗪、 1- (2-氯苯基)哌嗪、 N-叔丁氧羰基- 2-异丙基哌嗪、 N-叔丁 氧羰基 -2-异丁基哌嗪、 4-哌嗪 -1-基苯曱腈、 4- (1-苄基哌嗪- 4-基)哌啶、 1, 4- 苯并二恶烷- 2-羰基哌嗪、 1- [2- (4-氟苯基）乙基]哌嗪、 5-氯- 2-曱基苯基哌嗪、 说 明 书 2-oxopiperazineacetic acid, piperidazine piperazine, diphenylhydrazine piperazine, 1-(2-methoxyphenyl) piperazine, 1-(2-fluorophenyl) piperazine, 1-( 2,3-Dimercaptophenyl)piperazine, 1-(2,4-dimercaptophenyl)piperazine, 1-(3,4-didecylphenyl)piperazine, N-hydroxyethyl Piperazine, 1-(5-fluorenyl-2-pyridyl)piperazine, 2,5-dimercaptopiperazine, 2,6-dimercaptopiperazine, 2-mercaptopiperazine, 1- (2 , 4-difluorophenyl)piperazine, 1-(2,3-dichlorophenyl)piperazine, ethoxycarbonylpyrazine, 4 butoxycarbonyl-2-methyl-piperazine, 2-indenyl "^-butoxycarbonylpiperazine, 2-carboxypiperazine, 4-butoxycarbonylpiperazine-2-carboxylic acid, 1-(2-chlorophenyl)piperazine, 1-[2-(2-hydroxyethyl) Oxy)ethyl]piperazine, 1-(2-decyloxyethyl)piperazine, 1-isopropylpiperazine, N-acetylpiperazine, 2-ethylpiperazine, butoxycarbonylpiper Pyrazine, 4-butoxycarbonyl-2-methylpiperazine, 4-(butoxycarbonyl-piperazine tert-butyramide, 1-(2-fluoro-4-nitrophenyl)piperazine, 1-( 3-trifluoromethyl)phenylpiperazine, 4-tert-butoxycarbonylpiperazine-2-carboxylic acid, di(2-mercaptophenyl)piperazine, 1-[3, 5-di( Fluorinyl)phenyl]piperazine, butoxycarbonyl-2-indolylpiperazine, 1-cyclohexylpiperazine, 1-(thiazol-2-yl)piperazine, 1-(2-pyrimidinyl)piperidin Pyrazine, 1-cyclopentylpiperazine, N-propylpiperazine, 1-(4-fluorophenyl)piperazine, 2-oxo-1-piperazineacetic acid, 4-benzyl-2-(benzyloxy) Methyl) piperidine "Qin, 4, 4'-difluorobenzophenazine, decanoylpiperazin, 1-(2-indolyl)benzylpiperazine, 1-(4-chlorodiphenyl) Piperazine, benzyl-piperazine carbonate, 1-(3-bromophenyl)piperazine, N-1-benzyl-3-ethylidene. Qin, N- 1-benzyl-3-mercaptopiperazine, piperidazine piperazine, N-1-benzyl-3-isopropyl piperazine, N-tert-butoxycarbonyl-2-ethylpiperazine , 1-(pyridin-3-ylindenyl)piperazine, 1-(2-pyridyl)piperazine, 1-(2-decyloxyphenyl)piperazine, 1-(4-decyloxyphenyl) Piperazine, 1-(4-chlorophenyl)piperazine, tert-butyl. Qin, 1 butoxycarbonyl- 2-ethylpiperazine, 1-(2-chlorophenyl)piperazine, 1-(2-methylphenyl)piperazine, 1-(2-furoyl)piperidin Pyrazine, 1-(3,4-dichlorophenyl)piperazine, 1-(thiazol-2-yl)piperazine, 1 butoxycarbonyl-3-ethylpiperazine, 2-methylpiperazine-1 - benzyl decanoate, N4-benzyl-2-isobutylpiperazine, 4-phenylmercapto-2-piperazineethanol, N-tert-butoxycarbonyl-2-benzylpiperazine, oxycarbonyl-3- Phenylpiperazine, butoxycarbonyl-3-benzylpiperazine, 2-phenylpiperazine, 1-indolyl-3-phenylpiperazine, N-(2,6-dimethylphenyl)- 1-piperazinacetamide, N-ethylpiperazine, N-isobutylpiperazine, N-butylpiperazine, N- 1-benzyl-3-phenylpiperazine, N- 1-benzyl- 2-phenylpiperazine, 2-piperazinone, 1-(6-chloropyridazin-3-yl)piperazine, 1-(2-nitrophenyl)piperazine, N-ethyldioxypiperazine , m-hydroxyphenylpiperazine, 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline, 1-(2-furoyl)piperazine, 1-(4-nitrobenzene Piperazine, tetrahydrofurfuryl piperazine, di(4-fluorophenyl)pyrazine, 1-(2-chlorophenyl)piperazine, N-tert-butoxycarbonyl-2-isopropylpiperazine, N- Tert-Butoxycarbonyl-2-isobutylpiperazine, 4-piperazin-1-ylbenzonitrile, 4-(1-benzylpiperazine-4-yl)piperidine, 1, 4-benzo dioxin Alkano-2-carbonylpiperazine, 1-[2-(4-fluorophenyl)ethyl]piperazine, 5-chloro-2-nonylphenylpiperazine, Instruction manual
N-曱酰基哌嗪、 1- (5-硝基吡啶- 2-基)哌嗪、 1-二苯甲基哌嗪、 2-苄基哌嗪、 N-1- 叔丁氧羰基- 2-苯基哌嗪、 1- (3-硝基吡啶- 2-基)哌嗪、 1， 2-苯并异噻唑 -3-哌嗪、 1- (2-三氟曱基苄基)哌嗪等。  N-decanoyl piperazine, 1-(5-nitropyridin-2-yl)piperazine, 1-diphenylmethylpiperazine, 2-benzylpiperazine, N-1-tert-butoxycarbonyl-2- Phenylpiperazine, 1-(3-nitropyridine-2-yl)piperazine, 1,2-benzisothiazol-3-piperazine, 1-(2-trifluorodecylbenzyl)piperazine, etc. .
本发明中除哌，秦外其它任意取代的含氮杂环化合物可以参考如上哌嗪类取 代基团进行取代。  In the present invention, an optionally substituted nitrogen-containing heterocyclic compound other than piperazine may be substituted with reference to the above piperazine-based substituent.
本发明化合物的可药用盐可以用常规化学方法由包含碱性或酸性部分的本 发明的化合物来合成。 一般而言， 碱性化合物的盐是通过离子交换色谱或通过 将游离碱与化学计量的或过量的所需的成盐的无机酸或有机酸在适宜的溶剂或 溶剂的各种组合中进行反应来进行制备的。 类似地， 酸性化合物的盐是通过与 适宜的无机或有积 进行反应来形成的。  The pharmaceutically acceptable salts of the compounds of the present invention can be synthesized from the compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. In general, the salt of the basic compound is reacted by ion exchange chromatography or by various combinations of the free base with a stoichiometric or excess amount of the desired salt-forming mineral or organic acid in a suitable solvent or solvent. To carry out the preparation. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic product.
本发明化合物的可药用盐包括通过将碱性的本发明化合物与无机或有机酸' 反应而形成的本发明化合物的常规无毒盐。 例如， 常规无毒盐包括得自无机酸 和有机酸的那些， 所述无机酸是例如盐酸、 氢溴酸、 硫酸、 氨基磺酸、 磺酸、 磷酸、 硝酸等， 所述有机酸是例如乙酸、 丙酸、 琥珀酸、 乙醇酸、 硬脂酸、 乳 酸、 苹果酸、 酒石酸、 柠檬酸、 抗坏血酸、 朴酸、 枸橼酸、 马来酸、 羟基马来 酸、 苯乙酸、 谷氨酸、 苯曱酸、 水杨酸、 对氨基苯磺酸、 2-乙酰氧基-苯甲酸、 富马酸、 曱苯磺酸、 曱磺酸、 乙烷二磺酸、 草酸、 羟乙基磺酸、 三氟乙酸等。  Pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by reacting a basic compound of the invention with an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, sulfonic acid, phosphoric acid, nitric acid, etc., and organic acids such as acetic acid. , propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, citric acid, citric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzene Capric acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, terephthalic acid, sulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, three Fluoroacetic acid, etc.
本发明化合物的可药用盐中优选的酸包括乙酸、 盐酸、 硫酸、 磺酸、 磷酸、 琥珀酸、 乳酸、 苹果酸、 酒石酸、 柠檬酸、 枸橼酸、 马来酸、 草酸、 富马酸、 曱磺酸。  Preferred acids in the pharmaceutically acceptable salts of the compounds of the invention include acetic acid, hydrochloric acid, sulfuric acid, sulfonic acid, phosphoric acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, citric acid, maleic acid, oxalic acid, fumaric acid. , sulfonic acid.
本发明化合物的可药用盐中最优选的酸包括乙酸、 琥珀酸、 酒石酸、 枸橼 酸、 马来酸、 草酸、 盐酸、 硫酸、 磷酸。  The most preferred acids among the pharmaceutically acceptable salts of the compounds of the present invention include acetic acid, succinic acid, tartaric acid, citric acid, maleic acid, oxalic acid, hydrochloric acid, sulfuric acid, phosphoric acid.
当本发明化合物是酸性时， 合适的 "可药用盐" 是指由可药用无机碱和有 机碱制得的盐。 得自无机碱的盐包括铝盐、 铵盐、 钙盐、 铜盐、 三价铁盐、 二 价铁盐、 锂盐、 镁盐、 锰盐、 二价锰盐、 钾盐、 钠盐、 锌盐等。 铵盐、 钙盐、 镁盐、 钾盐和钠盐是特别优选的。 得自可药用无毒有机碱的盐包括下列碱的盐： 伯胺、 仲胺和叔胺， 取代的胺， 包括天然取代的胺、 环胺和碱性离子交换树脂， 例如精氨酸、 甜菜碱、 咖啡因、 胆碱， N，N1-二苄基乙二胺、 二乙胺、 2-二乙基 氨基乙醇、 2-二曱基氨基乙醇、 乙醇胺、 乙二胺、 N-乙基吗啉、 N-乙基哌啶、 葡糖胺、 黄连素、 氨基葡糖、 组氨酸、 哈胺（ hydrabamine )、 异丙基胺、 赖氨 说 明 书 When the compound of the invention is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, divalent iron salts, lithium salts, magnesium salts, manganese salts, divalent manganese salts, potassium salts, sodium salts, zinc salts. Salt and so on. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable non-toxic organic bases include the salts of the following bases: primary, secondary and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines and basic ion exchange resins such as arginine, Betaine, caffeine, choline, N,N1-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-didecylaminoethanol, ethanolamine, ethylenediamine, N-ethyl Morpholine, N-ethylpiperidine, glucosamine, berberine, glucosamine, histidine, hydrabamine, isopropylamine, lysine Description
酸、 甲基葡糖胺、 吗啉、 哌嗪、 哌啶、 聚胺树脂、 普鲁卡因、 嘌呤、 可可碱、 三乙胺、 三曱胺、 三丙胺、 氨丁三醇等。 当本发明化合物是酸性的时， 术语 "游 离形式" 是指其非盐形式的化合物， 这样的酸性官能团仍然是质子化的。 Acid, methyl glucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, tridecylamine, tripropylamine, tromethamine, and the like. When the compound of the invention is acidic, the term "free form" refers to a compound in its non-salt form which is still protonated.
本发明化合物的可药用盐中优选的碱包括甜菜碱、 咖啡因、 可可碱、 氨基 葡糖、 曱基葡糖胺、 三乙胺、 普鲁卡因、 季铵、 氢氧化钾、 氢氧化钠。  Preferred bases in the pharmaceutically acceptable salts of the compounds of the invention include betaines, caffeine, theobromine, glucosamine, decyl glucosamine, triethylamine, procaine, quaternary ammonium, potassium hydroxide, hydroxide sodium.
本发明化合物的可药用盐中最优选的碱包括氨基葡糖、 甲基葡糖胺、 三乙 胺、 氢氧化钾、 氢氧化钠。  The most preferred bases among the pharmaceutically acceptable salts of the compounds of the present invention include glucosamine, methyl glucosamine, triethylamine, potassium hydroxide, sodium hydroxide.
上述可药用盐和其它常见的可药用盐的制备由 Berg 等人， 更详细描述在 "Pharmaceut ical Sal ts, " J. Pharm. Sci.， 1977: 66: 1— 19中。  The preparation of the above pharmaceutically acceptable salts and other common pharmaceutically acceptable salts is described in more detail by Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977: 66:1-19.
本发明大黄酸衍生物 （ I )或其药学上可接受的盐包括其分子内盐或其含 结晶水的盐。  The rhein derivative (I) of the present invention or a pharmaceutically acceptable salt thereof includes an intramolecular salt thereof or a salt thereof containing crystal water.
本发明化合物的内盐或两性离子， 在生理条件下， 化合物中的去质子化酸 性部分例如羧基可以是阴离子， 并且该电荷可由质子化或烷基化的碱性部分例 如季氮原子的阳离子电荷在内部平衡。 具有内部平衡电荷， 并因此不与分子间 抗衡离子締合的分离的化合物也可以视为 "游离形式" 的化合物。  An internal salt or a zwitterion of a compound of the invention, under physiological conditions, a deprotonated acidic moiety such as a carboxyl group in the compound may be an anion, and the charge may be a protonated or alkylated basic moiety such as a cationic charge of a quaternary nitrogen atom Balanced internally. An isolated compound having an internal equilibrium charge and thus not associated with an intermolecular counterion can also be considered a "free form" compound.
该类衍生物优选的化合物有大黄酸吡咯烷酰胺、 大黄酸哌嗪酰胺、 大黄酸哌 啶酰胺、 大黄酸 3-甲基哌啶酰胺、 大黄酸 N-曱基哌嗪酰胺、 大黄酸曲美他嗪酰 胺、 大黄酸阿替洛尔酰胺、 大黄酸牛横酸酰胺、 大黄酸氨基葡萄糖酰胺、 大黄 酸 3-羟曱基哌啶酰胺、 大黄酸吗啉酰胺、 大黄酸苄基哌嗪酰胺、 大黄酸苯基哌 嗪酰胺、 大黄酸哌啶并哌嗪酰胺、 大黄酸二苯曱基哌嗪酰胺、 大黄酸脯氨酸酰 胺、 大黄酸甘氨酸酰胺、 大黄酸 β -丙氨酸酰胺。  Preferred derivatives of such derivatives are pyrrolizyl rhein, piperazine amide, piperidamide of rhein, 3-methylpiperidinamide of rhein, N-mercapto piperazine amide, and rhein Oxazinamide, altolinamide of rhein, leucovoramide of rhein, glucosamine amide of rhein, 3-hydroxymethyl piperidamide of rhein, morpholinamide of rhein, benzyl piperazamide of rhein, Phenyl piperazine amide, piperidazine piperazine amide, diphenyl hydrazino piperazine amide, rhein glutamic acid amide, rhein glycine amide, rhein β-alanine amide.
此外， 本发明还提供了一种含有大黄酸衍生物或其互变立体异构体或其药 学上可接受的载体的药物组合物。 的载体的药物组合物的制备方法， 此方法包括将大黄酸衍生物或其互变异构体 或其药学上可接受的溶剂化物与药学上可接受的载体相混合或者溶解。  Further, the present invention provides a pharmaceutical composition comprising a rhein derivative or a tautomeric stereoisomer thereof or a pharmaceutically acceptable carrier thereof. A method of preparing a pharmaceutical composition of a carrier which comprises mixing or dissolving a rhein derivative or a tautomer thereof, or a pharmaceutically acceptable solvate thereof, with a pharmaceutically acceptable carrier.
此处术语 "药学上可接受的" 包括人用和兽用的化合物、 组合物和组分。 如果需要， 组合物可以进行包装， 并附有书写或者印刷的使用说明。  The term "pharmaceutically acceptable" as used herein includes both human and veterinary compounds, compositions and components. If desired, the composition can be packaged with instructions for writing or printing.
本发明的药物组合物， 制备成各种药物制剂， 该制剂为口服给药制剂、 注 射给药制剂或局部给药制剂， 其中： 说 明 书 The pharmaceutical composition of the present invention is prepared into various pharmaceutical preparations, which are oral administration preparations, injection administration preparations or topical administration preparations, wherein: Instruction manual
( 1 ) 口服给药制剂包括普通片、 緩释片、 颗粒剂、 硬或软胶嚢、 糖浆剂、 溶液剂、 乳剂； 口服给药制剂的载体包括填充剂、 崩解剂、 粘合剂、 润滑剂、 着色剂、 矫味剂或者其他常规添加剂， 具体包括淀粉、 乳糖、 微晶纤维素、 羧 曱基淀粉钠、 交联聚乙烯吡咯烷酮、 聚乙烯吡咯烷酮、 羟丙甲纤维素、 硬脂酸 镁、 二氧化硅和聚山梨脂一80、 十二烷基^ <酸钠；  (1) Oral administration preparations include ordinary tablets, sustained release tablets, granules, hard or soft capsules, syrups, solutions, emulsions; carriers for oral administration include fillers, disintegrators, binders, Lubricants, colorants, flavors or other conventional additives, including starch, lactose, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, polyvinylpyrrolidone, hypromellose, stearic acid Magnesium, silica and polysorbate-80, dodecyl^ sodium;
( 2 )注射给药制剂包括无菌注射的水溶液、 无菌注射的水包油微乳液、 注 射用无菌粉末； 注射给药制剂的载体包括注射用溶剂、 注射用附加剂， 具体注 射溶剂包括注射用水、 注射用油如大豆油， 注射用增溶剂如乙醇、 丙二醇、 聚 乙二醇、 甘油， 等渗物质如氯化钠、 葡萄糖；  (2) The preparation for administration by injection includes a sterile injectable aqueous solution, a sterile injectable oil-in-water microemulsion, a sterile powder for injection; a carrier for injecting the preparation for injection includes a solvent for injection, an additional agent for injection, and the specific injection solvent includes Water for injection, oil for injection such as soybean oil, solubilizer for injection such as ethanol, propylene glycol, polyethylene glycol, glycerin, isotonic materials such as sodium chloride, glucose;
( 3 )局部给药制剂是贴剂、 栓剂、 霜剂、 膏剂、 凝胶剂、 溶液、 靶向制剂 或混悬液， 其中靶向制剂包括脂质体、 微球剂、 毫微粒、 包含物、 单克隆抗体 耦联物； 局部给药制剂的载体包括药学上用于局部给药的常规载体。  (3) The topical preparation is a patch, a suppository, a cream, a cream, a gel, a solution, a targeted preparation or a suspension, wherein the targeted preparation comprises a liposome, a microsphere, a nanoparticle, an inclusion. , monoclonal antibody conjugates; carriers for topical formulations include conventional carriers for pharmaceutically acceptable topical administration.
药物制剂给药形式包括： 静脉、 肌内、 腹膜、 皮下、 口服、 直肠栓剂插入 法、 阴道栓剂插入法、 靶向给药、 吸入式、 灌胃式、 鼻饲式、 舌下给药、 滴药 法、 微针式给药、 连续给药系统和局部给药， 局部给药方式如贴皮制剂、 或植 入式连续给药释放系统， 其中贴皮制剂载体包括骨架材料如疏水的聚硅氧烷和 亲水的聚乙烯醇等， 控释膜材料如聚硅氧烷和乙烯-醋酸乙烯共聚物等， 压敏胶 如聚异丁烯、 聚硅氧烷和聚丙烯酸酯， 活性成分一般分散在压敏胶中； 其中植 入式连续给药释放系统所选用的高分子材料包括聚乳酸一乙醇酸共聚物、 聚乙 二醇聚乳酸共聚物、 聚乳酸 /聚己内酯、 聚 [碳酸（亚丁酯 -co- ε -己内酯）酯]、 聚丁内酯戊内酯、 聚二氧环己酮（PDS )、 聚- 3 - 羟基丁酸酯（PHB )、 聚左旋 乳酸 (PLLA)、 聚乙醇酸 (PGA)、 聚 ε -己内酯（PCL )、 聚己内酯 /聚乙交酯丙交酯 (PCL / PLGA)、 曱基丙烯酸羟乙酯（HEMA)。  The pharmaceutical preparation forms include: intravenous, intramuscular, peritoneal, subcutaneous, oral, rectal suppository insertion, vaginal suppository insertion, targeted administration, inhalation, gavage, nasal feeding, sublingual administration, drip Method, microneedle administration, continuous administration system and topical administration, topical administration such as a skin preparation, or an implantable continuous administration release system, wherein the skin preparation carrier comprises a skeleton material such as hydrophobic silicone Alkane and hydrophilic polyvinyl alcohol, etc., controlled release membrane materials such as polysiloxane and ethylene-vinyl acetate copolymer, pressure sensitive adhesives such as polyisobutylene, polysiloxane and polyacrylate, the active ingredients are generally dispersed in pressure In the sensitive gel; the polymer materials selected for the implantable continuous drug delivery system include polylactic acid-glycolic acid copolymer, polyethylene glycol polylactic acid copolymer, polylactic acid/polycaprolactone, poly [carbonic acid (Aden) Ester-co-ε-caprolactone ester], polybutyrolactone valerolactone, polydioxanone (PDS), poly-3-hydroxybutyrate (PHB), poly-L-lactic acid (PLLA), Polyglycolic acid (PGA), poly ε-hex Ester (PCL), polycaprolactone / polyglycolide-lactide (PCL / PLGA), Yue hydroxyethyl methacrylate (HEMA).
本发明的药物组合物一般制成单位制剂， 单位制剂含有活性成分的剂量根 据给药途径、 患者年龄体重和病情、 或被治疗疾病的严重程度而变化， 通常剂 量在 0. 001-100mg/kg/天， 优选为 0. 01- 50mg/kg/天, 更优选为 0. 05-5mg/kg/ 天。  001-100mg/kg The dosage of the pharmaceutical composition of the present invention is generally in the form of a unit preparation, the dosage of the active ingredient in the unit preparation according to the route of administration, the patient's age and weight, or the severity of the disease to be treated, usually at a dose of 0.001-100 mg / kg 05-5mg/公斤/天。 More preferably 0. 01-5 50mg / kg / day, more preferably 0. 05-5mg / kg / day.
本发明中上述的药物组合物的活性成分的制备包括以下特征或其之一。  The preparation of the active ingredient of the above pharmaceutical composition in the present invention includes the following features or one of them.
( 1 )在本发明化合物（ I ) 中的化合物：
Figure imgf000010_0001
(1) a compound in the compound (I) of the present invention:
Figure imgf000010_0001
可通过始化合物（ II )与相应的氨基酸、 含氮的有机碱、 任意取代的含氮杂 环在碱性无水条件下进行制备：  It can be prepared by starting compound (II) with the corresponding amino acid, nitrogen-containing organic base, optionally substituted nitrogen-containing heterocycle under basic anhydrous conditions:
Figure imgf000010_0002
Figure imgf000010_0002
其中氨基酸、 含氮的有机碱、 任意取代的含氮杂环为如上所定义的化合物。 溶剂可以是任何不干扰反应的常规溶剂， 例如酯 （例如乙酸乙酯）、 卤代烃 The amino acid, the nitrogen-containing organic base, and the optionally substituted nitrogen-containing heterocyclic ring are compounds as defined above. The solvent may be any conventional solvent that does not interfere with the reaction, such as an ester (e.g., ethyl acetate), a halogenated hydrocarbon.
(例如二氯曱烷）、 酰胺类 （例如二曱基曱酰胺）、 醚类 （例如四氢呋喃）、 腈类(eg, dichloromethane), amides (eg, dinonyl amide), ethers (eg, tetrahydrofuran), nitriles
(乙腈）等或其混合物。 (acetonitrile) or the like or a mixture thereof.
该反应可在常温至加热温度下进行，优选温度为 20°C至 150°C，特别优选 40 °C至 120°C。  The reaction can be carried out at a normal temperature to a heating temperature, preferably at a temperature of from 20 ° C to 150 ° C, particularly preferably from 40 ° C to 120 ° C.
反应的碱性条件可以是吡啶、 三乙胺等非质子性有机碱。  The basic condition of the reaction may be an aprotic organic base such as pyridine or triethylamine.
( 2 )在本发明化合物 （ II ) 中的化合物：  (2) a compound in the compound (II) of the present invention:
Figure imgf000010_0003
可通过始化合物（III ) 与氯化剂在无水条件下进行制备:
Figure imgf000010_0003
It can be prepared by starting compound (III) and chlorinating agent under anhydrous conditions:
Figure imgf000010_0004
说 明 书
Figure imgf000010_0004
Instruction manual
溶剂可以是任何不干扰反应的常规溶剂， 例如酯（例如乙酸乙酯）、 卤代烃 (例如二氯曱烷）、 酰胺类（例如二曱基甲酰胺）、 醚类 （例如四氢呋喃）、 腈类 (乙腈）等或其混合物。  The solvent may be any conventional solvent which does not interfere with the reaction, such as an ester (e.g., ethyl acetate), a halogenated hydrocarbon (e.g., dichloromethane), an amide (e.g., dimethylformamide), an ether (e.g., tetrahydrofuran), a nitrile. Class (acetonitrile), etc. or a mixture thereof.
该反应可在常温至加热温度下进行，优选温度为 20Ό至 15(TC ,特别优选 40 至 120°C。  The reaction can be carried out at a normal temperature to a heating temperature, preferably at a temperature of from 20 Torr to 15 (TC, particularly preferably from 40 to 120 °C.
氯化剂可以是氯化亚砜、 草酰氯。  The chlorinating agent may be thionyl chloride or oxalyl chloride.
本发明化合物用来制备治疗糖尿病、糖尿病肾病以及糖尿病引起的脂肪、蛋 白质代谢障碍， 并由此导致的心血管病变、 腎功能衰竭、 视网膜病变、 延迟伤 口愈合、 胰岛素抗性、 高血糖、 高胰岛素血症、 脂肪酸或甘油的升高的血水平、 高脂血症、 肥胖症、 高甘油三酯血症、 X综合症、 动脉粥样硬化、 高血压以及神 经系统障碍等糖尿病并发症的药物中的应用。  The compound of the invention is used for preparing diabetes, diabetic nephropathy and diabetes caused by fat, protein metabolism disorder, and thereby causing cardiovascular disease, renal failure, retinopathy, delayed wound healing, insulin resistance, hyperglycemia, high insulin Hyperglycemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, atherosclerosis, hypertension, and neurological disorders such as diabetes complications Applications.
本发明化合物可用来制备治疗代谢性疾病包括水和电解质代谢紊乱、 酸碱 平衡紊乱、 糖尿病、 乳酸性酸中毒、 低血糖症、 糖原累积病、 血脂蛋白紊乱、 卟啉病、 高氨基酸尿症、 黄瘤、 血色病、 粘多糖病、 果糖不耐受症、 半乳糖血 症、 其他嘌呤和嘧啶代谢疾病。  The compounds of the present invention can be used for the preparation of therapeutic metabolic diseases including water and electrolyte metabolism disorders, acid-base balance disorders, diabetes, lactic acidosis, hypoglycemia, glycogen accumulation diseases, dyslipoprotein disorders, porphyria diseases, high amino aciduria , xanthoma, hemochromatosis, mucopolysaccharidosis, fructose intolerance, galactosemia, other sputum and pyrimidine metabolic diseases.
本发明化合物用来制备治疗肿瘤、 骨质疏松、 黄疸、 免疫力下降等药物中 的应用。  The compounds of the present invention are useful for the preparation of a medicament for the treatment of tumors, osteoporosis, jaundice, and decreased immunity.
本发明化合物用来制备治疗肿瘤药物， 其中肿瘤包括急性粒细胞性白血病、 腎透明性癌、 乳腺癌、 淋巴细胞白血病、 前列腺癌、 肝癌、 淋巴瘤、 肺癌、 胃 癌、 食道癌、 结肠癌等多种肿瘤。  The compound of the invention is used for preparing a medicament for treating tumor, wherein the tumor comprises acute myeloid leukemia, renal transparent cancer, breast cancer, lymphocytic leukemia, prostate cancer, liver cancer, lymphoma, lung cancer, gastric cancer, esophageal cancer, colon cancer and the like. Tumors.
此外， 根据本发明， 提供一种治疗如在此前和此后定义的糖尿病和相关疾 病的方法， 其中治疗有效量的结构（I )的化合物与其它类型的抗糖尿病药物和 /或其它类型的治疗剂的药物组合物被给予需要治疗的病人。  Further, according to the present invention, there is provided a method of treating diabetes and related diseases as defined hereinbefore and hereinafter, wherein a therapeutically effective amount of a compound of structure (I) with other types of anti-diabetic agents and/or other types of therapeutic agents The pharmaceutical composition is administered to a patient in need of treatment.
本发明的化合物或药物组合物在制备治疗下列疾病的药物中的应用： Use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of:
增加高密度脂蛋白的水平、 增强记忆力、 改善学习能力、 衰老、 代谢类疾 病、 糖尿病、 糖尿病腎病、 糖尿病足病、 糖尿病视网膜病、 糖尿病性神经病、 糖尿病并发症、 延迟伤口愈合、 胰岛素抗性、 高血糖、 高胰岛素血症、 脂肪酸 或甘油的水平升高、 高脂血症、 肥胖症、 高甘油三酯血症、 动脉粥样硬化、 高 血压、 代谢综合症（X综合症）、 贫血（如镰刀细胞贫血）、 粉刺、 肿瘤、 风湿性 关节炎、 关节炎、 肠炎、 银屑病、 多发性硬化症、 神经变性紊乱、 充血性心力 说 明 书 Increases HDL levels, enhances memory, improves learning ability, aging, metabolic diseases, diabetes, diabetic nephropathy, diabetic foot disease, diabetic retinopathy, diabetic neuropathy, diabetic complications, delayed wound healing, insulin resistance, Hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis, hypertension, metabolic syndrome (X syndrome), anemia ( Such as sickle cell anemia), acne, tumor, rheumatoid arthritis, arthritis, enteritis, psoriasis, multiple sclerosis, neurodegenerative disorders, congestive heart Description
衰竭、 中风、 主动脉瓣狭窄、 腎炎、 肾衰竭、 痛风、 红斑狼疮、 IgA腎病、 阑尾 炎、 胰腺炎、 变态反应 （如鼻炎、 鼻窦炎）、 纤维症、 骨病、 骨质疏松、 心血管 疾病（如心律失常、心血管休克、心绞痛）、放疗及化疗并发症、肝病（如肝炎）、 胃肠道病症（如胃炎和胃肠炎）、 结膜炎、 斯耶格伦 ( Sjogren' s ) 综合症、 肺 病、 肾病（如多嚢肾病）、 皮炎、 HIV相关病症、 疟疾（如脑疟）、 强直性脊推炎、 麻风病、 免疫性疾病、 抑郁症、 老年痴呆症、 水肿、 溃疡、 精神分裂症、 精神 障碍性疾病、 过敏性休克、 尿崩症、 哮喘、 青光眼、 线粒体疾病、 帕金森、、 病 理老化的糖基化终端产物、 能量代谢异常、 基质金属蛋白酶病理性疾病。 Failure, stroke, aortic stenosis, nephritis, renal failure, gout, lupus erythematosus, IgA nephropathy, appendicitis, pancreatitis, allergies (eg rhinitis, sinusitis), fibrosis, bone disease, osteoporosis, cardiovascular disease (such as arrhythmia, cardiovascular shock, angina), radiotherapy and chemotherapy complications, liver disease (such as hepatitis), gastrointestinal disorders (such as gastritis and gastroenteritis), conjunctivitis, Sjogren's (Sjogren's) synthesis Disease, lung disease, kidney disease (such as polynephropathy), dermatitis, HIV-related illness, malaria (such as cerebral malaria), ankylosing spondylitis, leprosy, immune disease, depression, Alzheimer's disease, edema, ulcer, spirit Schizophrenia, Mental Disorders, Anaphylactic Shock, Diabetes Insipidation, Asthma, Glaucoma, Mitochondrial Diseases, Parkinson's, Glycosylation End Products of Pathological Aging, Abnormal Energy Metabolism, Pathogenic Diseases of Matrix Metalloproteinases
本发明所说的化合物 （I ) 的前药包括但不限于化合物 （I ) 的一种或多种 醇羟基和 /或酚羟基酰化物如乙酰、 丙酰、 丁酰产物及一种或多种醇羟基和 /或 酚羟基苄基、 甲基、 乙基产物等。  The prodrug of the compound (I) according to the present invention includes, but is not limited to, one or more alcoholic hydroxyl groups and/or phenolic hydroxyl acylates of the compound (I) such as acetyl, propionyl, butyryl product and one or more Alcoholic hydroxyl and/or phenolic hydroxybenzyl, methyl, ethyl, and the like.
本发明所说的病理老化的糖基化终端产物相关疾病包括但不限于糖尿病、 老年痴呆症、 动脉粥样硬化、 肾病、 骨关节炎、 骨质疏松、 衰老等疾病中的一 种或多种。  The pathologically aged glycosylation end product related diseases of the present invention include, but are not limited to, one or more of diabetes, Alzheimer's disease, atherosclerosis, kidney disease, osteoarthritis, osteoporosis, aging and the like. .
本发明所说的基质金属蛋白酶病理性疾病包括但不限于动脉粥样硬化、：中 枢神经系统炎症、 阿耳茨海默（氏）病、 哮喘、 皮肤老化、 类风湿性关节炎、 骨 关节炎、 骨质疏松、 脓毒性关节炎、 子宫内膜异位症、 角膜溃疡粘连、 骨病、 蛋白尿、 腹主动脉瘤、 退化性软骨损耗、 多动性硬化症、 髓鞘神经耗损、 肝纤 维化、 nephroglomerular 病、 胚膜破裂、 肠炎、 牙周病、 老年黄斑变性、 糖 尿病视网膜疾病、 视网膜玻璃体增生、 视网膜发育不良、 眼炎、 角膜溃疡、 S jogren' s 并发症、 目艮近视瘤、 肿瘤转移中的一种或多种。  The matrix metalloproteinase pathological diseases of the present invention include, but are not limited to, atherosclerosis,: central nervous system inflammation, Alzheimer's disease, asthma, skin aging, rheumatoid arthritis, osteoarthritis , osteoporosis, septic arthritis, endometriosis, corneal ulcer adhesion, bone disease, proteinuria, abdominal aortic aneurysm, degenerative cartilage loss, hyperactivity sclerosis, myelin nerve loss, liver fibrosis , nephroglomerular disease, rupture of the blastum, enteritis, periodontal disease, age-related macular degeneration, diabetic retinopathy, retinal vitreous hyperplasia, retinal dysplasia, ophthalmia, corneal ulcer, S jogren's complications, witness myopia, tumor One or more of the transitions.
本发明所说的线粒体疾病包括但不限于眼肌麻痹、 肌肉病变、 运动失调、 癫痫发作、 肌阵挛、 中风、 视神经病变、 感音神经性聋、 痴呆、 周围神经病、 肌张力障碍、 脊髓病变、 心肌病、 白内障、 色素性视网膜病变、 代谢性酸中毒、 恶心、 呕吐、 肝病、 肾病、 假性肠梗阻、 铁粒幼细胞贫血、 糖尿病、 胰腺外分 泌功能障碍和曱状旁腺功能低下症中的一种或多种。  The mitochondrial diseases of the present invention include, but are not limited to, ophthalmoplegia, muscle lesions, movement disorders, seizures, myoclonus, stroke, optic neuropathy, sensorineural hearing loss, dementia, peripheral neuropathy, dystonia, spinal cord lesions. , cardiomyopathy, cataract, pigmented retinopathy, metabolic acidosis, nausea, vomiting, liver disease, kidney disease, pseudo-intestinal obstruction, iron granulocyte anemia, diabetes, pancreatic exocrine dysfunction and hypoparathyroidism One or more.
本发明所说的能量代谢异常疾病包括但不限于创伤、 缺血及再灌注损伤导 致的疾病， 如各种急性化学物理因素所致的创伤、 中毒、 休克、 高原病、 放射 病、 尘肺、 电击伤、 暈动病、 急慢性心功能不全， 心律失常、 心脏传导异常、 人工心脏起搏、心血管介入疗法、瓣膜病、动脉粥样硬化、冠心病、（包括猝死）、 说 明 书 The abnormal energy metabolism diseases according to the present invention include, but are not limited to, diseases caused by trauma, ischemia and reperfusion injury, such as trauma, poisoning, shock, altitude sickness, radiation sickness, pneumoconiosis, electric shock caused by various acute chemical and physical factors. , motion sickness, acute and chronic cardiac insufficiency, arrhythmia, abnormal cardiac conduction, artificial cardiac pacing, cardiovascular interventional therapy, valvular disease, atherosclerosis, coronary heart disease, (including sudden death), Instruction manual
先天性心脏病、 高血压、 感染性心内膜炎、 肺源性心脏病、 心包炎、 心肌病、 周围血管疾病 （包括多发性大动脉炎、 雷诺综合症、 血栓闭塞性脉管炎、 闭塞 性动脉硬化等）、 心脏移植手术、 神经痛、 神经炎、 各种周围神经病、 各种脊髓 疾病、 急性脑血管疾病 （包括脑梗死、 脑栓塞、 脑出血、 蛛网膜下腔出血等）、 颅内肿瘤、 中枢神经系统感染（包括病毒和细菌性脑炎、 脑膜炎等）、 运动障碍 性疾病 （帕金森病、 舞蹈病、 肝豆状核变性、 肌张力障碍、 抽搐与振颤）发作 性疾病（包括癩痫、 偏头痛、 发作性睡病与猝倒症等）、 脱髓鞘性疾病（包括多 发性硬化症、 视神经脊髓炎、 脑白质营养不良）、 骨酪肌肉病 （包括肌营养不良 症、 强直性肌病、 重症肌无力、 炎症性肌病、 代谢性肌病、 周期性瘫痪）、 自主 神经疾病 （包括雷诺病、 红斑性肢痛、 间脑综合症）、 弥散性血管内凝血等； 胰 岛素抵抗及内分泌等因素引起的疾病， 如肥胖症、 各种原因所致低血糖、 胰岛 素抵抗综合症、 代谢综合症、 营 不良（营养不良性干瘦、 恶性营养不良、 继 发性蛋白盾能量营养不良）、 肠内营养、 肠外营养、 水电解质代谢紊乱、 酸碱平 衡紊乱、 糖尿病、 糖尿病心血管疾病、 糖尿病周围神经病变、 糖尿病视网膜病 变、 糖尿病肾病、 糖尿病足、 妊娠与糖尿病、 糖尿病并发感染、 糖尿病急性代 谢并发症、 乳酸性酸中毒、 各型糖原累积病、 血脂蛋白紊乱、 高氨基酸尿症、 黄瘤、 粘多糖病、 果糖不耐受症、 半乳糖血症、 其他嘌呤和嘧啶代谢疾病、.营 养与代谢障碍性皮肤病 （维生素缺乏、 肠病性肢端皮炎、 原发性皮肤淀粉样变、 皮肤卟啉病、 黄瘤病）、 糖尿病视网膜并发症、 生长激素缺乏性侏儒症、 成年人 腺垂体功能减退症、 腎上腺病、 曱状腺病、 曱状旁腺病、 卵巢病、 性早熟、 胰 岛内分泌肿瘤、 多发性内分泌腺病等疾病； 肿瘤等疾病， 如各种肿瘤、 癌症、 肉瘤、 血癌、 急慢性白细胞及粒细胞性白血病、 各种原因所致的贫血（包括骨 髓性贫血、 再生障碍性贫血、 镰状红细胞性贫血）、 淋巴组织细胞病、 自身免疫 性疾病、 原发性和继发性免疫缺陷病、 肺部肿瘤、 肺肉瘤、 消化性溃疡、 食道 癌、 胃癌、 胃肿瘤、 大肠癌、 肾脏肿瘤、 口腔肿瘤、 原发性和继发性肝癌、 胆 管肿瘤、 艾滋病、 各种皮肤癌、 骨髓肿瘤等疾病； 炎症、 严重感染和免疫反应 导致的疾病， 如感染性休克、 多脏器功能衰竭、 高温、 低温综合症、 感染性疾 病 （呼吸道感染、 哮喘、 严重急性呼吸综合症、 病毒性肝炎、 流行性腮腺炎、 流行性乙型脑炎、 ：狂犬病、 脊髓灰质炎、 麻疹、 风疹、 天花、 水痘、 单纯疱疹、 带状疱疹、 流行性出血热、 黄热病、 肠道病毒所致的各系统感染、 传染性单核 说 明 书 Congenital heart disease, hypertension, infective endocarditis, pulmonary heart disease, pericarditis, cardiomyopathy, peripheral vascular disease (including multiple arteritis, Raynaud's syndrome, thromboangiitis obliterans, occlusion) Arteriosclerosis, etc., heart transplant surgery, neuralgia, neuritis, various peripheral neuropathy, various spinal cord diseases, acute cerebrovascular diseases (including cerebral infarction, cerebral embolism, cerebral hemorrhage, subarachnoid hemorrhage, etc.), intracranial Tumors, central nervous system infections (including viral and bacterial encephalitis, meningitis, etc.), dyskinesias (Parkinson's disease, chorea, Wilson's disease, dystonia, convulsions and chattering) (including epilepsy, migraine, narcolepsy and cataplexy, etc.), demyelinating diseases (including multiple sclerosis, optic neuromyelitis, leukodystrophy), bone meal muscle disease (including muscular dystrophy) Symptoms, myotonic myopathy, myasthenia gravis, inflammatory myopathy, metabolic myopathy, periodic paralysis, autonomic diseases (including thunder Disease, erythema limb pain, diencephalon syndrome), disseminated intravascular coagulation, etc.; diseases caused by factors such as insulin resistance and endocrine, such as obesity, hypoglycemia caused by various causes, insulin resistance syndrome, metabolic syndrome Poor camp (nutrition thin, malignant malnutrition, secondary protein shield energy malnutrition), enteral nutrition, parenteral nutrition, water and electrolyte metabolism disorders, acid-base balance disorders, diabetes, diabetes cardiovascular disease, diabetes around Neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic foot, pregnancy and diabetes, diabetes complicated by infection, acute metabolic complications of diabetes, lactic acidosis, various types of glycogen accumulation disease, dyslipoprotein disorders, high amino aciduria, xanthoma , mucopolysaccharidosis, fructose intolerance, galactosemia, other metabolic diseases of sputum and pyrimidine, nutritional and metabolic disorders (vitamin deficiency, enteropathic dermatitis, primary skin amyloidosis, Skin porphyria, xanthomatosis), diabetic retinal complications, Growth hormone deficiency dwarfism, adult pituitary dysfunction, adrenal gland disease, verrucous adenopathy, parathyroid disease, ovarian disease, precocious puberty, islet endocrine tumor, multiple endocrine adenopathy, etc.; tumor and other diseases , such as various tumors, cancer, sarcoma, blood cancer, acute and chronic leukocyte and granulocyte leukemia, anemia caused by various causes (including myeloid anemia, aplastic anemia, sickle cell anemia), lymphoid cell disease , autoimmune diseases, primary and secondary immunodeficiency diseases, lung tumors, pulmonary sarcoma, peptic ulcer, esophageal cancer, gastric cancer, stomach cancer, colorectal cancer, kidney tumor, oral tumor, primary and secondary Diseases such as liver cancer, biliary tract cancer, AIDS, various skin cancers, bone marrow tumors; diseases caused by inflammation, serious infections and immune reactions, such as septic shock, multiple organ failure, high temperature, hypothermia syndrome, infectious diseases (Respiratory tract infection, asthma, severe acute respiratory syndrome, viral hepatitis, epidemic sputum Adenitis, epidemic encephalitis, rabies, poliomyelitis, measles, rubella, smallpox, chickenpox, herpes simplex, herpes zoster, epidemic hemorrhagic fever, yellow fever, various systemic infections caused by enterovirus Infectious single core Description
细胞增多症、 巨细胞病毒感染、 艾滋病、 立克次体病、 衣原体感染、 支原体感 染、 细菌性疾病 （包括结核性疾病厌氧菌感染、 败血症、 破伤风等）、 真菌性疾 病、 螺旋体病、 寄生虫病、 各种原因引起的感染性腹泻、 急性出血坏死性小肠 炎、 溃疡性结肠炎、 肠梗阻、 胃动力性和功能性疾病、 急性腹膜炎、 急性胰腺 炎、 各种原因引起肝硬化、 脂肪肝、 黄疸、 腹泻、 消化道出血、 反流性食管炎、 爆发性肝功能衰竭、 肝性脑病、 胆石病、 胆嚢炎、 急慢性腎功能衰竭、 血液净 化疗法、 急慢性呼吸功能不全、 慢性阻塞性肺疾病、 支气管哮喘、 支气管扩张、 各种原因引起的肺炎、 肺脓肿、 肺水肿、 肺栓塞、 肺静脉瘘、 肺结核、 先天性 肺发育不全、 阻塞性睡眠呼吸暂停综合症、 呼吸衰竭、 急性呼吸窘迫综合征、 急慢性肾炎、 肾病综合症、 微小病变性肾病、 膜性肾病、 局灶性肾小球硬化症、 系膜增殖性腎小球腎炎、 系膜毛细血管增生性肾炎、 继发性肾小球疾病、 遗传 性肾炎、 泌尿道感染、 间质性腎炎、 肾小管疾病、 肾石病、 牙周脓肿、 病毒性 皮肤疾病、 细菌性皮肤疾病、 真菌性皮肤病、 荨麻疹类皮肤病、 失聪、 美尼尔 氏综合症、 急慢性中耳炎、 结膜病、 角膜病、 白内障、 青光眼、 葡萄膜病、 视 网膜病、 视神经病、 急慢性扁桃体炎、 扁桃体脓肿、 骨关节炎、 代谢性骨病、 骨质疏松症、 痛风和高尿酸血症、 结节病、 淀粉样变性、 大骨节病、 色素性皮 肤病 （白癜风、 黄褐斑、 雀斑、 黑变病、 遗传性大疱性表皮松解症、 鱼鳞病、 毛周角化病、 家族性良性天疱疮、 日光性皮肤病、 冻疮、 放射性皮肤病、 痤疮、 脂溢性皮炎、 斑秃、 雄激素源性脱发、 风湿热、 系统性红斑嚢疮、 类风湿性关 节炎、 脊柱关节病、 多发性肌炎和皮肌炎、 硬皮病和系统性硬化症、 过敏性疾 病等； 各种原因所致线粒体功能障碍导致的退行性病变以及神经精神性疾病， 如衰老、 阿尔兹海默病、 各种原因导致的线粒体疾病， 如亨廷顿氏疾病、 帕金 森病（PD)、 肌萎缩性侧索硬化、 线粒体脑肌病伴乳酸中毒及中风样发作综合征 (MELAS)、 肌阵挛性癫痫伴破碎红纤维病（MERRF) 、 Leber 遗传性视神经病 (LH0N)、 线粒体心肌病、 肌病、 痴呆、 突发的不能控制的肌肉收缩（肌阵挛性的 癫痫）、精神疾病包括器质性精神障碍（痴呆综合症、谵妄综合症、 遗忘综合症、 艾滋病所致精神障碍）、 精神活性物质所致精神障碍（酒精中毒和酒精依赖、 药 物依赖）、 精神分裂症、 情感障碍、 神经症性障碍（恐怖症、 焦虑症、 强迫症、 神经衰弱、 癔症、 疑病症）、 进食障碍、 睡眠障碍、 广泛性发育障碍、 精神发育 迟滞、 多动障碍、 抽动障碍、 男性性功能障碍等疾病急慢性缺血、 创伤、 严重 说 明 书 Cytomegalox, cytomegalovirus infection, AIDS, rickettsial disease, chlamydia infection, mycoplasma infection, bacterial disease (including tuberculosis anaerobic infection, sepsis, tetanus, etc.), fungal diseases, spirochetes, Parasitic diseases, infectious diarrhea caused by various causes, acute hemorrhagic necrotizing enterocolitis, ulcerative colitis, intestinal obstruction, gastric motility and functional diseases, acute peritonitis, acute pancreatitis, cirrhosis caused by various causes, Fatty liver, jaundice, diarrhea, gastrointestinal bleeding, reflux esophagitis, fulminant hepatic failure, hepatic encephalopathy, cholelithiasis, cholestasis, acute and chronic renal failure, blood purification therapy, acute and chronic respiratory insufficiency, chronic Obstructive pulmonary disease, bronchial asthma, bronchiectasis, pneumonia caused by various causes, lung abscess, pulmonary edema, pulmonary embolism, pulmonary venous fistula, tuberculosis, congenital pulmonary hypoplasia, obstructive sleep apnea syndrome, respiratory failure, acute Respiratory distress syndrome, acute and chronic nephritis, nephropathy Syndrome, minimally pathological nephropathy, membranous nephropathy, focal glomerulosclerosis, mesangial proliferative glomerulonephritis, mesangial capillary proliferative nephritis, secondary glomerular disease, hereditary nephritis, Urinary tract infection, interstitial nephritis, renal tubular disease, nephrolithiasis, periodontal abscess, viral skin disease, bacterial skin disease, fungal skin disease, urticaria skin disease, deafness, Meniere's syndrome Acute and chronic otitis media, conjunctival disease, corneal disease, cataract, glaucoma, uveopathy, retinopathy, optic neuropathy, acute and chronic tonsillitis, tonsil abscess, osteoarthritis, metabolic bone disease, osteoporosis, gout and high Uric acidemia, sarcoidosis, amyloidosis, Kashin-Beck disease, pigmented skin disease (chamomile, chloasma, freckles, melanosis, hereditary bullous epidermolysis, ichthyosis, keratinization Disease, familial benign pemphigus, solar dermatosis, frostbite, radiation skin disease, acne, seborrheic dermatitis, alopecia areata, androgenetic alopecia, Damp heat, systemic rosacea, rheumatoid arthritis, spondyloarthropathy, polymyositis and dermatomyositis, scleroderma and systemic sclerosis, allergic diseases, etc.; mitochondrial dysfunction caused by various causes Degenerative diseases and neuropsychiatric diseases such as aging, Alzheimer's disease, mitochondrial diseases caused by various causes, such as Huntington's disease, Parkinson's disease (PD), amyotrophic lateral sclerosis, mitochondrial myopathy With lactic acidosis and stroke-like seizure syndrome (MELAS), myoclonic epilepsy with broken red fiber disease (MERRF), Leber hereditary optic neuropathy (LH0N), mitochondrial cardiomyopathy, myopathy, dementia, sudden uncontrollable Muscle contraction (myoclonic epilepsy), mental illness including organic mental disorder (dementia syndrome, sputum syndrome, amnesia syndrome, mental disorder caused by AIDS), psychoactive substance-induced mental disorder (alcoholism) And alcohol dependence, drug dependence), schizophrenia, affective disorder, neurosis (phobia, anxiety, obsessive-compulsive disorder, god Debilitating, snoring, suspected illness, eating disorders, sleep disorders, generalized developmental disorders, mental retardation, hyperactivity disorder, tic disorder, male sexual dysfunction, etc. Acute and chronic ischemia, trauma, severe Description
感染、 糖尿病和肿瘤等。 Infection, diabetes and tumors, etc.
本发明所说的糖尿病并发症包括但不限于糖尿病腎病、 糖尿病足病、 糖尿 病视网膜病、 糖尿病性神经病等与糖尿病相关的微血管疾病。  The diabetic complications referred to in the present invention include, but are not limited to, diabetic nephropathy, diabetic foot disease, diabetic retinopathy, diabetic neuropathy, and the like.
统称为 "X综合症" （也称做代谢综合症） 的病症、 疾病和疾患是以中心性 肥胖为核心， 合并血压、 血糖、 甘油三酯升高和 /或 HDL-C P条低， 是胰岛素抵 抗所致的糖， 脂代谢紊乱， 以合并出现多种代谢性疾病为临床特点的一组严重 影响健康的症候群。 详述于 Johannsson J. Cl in. Endocr inol. Metab.， 82 , 727-34 ( 1997 ) 中。  The diseases, diseases, and diseases collectively referred to as "X Syndrome" (also known as metabolic syndrome) are centered on obesity, combined with blood pressure, blood sugar, elevated triglycerides, and/or low HDL-C P. Insulin resistance caused by sugar, lipid metabolism disorder, combined with the emergence of a variety of metabolic diseases as a clinical feature of a group of severely affected health syndrome. Details are described in Johannsson J. Cl in. Endocr inol. Metab., 82, 727-34 (1997).
此处所用的术语 "其它类型的治疗剂" 包括治疗糖尿病并发症的药物、 抗 肥胖症药物、 抗高血压药物、 抗血小板药物、 抗动脉粥样硬化药物 /或降血脂药 物、 抗氧化剂、 肉碱（尤其是左旋肉碱）及其相关的盐、 肉碱衍生物（尤其是 左旋肉碱衍生物如乙酰肉碱、 丙酰肉碱）、 肉碱棕榈酰转移酶抑制剂、 肉碱辛酰 基转移酶抑制剂、 乙酰肉碱兴奋剂、 抗肿瘤药物、 抗痛风药物、 治疗骨质疏松 药物、 抗抑郁症药物、 治疗贫血药物、 治疗老年痴呆症药物、 抗炎药物、 免疫 性药物及根皮苷提取物中的一种或多种。  The term "other types of therapeutic agents" as used herein includes drugs for treating diabetic complications, anti-obesity drugs, antihypertensive drugs, antiplatelet drugs, antiatherogenic drugs or hypolipidemic drugs, antioxidants, meat. Alkali (especially L-carnitine) and its related salts, carnitine derivatives (especially L-carnitine derivatives such as acetylcarnitine, propionylcarnitine), carnitine palmitoyltransferase inhibitors, carnitine octanoyl Transferase inhibitors, acetylcarnitine stimulants, antitumor drugs, anti-gout drugs, osteoporosis drugs, antidepressants, anemia drugs, Alzheimer's drugs, anti-inflammatory drugs, immunological drugs and root bark One or more of the glycoside extracts.
本发明药物组合物中作为第一活性成分的治疗有效量的结构 （I )的化合 物和作为第二活性成分的一种或多种其它类型的治疗剂的比例为 1 : 0. 0001-1： 0. 01。  The ratio of the therapeutically effective amount of the compound of the structure (I) as the first active ingredient in the pharmaceutical composition of the present invention to one or more other types of therapeutic agents as the second active ingredient is 1: 0001-1: 0. 01.
本发明中的药物组合物， 其中活性成分占组合物重量的 0. 1-99. 9%。  9%。 The composition of the composition of the composition 0. 1-99. 9%.
本发明中的药物组合物， 最适宜的组合物是制成单位制剂的， 单位制剂通 常含有活性成分的剂量根据给药途径， 患者年龄体重和病情， 或被治疗疾病的 严重程度而变化。 成人日用药剂量按每公斤体重用量是大鼠的 1/6，是小鼠的 1八 2计算得到 （药理试验中动物间和动物与人体间的等效剂量换算， 中国临床 药理学与治疗学， 2004 Sep ; 9 (9) : 1069-1072 )。 通常对于口服给药， 剂量在 0. 05- 100mg/kg/天， 优选为 0. 1- 50mg/kg/天， 更优选为 0. 5- 50mg/kg/天。 对于 胃肠道给药， 剂量在 0. 005- 100mg/kg/天， 优选为 0. 01- 50mg/kg/天， 更优选为 0. 05-5mg/kg/天。 In the pharmaceutical composition of the present invention, the most suitable composition is a unit preparation, and the unit preparation usually contains the active ingredient in a dose depending on the route of administration, the age and condition of the patient, or the severity of the disease to be treated. The dosage of adult daily dose is 1/6 of that of rats per kilogram of body weight, which is calculated from 1-8 of mice. (Equivalent dose conversion between animals and animals and human body in pharmacological test, Chinese clinical pharmacology and therapeutics , 2004 Sep ; 9 (9) : 1069-1072 ). 5-50mg/公斤/天。 The dosage is usually 0. 05-100mg / kg / day, preferably 0. 1- 50mg / kg / day, more preferably 0. 5- 50mg / kg / day. 05-5mg/公斤/天。 For gastrointestinal administration, the dose is 0. 005-100mg / k g / day, preferably 0. 01- 50mg / kg / day, more preferably 0. 05-5mg / kg / day.
此处所用的术语 "其它类型的治疗剂"指一种或一种以上的抗糖尿病药物、 一种或一种以上的抗肥胖症药物、 抗高血压药物、 抗血小板药物、 抗动脉粥样 硬化药物和 /或一种或一种以上降血脂药物 （包括抗动脉粥样硬化药物）、 抗炎 说 明 书 The term "other types of therapeutic agents" as used herein refers to one or more anti-diabetic agents, one or more anti-obesity drugs, antihypertensive drugs, anti-platelet drugs, anti-atherosclerosis. Drugs and / or one or more hypolipidemic drugs (including anti-atherosclerotic drugs), anti-inflammatory Description
药物、 抗肿瘤药物。 Drugs, anti-tumor drugs.
可以任选式（I )化合物联合给予其它类型的抗糖尿病药物中 1、 2、 3种 或更多种抗糖尿病药物或抗高血糖药物， 包括胰岛素、 促分泌素或胰岛素增敏 剂及其它抗糖尿病药物。 优选包括双缩胍类、磺酰脲类、 葡糖苷酶抑制剂、 PPAR γ激动剂如噻唑烷二酮、 aP2抑制剂、 PPAR α I γ双重激动剂、二肽基肽酶 IV( DP4 ) 抑制剂和 /或氯茴苯酸， 以及胰岛素、 胰高血糖素 -样肽 -1 ( GLP- 1 )、 PTP1B抑制 剂、 糖原磷酸化酶抑制剂和 /或葡糖 -6-磷酸酶抑制剂。  The compound of formula (I) may optionally be administered in combination with 1, 2, 3 or more anti-diabetic or anti-hyperglycemic agents, including insulin, secretagogue or insulin sensitizer, and other anti-diabetic agents in other types of anti-diabetic drugs. Diabetes medication. Preferably, it includes a bifloconazole, a sulfonylurea, a glucosidase inhibitor, a PPAR gamma agonist such as a thiazolidinedione, an aP2 inhibitor, a PPAR α I γ dual agonist, and a dipeptidyl peptidase IV (DP4 ) inhibition. And/or meglitinide, and insulin, glucagon-like peptide-1 (GLP-1), PTP1B inhibitor, glycogen phosphorylase inhibitor and/or glucose-6-phosphatase inhibitor .
可以任选用于与式（I )化合物联合给予的其它类型的治疗剂包括抗肥胖 药物、 抗高血压药物、 抗血小板药物、 抗动脉粥样硬化药物和 /或降血酯药物。  Other types of therapeutic agents that may optionally be administered in combination with a compound of formula (I) include anti-obesity agents, anti-hypertensive drugs, anti-platelet drugs, anti-atherosclerotic drugs, and/or hypocholesterolemic drugs.
结构（I )化合物与 1、 2、 3或更多种其它抗糖尿病药物联合使用产生的抗 高血糖效果大于单独使用这些药物的每一种可能获得的效果， 并且大于这些药 物产生的联合的加和的抗高血糖效果。  The anti-hyperglycemic effect of the compound of structure (I) in combination with 1, 2, 3 or more other anti-diabetic drugs is greater than that which may be obtained by using each of these drugs alone, and is greater than the combined increase produced by these drugs. And anti-hyperglycemic effect.
其它的抗糖尿病药物可以是口服降高血糖药物， 优选双胍类如二曱双胍或 苯乙双胍及其盐， 最优选二甲双胍盐酸盐。  Other antidiabetic agents may be oral hypoglycemic agents, preferably biguanides such as diterpene or phenformin and its salts, most preferably metformin hydrochloride.
其它口服的抗糖尿病药物也可优选磺酰脲如格列本脲、 格列吡嗪、 格列美 脲、 格列齐特、 氯磺丙脲等， 最优选格列本脲和格列吡嗪。  Other oral antidiabetic agents may also be preferably sulfonylureas such as glibenclamide, glipizide, glimepiride, gliclazide, chlorpropamide, etc., most preferably glibenclamide and glipizide. .
其它口服的抗糖尿病药物还可优选葡糖苷酶抑制剂如阿卡波糖、 伏格列波 糖、 米格列醇。  Other oral anti-diabetic agents may also preferably be glucosidase inhibitors such as acarbose, voglibose, miglitol.
其它口服的抗糖尿病药物还可优选噻唑烷二酮如罗格列酮、 吡格列酮、 恩 格列酮、 达格列酮等， 最优选罗格列酮和吡格列酮。  Other oral antidiabetic agents may also be preferably thiazolidinediones such as rosiglitazone, pioglitazone, engglitazone, daglitazone, etc., most preferably rosiglitazone and pioglitazone.
其它口服的抗糖尿病药物还可优选高血糖素-样肽- 1 ( GLP-1 ) 如 GLP-1 ( 1-36 )酰胺、 GLP- 1 ( 7-36 )酰胺、 GLP- 1 ( 1-36 )酰胺、 GLP- 1 ( 7-37 )酰胺、 GLP-K S3-20-32 )、 GLP- 1 ( S3- 11- 14 )、 GLP- 1 ( S6- 14 )、 GLP- 1 ( S8 )(如在 Habener 的美国专利 5614492， 中国科学院上海药物研究所的中国公开专利 1884278 ), 以及 AC2993 ( Amylen )和 LY-315902 ( Li l ly )0 Other oral antidiabetic agents may also preferably be glucagon-like peptide-1 (GLP-1) such as GLP-1 (1-36) amide, GLP-1 (7-36) amide, GLP-1 (1-36). ) amide, GLP-1 (7-37) amide, GLP-K S3-20-32), GLP-1 (S3- 11-14), GLP-1 (S6-14), GLP-1 (S8) ( For example, in US Patent 5,941,492 of Hamener, Chinese Open Patent 1884278 of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and AC2993 (Amylen) and LY-315902 (Li lly) 0
可任选的本发明式（I )化合物联合使用的氯茴苯酸优选瑞格列奈、 那格列 奈。  Optionally, the meglitinic acid used in combination with the compound of the formula (I) of the present invention is preferably repaglinide or nateglinide.
其它 口月良的抗糖尿病药物也可以是 PPAR oc / γ 双重激动剂如 AR-H039242 (As tra/Zeneca) 、 GW-409544 (G 1 axo-We 11 come) 、 KRP297 ( yor in Merck)以及由 Murakami 等在 "充当过氧化物酶体增殖-激活的 α受体（PPRA ot ) 说 明 书 Other anti-diabetic drugs may also be PPAR oc / γ dual agonists such as AR-H039242 (As tra/Zeneca), GW-409544 (G 1 axo-We 11 come), KRP297 (yor in Merck), and Murakami et al. "acting as a peroxisome proliferator-activated alpha receptor (PPRA ot) Instruction manual
和 PPRA y的共配体 ( col igand )的新的胰岛素增敏剂。 对 PPRA a在 Zucker肥 胖大鼠的肝中激活异常脂质代谢的作用"， Diabetes, 47, 1841-1847 (1998)。 A new insulin sensitizer with a co-ligand (col igand ) of PPRA y. The role of PPRA a in activating abnormal lipid metabolism in the liver of Zucker fattened rats", Diabetes, 47, 1841-1847 (1998).
其它口服的抗糖尿病药物还可以是 DP4 抑制剂， 如专利 WO99/38501、 W099/46272, 應 9/67279、 由 Hughes等, Biochemi s try, 38 (36)， 11597- 11603， 1999年公开的 NVP-DPP728A ( Novart i s )等。  Other oral anti-diabetic agents may also be DP4 inhibitors, such as patents WO 99/38501, W099/46272, 9/67279, by Hughes et al, Biochemi s try, 38 (36), 11597-11603, NVP published in 1999. -DPP728A ( Novart is ) and so on.
式（ I )化合物可以与氯茴苯酸、 PPRA y激动剂、 PPAR ct / γ双重激动剂、 DP4抑制剂的重量比约 0. 01： 1至约 100: 1 , 优选在约 0. 2： 1至约 10: 1。  2: The ratio of the compound of the formula (I) to the megdophenone, the PPRA y agonist, the PPAR ct / γ dual agonist, and the DP4 inhibitor is from about 0.01:1 to about 100:1, preferably at about 0.2. 1 to about 10: 1.
可任选与本发明的式（ I )化合物联合使用的降血脂药或降脂剂包括 1、 2、 3种或更多贝丁酸类、 HMG-CoA还原酶抑制剂、 角鲨烯合成酶抑制剂、 烟酸 4汙生 物、 LDL受体活性的上调物、 脂氧化酶抑制剂、 ACAT抑制剂、 胆固醇吸收抑制 剂、 回肠钠 +/胆酸协同转运蛋白抑制剂、 胆酸螯合剂。  A hypolipidemic or lipid lowering agent which may optionally be used in combination with a compound of formula (I) of the present invention includes 1, 2, 3 or more benbutyric acids, HMG-CoA reductase inhibitors, squalene synthetase Inhibitors, niacin 4 staining organisms, upregulation of LDL receptor activity, lipoxygenase inhibitors, ACAT inhibitors, cholesterol absorption inhibitors, ileal sodium +/cholic acid cotransporter inhibitors, bile acid sequestrants.
降血脂药物可以是贝丁酸类， 包括但不限于氯贝丁酯、 苯扎贝特、 非诺贝 特、 吉非贝齐、 环丙贝特、 克利贝特、 普罗布考。  The hypolipidemic drug may be benbutin, including but not limited to, clofibrate, bezafibrate, fenofibrate, gemfibrozil, ciprofibrate, clebate, probucol.
降血脂药物可以是 HMG-CoA还原酶抑制剂， 包括但不限于美伐他汀、 洛伐 他汀、 普伐他汀、 辛伐他汀、 氟伐他汀、 阿托伐他汀等。  The hypolipidemic drug can be an HMG-CoA reductase inhibitor including, but not limited to, mevastatin, lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, and the like.
降血脂药物可以是角鲨烯合成酶抑制剂， 包括但不限于美国专利 5712396 中的 ot -膦酰基-碌酸酯、 由 Bi l ler等， L Med. Chem.， 1988，第 31卷， 10期， 1869-1871公开的化合物。  The hypolipidemic drug may be a squalene synthetase inhibitor, including, but not limited to, the ot-phosphono-lipidate of U.S. Patent No. 5,712,396, by Biler et al, L Med. Chem., 1988, Vol. 31, 10 The compound disclosed in 1869-1871.
其它降血酯药物包括但不限于胆酸鏊合剂如考来烯胺、 考来替泊， 胆固醇 吸收抑制剂如依替米贝， 烟酸类如烟酸、 阿昔莫司及其它药物如普罗布考、 泛 硫乙胺等。  Other hypocholesterolemic drugs include, but are not limited to, cholic acid chelating agents such as cholestyramine, colestipol, cholesterol absorption inhibitors such as ezetimibe, niacins such as niacin, acipimox, and other drugs such as pro Clocoan, pantethine, etc.
可任选与本发明的式（I )化合物联合使用的抗肥胖药物包括 1、 2、 3种或 更多 P 3腎上腺素能激动剂、 脂酶抑制剂、 血清素 （和多巴胺）重摄取抑制剂、 甲状腺 P受体药物、 减食欲剂、 NPY拮抗剂、 MC4激动剂。  Anti-obesity agents which may optionally be used in combination with a compound of formula (I) of the invention include 1, 2, 3 or more P 3 adrenergic agonists, lipase inhibitors, serotonin (and dopamine) reuptake inhibition Agent, thyroid P receptor drug, anorectic agent, NPY antagonist, MC4 agonist.
抗肥胖药物可以是 β 3 肾上腺素能激动剂 , 包括但不限于 AJ9677 (Takeda/Da ini pon) , L750355 (Merck)、 以及 US5541204、 US5770615、 US5491134, US5776983和 US5488064中的 β 3腎上腺素能激动剂。  The anti-obesity agent may be a β 3 adrenergic agonist, including but not limited to AJ9677 (Takeda/Da ini pon), L750355 (Merck), and US 3,541,204, US 5,770, 615, US 5,491, 134, US 5,776, 983 and US 5, 486, 064. .
抗肥胖药物可以是脂酶抑制剂， 包括但不限于奥利司他、 Al izyme。  The anti-obesity agent can be a lipase inhibitor including, but not limited to, orlistat, Al izyme.
抗肥胖药物可以是血清素 （和多巴胺） 重摄取抑制剂包括但不限于西布曲 明、 托 p比酯、 axokine。 说 明 书 The anti-obesity agent may be a serotonin (and dopamine) reuptake inhibitor including, but not limited to, sibutramine, tol-p-ester, axokine. Instruction manual
其它抗肥胖药包括但不限于减食欲剂如右苯丙胺、 芬特明、 苯丙醇胺、 马 吲哚。  Other anti-obesity agents include, but are not limited to, anorectic agents such as dextroamphetamine, phentermine, phenylpropanolamine, and horseshoe.
可任选与本发明的式（I )化合物联合使用的抗血小板药物包括阿昔单抗、 噻氯匹定、 双密达莫、 阿司匹林、 阿那格雷、 t i rof iban、 ept if ibat ide, 氯吡 格雷。  Antiplatelet agents which may optionally be used in combination with a compound of formula (I) of the invention include abciximab, ticlopidine, dimetamol, aspirin, anagrelide, ti rof iban, ept if ibat ide, chlorine Pigre.
可任选与本发明的式（I )化合物联合使用的抗高血压药物包括 ACE抑制剂 如依那普利、 卡托普利、 喹那普利、 贝那普利、 培哚普利， 钙拮抗剂如氨氯地 平、 硝苯地平、 尼群地平、 尼莫地平、 地尔硫卓、 维拉帕米， α -阻断剂包括特 拉唑嗪、 多沙峻嗪、 哌唑嗪， 利尿剂包括氢氯噻嗪、 呋塞咪、 螺内酯、 吲达帕 胺， 中枢系统作用剂包括利血平、 可乐定、 胍法辛， 血管紧张素 II拮抗剂包括 氯沙坦、 缬沙坦、 替米沙坦， β -阻断剂包括米托洛尔、 普萘洛尔、 阿替洛尔、 卡维地洛、 索他洛尔， 血管胎酶抑制剂包括 omapatr i lat、 gemopatr i lat。  Antihypertensive agents which may optionally be used in combination with a compound of formula (I) of the invention include ACE inhibitors such as enalapril, captopril, quinapril, benazepril, perindopril, calcium Antagonists such as amlodipine, nifedipine, nitrendipine, nimodipine, diltiazem, verapamil, alpha-blockers including terazosin, doxapazine, prazosin, diuretics including hydrochlorothiazide , furosemide, spironolactone, indapamide, central systemic agents including reserpine, clonidine, guanfacine, angiotensin II antagonists including losartan, valsartan, telmisartan, beta - Blockers include mitoxolol, propranolol, atenolol, carvedilol, sotalol, and vasopressin inhibitors including omapatr i lat, gemopatr i lat.
可任选与本发明的式（ I )化合物联合使用的抗炎药物包括但不限于阿司匹 林、 保泰松、 蔡普生、 芬布芬、 布洛芬、 吲哚美辛、 萘丁酮、 二氟尼柳、 对乙 酰氨基酚、 贝诺酯、 水杨酸、 依托芬那酯、 依托度酸、 酮洛芬、 双氯芬酸、 青 霉胺、 塞来昔布、 尼美舒利、 美洛昔康、 洛索洛芬、 来氟米特、 非普拉宗、 苯 并氧酰胺、 奥沙普嗪、 舒林酸、 安替比林、 金诺芬、 吡罗昔康、 咪唑酯、 托美 汀、 曱氯芬那酸、 阿西美辛。  Anti-inflammatory drugs which may optionally be used in combination with a compound of formula (I) of the present invention include, but are not limited to, aspirin, phenylbutazone, cilampan, fenbufen, ibuprofen, indomethacin, nabumetone, diflunis Willow, acetaminophen, benol ester, salicylic acid, etofenamate, etodolac, ketoprofen, diclofenac, penicillamine, celecoxib, nimesulide, meloxicam, lo Soprofen, leflunomide, non-Prazin, benzoxamide, oxaprozine, sulindac, antipyrine, auranofin, piroxicam, imidazoxil, tometetine, chlorpheniramine That acid, asimin.
可任选与本发明的式（ I )化合物联合使用的抗肿瘤药物包括但不限于烷化 剂、 抗肿瘤抗生素、 二氢叶酸还原酶抑制剂、 嘌呤类、 嘧啶类、 拓朴异构酶抑 制剂、 肿瘤新生血管生成抑制剂、 天然药物等。  Antitumor agents which may optionally be used in combination with a compound of formula (I) of the invention include, but are not limited to, alkylating agents, antitumor antibiotics, dihydrofolate reductase inhibitors, terpenoids, pyrimidines, topoisomerase inhibitors, Tumor neovascularization inhibitors, natural drugs, and the like.
烷化剂包括但不限于环磷酰胺、 氮芥、 噻替派、 萘达铂、 奥沙利铂、 美法 仑、 氮甲、 卡莫司汀、 洛莫司汀、 司莫司汀、 尼莫司汀、 雷莫司汀、 特莫唑胺、 米托唑酶胺、 特洛西酮、 白消胺。  Alkylating agents include, but are not limited to, cyclophosphamide, nitrogen mustard, thiotepa, nadropaplatin, oxaliplatin, melphalan, carbamazepine, carmustine, lomustine, semustine, nitrite Mustine, ramustine, temozolomide, mitoxazole amine, troxidone, mesamine.
抗肿瘤抗生素包括但不限于阿霉素、 丝裂霉素、 争光霉素、 正定霉素、 表 柔比星、 丝裂霉素、 柔红霉素、 阿克拉霉素、 洋红霉素、 米托蒽醌、 依达柔比 星、 吡柔比星、 戊柔吡星。  Antitumor antibiotics include, but are not limited to, doxorubicin, mitomycin, bleomycin, gentamicin, epirubicin, mitomycin, daunorubicin, aclarithromycin, erythromycin, mito蒽醌, edarubicin, pirarubicin, pentopirin.
二氢叶酸还原酶抑制剂包括但不限于甲氨碟呤、 六曱蜜胺。  Dihydrofolate reductase inhibitors include, but are not limited to, methotrexate, hexamidine melamine.
嘌呤类药物包括但不限于包括但不限于巯嘌呤。  Terpenoids include, but are not limited to, including but not limited to sputum.
嘧啶类药物包括但不限于氟尿嘧啶、 卡莫氟。 说 明 书 Pyrimidine drugs include, but are not limited to, fluorouracil, carmofur. Instruction manual
抗肿瘤天然药物包括但不限于喜树碱、 长春新碱、 紫杉醇、 秋水仙碱、 绿 舒筋、 复方醋酸棉酚、 康莱特（薏苡仁提取物）、 榄香烯（莪术油提取物）、 三尖 杉酯碱、 猪苓多糖、 茯苓多糖、 香菇多糖、 人参多糖、 银耳多糖、 云芝多糖、 地黄多糖、 枸杞多糖、 猕猴桃多糖、 黄芪多糖、 当归多糖、 绞股蓝多糖、 竹荪 多糖、 刺五加多糖、 牛膝多糖等。  Anti-tumor natural drugs include, but are not limited to, camptothecin, vincristine, paclitaxel, colchicine, green gluten, compound acetate gossypol, Kanglaite (barley extract), elemene (arthritis oil extract), Cedar gum base, Polyporus polysaccharide, Lycium barbarum polysaccharide, Lentinus edodes polysaccharide, Ginseng polysaccharide, Tremella polysaccharide, Yunzhi polysaccharide, Rehmannia polysaccharide, Lycium barbarum polysaccharide, Kiwi polysaccharide, Astragalus polysaccharide, Angelica polysaccharide, Gynostemma pentaphyllum polysaccharide, Radix polysaccharide, Prickly ash Add polysaccharides, Achyranthes polysaccharides, etc.
拓朴异构酶抑制剂包括但不限于伊立替康、 拓朴替康、 芦比替坎。  Topoisomerase inhibitors include, but are not limited to, irinotecan, topotecan, and rebitantan.
肿瘤新生血管生成抑制剂包括但不限于 angios tat in、 endos tat in,舒拉明、 沙利度胺、 夫马洁林、 单克隆抗体、 巴马司他、 马立马司他、 geni s te in。  Tumor neovascularization inhibitors include, but are not limited to, angios tat in, endos tat in, suramin, thalidomide, fumagillin, monoclonal antibodies, bamastat, marimastat, geni s te in.
可任选与本发明的 ( I )化合物联合使用的免疫抑制药物包括但不限于泼 尼松、 强的松龙、 地塞米松、 氢化可的松、 达那唑、 环磷酰胺、 环孢菌素 、 霉 酚酸酯、 来氟米特、 雷公藤， 硫唑嘌呤、 肝素-华法林、 双密达莫、 他克莫司、 西罗莫司、 康乐霉素（、 咪唑立宾、 免疫球蛋白、 二十碳五烯酸、 二十二碳六烯 酸（DHA )、 益赛普、 达昔单抗、 利妥昔单抗、 英夫利昔单抗、 干扰素。  Immunosuppressive drugs which may optionally be used in combination with the compounds of the invention (I) include, but are not limited to, prednisone, prednisolone, dexamethasone, hydrocortisone, danazol, cyclophosphamide, cyclosporine , mycophenolate mofetil, leflunomide, tripterygium, azathioprine, heparin-warfarin, dimetamol, tacrolimus, sirolimus, kalemycin (imidazole, immunization) Globulin, eicosapentaenoic acid, docosahexaenoic acid (DHA), escital, daximab, rituximab, infliximab, interferon.
可任选与本发明的式（ I )化合物联合使用的痛风药物包括但不限于秋水仙 碱、 消炎痛、 布洛芬、 萘普生、 保泰松、 扶他林、 炎痛喜康、 西乐花、 美络昔 康、 别嘌呤醇、 枸橼酸钟、 碳酸氢钠、 丙磺舒、 苯溴马隆、 硫氧唑酮、 磺酰吡 唑、 痛风利仙等。  Gout drugs which may optionally be used in combination with the compounds of formula (I) of the present invention include, but are not limited to, colchicine, indomethacin, ibuprofen, naproxen, phenylbutazone, fustatin, inflammatory pain, xicola, Meloxicam, allopurinol, citric acid clock, sodium bicarbonate, probenecid, benzbromarone, thiazolone, sulfonylpyrazole, gout, etc.
本发明的式（ I )化合物联合使用的抗抑郁症药物为三环类、 单胺氧化酶抑 制剂、 5-羟色胺再摄取抑制剂、 乙酰胆碱再摄取抑制剂等。  The antidepressant drugs used in combination with the compound of the formula (I) of the present invention are tricyclics, monoamine oxidase inhibitors, serotonin reuptake inhibitors, acetylcholine reuptake inhibitors and the like.
抗抑郁症药物可以是三环类药物， 包括但不限于丙咪。秦、 氯丙咪嗪、 阿米 替林、 多虑平、 去曱丙咪嗪、 去曱替林。  The antidepressant drug can be a tricyclic drug, including but not limited to a propyl. Qin, clomipramine, amitriptyline, doxepin, imipramine, deferiline.
抗抑郁症药物可以是四环类药物， 包括但不限于米安色林、 马普替林。 抗抑郁症药物可以是单胺氧化酶抑制剂， 包括但不限于苯乙肼、 超苯环丙 胺、 吗氯贝胺。  Antidepressant drugs can be tetracyclic drugs including, but not limited to, mianserin, maprotiline. The antidepressant drug can be a monoamine oxidase inhibitor including, but not limited to, phenethyl hydrazine, benzophenone, and moclobemide.
抗抑郁症药物可以是选择性 5-HT再摄取抑制剂， 包括但不限于氟西汀、 帕 罗西定、 舍曲林、 西酞普兰、 伏氟沙明。  The antidepressant may be a selective 5-HT reuptake inhibitor including, but not limited to, fluoxetine, paroxetine, sertraline, citalopram, and flufen samine.
抗抑郁症药物可以是 5-HT和 NE再摄取抑制剂， 包括但不限于文拉法辛、 万拉法新。  Antidepressant drugs may be 5-HT and NE reuptake inhibitors including, but not limited to, venlafaxine, venlafaxine.
抗抑郁症药物还可以是其它药物， 包括但不限于瑞波西汀、 布普品、 曲唑 酮、 奈法唑酮、 米它扎平、 路优泰、 安非拉酮。 说 明 书 The antidepressant drug may also be other drugs including, but not limited to, reboxetine, buppe, trazodone, nefazodone, mtitapine, luteapine, amfepramone. Instruction manual
本发明的式（ I )化合物联合使用的治疗痴呆症药物包括但不限于四氢氨基 吖啶（他克林）、 四羟氨基吖啶、 毒扁豆碱、 庚烯毒扁豆碱、 加兰他敏、 美曲磷 脂（敌百虫）、 盐酸多奈哌齐、 石杉碱曱、 重酒石酸卡拉巴汀、 占诺美林、 利培 酮、 吗氯贝胺、 拉扎贝胺、 沙贝鲁唑、 依斯的明、 司来吉兰、 丙戊茶碱、 新曲 非思、 安帕来斯、 奈非西坦、 利诺吡啶、 孟替瑞林、 氮替瑞林、 奥氮平、 ζτ-ι、 普拉西坦、 二苯美仑、 依昔苯酮、 茚洛嗪、 甲氯芬酯、 吡拉西坦、 吡硫醇、 乙 酰谷酰胺、 克脑迷、 胞磷胆碱、 茴拉西坦、 尼莫地平、 乙酰 -L-肉毒碱、 L-肉毒 碱、 尼麦角林、 利伐司替明、 Sabcomedine hydrochlor icde、、 Mi lamel ine ^ Talsacl idine。  The medicament for treating dementia used in combination with the compound of the formula (I) of the present invention includes, but is not limited to, tetrahydroaminoacridine (tacrine), tetrahydroxyaminoacridine, physostigmine, heptene lenola, galantamine , koji lecithin (trichlorfon), donepezil hydrochloride, huperzine bismuth, carbaplatin heavy tartaric acid, nymeline, risperidone, moclobemide, lazabe, salbezole, ises Ming, Selegiline, Propofol, New Qufusi, Apelis, Nefiracetam, Linolididine, Montesporin, Nitrorelin, Olanzapine, ζτ-ι, Pu Racacetin, diphenylmethane, epoxone, oxazolidine, meclofenoxate, piracetam, pyrithione, acetyl glutamine, gram brain, citicoline, aniracetam, Nimodipine, acetyl-L-carnitine, L-carnitine, ergoline, rivastigmine, Sabcomedine hydrochlor icde, Mi lamel ine ^ Talsaclidine.
本发明的式（ I )化合物联合使用的治疗骨质疏松药物为骨吸收抑制剂、 骨 形成促进剂、 骨矿化物质及其它治疗骨质疏松药物。  The osteoporosis drugs used in combination with the compound of the formula (I) of the present invention are bone resorption inhibitors, bone formation accelerating agents, bone mineralizing substances and other osteoporosis drugs.
骨吸收抑制剂包括但不限于双膦酸盐、 雌激素、 降 4弓素、 孕激素、 异黄酮、 锶盐。  Bone resorption inhibitors include, but are not limited to, bisphosphonates, estrogens, cytokines, progestins, isoflavones, guanidinium salts.
双膦酸盐包括但不限于依替膦酸盐、 氯膦酸盐、 替鲁膦酸盐、 帕米膦酸盐、 阿仑膦酸盐、 利塞膦酸盐、 incadronate、 唑来膦酸盐、 dt idronate、 伊班膦酸 盐。  Bisphosphonates include, but are not limited to, etidronate, clodronate, tiludronate, pamidronate, alendronate, risedronate, incadronate, zoledronate , dt idronate, ibandronate.
雌激素包括但不限于雷洛昔芬、 克洛米芬 （舒筋芬）、 他莫昔芬、 droloxifene, noforxidine, 艾多昔芬、 巴多昔芬、 拉索昔芬、 替勃龙、 尼尔 雌醇。  Estrogens include, but are not limited to, raloxifene, clomiphene citrate, tamoxifen, droloxifene, noforxidine, idoxifene, bazedoxifene, lasofoxifene, tibolone, nis Estriol.
降 素包括但不限于密钙息、 益钙宁、 salcatonin。  Degradants include, but are not limited to, dense calcium, sulphate, and salcatonin.
骨形成促进剂包括但不限于氟化物（特乐定）、 曱状旁腺激素（PTH )、 同化 类固醇药物、 人免疫球蛋白 （IGF )。  Bone formation promoters include, but are not limited to, fluoride (telidine), parathyroid hormone (PTH), anabolic steroid drugs, human immunoglobulin (IGF).
其它治疗骨质疏松的药物还可以是他汀类， 丙氨酰组氨酸锌（ AHZ )、 组织蛋 白酶 K抑制剂、 内皮整合素受体阻断剂、 神经肽、 生长因子 （胰岛素样生长因 子、 转化生长因子、 骨形态发生蛋白）、 骨保护素 （os teoproteger in 0PG )。  Other drugs for the treatment of osteoporosis may also be statins, zinc alaninate (AHZ), cathepsin K inhibitors, endostein receptor blockers, neuropeptides, growth factors (insulin-like growth factors, Transforming growth factor, bone morphogenetic protein), osteoprotegerin (os teoproteger in 0PG).
具体实施例 Specific embodiment
本发明将结合实施例作进一步的说明。  The invention will be further illustrated in conjunction with the examples.
通过实施例来帮助进一步理解本发明。 所用的具体材料、 物种和条件都是为 了举例说明本发明， 而不是限制本发明的合理范围。 本发明的分子结构有的存 说 明 书 The invention is further understood by the examples. The specific materials, species and conditions employed are intended to illustrate the invention and not to limit the scope of the invention. The molecular structure of the present invention exists Description
立体异构体， 这些立体异构体在本实施例中未全部说明但不限制本发明。 实施例 1 大黄酸曲美他嗪酰胺的制备 Stereoisomers, these stereoisomers are not all described in this example but are not limiting of the invention. Example 1 Preparation of Trimetazolamide Rhomezamide
Figure imgf000021_0001
Figure imgf000021_0001
( 1 ) 大黄酸酰氯的制备  (1) Preparation of rhein acid chloride
称取大黄酸 2. lg, 置 500ml圆底烧瓶中， 加入二氯曱烷 200ml， 氯化亚砜 100ml, 置 50°C油浴锅加热至回流， 搅拌反应 5h后， 溶液由混浊变为澄清透明， 回收溶剂得到黄色固体粉末。  Weighing 2. Rg of rhein, placed in a 500 ml round bottom flask, adding 200 ml of dichloromethane, 100 ml of thionyl chloride, heating to reflux at 50 ° C in an oil bath, stirring the reaction for 5 h, the solution changed from turbid to clarified Transparent, the solvent was recovered to give a yellow solid powder.
( 2 ) 大黄酸曲美他嗪酰胺的制备  (2) Preparation of trimetazidine rhein
将上步制得的固体粉末用 300ml曱苯溶解， 置 70°C油浴中搅拌， 称取 1.9g 盐酸曲美他嗪用少量二氯曱烷溶解， 緩慢滴加到反应液中， 用三乙胺调节 pH至 碱性， 溶液变为棕红色， 反应 2小时停止。  The solid powder prepared in the previous step was dissolved in 300 ml of benzene, and stirred in an oil bath at 70 ° C, and 1.9 g of trimetazidine hydrochloride was dissolved in a small amount of dichlorosilane, and slowly added dropwise to the reaction solution. The pH of the ethylamine was adjusted to be alkaline, the solution turned brownish red, and the reaction was stopped for 2 hours.
(三）重结晶  (3) Recrystallization
将上述反应液用水洗至水层基本无色， 将反应液至 50°C旋蒸蒸干， 固体经 曱苯重结晶得红棕色固体粉末 3.6g。  The above reaction solution was washed with water until the aqueous layer was substantially colorless, and the reaction mixture was evaporated to dryness at 50 ° C. The solid was recrystallized from toluene to give 3.6 g of red brown solid powder.
分子量： 532, 分子式为： C29H28N208。 Molecular weight: 532, molecular formula: C 29 H 28 N 2 0 8 .
Element Analyzing: C 65.41%, H 5.30%, N 5.26%, 0 24.03%;  Element Analyzing: C 65.41%, H 5.30%, N 5.26%, 0 24.03%;
ESI-MS(m/s): 533 [M+1]+, 531[M-1]+; ESI-MS (m/s): 533 [M+1] + , 531 [M-1]+;
1H-NMR(CDC13)5: 12.11 (1H, brs), 12.00 (1H, brs), 7.86 (1H, dd, 1=1.4, 1.0Hz), 7.81 (1H, d, J=l.5Hz) , 7.72 (1H, t， J=8.4, 7.4Hz) , 7.33 (1H, dd, J=8.4, 1.0Hz), 7.30 (1H, d, J=l.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); 1 H-NMR (CDC1 3 ) 5: 12.11 (1H, brs), 12.00 (1H, brs), 7.86 (1H, dd, 1 = 1.4, 1.0 Hz), 7.81 (1H, d, J = 1.5 Hz) , 7.72 (1H, t, J=8.4, 7.4Hz), 7.33 (1H, dd, J=8.4, 1.0Hz), 7.30 (1H, d, J=l.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);
nC-NMR (CDC13)5: 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, 说 明 书 nC-NMR (CDC1 3 ) 5: 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, Instruction manual
42.3。  42.3.
大黄酸吡咯烷酰胺的制备 Preparation of pyrrolidinamide of Rhein
Figure imgf000022_0001
Figure imgf000022_0001
大黄酸： 吡咯烷 =1: 1 (摩尔比）投料， 按照实施例 1的操作方法制备大黄酸 吡咯烷酰胺， 得到黄的固体粉末 2.4g。  Rhein: pyrrolidine = 1 : 1 (molar ratio), pyruvic acid pyrrolidinamide was prepared according to the procedure of Example 1, to obtain a yellow solid powder of 2.4 g.
分子量： 337， 分子式为： C19H15N05。 Molecular weight: 337, The molecular formula is: C 19 H 15 N0 5 .
Element Analyzing: C 67.65%, H 4.48%, N 4.15%, 0 23.72%;  Element Analyzing: C 67.65%, H 4.48%, N 4.15%, 0 23.72%;
ESI-MS(m/s): 338 [M+1]+, 336 [M-1]+; ESI-MS (m/s): 338 [M+1] + , 336 [M-1] + ;
'H-NMRiCDCH) δ： 12.07 (1H, s) , 12.00 (1H, s), 7.92 (1H, d, J=l.5Hz) , 7.84 (1H, dd, J=7.6, 1.1Hz), 7.71 (1H, t, J=8.4, 7.6Hz) , 7.41 (1H, d, J=l.5Hz), 7.32 (1H, dd, J=8.4, 1. lHz)， 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);  'H-NMRiCDCH) δ: 12.07 (1H, s) , 12.00 (1H, s), 7.92 (1H, d, J=l.5Hz), 7.84 (1H, dd, J=7.6, 1.1Hz), 7.71 ( 1H, t, J=8.4, 7.6Hz) , 7.41 (1H, d, J=l.5Hz), 7.32 (1H, dd, J=8.4, 1. lHz), 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(CDC13) 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。 13 C-NMR (CDC13) 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.
实施例 3 大黄酸吗啉酰胺的制备 Example 3 Preparation of Rumonic Acid Morpholine Amide
Figure imgf000022_0002
Figure imgf000022_0002
大黄酸： 吗啉 =1: 1 (摩尔比）投料， 按照实施例 1的操作方法制备大黄酸 说 明 书 Rhein: morpholine = 1 : 1 (molar ratio), Rhein was prepared according to the procedure of Example 1. Description
吗啉酰胺， 得到黄的固体粉末 2.7g。 Morpholine amide gave 2.7 g of a yellow solid powder.
分子量： 353， 分子式为： C19H15N06。 Molecular weight: 353, molecular formula: C 19 H 15 N0 6 .
Element Analyzing: C 64.59%, H 4.28%, N 3.96%, 0 27.17%;  Element Analyzing: C 64.59%, H 4.28%, N 3.96%, 0 27.17%;
ESI-MS (m/s): 338 [M+1]+, 336 [M-1]+; ESI-MS (m/s): 338 [M+1] + , 336 [M-1] + ;
!H— NMR(CDC13) δ : 12.12 (IH, s)， 11.99 (IH, s) , 7.86 (IH, dd, J=7.5, 1.1Hz), 7.82 (IH, d, J=l.5Hz) , 7.73 (IH, t, J=8.4Hz)， 7.35 (IH, dd, J=8.4 1.1Hz), 7.33 (IH, d, J=l.6Hz) , 3.83 (4H, s)， 3.67 (2H, s)， 3.45 (2H, s) ;  !H-NMR (CDC13) δ : 12.12 (IH, s), 11.99 (IH, s) , 7.86 (IH, dd, J=7.5, 1.1 Hz), 7.82 (IH, d, J=l.5Hz), 7.73 (IH, t, J=8.4Hz), 7.35 (IH, dd, J=8.4 1.1Hz), 7.33 (IH, d, J=l.6Hz) , 3.83 (4H, s), 3.67 (2H, s ), 3.45 (2H, s);
13C-腿（CDC13) 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 (X2), 48.0 42.5。 13 C-legs (CDC13) 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 (X2), 48.0 42.5.
大黄酸 3-曱基派啶酰胺的制备 Preparation of Rhein 3-mercaptopyridamide
Figure imgf000023_0001
Figure imgf000023_0001
大黄酸： 3-甲基哌啶 =1: 1 (摩尔比）投料， 按照实施例 1的操作方法制备 大黄酸 3-曱基哌啶酰胺， 得到黄的固体粉末 3.6g。  Rhein: 3-methylpiperidine = 1 : 1 (molar ratio) was charged. According to the procedure of Example 1, rhodamine 3-mercaptopiperidinamide was obtained to obtain 3.6 g of a yellow solid powder.
分子量： 365， 分子式为： C21H19N05。 Molecular weight: 365, molecular formula: C 21 H 19 N0 5 .
Element Analyzing: C 69.03%, H 5.24%, N 3.83%, 0 21.89%;  Element Analyzing: C 69.03%, H 5.24%, N 3.83%, 0 21.89%;
ESI-MS (m/s): 366 [M+l]+， 364 [M-1]+; ESI-MS (m/s): 366 [M+l]+, 364 [M-1] + ;
'H-NMRiCDCU) δ： 12.12 (IH, s)， 11.99 (IH, s) , 7.88 (IH, dd, J=7.5, 1.1Hz), 7.83 (IH, d, J=l.5Hz), 7.87 (IH, t， J=8.4Hz) , 7.06 (IH, dd, J=8.4, 1.1Hz), 7.39 (IH, d, J=l.6Hz), 3.43 (IH, d， J=6.4Hz) , 3.34 (2H, t, J=5.8Hz) , 3.18 (IH, J=5.6Hz)， 1.34-1.59 (5H, m) , 0.96 (3H， d, J=6.6Hz);  'H-NMRiCDCU) δ: 12.12 (IH, s), 11.99 (IH, s), 7.88 (IH, dd, J=7.5, 1.1 Hz), 7.83 (IH, d, J=l.5Hz), 7.87 ( IH, t, J=8.4Hz) , 7.06 (IH, dd, J=8.4, 1.1Hz), 7.39 (IH, d, J=l.6Hz), 3.43 (IH, d, J=6.4Hz) , 3.34 (2H, t, J = 5.8 Hz), 3.18 (IH, J = 5.6 Hz), 1.34-1.59 (5H, m), 0.96 (3H, d, J = 6.6 Hz);
13C-NMR(CDC13) 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(X2), 51.2， 45.5， 32.2, 28.7， 22.9, 18.1。 说 明 书 13 C-NMR (CDC13) 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 (X2), 51.2, 45.5, 32.2, 28.7, 22.9, 18.1. Instruction manual
大黄酸哌嗪酰胺的制备 Preparation of piperazine amide
Figure imgf000024_0001
Figure imgf000024_0001
大黄酸： 派噪 =1: 1 (摩尔比）投料， 按照实施例 1的操作方法制备大黄酸 哌嗪酰胺， 得到黄的固体粉末 3.6g。  Rhein: A noise ratio = 1 : 1 (molar ratio) was charged, and rhein piperazine amide was prepared in accordance with the procedure of Example 1, to obtain 3.6 g of a yellow solid powder.
分子量: 352, 分子式为: C19H16N205。 Molecular weight: 352, molecular formula: C 19 H 16 N 2 0 5 .
Element Analyzing: C 64.77%, H 4.58%, N 7.95%, 0 22.7%;  Element Analyzing: C 64.77%, H 4.58%, N 7.95%, 0 22.7%;
ESI-MS (m/s): 353 [M+1]+, 351[M-1]+; ESI-MS (m/s): 353 [M+1] + , 351 [M-1] + ;
!H- NMR(CDC13) δ : 12.12 (1H, s)， 11.99 (1H, s)， 7.88 (1H, dd, J=7.5， 1.1Hz), 7.83 (1H, d, J=l.5Hz) , 7.87 (1H, t, J=8.4Hz) , 7.06 (1H, dd, J=8.4, !H-NMR (CDC13) δ : 12.12 (1H, s), 11.99 (1H, s), 7.88 (1H, dd, J=7.5, 1.1 Hz), 7.83 (1H, d, J=l.5Hz), 7.87 (1H, t, J=8.4Hz), 7.06 (1H, dd, J=8.4,
1.1Hz), 7.39 (1H, d, J=l.6Hz) , 3.46 (4H, t, J=6.4Hz) , 2.85 (4H, t, J=6.4Hz) ,1.1Hz), 7.39 (1H, d, J=l.6Hz), 3.46 (4H, t, J=6.4Hz), 2.85 (4H, t, J=6.4Hz),
2.0(1H, brs); 2.0(1H, brs);
13C-NMR(CDC13) 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(X2), 50.1(X2), 47.2(X2)。 大黄酸 N-曱基哌嗪酰胺的制备 13 C-NMR (CDC13) 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 (X2), 50.1 (X2), 47.2 (X2) ). Preparation of N-mercaptopiperazinamide of Rhein
Figure imgf000024_0002
Figure imgf000024_0002
大黄酸： N-曱基派嗪 =1: 1 (摩尔比）投料， 按照实施例 1的操作方法制备 大黄酸 N-曱基派嗪酰胺， 得到黄的固体粉末 3. lg。  Rhein: N-decylpyrazine = 1 : 1 (molar ratio) was charged, and Rheic acid N-nonylpyrazine amide was prepared according to the procedure of Example 1, to obtain a yellow solid powder 3. lg.
分子量: 366, 分子式为： CaoH18N20 说 明 书 Molecular weight: 366, molecular formula: CaoH 18 N 2 0 Instruction manual
Element Analyzing: C 65.57%, H 4.95%, N 7.65%, 0 21.84%;  Element Analyzing: C 65.57%, H 4.95%, N 7.65%, 0 21.84%;
ESI-MS (m/s): 367 [M+1]+, 365 [M-1]+; ESI-MS (m/s): 367 [M+1] + , 365 [M-1]+;
'H-NMR(CDC13) δ : 12.12 (1H, s)， 11.99 (1H, s)， 7.88 (1H, dd, J=7.5, 1.1Hz), 7.83 (1H, d, J=l.5Hz) , 7.87 (1H, t， J=8.4Hz), 7.06 (1H, dd, J=8.4 'H-NMR(CDC13) δ : 12.12 (1H, s), 11.99 (1H, s), 7.88 (1H, dd, J=7.5, 1.1 Hz), 7.83 (1H, d, J=l.5Hz), 7.87 (1H, t, J=8.4Hz), 7.06 (1H, dd, J=8.4
1.1Hz), 7.39 (1H, d, J=l.6Hz), 3.44 (4H, t, J=6.4Hz) , 2.31 (4H, t, J=6.4Hz)1.1Hz), 7.39 (1H, d, J=l.6Hz), 3.44 (4H, t, J=6.4Hz), 2.31 (4H, t, J=6.4Hz)
2.30 (3H, s); 2.30 (3H, s);
13C-NMR(CDC13) 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(X2), 49.0(X2), 47.6 (X2), 45.5。 实施例 7 大黄酸缬氨酸酰胺的制备 13 C-NMR (CDC13) 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 (X2), 49.0 (X2), 47.6 (X2), 45.5 . Example 7 Preparation of Rumin Acid Proline Amide
Figure imgf000025_0001
Figure imgf000025_0001
( 1 ) 大黄酸酰氯的制备  (1) Preparation of rhein acid chloride
称取大黄酸 2. lg，置 500ml圓底烧瓶中，加入二氯曱烷 200ml，氯化亚砜 100ml, 置 50°C油浴锅加热至回流， 搅拌反应 15h后， 溶液由混浊变为澄清透明， 回收 溶剂得到黄色固体粉末。 Weighed 2. lg of rhein, placed in a 500 ml round bottom flask, 200 ml of dichloromethane, 100 ml of thionyl chloride, heated to reflux in a 50 ° C oil bath, stirred for 15 h, the solution changed from turbid to clarified Transparent, the solvent was recovered to give a yellow solid powder.
( 2 ) 大黄酸与缬氨酸酰胺的制备  (2) Preparation of Rhein and Proline Amide
将上步制得的黄色固体粉末用 30ml二氧六环溶解后緩慢滴加到溶有 2g缬 氨酸的氢氧化钠碱水中，控制 PH值在 8以上， 并在 40°C以下搅拌反应 3-4小时 后薄层分析至基本无大黄酸为止。  The yellow solid powder obtained in the previous step was dissolved in 30 ml of dioxane and slowly added dropwise to sodium hydroxide alkali water in which 2 g of proline was dissolved to control the pH value to be 8 or more, and the reaction was stirred at 40 ° C or lower. After 4 hours, the layers were analyzed until substantially free of rhein.
( 3 )精制  (3) Refinement
回收反应溶剂后， 用水超声溶解后用二氯曱烷进行萃取得到二氯曱烷萃 取层回收溶剂并用二氯甲烷重结晶得到棕黄色固体粉末 2.5g。  After the reaction solvent was recovered, it was sonicated with water and then extracted with dichloromethane to give a solvent. The solvent was evaporated to methylene chloride.
分子量： 369， 分子式为： C19H15N07。 Molecular weight: 369, molecular formula: C 19 H 15 N0 7 .
Element Analyzing: C 61.79%, H 4.09%, N 3.79%, 0 30.32%; ESI-MS (m/s): 370 [M+1]+, 368 [M-1]+; Element Analyzing: C 61.79%, H 4.09%, N 3.79%, 0 30.32%; ESI-MS (m/s): 370 [M+1] + , 368 [M-1] + ;
^-NMRCCDCn) 6： 12.34 (IH, s)， 11.99 (IH, s)， 11.85 (IH, s) , 8.44 (IH, s)， 7.88 (IH, dd, J=7.5, 1. lHz)， 7.83 (IH, d, J=l.5Hz) , 7.87 (IH, t, J=8.4Hz) , 7.06 (IH, dd, J=8.4, 1. lHz)， 7.39 (IH, d, J=l.6Hz) , 1.56 (6H, s);  ^-NMRCCDCn) 6: 12.34 (IH, s), 11.99 (IH, s), 11.85 (IH, s), 8.44 (IH, s), 7.88 (IH, dd, J=7.5, 1. lHz), 7.83 (IH, d, J=l.5Hz), 7.87 (IH, t, J=8.4Hz), 7.06 (IH, dd, J=8.4, 1. lHz), 7.39 (IH, d, J=l.6Hz ), 1.56 (6H, s);
13C— NMR(CDCU) 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(X2)。 实施例 8 大黄酸 P -丙氨酸酰胺的制备 13 C-NMR (CDCU) 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 (X2). Example 8 Preparation of R-Alanine Amide
Figure imgf000026_0001
Figure imgf000026_0001
大黄酸： 丙氨酸 =1: 1 (摩尔比）投料， 按照实施例 6的操作方法制备 大黄酸 丙氨酸酰胺， 得到黄色固体粉末 3.5g。  Rhein: alanine = 1 : 1 (molar ratio) was charged, and rhein acid alanine amide was prepared according to the procedure of Example 6, to obtain 3.5 g of a yellow solid powder.
分子量: 355, 分子式为: C18H13N07。 Molecular weight: 355, molecular formula: C 18 H 13 N0 7 .
Element Analyzing: C 60.85%， H 3.69%, N 3.94%, 0 31.52%;  Element Analyzing: C 60.85%, H 3.69%, N 3.94%, 0 31.52%;
ESI-MS (m/s): 356 [M+1]+, 354 [M-1]+;ESI-MS (m/s): 356 [M+1] + , 354 [M-1] + ;
-醒 R(CDC13) δ : 12.18 (IH, s)， 11.99 (IH, s)， 11.85 (IH, s)， 8.56(1H; s)， 7.88 (IH, dd, J=7.5, 1.1Hz), 7.83 (IH, d， J=l.5Hz), 7.87 (IH, t, J=8.4Hz) , 7.06 (IH, dd, J=8.4, 1. lHz)， 7.39 (IH, d, J=l.6Hz) , 3.67 (2H, t J=5.6Hz) , 2.53 (2H, t， J=5.6Hz) ; - wake up R(CDC13) δ : 12.18 (IH, s), 11.99 (IH, s), 11.85 (IH, s), 8.56(1H ; s), 7.88 (IH, dd, J=7.5, 1.1Hz), 7.83 (IH, d, J=l.5Hz), 7.87 (IH, t, J=8.4Hz), 7.06 (IH, dd, J=8.4, 1. lHz), 7.39 (IH, d, J=l. 6Hz), 3.67 (2H, t J=5.6Hz), 2.53 (2H, t, J=5.6Hz);
13C-NMR(CDC13) 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。 说 明 书 13 C-NMR (CDC13) 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. Instruction manual
实施例 9 大黄酸肌氨酸酰胺的制备 Example 9 Preparation of Rare Earth Creatine Amide
Figure imgf000027_0001
Figure imgf000027_0001
大黄酸： 肌氨酸 =1: 1 (摩尔比）投料， 按照实施例 6的操作方法制备大黄 酸肌氨酸酰胺， 得到黄色固体粉末 3.7g。  Rhein: Creatine = 1 : 1 (molar ratio) was charged, and rhein sarcosine amide was prepared according to the procedure of Example 6, to obtain 3.7 g of a yellow solid powder.
分子量： 355， 分子式为： C18H13N07。 Molecular weight: 355, molecular formula: C 18 H 13 N0 7 .
Element Analyzing: C 60.85%, H 3.69%, N 3.94%， 0 31.52%;  Element Analyzing: C 60.85%, H 3.69%, N 3.94%, 0 31.52%;
ESI-MS (m/s): 356 [M+1]+, 354 [M-1]+; ESI-MS (m/s): 356 [M+1] + , 354 [M-1] + ;
!H -醒（CDC13) δ : 13.03(1H, s) , 11.99 (IH, s)， 11.85 (IH, s)， 7.88 (IH, dd, J=7.5, 1.1Hz), 7.83 (IH, d, J=l.5Hz), 7.87 (IH, t, J=8.4Hz) , 7.06 (IH, dd, J=8.4， 1.1Hz), 7.39 (IH, d, J=l.6Hz) , 3.90 (2H, t, s)， 3.47 (3H, s) ; ! H - awake (CDC13) δ: 13.03 (1H , s), 11.99 (IH, s), 11.85 (IH, s), 7.88 (IH, dd, J = 7.5, 1.1Hz), 7.83 (IH, d, J=l.5Hz), 7.87 (IH, t, J=8.4Hz), 7.06 (IH, dd, J=8.4, 1.1Hz), 7.39 (IH, d, J=l.6Hz), 3.90 (2H, t, s), 3.47 (3H, s) ;
13C-NMR(CDC13) 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(X2)， 53.4, 34.8。 13 C-NMR (CDC13) 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 (X2), 53.4, 34.8.
实施例 10 大黄酸天冬氨酸酰胺的制备 Example 10 Preparation of Rare Earth Aspartic Acid Amide
Figure imgf000027_0002
Figure imgf000027_0002
大黄酸： 天冬氨酸 =1: 1 (摩尔比）投料， 按照实施例 6的操作方法制备大 黄酸天冬氨酸酰胺， 得到黄色固体粉末 3.7g。  Rhein: Aspartic acid = 1 : 1 (molar ratio) was charged, and rhein aspartic acid amide was prepared according to the procedure of Example 6 to give 3.7 g of a yellow solid powder.
分子量： 399, 分子式为： C19H13N09。 Molecular weight: 399, molecular formula: C 19 H 13 N0 9 .
Element Analyzing: C 57.15%, H 3.28%, N 3.51%, 0 36.06%;  Element Analyzing: C 57.15%, H 3.28%, N 3.51%, 0 36.06%;
ESI-MS (m/s): 400 [M+1]+, 398 [M-1]+; ESI-MS (m/s): 400 [M+1] + , 398 [M-1] + ;
'H-NMRCCDCn) δ： 12.57 (2H, s)， 11.99(1H, s)， 11.85 (IH, s) , 8.88 (IH, 说 明 书 'H-NMRCCDCn) δ: 12.57 (2H, s), 11.99 (1H, s), 11.85 (IH, s), 8.88 (IH, Instruction manual
s)， 7.88 (IH, dd, J=7.5, 1.1Hz), 7.83 (IH, d， J=l.5Hz) , 7.87 (IH, t, J=8.4Hz), 7.06 (IH, dd, J=8.4, 1.1Hz), 7.39 (IH, d, J=l.6Hz), 4.76 (IH, t J=7.8, 5.4Hz)， 2.84(2H， dd, J=ll.6， 5.4Hz) ; s), 7.88 (IH, dd, J=7.5, 1.1 Hz), 7.83 (IH, d, J=l.5Hz), 7.87 (IH, t, J=8.4Hz), 7.06 (IH, dd, J= 8.4, 1.1 Hz), 7.39 (IH, d, J=l.6 Hz), 4.76 (IH, t J=7.8, 5.4 Hz), 2.84 (2H, dd, J=ll.6, 5.4 Hz);
13C-NMR(CDC13) 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。 13 C-NMR (CDC13) 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.
实施例 11 大黄酸赖氨酸酰胺的制备 Example 11 Preparation of Rhein Lysine Amide
Figure imgf000028_0001
Figure imgf000028_0001
大黄酸： 赖氨酸 =2: 1 (摩尔比）投料， 按照实施例 6的操作方法制备大黄 酸赖氨酸酰胺， 得到黄色固体粉末 3.7g。  Rhein: lysine = 2: 1 (molar ratio) was charged, and rhein lysine amide was prepared according to the procedure of Example 6, to give 3.7 g of a yellow solid powder.
分子量： 678， 分子式为： C36H26N2012。 Molecular weight: 678, molecular formula: C 36 H 26 N 2 0 12 .
Element Analyzing: C 63.72%, H 3.86%, N 4.13%, 028.29%;  Element Analyzing: C 63.72%, H 3.86%, N 4.13%, 028.29%;
ESI-MS (ra/s): 679 [M+1]+, 677 [M-1]+; ESI-MS (ra/s): 679 [M+1] + , 677 [M-1] + ;
'Η-醒（CDC13) δ : 12.57 (IH, s) , 11.99 (2H, s)， 11.85 (2H, s), 8.88 (IH, s)， 8.44(1H, s), 7.88 (2H, dd, 1=1.5, 1.1Hz) , 7.83 (2H, d, J=l.5Hz), 7.87(2H, t, J=8.4， 7.5Hz), 7.06 (2H, dd, J=8.4, 1.1Hz), 7.39 (2H, d, J=l.6Hz), 4.55 (IH, t, J=4.5Hz) , 3.30 (2H, t, J=4.8Hz) , 1.25— 1.82 (6H， m) ;  'Η-awake (CDC13) δ : 12.57 (IH, s) , 11.99 (2H, s), 11.85 (2H, s), 8.88 (IH, s), 8.44 (1H, s), 7.88 (2H, dd, 1=1.5, 1.1Hz), 7.83 (2H, d, J=l.5Hz), 7.87(2H, t, J=8.4, 7.5Hz), 7.06 (2H, dd, J=8.4, 1.1Hz), 7.39 (2H, d, J=l.6Hz), 4.55 (IH, t, J=4.5Hz), 3.30 (2H, t, J=4.8Hz), 1.25—1.82 (6H, m);
13C-NMR(CDC13) δ： 188.0(χ 2), 182.1(χ 2), 180.1， 167.5(x 2), 161.9(x 2), 160.3(χ 2), 139.0(χ 2), 136.2 (χ 2), 133.1 ( χ 2) , 131.7(χ 2), 124.1(χ 2), 120.1 (χ 2), 119.7(χ 2), 119.4(χ 2), 116.6(χ 2), 116.3(χ 2), 55.5, 39.7, 30.6， 29.7, 22.7。 说 明 书 13 C-NMR (CDC13) δ: 188.0 (χ 2), 182.1 (χ 2), 180.1, 167.5 (x 2), 161.9 (x 2), 160.3 (χ 2), 139.0 (χ 2), 136.2 (χ 2), 133.1 (χ 2), 131.7 (χ 2), 124.1 (χ 2), 120.1 (χ 2), 119.7 (χ 2), 119.4 (χ 2), 116.6 (χ 2), 116.3 (χ 2) , 55.5, 39.7, 30.6, 29.7, 22.7. Instruction manual
实施例 12 大黄酸牛磺酸酰胺的制备 Example 12 Preparation of Rhubarb Taurine Amide
Figure imgf000029_0001
Figure imgf000029_0001
大黄酸： 牛磺酸 =1: 1 (摩尔比）投料， 按照实施例 6的操作方法制备大黄 酸牛磺酸酰胺， 得到黄色固体粉末 3.3g。  Rhein: Taurine = 1 : 1 (molar ratio) was charged, and rhemic acid taurine amide was prepared according to the procedure of Example 6, to obtain a yellow solid powder (3.3 g).
分子量： 391， 分子式为： C„H13N08S。 Molecular weight: 391, molecular formula: C„H 13 N0 8 S.
Element Analyzing: C 52.17%, H 3.35%, N 3.58%, 0 32.71%, S 8.19% ESI-MS (m/s): 392 [M+1]+, 390 [M-1]+; Element Analyzing: C 52.17%, H 3.35%, N 3.58%, 0 32.71%, S 8.19% ESI-MS (m/s): 392 [M+1] + , 390 [M-1] + ;
^-NMR (CDC 13) 6： 11.99 (IH, s)， 11.85(1H, s) , 8.56 (IH, s)， 7.88 (IH, dd, J=7.5, 1.1Hz), 7.83 (IH, d, J=l.5Hz) , 7.87 (IH, t, J=8.4, 7.5Hz), 7.06 (IH, dd, J=8.4, 1.1Hz), 7.39 (IH, d, J=l.6Hz) , 3.76 (2H, t, J=5.6Hz) , 3.71 (2H, t， J=5.6Hz);  ^-NMR (CDC 13) 6: 11.99 (IH, s), 11.85 (1H, s), 8.56 (IH, s), 7.88 (IH, dd, J = 7.5, 1.1 Hz), 7.83 (IH, d, J=l.5Hz), 7.87 (IH, t, J=8.4, 7.5Hz), 7.06 (IH, dd, J=8.4, 1.1Hz), 7.39 (IH, d, J=l.6Hz), 3.76 ( 2H, t, J=5.6Hz), 3.71 (2H, t, J=5.6Hz);
13C-NMR(CDC13) 6： 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。 13 C-NMR (CDC13) 6: 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.
实施例 13 大黄酸阿替洛尔酰胺的制备 Example 13 Preparation of Atenolamide of Rhein
Figure imgf000029_0002
Figure imgf000029_0002
大黄酸： 阿替洛尔 =2: 1 (摩尔比）投料， 按照实施例 6的操作方法制备大 黄酸阿替洛尔酰胺， 得到黄色固体粉末 3. lg。 实施例 14 大黄酸氨基葡萄糖酰胺的制备 The gram of the yellow solid powder 3. lg was obtained by the method of the method of Example 6 to prepare the alkaloid. Example 14 Preparation of Rare Earth Glucosamine
Figure imgf000030_0001
Figure imgf000030_0001
大黄酸氨基葡糖酰胺； RD10=大黄酸 β -丙胺酸酰胺 Rhein glucosamine; RD10 = rhein β-alanine amide
( 2 )药效学观察指标： 转化生长因子（TGF- β )和纤维连接蛋白 （FN )  (2) Pharmacodynamic observation indicators: transforming growth factor (TGF-β) and fibronectin (FN)
TGF- β和 FN是糖尿病肾病（ DN )发病过程中的重要细胞因子。 TGF- β为已 知的在糖尿病肾病中致硬化作用最强的细胞因子， 在体外或体内实验中，短期阻 断 TGF- β活性能抑制细胞外基质的增加和减轻肾脏纤维化； FN主要分布于系膜 基质中， 是构成 ECM (基底膜） 的两种主要的非胶原糖蛋白之一， DN 时正是由 于肾小球 Col IV、 FN、 LN等正常 ECM成分的过度积聚， 才导致 GBM增厚和系膜 扩张， 成为出现蛋白尿、 肾功能进行性下降等临床症状的基础。  TGF-β and FN are important cytokines in the pathogenesis of diabetic nephropathy (DN). TGF-β is a known cytokine with the strongest sclerosis in diabetic nephropathy. In vitro or in vivo experiments, short-term blocking of TGF-β activity can inhibit the increase of extracellular matrix and reduce renal fibrosis; In the mesangial matrix, it is one of the two main non-collagen glycoproteins that constitute ECM (basement membrane). DN is due to the excessive accumulation of normal ECM components such as glomerular Col IV, FN, LN, which leads to GBM. Thickening and mesangial expansion are the basis for clinical symptoms such as proteinuria and progressive decline in renal function.
( 3 ) 实验方法：  (3) Experimental method:
本药物体外筛选试验， 选择 TGF- β和 FN作为靶指标， 在低糖（模拟正常对 照组）和高糖（模拟糖尿病肾病模型组）培养下的肾小球系膜细胞， 经试验药 物的处理后，利用实时荧光定量 PCR的方法观察 TGF- β和 FN在体外培养条件的 表达情况。 实验中以高糖培养中 TGF- β和 FN的表达为 1 , 正常对照组（低糖培 养）和试验药物组的表达与之比较得出的 XX值， <1为该药物对细胞因子有抑制 作用， 预示体外试 -睑有较好的抗 DN活性； >1者表示对该细胞因子无抑制作用， 体外抗 DN活性较弱。 细胞因子的表达实验中每种药物进行三组重复取样， 并进 说 明 书 行统计学处理。 In vitro screening test of this drug, TGF-β and FN were selected as target indicators, and mesangial cells cultured in low glucose (simulated normal control group) and high glucose (simulated diabetic nephropathy model group) were treated with test drugs. Real-time quantitative PCR was used to observe the expression of TGF-β and FN in vitro. In the experiment, the expression of TGF-β and FN in high glucose culture was 1, the expression of XX in the normal control group (low sugar culture) and the test drug group, <1 is the inhibitory effect of the drug on cytokines. It indicates that the in vitro test-睑 has better anti-DN activity; >1 indicates no inhibition of the cytokine, and the anti-DN activity in vitro is weak. Cytokine expression experiments in each group of three repeated sampling, and into Explain the statistical processing of books.
(4)结果（见表 1) (4) Results (see Table 1)
Figure imgf000032_0001
Figure imgf000032_0001
1. 待选药物对 TGF- b的抑制活性依次为 RD6>RD3〉RD5>RD2〉RD10; RD7、RD1、RD4、 RD8、 RD9则无抑制活性。  1. The inhibitory activity of the candidate drug against TGF-b was RD6>RD3>RD5>RD2>RD10; RD7, RD1, RD4, RD8 and RD9 had no inhibitory activity.
2. 待选药物对 FN的抑制活性依次为： RD2>RD10>RD4>RD6>RD5>RD7; RD1、 RD3、 RD8和 RD9则无 Φ=Ρ制活性。  2. The inhibitory activities of the selected drugs on FN are: RD2>RD10>RD4>RD6>RD5>RD7; RD1, RD3, RD8 and RD9 have no Φ=Ρ activity.

Claims

权 利 要 求 Rights request
1. 下式的大黄酸衍生物或其药物上可接受的盐或酯或其异构体或前药:  1. A rhein derivative of the formula: or a pharmaceutically acceptable salt or ester thereof or an isomer or prodrug thereof:
Figure imgf000033_0001
Figure imgf000033_0001
其中 R为氨基酸的基团；含氮有 咸药物的基团； 任选被下列的基团取代的含氮 杂环基团： 氨基 、 羟基、 6烷基、 -6烷氧基、 d-6烷氨基、 硝基、 腈基， 上 述基团是通过氮原子连接。 a group wherein R is an amino acid; a group containing a nitrogen-containing salty drug; a nitrogen-containing heterocyclic group optionally substituted by the following groups: amino group, hydroxyl group, 6 alkyl group, - 6 alkoxy group, d- 6 An alkylamino group, a nitro group, a nitrile group, and the above groups are bonded through a nitrogen atom.
2. 权利要求 1所述的化合物， 其中所述氨基 to团的氨基酸选自： 胱氨酸、 甘 氨酸、 丙氨酸、 β -丙氨酸、 缬氨酸、 亮氨酸、 异亮氨酸、 苯丙氨酸、 脯氨酸、 色氨酸、 酪氨酸、 丝氨酸、 半胱氨酸、 蛋氨酸、 天冬酰胺、 谷氨酰胺、 苏氨酸、 天冬氨酸、 谷氨酸、 赖氨酸、 精氨酸、 组氨酸和曱硫氨酸， 及其对映异构体。 2. The compound of claim 1, wherein the amino group of the amino group is selected from the group consisting of: cystine, glycine, alanine, beta-alanine, valine, leucine, isoleucine, Phenylalanine, valine, tryptophan, tyrosine, serine, cysteine, methionine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine , arginine, histidine and methionine, and their enantiomers.
3. 权利要求 1所述的化合物， 其中所述含氮有才; W成药物的基团选自药物： 葡甲 胺、 氨基葡萄糖、 依那普利、 噻吗洛尔、 牛磺酸、 乌苯美司、 左旋多巴、 沙丁 胺醇、 阿替洛尔、 间羟胺、 二甲双胍、 曱氧明、 多巴胺、 多巴酚丁胺、 肾上腺 素、 妥卡尼、 阿米洛利、 美西律、 倍他司汀、 麻黄碱、 氯丙那林、 氯胺酮、 普 罗帕酮、 普萘洛尔、 氨力农、 氨^风和苯丙胺。 3. The compound of claim 1, wherein the nitrogen-containing compound; the drug-forming group is selected from the group consisting of: meglumine, glucosamine, enalapril, timolol, taurine, uranium Benzis, levodopa, salbutamol, atenolol, m-hydroxylamine, metformin, oxime, dopamine, dobutamine, adrenaline, tonicani, amiloride, mexiletine, octave Statin, ephedrine, clorprenaline, ketamine, propafenone, propranolol, amrinone, ammonia, amphetamine.
4. 权利要求 1所述的化合物，其中所述任选取代的含氮杂环基团选自： 吗啉基、 哌啶基、 哌嗪基、 四氢吡咯基、 咪唑基、 吡唑基、 吲哚基、 吲哚啉基。  4. The compound of claim 1 wherein the optionally substituted nitrogen-containing heterocyclic group is selected from the group consisting of: morpholinyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, imidazolyl, pyrazolyl, Mercapto, porphyrin.
5. 权利要求 1的化合物，其中所述的药学上可接受的盐是： 当化合物是碱性时， 其与有机酸或无机酸成盐； 当化合物是酸性时， 其与有机碱或无机碱成盐。  5. The compound of claim 1 wherein said pharmaceutically acceptable salt is: when the compound is basic, it forms a salt with an organic or inorganic acid; when the compound is acidic, it is associated with an organic or inorganic base. A salt.
6. 权利要求 5的化合物， 其中所述的有机酸或无机酸选自： 乙酸、 丙酸、 琥珀 酸、 乙醇酸、 硬脂酸、 乳酸、 苹果酸、 酒石酸、 柠檬酸、 抗坏血酸、 朴酸、 枸 橼酸、 马来酸、 羟基马来酸、 苯乙酸、 谷氨酸、 苯甲酸、 水杨酸、 对氨基苯磺 酸、 大黄酸、 牛黄酸、 齐墩果酸、 熊果酸、 2-乙酰氧基-苯曱酸、 富马酸、 曱苯 磺酸、 曱磺酸、 乙烷二磺酸、 草酸、 羟乙基礒酸、 三氟乙酸、 盐酸、 氢溴酸、 石克酸、 磺酸、 碑酸和硝酸。  6. The compound of claim 5, wherein the organic or inorganic acid is selected from the group consisting of: acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, succinic acid, Capric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, rhein, taurine, oleanolic acid, ursolic acid, 2- Acetoxy-benzoic acid, fumaric acid, terephthalic acid, sulfonic acid, ethane disulfonic acid, oxalic acid, hydroxyethyl decanoic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, sulphur Acid, streponic acid and nitric acid.
7. 权利要求 5的化合物， 其中所述的有机酸或无机酸选自： 乙酸、 琥珀酸、 酒 石酸、 枸橼酸、 马来酸、 草酸、 盐酸、 硫酸和磷酸。  7. The compound of claim 5, wherein the organic or inorganic acid is selected from the group consisting of: acetic acid, succinic acid, tartaric acid, citric acid, maleic acid, oxalic acid, hydrochloric acid, sulfuric acid, and phosphoric acid.
8. 权利要求 5的化合物， 其中所述的有才 咸或无才/ 咸选自： 甜菜碱、 咖啡因、 权 利 要 求 8. The compound of claim 5, wherein said salty or odorless/salt is selected from the group consisting of: betaine, caffeine, Rights request
胆碱， N，N，-二苄基乙二胺、 二乙胺、 二乙醇胺、 2-二乙基氨基乙醇、 2-二曱基 氨基乙醇、 乙醇胺、 乙二胺、 N-乙基吗啉、 N-乙基哌啶、 葡糖胺、 黄连素、 氨 基葡糖、 组氨酸、 异丙基胺、 赖氨酸、 曱基葡糖胺、 吗啉、 哌嗪、 哌啶、 聚胺 树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三曱胺、三- (羟曱基)氨基曱烷（TRIS )、 N-曱基葡萄糖胺（NMG )、 三乙醇胺、 三丙胺、 氨丁三醇和二氢枞胺、 季铵、 氢 氧化钾、 氢氧化钠。 Choline, N, N,-dibenzylethylenediamine, diethylamine, diethanolamine, 2-diethylaminoethanol, 2-didecylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine , N-ethylpiperidine, glucosamine, berberine, glucosamine, histidine, isopropylamine, lysine, decyl glucosamine, morpholine, piperazine, piperidine, polyamine resin , procaine, guanidine, theobromine, triethylamine, tridecylamine, tris-(hydroxyindenyl)aminodecane (TRIS), N-mercaptoglucosamine (NMG), triethanolamine, tripropylamine, ammonia Butanetriol and indoleamine, quaternary ammonium, potassium hydroxide, sodium hydroxide.
9. 权利要求 5所述的化合物， 其中所述的有机碱或无机碱选自： 氨基葡糖、 甲 基葡糖胺、 三乙胺、 氢氧化钾、 氢氧化钠。  9. The compound of claim 5, wherein the organic or inorganic base is selected from the group consisting of: glucosamine, methyl glucosamine, triethylamine, potassium hydroxide, sodium hydroxide.
10. 一种药物组合物， 其含有权利要求 1-9任一项所述的化合物和药用载体。 A pharmaceutical composition comprising the compound of any one of claims 1-9 and a pharmaceutically acceptable carrier.
11. 一种药物组合物， 其含有权利要求 1-9任一项的化合物作为第一活性成分 和一种或多种选自下列的药物作为第二活性成分： 抗糖尿病药物、 治疗糖尿病 并发症的药物、 抗肥胖症药物、 抗高血压药物、 抗血小板药物、 抗动脉粥样硬 化药物 /或降血脂药物、 抗氧化剂、 肉碱、 肉碱衍生物、 肉碱棕榈酰转移酶抑制 剂、 肉碱辛酰基转移酶抑制剂、 乙酰肉碱兴奋剂、 抗肿瘤药物、 抗痛风药物、 治疗骨盾疏松药物、 抗抑郁症药物、 治疗贫血药物、 治疗老年痴呆症药物、 抗 炎药物和免疫性药物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 as a first active ingredient and one or more drugs selected from the group consisting of: an antidiabetic agent, a diabetic complication Drug, anti-obesity drug, antihypertensive drug, antiplatelet drug, anti-atherosclerotic drug/or hypolipidemic drug, antioxidant, carnitine, carnitine derivative, carnitine palmitoyltransferase inhibitor, meat Alkali octyl acyltransferase inhibitor, acetylcarnitine stimulant, antitumor drug, anti-gout drug, anti-depressant drug, antidepressant drug, anemia drug, dementia drug, anti-inflammatory drug and immune drug .
12. 权利要求 11的药物组合物，其中所述的第二活性成分选自： 抗糖尿病药物、 治疗糖尿病并发症的药物、 抗肥胖症药物、 抗高血压药物、 抗动脉粥样硬化药 物 /或降血脂药物、 左旋肉碱、 左旋肉碱衍生物、 抗肿瘤药物、 抗炎药物和免疫 性药物。  12. The pharmaceutical composition of claim 11 wherein said second active ingredient is selected from the group consisting of: an anti-diabetic agent, a drug for treating diabetic complications, an anti-obesity agent, an antihypertensive drug, an anti-atherosclerotic drug/ Hypolipidemic drugs, L-carnitine, L-carnitine derivatives, antitumor drugs, anti-inflammatory drugs and immunological drugs.
13. 权利要求 11的药物组合物， 其特征在于其中所述第一活性成分与所述第二 活性成分的比例为 1 : 0. 0001-1： 0. 01。  The ratio of the first active ingredient to the second active ingredient is 1: 0001-1: 0.01.
14. 权利要求 10或 11的药物组合物，其中活性成分占组合物重量的 0. 1-99. 9%。  9%。 The composition of the composition of the composition of the composition of the composition of the composition of the composition.
15. 权利要求 10或 11的药物组合物， 其特征在于该药物组合物是一种口服给 药制剂、 注射给药制剂或局部给药制剂， 其中：  The pharmaceutical composition according to claim 10 or 11, wherein the pharmaceutical composition is an oral administration preparation, an injection administration preparation or a topical preparation, wherein:
( 1 ) 口服给药制剂包括普通片、 緩释片、 颗粒剂、 硬或软胶嚢、 糖浆剂、 溶液剂、 乳剂； 口服给药制剂的载体包括填充剂、 崩解剂、 粘合剂、 润滑剂、 着色剂、 矫味剂或者其他常规添加剂， 具体包括淀粉、 乳糖、 微晶纤维素、 羧 曱基淀粉钠、 交联聚乙烯吡咯烷酮、 聚乙烯吡咯坑酮、 羟丙曱纤维素、 硬脂酸 镁、 二氧化硅和聚山梨脂一80、 十二烷基硫酸钠； 权 利 要 求 (1) Oral administration preparations include ordinary tablets, sustained release tablets, granules, hard or soft capsules, syrups, solutions, emulsions; carriers for oral administration include fillers, disintegrators, binders, Lubricants, colorants, flavoring agents or other conventional additives, including starch, lactose, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl cellulose, hard Magnesium oleate, silica and polysorbate-80, sodium lauryl sulfate; Rights request
( 2 )注射给药制剂包括无菌注射的水溶液、 无菌注射的水包油微乳液、 注 射用无菌粉末； 注射给药制剂的载体包括注射用溶剂、 注射用附加剂， 具体注 射溶剂包括注射用水、 注射用油如大豆油， 注射用增溶剂如乙醇、 丙二醇、 聚 乙二醇、 甘油， 等渗物质如氯化钠、 葡萄糖；  (2) The preparation for administration by injection includes a sterile injectable aqueous solution, a sterile injectable oil-in-water microemulsion, a sterile powder for injection; a carrier for injecting the preparation for injection includes a solvent for injection, an additional agent for injection, and the specific injection solvent includes Water for injection, oil for injection such as soybean oil, solubilizer for injection such as ethanol, propylene glycol, polyethylene glycol, glycerin, isotonic materials such as sodium chloride, glucose;
( 3 )局部给药制剂是贴剂、 栓剂、 霜剂、 膏剂、 凝胶剂、 溶液、 混悬液或靶向 制剂， 其中靶向制剂包括脂盾体、 微球剂、 毫微粒、 包含物、 单克隆抗体耦联 物； 局部给药制剂的载体包括药学上用于局部给药的常规载体。  (3) The topical preparation is a patch, a suppository, a cream, a cream, a gel, a solution, a suspension or a targeted preparation, wherein the targeted preparation comprises a lipid shield, a microsphere, a nanoparticle, an inclusion , monoclonal antibody conjugates; carriers for topical formulations include conventional carriers for pharmaceutically acceptable topical administration.
16. 权利要求 10或 11的药物组合物， 其特征在于其中所述的药物组合物的给 药形式包括： 静脉、 肌内、 «、 皮下、 口服、 直肠栓剂插入法、 阴道栓剂插 入法、 靶向给药、 吸入式、 灌胃式、 鼻饲式、 舌下给药、 滴药法、 ^十式给药、 连续给药系统和局部给药， 局部给药方式如贴皮制剂、 或植入式连续给药释放 系统， 其中贴皮制剂载体包括骨架材料如疏水的聚硅氧烷和亲水的聚乙烯醇等， 控释膜材料如聚硅氧烷和乙烯-醋酸乙烯共聚物等， 压敏胶如聚异丁烯、 聚硅氧 烷和聚丙烯酸酯， 活性成分一般分散在压敏胶中； 其中植入式连续给药释放系 统所选用的高分子材料包括聚乳酸一乙醇酸共聚物、 聚乙二醇聚乳酸共聚物、 聚乳酸 /聚己内酯、 聚 [碳酸（亚丁酯 -co- ε -己内酯） 酯]、 聚丁内酯戊内酯、 聚二氧环己酮（PDS )、 聚- 3 -羟基丁酸酯（ΡΗΒ )、 聚左旋乳酸 (PLLA)、 聚乙 醇酸 (PGA)、 聚 ε -己内酯（PCL )、 聚己内酯 /聚乙交酯丙交酯 （PCL / PLGA)、 曱 基丙烯酸羟乙酯（HEMA)。  16. The pharmaceutical composition according to claim 10 or 11, wherein the pharmaceutical composition is administered in the form of: intravenous, intramuscular, «, subcutaneous, oral, rectal suppository insertion, vaginal suppository insertion, target Administration, inhalation, gavage, nasal feeding, sublingual administration, drip administration, tetra-dosing, continuous administration system and topical administration, topical administration such as skin preparation, or implantation Continuous drug delivery system, wherein the skin preparation carrier comprises a skeleton material such as hydrophobic polysiloxane and hydrophilic polyvinyl alcohol, and a controlled release film material such as polysiloxane and ethylene-vinyl acetate copolymer, etc. Sensitive adhesives such as polyisobutylene, polysiloxane and polyacrylate, the active ingredients are generally dispersed in the pressure sensitive adhesive; wherein the polymer materials selected for the implantable continuous drug delivery system include polylactic acid monoglycolic acid copolymer, poly Ethylene glycol polylactic acid copolymer, polylactic acid/polycaprolactone, poly[butylene carbonate-co-ε-caprolactone), polybutyrolactone, polydioxanone (PDS) ), poly-3-hydroxybutyric acid (ΡΗΒ), poly-L-lactic acid (PLLA), polyglycolic acid (PGA), poly-ε-caprolactone (PCL), polycaprolactone/polyglycolide lactide (PCL / PLGA), hydroxy methacrylate Ethyl ester (HEMA).
17. 权利要求 1-9任一项的化合物或权利要求 10或 11的药物组合物在制备治 疗下列疾病的药物中的应用：  17. Use of a compound according to any one of claims 1-9 or a pharmaceutical composition according to claim 10 or 11 for the manufacture of a medicament for the treatment of:
增加高密度脂蛋白的水平、 增强记忆力、 改善学习能力、 衰老、 代谢类疾 病、 糖尿病、 糖尿病肾病、 糖尿病足病、 糖尿病视网膜病、 糖尿病性神经病、 糖尿病并发症、 延迟伤口愈合、 胰岛素抗性、 高血糖、 高胰岛素血症、 脂肪酸 或甘油的水平升高、 高脂血症、 肥胖症、 高甘油三酯血症、 动脉粥样硬化、 高 血压、 代谢综合症（X综合症）、 贫血（如镰刀细胞贫血）、 粉刺、 肿瘤、 风湿性 关节炎、 关节炎、 肠炎、 银屑病、 多发性硬化症、 神经变性紊乱、 充血性心力 衰竭、 中风、 主动脉瓣狭窄、 肾炎、 肾衰竭、 痛风、 红斑狼疮、 IgA肾病、 阑尾 炎、 胰腺炎、 变态反应 （如鼻炎、 鼻窦炎）、 纤维症、 骨病、 骨质疏松、 心血管 疾病（如心律失常、 心血管休克、心绞痛）、放疗及化疗并发症、肝病（如肝炎）、 Increases HDL levels, enhances memory, improves learning ability, aging, metabolic diseases, diabetes, diabetic nephropathy, diabetic foot disease, diabetic retinopathy, diabetic neuropathy, diabetic complications, delayed wound healing, insulin resistance, Hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis, hypertension, metabolic syndrome (X syndrome), anemia ( Such as sickle cell anemia), acne, tumor, rheumatoid arthritis, arthritis, enteritis, psoriasis, multiple sclerosis, neurodegenerative disorders, congestive heart failure, stroke, aortic stenosis, nephritis, renal failure, Gout, lupus erythematosus, IgA nephropathy, appendicitis, pancreatitis, allergies (such as rhinitis, sinusitis), fibrosis, bone disease, osteoporosis, cardiovascular disease (such as arrhythmia, cardiovascular shock, angina pectoris), radiation therapy and Chemotherapy complications, liver disease (such as hepatitis),
权 利 要 求 Rights request
胃肠道病症（如胃炎和胃肠炎）、 结膜炎、 斯耶格伦 ( Sjogren' s )综合症、 肺 病、 肾病（如多嚢肾病）、 皮炎、 HIV相关病症、 疟疾（如脑疟）、 强直性脊推炎、 麻风病、 免疫性疾病、 抑郁症、 老年痴呆症、 水肿、 溃疡、 精神分裂症、 精神 障碍性疾病、 过敏性休克、 尿崩症、 哮喘、 青光眼、 线粒体疾病 帕金森、 病 理老化的糖基化终端产物、 能量代谢异常、 基盾金属蛋白酶病理性疾病。 Gastrointestinal disorders (such as gastritis and gastroenteritis), conjunctivitis, Sjogren's syndrome, lung disease, kidney disease (such as polynephropathy), dermatitis, HIV-related disorders, malaria (such as cerebral malaria) , ankylosing spondylitis, leprosy, immune disease, depression, Alzheimer's disease, edema, ulcer, schizophrenia, mental disorders, anaphylactic shock, diabetes insipidus, asthma, glaucoma, mitochondrial disease Parkinson , pathologically aged glycosylation end products, abnormal energy metabolism, basal metalloproteinase pathological disease.
18. 权利要求 17的应用， 其中所述的疾病包括： 代谢类疾病、 糖尿病、 糖尿病 腎病、 糖尿病足病、 糖尿病视网膜病、 糖尿病性神经病、 糖尿病并发症、 高脂 血症、 肥胖症、 高血压、 肿瘤。  18. The use of claim 17, wherein the diseases include: metabolic diseases, diabetes, diabetic nephropathy, diabetic foot disease, diabetic retinopathy, diabetic neuropathy, diabetic complications, hyperlipidemia, obesity, hypertension , tumor.
19. 权利要求 17的应用， 其中所述药物成人每天的用量为 0. 001- 100mg/kg体 重。  19. The use according to claim 17, wherein the dosage of the drug adult is 0. 001-100 mg/kg body weight per day.
20. 权利要求 17的应用， 其中所述药物成人每天的用量为 0. 01- 50mg/kg体重。 The use of the drug in an amount of 0.01 to 50 mg / kg body weight per day.
21. 权利要求 17的应用， 其中所述药物成人每天的用量为 0. 05- 5mg/kg体重。 21. The use according to claim 17, wherein the dosage of the drug adult is 0. 05-5 mg/kg body weight per day.
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