CN1705473A - Chromones and chromone derivatives and uses thereof - Google Patents

Chromones and chromone derivatives and uses thereof Download PDF

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CN1705473A
CN1705473A CN200380101821.4A CN200380101821A CN1705473A CN 1705473 A CN1705473 A CN 1705473A CN 200380101821 A CN200380101821 A CN 200380101821A CN 1705473 A CN1705473 A CN 1705473A
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chemical compound
disease
cancer
carcinoma
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颜茂雄
E·S·C·吴
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Jenken Biosciences Inc
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The present invention relates to chromones, novel chromone derivatives, and pharmaceutical formulations containing the same and methods of use thereof. Uses of the present invention include, but are not limited to, use for the prevention and treatment of septic shock, organ injury and other disorders. The compounds described herein can be salt forms and also water-soluble compounds.

Description

Chromone and chromone derivative and uses thereof
Related application data
It is 60/420 that the application requires to enjoy the series number of submitting on October 22nd, 2002, the series number that 306 U.S. Provisional Application and on March 11st, 2003 submit to is 60/453,771 U.S. Provisional Application No. is incorporated herein by reference its disclosure in full at this.
Invention field
The present invention relates to chromone, new chromone derivative, its pharmaceutical preparation with and purposes in prevention and treatment disease such as septic shock and organ injury.
Background of invention
Septic shock may be defined as the immunoreation caused clinical disease category of host to infection or wound, be characterized in systemic inflammatory and blood coagulation (Mesters RM etc., the rising prediction leukopenia patient and the pyemic result of plasminogen activator inhibitor level.ThrombHaemost.1996a; 75:902-907; Wheeler AP and Bernard GR, severe sepsis patient's treatment.NEngl?J?Med.340：207-214(1999))。Described disease comprise systemic inflammatory reaction to organ dysfunction to the multiple organ failure, MOF, until last death.Old, immunity weakens and the patient that is in a bad way in, is septic shock that (whether Friedman G etc., the mortality rate of septic shock change in time for the main cause of M ﹠ M in the whole world intensive care unit(ICU)? Crit Care Med.26:2078-2086 (1998)).In the U.S., septic shock is first cause (Sands KE etc., the epidemiology of the sepsis syndrome of 8 academic medical centres of non-coronary heart disease intensive care unit(ICU) (ICU) death.JAMA?278：234-240(1997))。In addition, the data in 1998 from Center for Disease Control (CDC) shows that septic shock is all ranking the 11 (National Vital Statistics Report, 2000) in the cause of death.
Flavonoid or bioflavonoids comprise the ubiquitous polyphenol substance of a class, and it is present in most of plants, in concentrating on seed, peel, bark and spending.Flavonoid has a lot of classes, comprising: flavonol, flavanone, flavone (2-phenylchromone), flavan-3-alcohol (catechin), anthocyanin and isoflavone (3-phenylchromone).Noroxylin, baicalin and wogonin (as follows) are the biologic activity flavonoid in oneself Radix Scutellariae (Scutellaria baicalensis GEORGI) known.In recent research, existing reporting noroxylin, baicalin and wogonin has anti-inflammatory activity [Bao, QL etc. is by showing anti-inflammatory activity with chemotactic factor association class flavone baicalin.Immunopharmacology.49:295-306 (2000); Wakabayashi I and Yasui K, wogonin suppresses induction type prostaglandin E in the macrophage 2Generation.Eur J Pharmacol.406:477-481 (2000); Kimura etc., isolated noroxylin is to interleukin-11 β in the Human umbilical vein endothelial cells of cultivating-and the influence of tumor necrosis factor-inductive adhesion molecule expression from Radix Scutellariae.J Ethnopharmacol.57:63-67 (1997); And Lin CC and Shieh DE, the anti-inflammatory activity of small stream bank Radix Scutellariae (Scutellaria rivularis) extract and active component baicalin, noroxylin and wogonin.Am J Chin Med.24:31-36 (1996)], [kyo etc., a kind of composition baicalin of important medicinal plants and noroxylin are by reducing the active interior Ca of cell that suppresses of phospholipase C in the C6 rat neuroglial cytoma for antiallergic activity 2+Increase.J.Pharm Pharmacol.50:1179-1182 (1998); Gao etc., the free radical scavenging activity and the antioxidant activity of the flavonoid that extracts by scutellariae,radix.Biochemica et BiophysicaActa is (1999) B.1472:643-650; Gabrielska J, the antioxidant activity in lecithin liposome from the flavone of Radix Scutellariae.J Biosci.52:817-823 (1997)], antioxidant activity [Shieh etc., the antioxidation of noroxylin, baicalin and wogonin and free radical scavenging effect.AnticancerRes.20:2861-2865 (2000)] and active anticancer [Ikemoto S etc., scutellariae,radix and composition noroxylin, baicalin and wogonin are to the antitumor action of bladder cancer cell lines.Urology 55:951-955 (2000); Chan FL etc., the flavonoid baicalin is induced the apoptosis of prostate cancer cell line.Cancer?Lett.(2000)]。In addition, also prove to have antiviral activity by baicalin [Nagai T etc. are from the binding mode of plant flavonoids 5,7, the 4 '-trihydroxy-8-methoxy flavone anti-influenza virus activity of scutellariae,radix.Antiviral Res.26:11-25 (1995); Nagai T etc., from the binding mode of plant flavonoids 5,7, the 4 '-trihydroxy-8-methoxy flavone anti-influenza virus activity of scutellariae,radix and drug delivery system to its active facilitation.Antiviral Res.30:A1-A62 (1995); And Kitamura K etc., baicalin, the vitro inhibition agent that a kind of HIV-1 generates.Antiviral Res.37:131-140 (1998)], also prove can produce hypotensive effect by noroxylin [Takizawa etc., prostacyclin I2 helps the vasodepression effect of noroxylin in Hypertensive Rats.Hypertension 31:866-871 (1998) and Chen ZY etc., the inductive endothelium-dependent relaxation of noroxylin is shunk and directly diastole in rat mesenteric artery.Eur?J?Pharmacol.374：41-47(1999)]。Recently, [scutellariae,radix and composition noroxylin, baicalin and wogonin are to the antitumor action of bladder cancer cell lines for Ikemoto, S etc. in the adhesion molecule expression of the cytokine induction in the discovery noroxylin participation inhibition Human umbilical vein endothelial cells.Urology.55:951-955 (2002); Middleton, EJ and Kandaswani C, flavonoid is to the influence of immunity and inflammatory cell function.Biochem.Pharmacol.43：1167-1179(1992)]。
Figure A20038010182100121
Noroxylin baicalin wogonin
Fig. 1. the biologic activity flavonoid of Radix Scutellariae
The existing treatment of treatment septic shock comprises that antibiotic, vasoconstrictor, steroid and liquid replenish to keep circulation volume; Yet, in many cases, these fail to respond to any medical treatment (Barron RL, the pathophysiology of septic shock and enlightenments to treating.Clin.Pharm.12：829-845(1993))。Need provide prevention or the useful chemical compound of treatment septicemia gonosome gram.
In the sepsis process, produce nitrogen oxide (NO).The normal vascular reactivity of the common damage of the level of endotoxin of its metabolite and rising.The NO synthetase inhibitors can recover blood pressure, reduce the vascular resistance of cardiac index and increase lung and whole body.Can prove that targeting is useful in the selective N OS of iNOS inhibitor.With the NOS function inhibitor that suppresses relevant guanylate cyclase, be that small research that methylene blue carries out demonstrates the beneficial effect [Preiser to septic shock patient's above-mentioned cardio-vascular parameters, JC, Lejeune P, Roman A etc. use methylene blue: clinical trial in septic shock.Crit.Care Med., 23:259-64 (1995); Gachot B, Bedos JP, Veber B etc., methylene blue be to the temporal effect of septic shock patient's hematodinamics and gas exchange, Intensive CareMed 21:1027-31; Vincent, JL, Sun Q, Dubois, M-J, the clinical trial of the immune modulating treatment of severe sepsis and septicemia gonosome gram, CID, 34:1084-1093 (2002)].
TNF-α (the tissue necrosis factor) is a kind of cytokine that plays a significant role in bringing out the health inflammatory reaction, it is present in the joint of the individuality of suffering from rheumatoid arthritis with unusual high level, and it plays a role as immunomodulator in immune system.Proved that the TNF-alpha inhibitor can stop the gentle heavy arthritic symptom of lifting a curfew of development of cartilage destruction.About 30% moderate to the severe arthritic to these treatments reactionless (Feldman M, Maini RN, THF-α in rheumatoid arthritis as the treatment target discovery: clinical before and clinical research.Joint Bone Spine 2002,69,12-18; Lipsky PE etc., English husband monoclonal antibody and methotrexate are used for the treatment of rheumatoid arthritis.N.Engl.J.Med.2000，343?1954-1602)。The zooscopy that the research of carrying out with personnel selection is relevant shows that TNF regulates (the Newton RC that may play a role in segmental enteritis, ulcerative colitis, insulin resistance, multiple sclerosis, multiple organ failure, MOF, pulmonary fibrosis and atherosclerosis, DeciccoCP, the treatment potential and the strategy of inhibition tumor necrosis factor-alpha.J.Med.Chem.1999，42，2295-2314)。
The aerobe that is obtained energy by hydrogen reduction is to a small amount of O 2-, OH and H 2O 2The detrimental effect sensitivity, these materials are in oxygen metabolism, especially can produce inevitably in to the reduction process of oxygen in mitochondrial electron transfer system.The unstable intermediate of these three kinds of materials in lipid peroxidation is called as reactive oxygen species (Reactive Oxygen Species (ROS)).The unbalance ROS infringement (a kind of situation that is called oxidative stress) that causes between numerous disease and free-radical generating and the free radical scavenging system is relevant, and described disease non-limiting has Alzheimer, parkinson disease, aging, cancer, myocardial infarction, atherosclerosis, autoimmune disease, radiation injury, edema due to disorder of QI, sunburn and joint disease (a.Everything cytokine ﹠amp for example; Beyond, the little summary of cytokine, chapters and sections: reactive oxygen species (ROS), copyright 2003 R﹠amp; D Systems; B.Channon KM, Guzik TJ, the mechanism that peroxide produces in people's blood vessel: with the relation of endothelial function disturbance, clinical and genetic risk factor.J.Physiol.Pharmacol.2002,53 (4), 515-524; C.Henrotin, YE etc., the effect of reactive oxygen species in homeostasis and cartilage degradation.OsteoArthritis and Cartilage2003,11,747-755; D.Arzimanoglou A etc., epilepsy and neuroprotective: diagram summary paper.Epileptic Disord 2002,3,173-82; E.Seidrnan MD etc., the mitochondrion metabolite is to the biologic activity of old and feeble and senile auditory dysesthesia.Am?J?Otol?2000，21(2)：161-7)。McCord and Fridovich are to the active discovery of superoxide dismutase (SOD) (Mc Cord, the J.M.﹠amp of erythrocuprein; I.Fridovich, J.Biol.Chem.1969,244:6049) and nearly all mammalian cell table of discovery of all containing SOD understand the physiological role of maincenter ROS peroxide at least.
Summary of the invention
Compare with above-mentioned conventional therapy, the present invention can provide more effective treatment to be used to prevent or treat septic shock, organ injury produces relevant disease and disease with the generation of TNF-α excess or with superoxide anion base excess.
According to embodiment of the present invention, the present invention relates to the chemical compound of formula I:
Figure A20038010182100141
Wherein:
R 1, R 2And R 3Be independently of one another H, alkyl, alkenyl, alkynyl ,-SO 3H ,-PO 3H 2Or carbohydrate;
Perhaps R 1And R 2Be (CH independently of one another 2) nY and [CH 2CH (OH) CH 2] Y, wherein Y is H, OR 4, NR 5R 6, COOR 4Or OONR 5R 6, R wherein 4, R 5And R 6Be H, alkyl, alkenyl, alkynyl or carbohydrate independently of one another, and R 5And R 6Can form 5 to 7-unit's rings together;
Perhaps R 1And R 2Be heterocycle together;
Perhaps R 2And R 3Be heterocycle together; And
X 1And X 2Be formula independently of one another:
Ar-X 3-T，
Wherein Ar can exist or not exist, and when Ar existed, Ar was phenyl, furyl, thienyl, pyridine radicals, cyclohexyl or benzyl; X wherein 3Be H, C, N, NR ', NR ' R ", NR ' SO 2R ", O or S, condition is that formula I chemical compound is not noroxylin or 5,6,7-trihydroxy-isoflavone, wherein R ' and R " are H, alkyl, alkenyl, alkynyl or carbohydrate independently of one another; Wherein T is (CH 2) nY or [CH 2CH (OH) CH 2] Y, wherein Y is H, OR 4, NR 5R 6, COOR 4Or OONR 5R 6, R wherein 4, R 5And R 6Be H, alkyl, alkenyl, alkynyl or carbohydrate independently of one another; And R 5And R 6Can form 5 to 7-unit's rings together; Or its pharmaceutically useful salt.
According to other embodiments of the present invention, the present invention relates to prevent or treatment produces with TNF-α excess, produces relevant disease or disease, septic shock, inflammation, organ injury, neurodegenerative disease, cancer and cardiopathic method with superoxide anion base excess, this method comprises uses the pharmaceutical composition that comprises the above-mentioned formula I chemical compound for the treatment of effective dose to its object of needs.
According to other embodiments, the present invention relates to prevent or treatment produces with TNF-α excess, produces relevant disease or disease, organ injury, neurodegenerative disease, cancer and cardiopathic method with superoxide anion base excess, this method comprises uses the pharmaceutical composition that comprises the formula II chemical compound for the treatment of effective dose to its object of needs:
According to other embodiments, the present invention relates to prevent or treatment produces with TNF-α excess, produces relevant disease or disease, organ injury, neurodegenerative disease, cancer and cardiopathic method with superoxide anion base excess, this method comprises uses the pharmaceutical composition that comprises the formula III chemical compound for the treatment of effective dose to its object of needs:
According to other embodiments, the present invention relates to prevent or treatment produces with TNF-α excess, produces relevant disease or disease, organ injury, neurodegenerative disease, cancer and cardiopathic method with superoxide anion base excess, this method comprises uses the pharmaceutical composition that comprises the formula IV chemical compound for the treatment of effective dose to its object of needs:
According to other embodiments of the present invention, the present invention relates to prevent or treatment with septic shock, produce with TNF-α excess, produce relevant disease or disease, organ injury, neurodegenerative disease, cancer and cardiopathic method with superoxide anion base excess, this method comprises uses the pharmaceutical composition that comprises the formula V compound or pharmaceutically acceptable salt thereof for the treatment of effective dose to its object of needs:
Figure A20038010182100163
Wherein:
R 7, R 8And R 9Be independently of one another H, alkyl ,-SO 3H ,-PO 3H 2, carbohydrate or benzyl;
Perhaps R 7And R 8Be heterocycle together;
Perhaps R 8And R 9Be heterocycle together;
X 1Be H, C, NH 2, NHCOCH 3, NO 2Or OR 10, R wherein 10Be H, alkyl, carbohydrate or benzyl,
Condition is to work as Ph-X 1Be positioned at 2-position and R 7, R 8And R 9When being H, alkyl or carbohydrate independently of one another, this chemical compound is not used in the treatment septic shock.
According to other embodiments of the present invention, the present invention relates to the method for noval chemical compound synthetic described herein, this method comprises makes reaction under the described herein suitable condition of chemical compound described herein, generates required compound.
According to other embodiments, chemical compound of the present invention can be the salt form of chemical compound, and can select so that chemical compound has water solublity micel.
Brief Description Of Drawings
Fig. 1 has illustrated the influence of chemical compound 11a to the mean arterial blood pressure variation of the rat of lipopolysaccharide (LPS) processing.
Fig. 2 has illustrated the influence of chemical compound 11a to the changes in heart rate of the rat of LPS processing.
Fig. 3 has illustrated the influence of chemical compound 11a to Plasma TNF-alpha levels of the rat of LPS processing.
Fig. 4 has illustrated the influence of chemical compound 11a to the superoxide anion of the rat of LPS processing.
Fig. 5 has illustrated 8 hours chemical compounds after the administration 11aThe influence of the SGPT level of the rat that LPS is handled.
Fig. 6 has illustrated 8 hours chemical compounds after the administration 11aThe influence of the SGOT level of the rat that LPS is handled.
Fig. 7 has illustrated the influence of noroxylin to Plasma TNF-alpha levels of the rat of LPS processing.
Fig. 8 has illustrated the influence of noroxylin to the superoxide anion of the rat of LPS processing.
Fig. 9 has illustrated 8 hours chemical compounds after the administration 11aThe influence of the lung tissue of the rat that LPS is handled.
                      Detailed Description Of The Invention
Hereinafter the present invention is done to describe more fully referring now to accompanying drawing, these accompanying drawings furtherly Understand invention described herein. Yet the present invention also can implement with different forms, should not twist For only limiting to the embodiment that goes out given herein. The purpose of these embodiments more accurately, is provided It is abundant and complete to be to expose, and makes those skilled in the art fully understand scope of the present invention.
Used term purpose only is to describe specific embodiments in the description of the invention herein, is not Be intended to limit the present invention. Unless offer some clarification in addition in the context, otherwise specification of the present invention and institute Singulative used in the attached claim also comprises plural form.
Except as otherwise noted, otherwise all technical terms used herein and scientific terminology have and this Bright those of ordinary skill in the field the identical implication of implication usually understood.
For the instruction relevant with the sentence that wherein has reference and/or paragraph, with cited herein All publications, patent application, patent and other list of references are incorporated herein by reference in full.
Term used herein " alkyl " refers to C1-C20 and comprises C1 and the straight chain of C20, side chain Or ring-type, saturated or undersaturated hydrocarbon chain, for example comprise methyl, ethyl, propyl group, isopropyl, Butyl, isobutyl group, the tert-butyl group, amyl group, hexyl, octyl group, vinyl, acrylic, cyclobutenyl, Amyl group, hexenyl, octenyl, butadienyl and allene base. Alkyl can be unsubstituted or quilt One or more glitch-free substituting groups replace, and described substituting group is halogen, alkoxyl, acyl-oxygen for example The suitable blocking-up of base, hydroxyl, sulfydryl, carboxyl, benzyloxy, phenyl, benzyl or other protected base In order to make its not disturbed functional group. Each substituting group can be randomly by other glitch-free getting Generation base replacement. Term " glitch-free " means to any reaction of carrying out according to method of the present invention invariably The substituting group of sharp impact.
" low alkyl group " used herein refers to C1 to C4, C6 or C8 alkyl, and it can be straight chain Or side chain, and can be saturated or unsaturated.
" cycloalkyl " be the place regulation so, normally C3, C4 or C5 to C6 or C8 cycloalkyl.
" hydroxy alkyl " used herein refers to the alkyl that is replaced by hydroxyl of the straight or branched of C1 to C4, namely-and CH2OH、-(CH 2) 2OH etc.
" aminoalkyl " used herein refers to the alkyl that is replaced by amino of the straight or branched of C1 to C4, term wherein " amino " refers to group NR ' R "; wherein R ' and R " is independently selected from H or low alkyl group defined above, namely-and NH2、-NHCH 3、-N(CH 3) 2Deng.
" alkoxyl " used herein refers to the alkyl that is replaced by oxygen of C1 to C4, namely-and OCH3, term " aryloxy group " refers to the ring-type aryl that is replaced by oxygen of C3 to C10.
" alkenyl " refer to derived from corresponding alkyl and contain at least one two key alkyl, be generally C2 To C4 alkyl (for example butadienyl). " low-grade alkenyl " used herein refers to C1 to C4 alkene equally Base.
" alkynyl " refer to derived from corresponding alkyl and contain at least one triple bond alkyl, be generally C2 extremely C4 alkyl (for example diacetylene base).
" aryl " used herein refers to C6 to C10 ring-type aryl, such as phenyl, naphthyl etc., comprises and getting The aryl in generation such as tolyl.
" heterocycle " used herein refers to saturated, the undersaturated or aromatic carbocyclic group of unit price, its Contain a ring or a plurality of condensed ring and contain at least one hetero atom at ring, such as N, O or S, its Can randomly be unsubstituted or dried by hydroxyl, alkyl, alkoxyl, halogen, sulfydryl and other nothing The substituting group of disturbing replaces. The example of azacyclo-include but not limited to pyrroles, imidazoles, pyrazoles, pyridine, Pyrazine, pyrimidine, pyridazine, indolizine, iso-indoles, indoles, indazole, purine, quinolizine, isoquinolin, Quinoline, 2,3-benzodiazine, 1,5-benzodiazine, quinoxaline, quinazoline, cinnolines, pteridine, carbazole, Carboline, phenanthridines, acridine, phenanthroline, isothiazole, azophenlyene, isoxazole, phenoxazine, phenthazine, Imidazolidine, imidazoline, piperidines, piperazine and indoline.
" halogen " used herein refers to any halogen group, such as chlorine, fluorine, bromine or iodine.
The compound of " carbohydrate " indication used herein is to contain at least 6 by one or more Carbon atom (it can be straight chain, side chain or ring-type) and the oxygen that is bonded on each carbon atom are former The carbohydrate itself that the monosaccharide units of son consists of; Or contain by one or more monosaccharide units The carbohydrate molecule group that consists of is as its a part of compound, and each monosaccharide units contains at least 6 Individual carbon atom (it can be straight chain, side chain or ring-type) and to be bonded in the oxygen of each carbon on former former Son. Representational carbohydrate comprises that sugar (monosaccharide and disaccharide, trisaccharide and oligosaccharides) and polysaccharide are as forming sediment Powder, glycogen, cellulose and polysaccharide gum (polysaccharide gum). Concrete monose comprise C6 and with The sugar of upper (preferred C6 to C8) is such as glucose, fructose, mannose, galactolipin, ribose and red-spotted stonecrop heptan Ketose; Disaccharide and trisaccharide comprise the sugar that contains 2 or 3 monosaccharide units (preferred C5 to C8), as sucrose, Cellobiose, maltose, lactose and gossypose.
" flavonoids " used herein or " bioflavonoid " relate to the ubiquitous polyphenol substance of a class, It is present in the most plants, in concentrating on seed, pericarp, bark and spending. Flavonoids has multiclass, Comprise: flavanols, flavanones, flavones (2-phenylchromone), flavan-3-alcohol (catechin), anthocyanin And isoflavones. The flavonoids of illustrative includes but not limited to that baicalein, scutelloside, Wogonin reach Its analog.
" chromone " refers to chromone. Chromone represents flavones and isoflavones parent nucleus, often is the plant look Plain composition.
Used herein " treatment " is the treatment of instigating any type that the patient that is subjected to the disease puzzlement is benefited, Comprise the state of an illness (for example improving one or more symptoms) of improving the patient, development, the prevention that delays the state of an illness Or delay outbreak of disease etc.
" state of an illness ", " disease " and " illness " are used interchangeably, and referring to can be by using basis described herein The compound of invention and the physiological status of being prevented or treating.
" pharmaceutically useful " composition (such as salt, carrier, excipient or diluent) used herein means chemical combination Thing or composition are suitable for being applied to subject realizing treatment described herein, and with respect to disease The needs of the order of severity and treatment do not produce excessively harmful side effect.
Used herein " treatment effective dose " refers to prevent, delay or alleviates the serious of the illness paid close attention to The amount that degree is required also comprises strengthening the required amount of normal physiological function.
Generally speaking, reactive compound of the present invention comprises the structure of following formula:
Figure A20038010182100201
Wherein:
R 1、R 2And R3Be independently of one another H, alkyl, alkenyl, alkynyl ,-SO3H、-PO 3H 2Or carbohydrate;
Perhaps R1And R2(CH independently of one another2) nY and [CH2CH(OH)CH 2] Y, wherein Y is H, OR4、NR 5R 6、COOR 4Or OONR5R 6, R wherein4、R 5And R6H, alkyl, alkenyl, alkynyl or carbohydrate independently of one another, and R5And R6Can form together 5 to 7-unit's rings;
Perhaps R1And R2Heterocycle together;
Perhaps R 2And R 3Be heterocycle together; And
X 1And X 2Be formula independently of one another:
Ar-X 3-T，
Wherein Ar can exist or not exist, and when Ar existed, Ar was phenyl, furyl, thienyl, pyridine radicals, cyclohexyl or benzyl; X wherein 3Be H, C, N, NR ', NR ' R ", NR ' SO 2R ", O or S, condition is that formula I chemical compound is not noroxylin or 5,6,7-trihydroxy-isoflavone, wherein R ' and R " are H, alkyl, alkenyl, alkynyl or carbohydrate independently of one another; Wherein T is (CH 2) nY or [CH 2CH (OH) CH 2] Y, wherein Y is H, OR 4, NR 5R 6, COOR 4Or OONR 5R 6, R wherein 4, R 5And R 6Be H, alkyl, alkenyl, alkynyl or carbohydrate independently of one another, and R 5And R 6Can form 5 to 7-unit's rings together; Or its pharmaceutically useful salt.
Formula (I) chemical compound can be water miscible.In some embodiments, R 1, R 2And R 3Can be that the chemical compound of selecting that makes has water miscible micel so that new water soluble compound to be provided.Except said circumstances, as selection, R 1, R 2And R 3Can also be sulfate radical (SO 3H), sulfonate radical, phosphate radical (PO 3H 2) or phosphonate radical so that new water soluble compound to be provided.And sulfate radical, sulfonate radical, phosphate radical or phosphonate radical can be water miscible salt forms.As representational nonrestrictive example, can form water soluble salt with alkali metal salt such as sodium, potassium or ammonium salt.Water soluble salt can be single-, two-or three-alkali metal salt.
Reactive compound of the present invention also comprises the structure of following formula:
Figure A20038010182100211
Figure A20038010182100221
Figure A20038010182100222
Wherein:
R 7, R 8And R 9Be independently of one another H, alkyl ,-SO 3H ,-PO 3H 2, carbohydrate or benzyl;
Perhaps R 7And R 8Be heterocycle together;
Perhaps R 8And R 9Be heterocycle together;
X 1Be H, C, NH 2, NHCOCH 3, NO 2Or OR 10, R wherein 10Be H, alkyl, carbohydrate or benzyl, or its pharmaceutically useful salt, wherein X 1Can be connected in ortho position, a position or the para-position, condition is to work as Ph-X 1When being positioned at the 2-position, this chemical compound is not used in the treatment septic shock.
R 7, R 8And R 9Can be that the chemical compound of selecting that makes has water miscible micel so that new water soluble compound to be provided.Except said circumstances, as selection, R 7, R 8And R 9Can also be sulfate radical (SO 3H), sulfonate radical, phosphate radical (PO 3H 2) or phosphonate radical so that new water soluble compound to be provided.And sulfate radical, sulfonate radical, phosphate radical or phosphonate radical can be water miscible salt forms.As representational nonrestrictive example, can form water soluble salt with alkali metal salt such as sodium, potassium or ammonium salt.Water soluble salt can be single-, two-or three-alkali metal salt.
Reactive compound of the present invention also comprises known water solublity noroxylin derivant, include but not limited to noroxylin-6-sulfuric ester, noroxylin-6,7-di-sulfate, noroxylin-6-phosphate ester, noroxylin-6,7-bisphosphate, noroxylin-5,6,7-triguaiacyl phosphate and its pharmaceutically useful salt, as NagaiH etc., water solublity noroxylin derivant is to the inhibitory action .Jpn J Pharmacol December of allergy; 25 (6): 763-7 (1975); Nohara, A. etc., Takeda Kenkyushoho 30 (4): 677-81 (1971); With US 3,549, in 662 disclosed those.
A. noval chemical compound is synthetic
To those skilled in the art, below the variant of general synthetic method be very conspicuous, these variants include within the scope of the invention.
The general synthetic method of scheme 1. flavones
Figure A20038010182100241
Scheme 1 for example understand noroxylin 4 '-amino-and 4 '-the general synthetic method of oxygen radical derivative.Noroxylin analog (1) synthesizes as shown in scheme 2 and 3.At alkali (K for example 2CO 3) or tertiary amine (Et for example 3N) exist down with electrophilic reagent noroxylin analog (1) alkylation, generate noroxylin derivant (being respectively 2a and 2b), described electrophilic reagent such as W (CH2) nY, wherein Y as defined above, W (CH2) nOR, W (CH2) nCO 2R or W (CH2) nCONR 1R 2, wherein W is leaving group and R, R 1And R 2WCH2CH (O) CH2 or HOCH as hereinbefore defined, 2CH (O) CH 2Making Y wherein is the alkylate (2) and MsCl reaction of OH, with the amine reaction, generates the noroxylin analog shown in (3) then.
The synthetic method of scheme 2:4 '-oxygen base noroxylin derivant
Figure A20038010182100251
The synthetic method of scheme 3:4 '-amino noroxylin derivant
Figure A20038010182100261
Other chemical compound and synthetic method can be with reference to the U.S. Patent No.s 4,495,198 of following patent and document: Wu; The U.S. Patent No. 4,797,498 of Albrecht etc.; The U.S. Patent No. 4,758,679 of Schmitthenner etc.; The U.S. Patent No. 4,668,805 of Wu; The U.S. Patent No. 4,668,804 of Wu; The U.S. Patent No. 4,495,198 of Wu; The WO 01/30342 of Lee etc.; Suk K. etc., the flavonoid noroxylin reduces the cell death of the inductive brain microgliacyte of activation.J.Pharmacol.Exp.Therap.2003,305,638-645; Riseman .Am.J.Cardiol.1965 such as JEF, 15,220; And Wu, ESC etc., flavonoid.3. synthetic, the biologic activity of isoflavone derivative and allied compound and conformational analysis.J.Med.Chem.1992，35，3519-3525。
B. pharmaceutically useful salt
Term used herein " activating agent " comprises the pharmaceutically useful salt of chemical compound.Pharmaceutically useful salt is the salt of having preserved the biologic activity of required parent compound and not produced undesirable toxicology effect.The example of this type of salt has for example acid-addition salts of formation such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid of (a) and mineral acid; With the salt that forms as for example acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannin, Palmic acid, alginic acid, polyglutamic acid, LOMAR PWA EINECS 246-676-2, methanesulfonic acid, p-methyl benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid etc. with organic acid; (b) salt that forms with element anion such as chlorine, bromine and iodine.In specific embodiments, pharmaceutically useful salt is the salt that forms with hydrochloric acid.In other specific embodiments, pharmaceutically useful salt is the salt that forms with malic acid.
Prepare the pharmaceutically useful free alkali form that the used activating agent of compositions of the present invention also can be an activating agent.Because the free alkali of chemical compound is poor than the salt water solublity, so the free alkali compositions can provide activating agent to targeting moiety by slow release effect more strongly.The activating agent that does not enter solution that exists in targeting moiety can not cause physiological reaction, but can be used as the biological available drug depot that progresses into solution.
C. pharmaceutical preparation
Flavonoid of the present invention and flavonoid analog can be used as forms of pharmacologically active agents, and can use with the crude drug form.But more preferably these chemical compounds being mixed with pharmaceutical preparation uses.Can use the carrier of chemical compound of the present invention with any conduct in a large amount of appropriate drug preparations.
Be to be understood that: above some various chemical compound may contain one or more asymmetric carbon atoms, therefore can exist with enantiomeric form.Except as otherwise noted, otherwise the present invention includes this type of enantiomer, described enantiomer comprises racemate.Can be with the synthetic independent enantiomer of chirality initiation material, perhaps can be with the resolution of racemic things such as fractional crystallization of well-known method in the chemical field such as chiral chromatography, diastereoisomeric salt.
Chemical compound of the present invention can be prepared and be used to use to treat various diseases.In the preparation of pharmaceutical preparation of the present invention, usually with chemical compound of the present invention and its physiologically acceptable salt or in the two any acid derivative (hereinafter being called " reactive compound ") mix mutually with acceptable carrier especially.Certainly carrier must be acceptable, implication be with preparation in any other composition compatible and must be harmless to the patient.Carrier can be solid or liquid or solid and liquid, and preferably is mixed with the preparation of unit dose with chemical compound, tablet for example, and the preparation of described unit dose can contain the reactive compound of 0.5% to 95% weight ratio.In a specific embodiments, pharmaceutical composition comprises the reactive compound less than 80% weight ratio.In other specific embodiments, pharmaceutical composition comprises the reactive compound less than 50% weight ratio.Can mix in every class reactive compound one or more in the preparation of the present invention, it can mainly comprise becoming phase-splitting to mix each by any preparation the in the known pharmaceutical technology, wherein randomly comprises one or more auxiliary elements.
Preparation of the present invention comprises that those are suitable for oral, rectum, part, suck (for example Sublingual), parenteral the preparation of (for example subcutaneous, intramuscular, Intradermal or intravenous) and transdermal administration, but optimum approach depends on the character of the character of disease to be treated and the order of severity and used concrete reactive compound under any given situation.
Being suitable for Orally administered preparation can be the discrete unit form, and as capsule, cachet, lozenge, tablet, dragee or syrup, each discrete unit contains the reactive compound of scheduled volume; Powder or granule; Solution in aqueous or non-aqueous liquid or suspensoid; Or oil-in-water type or water-in-oil emulsion.This type of preparation can prepare with any suitable pharmaceutical methods, and described method comprises reactive compound and the mutually blended step of appropriate carrier (it can contain one or more above-mentioned auxiliary elements).
Generally speaking, preparation of the present invention prepares by the following method: evenly and fully mix with reactive compound and liquid or levigated solid carrier or with liquid and levigated solid carrier, then if necessary, the gained mixture is shaped.For example, powder or granule that can be by will containing reactive compound, randomly suppress or mold pressing prepares tablet with one or more auxiliary elements.Can prepare compressed tablet by the chemical compound of stranglehold liquid form such as powder or particle form in suitable machine, described chemical compound can randomly mix with binding agent, lubricant, inert diluent and/or surfactant/dispersant.Can prepare molded tablet with the powder compound of inert liquid binder moistening by mold pressing in suitable machine.
Being suitable for sucking the preparation of (Sublingual) using comprises containing and is in flavoring substrate, the lozenge of the reactive compound in sucrose and arabic gum or the tragakanta normally; With contain the lozenge that is in the chemical compound in inert base such as gelatin and glycerol or sucrose and the arabic gum.
Of the present inventionly be suitable for the sterile aqueous preparation that preparation that parenteral uses comprises reactive compound suitably, said preparation is preferably opened with expection receiver's blood etc.These preparations can be used by subcutaneous, intravenous, intramuscular or intradermal injection.This type of preparation can be by mixing chemical compound and making gained solution aseptic and open with blood etc. and to prepare easily with water or glycine buffer.
The preparation that is suitable for rectal administration is preferably the suppository form of unit dose.These can be by for example cocoa butter mixes, the gained mixture is shaped prepares then with the conventional solid carrier of reactive compound and one or more.
The preparation that is suitable for being applied topically to skin preferably adopts ointment, ointment, lotion, paste, gel, spray, aerosol or oil preparation (oil) form.
The preparation that is suitable for transdermal administration can be to be suitable for and the long-time discrete patch form that closely contacts of receiver's epidermis.The preparation that is suitable for transdermal administration also can send by iontherapy (referring to, for example, Pharmaceutical Research 3 (6): 318 (1986)), and usually adopt the aqueous solution form of the optional reactive compound that is cushioned.Suitable preparation comprises citrate or two/ternary buffer (pH6) or ethanol/water, and contains 0.01 to 0.2M active component.
The present invention also can be mixed with slow releasing preparation.Slow releasing composition includes but not limited to that active component wherein is bonded in those compositionss on the ion exchange resin, and described ion exchange resin randomly is coated with diffusion-barrier coating to adjust the releasing properties of resin.
Spendable carrier and/or diluent comprise that vaseline, lanoline, glycerol, vegetable oil or fat prevents breast, Polyethylene Glycol, alcohol, transdermal enhancer, natural or hydrogenated oil and fat or wax and wherein two or more combination.
In specific embodiments, the invention provides water miscible various chemical compound described herein.In some embodiments, make chemical compound described herein have water solublity by preparing its water soluble salt.As nonrestrictive example, available bases slaine such as sodium, potassium or ammonium salt make chemical compound have water solublity.Water soluble salt can be single-, two-or three-alkali metal salt.In some embodiments, can add and to make chemical compound have water miscible micel so that new water soluble compound to be provided.This type of micel includes but not limited to sulfate radical, sulfonate radical, phosphate radical or phosphonate radical micel, and it can be selected for the water soluble compound that provides new.In addition, sulfate radical, sulfonate radical, phosphate radical or phosphonate radical also can be above-mentioned water soluble salt forms.In some embodiments, can make chemical compound have water miscible micel can be SO 3H or PO 3H 2With its salt, include but not limited to sodium and potassium salt.In some embodiments, reactive compound of the present invention comprises known water solublity noroxylin derivant, it includes but not limited to noroxylin-6-sulfuric ester, noroxylin-6,7-di-sulfate, noroxylin-6-phosphate ester, noroxylin-6,7-bisphosphate, noroxylin-5,6,7-triguaiacyl phosphate and its pharmaceutically useful salt.
D. using method
Except various chemical compound described herein, the present invention also provides useful Therapeutic Method.For example, the invention provides prevention or treatment produces with TNF-α excess, produces relevant disease or disease, septic shock, inflammation, organ injury, neurodegenerative disease, cancer and cardiopathic method with superoxide anion base excess.
In specific embodiments, produce relevant disease or disease with TNF-α excess and include but not limited to arthritis, rheumatoid arthritis, segmental enteritis, ulcerative colitis, insulin resistance, multiple sclerosis, organ failure, pulmonary fibrosis and atherosclerosis.
In specific embodiments, produce relevant disease or disease with superoxide anion base excess and include but not limited to Alzheimer, parkinson disease, aging, cancer, myocardial infarction, atherosclerosis, autoimmune disease, radiation injury, edema due to disorder of QI, sunburn, joint disease and oxidative stress.
In specific embodiments, organ injury includes but not limited to hepatic injury, injury of kidney and injury of lung.In addition, organ injury can be caused by multiple reason, and described reason includes but not limited to cancer, infects, is exposed to environmental toxin or anaphylactogen, is exposed to chemical substance such as medicine (recuperation property or curative medicine) and ethanol and disease such as hepatitis, sclerosis, diabetes, hypertension, glomerulonephritis, renal calculus, multicystic kidney disease, pneumonia, tuberculosis, edema due to disorder of QI, bronchitis and asthma.
In specific embodiments, neurodegenerative disease includes but not limited to parkinson disease, Alzheimer, cognitive defect (cognition deficit), the loss of memory (memory loss) and apoplexy.
In other specific embodiments, the cancer of illustrative includes but not limited to leukemia, lymphoma, colon cancer, renal carcinoma, hepatocarcinoma, breast carcinoma, pulmonary carcinoma, carcinoma of prostate, ovarian cancer, melanoma, small cell lung cancer, carcinoma of testis, esophageal carcinoma, gastric cancer, carcinoma of endometrium, central nervous system's cancer etc.The implication that term " cancer " has in this area to be understood for example has and diffuses to the out of control tissue growth that may (promptly shift) of body away from the position.The method of treatment and prophylaxis of tumours formation property cancer preferably.Term " tumor " also is understood that for example unusual agglomerate of the interior undifferentiated cell of multicellular organisms in the art.Tumor can be virulent or benign.Preferably, Compounds and methods for of the present invention disclosed herein is used for prevention and treatment malignant tumor.
In other specific embodiments, heart disease includes but not limited to myocardial ischemia, congestive heart failure and hypertension.
Suitable object for the treatment of of the present invention comprises birds and mammals object, preferred mammals.According to the present invention, mammal includes but not limited to Canis animals, felid, bovine, goat class animal, equine species, sheep class animal, porcine animals, rodent (for example rat and mice), lagomorph, primate etc., and is included in intrauterine mammal.Preferred people.
According to the present invention, the birds of illustrative comprise that chicken, duck, turkey, goose, quail, Phasiana, ratite (for example Ostriches) and family keep pet (for example Psittacula alexandri fasciata and canary), and are included in the bird in the ovum.Preferred chicken and turkey.
According to the present invention, any mammalian object of treatment that needs all is fit to.Preferred human subjects.According to the present invention, two kinds of sexes and be in (being neonate, baby, teenager, youth, adult) human subjects of any stage of development and all can be treated.
As mentioned above, the invention provides and comprise the pharmaceutical preparation that is in the various compound or pharmaceutically acceptable salt thereof described herein in pharmaceutically suitable carrier, pharmaceutical preparation can be used through any suitable route, includes but not limited to oral, rectum, part, sucks, parenteral, intramuscular, Intradermal, intravenous and transdermal administration.
According to the present invention, method of the present invention comprises that the above-mentioned composition of the present invention with effective dose is applied to subject.The effective dose of compositions (its use comprises within the scope of the invention) changes because of subject is different to a certain extent, and depends on age and the state of an illness and the route of delivery of multiple factor such as subject.Described dosage can be definite according to well known to a person skilled in the art conventional pharmacological method.For example, chemical compound of the present invention can be from about 0.01 with amount, 0.02,0.03,0.04,0.05,0.06,0.07,0.08,0.09,0.10,0.20,0.30,0.40,0.50,0.60,0.70,0.80,0.90,1.0,2.0,3.0,4.0,5.0,6.0,7.0,8.0,9.0 or the lower limit of 10% composition weight ratio is to about 10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98, the upper limit of 99 or 100% composition weight ratio is applied to subject.In some embodiments, chemical compound accounts for about 0.05 to about 95% of composition weight.In other embodiments, chemical compound accounts for about 0.05 to about 60% of composition weight.In other embodiments, chemical compound accounts for about 0.05 to about 10% of composition weight.
The treatment effective dose of any specific compound all changes, and depends on patient's the state of an illness and route of delivery because of chemical compound difference, patient's difference to a certain extent.As general recommendations, have therapeutic efficiency from about dosage of 0.1 to about 50mg/kg, used dosage may be higher when oral and/or aerosol was used.Toxicity under the higher level is considered intravenous dosages to be limited to more low-level as to be no more than about 10mg/kg, and all wt is that benchmark calculates with active alkali weight all, comprises the situation of using salt.Usually, the used dosage of intravenous or intramuscular administration is that about 0.5mg/kg is to about 5mg/kg.Orally administered used dosage is that about 10mg/kg is to about 50mg/kg.
In specific embodiments, chemical compound of the present invention can be used to the daily dose of about 20mg/kg the weight of animals with about 0.1mg, and this daily dose can give or give with the slow release form with the divided dose to four times a day once a day.For the people, every day accumulated dose can for about 5mg to about 1,400mg, in other specific embodiments, every day, accumulated dose was about 10mg about 100mg extremely.In other embodiments, be suitable for Orally administered dosage form can comprise randomly with about 2mg of solid or liquid, medicinal carrier or mixing diluents to about 1, the 400mg chemical compound.
In specific embodiments, reactive compound of the present invention can use separately or with other therapeutic agent combined administration, for example, reactive compound of the present invention can with other chemical compound of the present invention and at present compound known or later on compounds identified use, be used to prevent or treatment produces with TNF-α excess, with relevant disease or disease, septic shock, inflammation, organ injury, neurodegenerative disease, cancer and the heart disease of superoxide anion base excess generation.The chemical compound of illustrative includes but not limited to antibiotic, antimicrobial drug, antiviral agents, vaccine etc.
Generally speaking, chemical compound of the present invention can be used treating the disease of required treatment with any amount that is suitable for being applied to subject, and this amount can be determined with reference to relevant books and document and/or by normal experiment by those of ordinary skills.(referring to, for example, Remington, The Science AndPractice of Pharmacy (the 9th edition, 1995)).
In following non-limiting example, explained the present invention in more detail.
Embodiment 1
The preparation of new noroxylin analog
Acetic acid 3,4, the preparation of 5-trimethoxyphenyl ester (4).With 3,4, (5.52g, 30mmol) solution in acetic anhydride (15mL) refluxed 4 hours 5-trimethoxy phenol.Reactant mixture is poured on the trash ice (50g).Collection gained precipitation also washes with water.Residue obtains white crystal (6.31g, 93%), 74-75 ℃ in 50 ℃ of following vacuum dryings 24 hours; 1H NMR (CDCl 3, 200M Hz) δ 6.34 (s, 2H), 3.83 (s, 6H), 3.82 (s, 3H), 2.29 (s, 3H); 13C NMR (CDCl 3, 50M Hz) and δ 169.6 (s), 153.5 (s, 2C), 146.7 (s), 135.8 (s), 99.1 (d, 2C), 60.9 (q), 56.1 (q, 2C), 21.1 (q).
The preparation of 1-(6-hydroxyl-2,3,4-trimethoxyphenyl) ethyl ketone (5).(13.0mL) drops to acetic acid 3,4 with the boron trifluoride diethyl etherate compound, and (6.78g is 30mmol) in the solution in glacial acetic acid (10mL) for 5-trimethoxyphenyl ester 4.This mixture was stirred 2 hours down at 70 ℃.Then, mixture is poured on the trash ice (80g).Isolate light brown oily thing and distilling under reduced pressure, obtain light yellow oil (5.56g, 82%); 1H NMR (CDCl 3, 200M Hz) δ 13.42 (br s, 1H), 6.23 (s, 3H), 3.82 (s, 3H), 3.99 (s, 3H), 3.88 (s, 3H), 3.79 (s, 3H), 2.65 (s, 3H); 13C NMR (CDCl 3, 50M Hz) and δ 203.3 (s), 161.8 (s), 160.0 (s), 155.2 (s), 134.7 (s), 108.4 (s), 96.0 (d), 60.9 (q, 2C), 56.0 (q), 31.8 (q).
6-hydroxyl-1-(4-methoxyl group cinnamoyl)-2,3, the preparation of 4-trimethoxy-benzene (6).With 1-(6-hydroxyl-2,3,4-trimethoxyphenyl) ethyl ketone 5 (2.26g, 10mmol), the 4-methoxybenzaldehyde (1.63g, 12mmo1) and t-BuOK (2.11g, 22mmol) solution in ethanol (30mL) refluxed 4 hours.Reactant mixture is poured on the trash ice (100g).Leach gained precipitation and wash with water.Residue is at room temperature air-dry.The crude product re-crystallizing in ethyl acetate obtains chalcone derivative, is orange crystal (2.99g, 87%): 1H NMR (CDCl 3, 200M Hz) δ 11.75 (br s, 1H), 7.84 (s, 2H), 7.60 (d, J=8.8Hz, 2H), 6.93 (d, J=8.8Hz, 2H), 6.29 (s, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3,85 (s, 3H), 3.84 (s, 3H); 13C NMR (CDCl 3, 50M Hz) and δ 192.7 (s), 162.6 (s), 161.5 (s), 159.9 (s), 154.9 (s), 143.3 (d), 135.2 (s), 130.1 (d, 2C), 128.0 (s), 124.0 (d), 114.4 (d, 2C), 108.7 (s), 96.5 (d), 61.8 (q), 61.2 (q), 56.0 (q), 55.3 (q).
4 ', 5,6, the preparation of 7-tetramethoxy flavone (1c).With chalcone derivative 6 (1.72g, 5mmol) and the solution of iodine (catalytic amount) in dimethyl sulfoxine (6mL) refluxed 30 minutes, reactant mixture is poured on the trash ice (50g) then.Collect the gained precipitate also with 5% hypo solution (30mL) and water washing.Use ethyl alcohol recrystallization, obtain the flavone (1.38g, 81%) in the title, be pale yellow crystals: 1H NMR (CDCl 3, 200M Hz) δ 7.81 (d, J=9.0Hz, 2H), 6.98 (d, J=9.0Hz, 2H), 6.79 (s, 1H), 6.57 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H); 13C NMR (CDCl 3, 50M Hz) and δ 177.1 (s), 162.0 (s), 161.0 (s), 157.5 (s), 154.3 (s), 152.4 (s), 140.2 (s), 127.5 (d, 2C), 123.6 (s), 114.2 (d, 2C), 122.7 (s), 106.8 (d), 96.1 (d), 62.0 (q), 61.4 (q), 56.1 (q), 55.3 (q).
4 ', 5,6, the preparation of 7-kaempferol (1d).Under 0 ℃, Boron tribromide (0.7mL) is dropped to flavone 1c, and (68.4mg is 0.2mmol) in the solution in dichloromethane (3mL).Making mixture be warmed to room temperature after 30 minutes also at room temperature stirred 20 hours.Mixture is poured in the frozen water (20mL) then.Separate organic layer and concentrating under reduced pressure.Water layer is poured on the organic remains.After the stirring, leach precipitate and wash with water.Use ethyl alcohol recrystallization, obtain title compound (50mg, 88%), be yellow crystals: 1H NMR (DMSO, 200M Hz) δ 10.20 (br s, 2H), 7.90 (d, J=8.7Hz, 2H), 6.90 (d, J=8.7Hz, 2H), 6.72 (s, 1H), 6.57 (s, 1H), 3.75 (br s, 2H); 13C NMR (DMSO, 50M Hz) δ 182.1 (s), 163.6 (s), 161.0 (s), 153.3 (s), 149.7 (s), 147.1 (s), 129.2 (s), 128.4 (d, 2C), 121.5 (s), 116.0 (d, 2C), 104.1 (s), 102.3 (d), 93.9 (d).
7-methoxyl group-4 ', 5, the preparation of 6-trihydroxyflavone (1f).Similar with the preparation method of 1c, by 6-hydroxyl-1-(4-benzyloxy cinnamoyl)-2,3,4-trimethoxy-benzene (6b) preparation 1e (4 '-benzyloxy-5,6,7-trimethoxy flavone), and 6b obtains by 1-Phenylethanone. 5 and the reaction of 4-benzyloxy benzaldehyde.(500mg, 1.20mmol) solution in 48%HBr (5mL) and glacial acetic acid (10mL) refluxed 2 hours with 1e.Then, reactant mixture is poured on the trash ice (about 100g).Leach the gained precipitate and wash with water.Use ethyl alcohol recrystallization, obtain chemical compound 1f (305mg, 85%). 1H?NMR(DMSO，200M?Hz)δ12.63(br?s，1H)，10.30(br?s，1H)，8.70(br?s，1H)，7.93(d，J＝8.8Hz，2H)，6.92(d，J＝8.8Hz，2H)，6.88(s，1H)，6.78(s，1H)，3.90(s，3H)； 13C?NMR(DMSO，50MHz)δ182.2(s)，163.8(s)，161.1(s)，154.3(s)，149.6(s)，146.2(s)，129.9(s)，128.4(d，2C)，121.4(s)，116.0(d，2C)，105.0(s)，102.5(d)，91.1(d)，56.3(q)。The spatial chemistry of chemical compound 1f is by cosy and nosy experiment conclusive evidence.
4 ', 7-methoxyl group-5, the preparation of 6-dihydroxyflavone (1g).Similar with the preparation method of 1f, by 1c (500mg, 1.46mmol) preparation title compound (407mg), productive rate 89%. 1H?NMR(DMSO，200M?Hz)δ12.59(br?s，1H)，8.70(br?s，1H)，8.02(d，J＝8.6Hz，2H)，7.08(d，J＝8.6Hz，2H)，6.90(s，1H)，6.85(s，1H)，3.91(s，3H)，3.84(s，3H)； 13C?NMR(DMSO，50MHz)δ182.2(s)，163.3(s)，161.3(s)，154.4(s)，149.7(s)，146.2(s)，130.0(s)，128.2(d，2C)，123.0(s)，114.6(d，2C)，105.1(s)，103.1(d)，91.2(d)，56.3(q)，55.6(q)。The spatial chemistry of chemical compound 1g is by cosy and nosy experiment conclusive evidence.
4 '-hydroxyl-5,6, the preparation of 7-trimethoxy flavone (1h).With 1e 4 '-benzyloxy-5,6, and 7-trimethoxy flavone (120mg, 0.29mmol) and the hydrogenation 4 hours under atmospheric pressure of the suspension of palladium on carbon (10%) in ethanol (15mL) of catalytic amount.Filtration catalizer also removes and desolvates, and obtains title compound 1h (89mg, 95%), is pale yellow crystals.Not purified, the purity of this chemical compound is greater than 95%. 1HNMR(DMSO，200M?Hz)δ7.88(d，J＝8.6Hz，2H)，7.16(s，1H)，6.90(d，J＝8.6Hz，2H)，6.60(s，1H)，3.93(s，3H)，3.93(S，3H)，3.78(s，3H)，3.75(s，3H)。
2 '-hydroxyl-4 ', 5 ', 6 '-preparation of trimethoxy-4-nitro chalcone derivative (7a).With 3,4, (1.85g, 10mmol) (2.11g, mixture 10mmol) is dissolved in BF to 5-trimethoxy phenol with 4-nitro cinnamoyl chloride 3-Et 2In the O complex (10mL) and be heated to 80 ℃ and reach 10 minutes, use the excessive water stopped reaction then.Use the dichloromethane extraction water layer.The organic layer that merges is concentrated residue silica gel chromatography (CH 2CH 2: EtOAc: hexane=1: 1: 3), obtain 7a (0.79g, 22%) and 7b (1.54g, 43%). 1H?NMR(400M?Hz，CDCl 3)δ3.81(s，3H)，3.90(s，3H)，3.91(s，3H)，6.29(s，1H)，7.74(d，J＝8.8Hz，2H)，7.76(d，J＝16.0Hz，1H)，8.01(d，J＝16.0Hz，1H)，8.26(d，J＝8.8Hz，2H)，13.44(s，1H)。
5,6,7-trimethoxy-4 '-preparation of nitro flavone (8).With 7a (0.80g, 2.2mmol) and the mixture of iodine (20mg) in DMSO (5mL) refluxed 1 hour, be poured on the trash ice carefully then.Leach precipitate and use 20%Na 2SO 3Washing.With the precipitate acetone recrystallization, obtain 8 (0.73g, 93%). 1H?NMR(400MHz，CDCl 3)δ3.91(s，3H)，3.97(s，3H)，3.98(s，3H)，6.74(s，1H)，6.82(s，1H)，8.03(d，J＝8.8Hz，2H)，8.34(d，J＝8.8Hz，2H)。
6,7-dimethoxy-5-hydroxyl-4 '-preparation of nitro-flavone (9a).(0.11g, 0.32mmol) solution in 47%HBr (2.5mL) and glacial acetic acid (5mL) refluxed 1 hour, was poured on the trash ice then with 8.Leach precipitate, use ethyl alcohol recrystallization, obtain 9 (0.09g, 88%). 1H?NMR(400MHz，CDCl 3)δ3.91(s，3H)，3.98(s，3H)，6.58(s，1H)，6.75(s，1H)，8.05(d，J＝8.8Hz，2H)，8.36(d，J＝8.8Hz，2H)。
5,7-dihydroxy-6-methoxyl group-4 '-preparation of nitro flavone (9b).Under-78 ℃, (71mg is 0.2mmol) at CH to flavone 8 2Cl 2(0.4mL is 0.4mmol) at CH for the Boron tribromide of adding 1M in the solution (5mL) 2Cl 2In solution.Stirred 5 hours down with solution restir 2 hours and at-20 ℃, then water (10mL) stopped reaction.By filtering the collecting precipitation thing, use CH 2Cl 2Recrystallization obtains crude product 5 (30mg, 46%). 1H?NMR(400MHz，DMSO)δ3.93(s，3H)，7.01(s，1H)，7.21(s，1H)，8.38-8.39(m，4H)。
4 '-amino-5,6, the preparation of 7-trimethoxy flavone (10a).With flavone 8 (0.07g, the 0.2mmol) hydrogenation 8 hours in the presence of 5% palladium on carbon (20mg) under 40psi of the solution in the Zai diox (10mL), filtration catalizer.Under reduced pressure from filtrate, remove diox, obtain 10a (0.05g, 87%). 1H?NMR(400MHz，CDCl 3)δ3.98(s，3H)，3.94(s，3H)，3.95(s，3H)，6.45(s，1H)，6.71(d，J＝8.8Hz，2H)，6.75(s，1H)，7.65(d，J＝8.8Hz，2H)。
4 '-amino-5, the preparation of 7-dihydroxy-6-methoxy flavone (10b).Under-78 ℃, (130mg is 0.4mmol) at CH to flavone 10a 2Cl 2(1.5mL is 1.5mmol) at CH for the Boron tribromide of adding 1M in the solution (10mL) 2Cl 2In solution.Stirred 5 hours down with solution restir 2 hours and at-20 ℃, then water (10mL) stopped reaction.By filtering the collecting precipitation thing, obtain crude product 10b (51mg, 43%). 1H?NMR(400MHZ，DMSO)δ3.89(s，3H)，6.68(s，1H)，6.74(d，J＝8.8Hz，2H)，6.87(s，1H)，7.82(d，J＝8.8Hz，2H)。
4 '-(N, N-dimethylamino)-5,6,7-trimethoxy flavone (10c) and 4 '-(methylamino)-5,6, the preparation of 7-trimethoxy flavone (10d).With amino flavone 10a (0.54g, 1.65mmol), Anhydrous potassium carbonate (0.91g, 6.6mmol) and iodomethane (0.2mL, 3.3mmol) mixture in acetone (20mL) stirred 48 hours, removed acetone then.Also use silica gel chromatography (acetone: toluene=1: 5), obtain the 10a (65mg, 12%) of 7 (0.22g, 38%), 10d (0.26g, 46%) and recovery with the dichloromethane extraction residue.10c： 1H?NMR(400MHz，CDCl 3)δ3.04(s，6H)，3.89(s，3H)，3.95(s，3H)，3.96(s，3H)，6.52(s，1H)，6.72(d，J＝8.8Hz，2H)，6.76(s，1H)，7.73(d，J＝8.8Hz，2H)。10d: 1H NMR (400MHz, acetone) δ 2.82 (d, J=13.6Hz, 3H), 3.80 (s, 3H), 3.86 (s, 3H), 3.99 (s, 3H), 6.41 (s, 1H), 6.72 (d, J=8.8Hz, 2H), 7.06 (s, 1H), 7.79 (d, J=8.8Hz, 2H).
4 '-(sulfonyloxy methyl amino)-5,6, the preparation of 7-trimethoxy flavone (10e).(0.13g 0.40mmol) is dissolved in the 5mL dry methylene chloride, then, adds the new distillatory pyridine of 2mL with amino flavone 10a.This solution is cooled to 0 ℃, drips new distillatory mesyl chloride (0.6mmol) then.Reactant mixture was stirred 1 hour down and restir 1 hour at room temperature at 0 ℃, pour the saturated NaHCO of 30mL then into 3In.With dichloromethane extraction gained mixture.The organic layer that merges with 5%HCl washing is used Na to remove pyridine 2SO 4Dry and concentrated.Residue silica gel chromatography (acetone: toluene=1: 5), obtain 10e (0.12g, 74%). 1H NMR (400MHz, acetone) δ 3.11 (s, 3H), 3.81 (s, 3H), 3.87 (s, 3H), 4.00 (s, 3H), 6.60 (s, 1H), 7.11 (s, 1H), 7.50 (d, J=8.8Hz, 2H), 8.02 (d, J=8.8Hz, 2H).
The preparation of noroxylin-6-sulfuric ester sodium salt (11a).To noroxylin (300mg, 1.11mmol) add in the solution in DMF (0.4mL) and oxolane (5mL) sulfur trioxide trimethylamine complex (310mg, 2.23mmol).Reactant mixture was at room temperature stirred 4 hours.Then reactant mixture is poured on the trash ice (about 100g).Leach the gained precipitate and wash with water.Precipitate is suspended in the water (10mL), adds Na-type Amberlite IR-120 cation exchange resin (3g) afterwards.With mixture heated to 50 ℃ and keep this temperature and reach 5 hours with the dissolution precipitation thing.The filtering resin is concentrated into filtrate dried.By adding dehydrated alcohol (3mL) residue is solidified.Leach solid and, obtain title compound (390mg, 85%) with the ether washing.
The preparation of noroxylin-6-organic phosphate disodium salt (11b).Use U.S. Patent No. 3,549, the method described in 662 prepares this product by noroxylin.
4 '-(methoxycarbonyl group methoxyl group)-5,6, the preparation of 7-trimethoxy flavone (12a).With 1h (100mg, 0.30mmol), methyl bromoacetate (150mg, 1.0mol), potassium carbonate (300mg) and potassium iodide (200mg) suspension in acetone (15mL) refluxed 5 hours.Then, reactant mixture is concentrated.In residue, add entry and use ethyl acetate extraction.With organic layer salt water washing, drying, the filtration and concentrated that merges.Residue obtains chemical compound 12a (101mg, 83%) with silicagel column purification (ethyl acetate/normal hexane=2: 1), is white solid. 1H?NMR(CDCl 3，200M?Hz)δ7.83(d，J＝9.0Hz，2H)，7.01(d，J＝9.0Hz，2H)，6.79(s，1H)，6.57(s，1H)，4.72(s，2H)，3.99(s，3H)，3.98(s，3H)，3.92(s，3H)，3.83(s，3H)； 13C?NMR(CDCl 3，50M?Hz)δ177.1(s)，168.7(s)，160.7(s)，160.0(s)，157.6(s)，154.4(s)，152.5(d)，140.3(s)，127.6(d，2C)，124.9(s)，114.9(d，2C)，112.8(s)，107.3(d)，96.2(d)，65.0(t)，62.1(q)，61.4(q)，56.2(q)，52.3(q)。
6-(carbethoxyl group methoxyl group)-5-hydroxyl-4 ', the preparation of 7-dimethoxy flavone.With 4 '-(methoxycarbonyl group methoxyl group)-5,6, the preparation method of 7-trimethoxy flavone is similar, by 5,6-dihydroxy-4 ', the 7-dimethoxy flavone (628mg, 2mmol), bromoacetate (367mg, 2.2mmol) and the suspension of Anhydrous potassium carbonate (0.5g) in acetone (50mL) prepare title compound.
4 '-(ethoxycarbonylmethyl group amino)-5,6, the preparation of 7-trimethoxy flavone.Similar with the preparation method of 12a, by make 4 '-amino-5,6,7-trimethoxy flavone 10a (654mg, 2mmol), bromoacetate (367mg, 2.2mmol) and Anhydrous potassium carbonate (0.5g) prepared in reaction title compound in methanol (40mL).
4 '-[N-methyl-N-(3-methoxy-propyl) amino]-5,6, the preparation of 7-trimethoxy flavone.Similar with the preparation method of 12a, by making 10d and 3-methoxy-propyl bromine prepared in reaction title compound in the presence of potassium carbonate.
4 '-[N, N-two (2-hydroxyethyl) amino]-5,7-dihydroxy-6-methoxy flavone and 4 '-(2-hydroxyethyl amino)-5, the preparation of 7-dihydroxy-6-methoxy flavone.Similar with the preparation method of 10c and 10d, by make 4 '-amino-6-methoxyl group noroxylin (1.5g, 5mmol) (Phadke, P.S.; Rao, A.V.R.; Venkataraman, K.Indian J.Chem.1967,5,131-3), ethylene bromohyrin (749mg, 6mmol) and Anhydrous potassium carbonate (1g) prepared in reaction title compound in acetone (20mL).
4 '-(2-mesyloxy ethylamino)-5, the preparation of 7-dihydroxy-6-methoxy flavone.To 0 ℃ under nitrogen 4 '-(2-hydroxyl-ethylamino)-5,7-dihydroxy-6-methoxy flavone (1.72g, 5mmol) drip mesyl chloride (801mg in the solution in dichloromethane (40mL), 10mmol) handle, (1.518g 15mmol) handles to drip triethylamine afterwards.Reactant mixture was kept 1 hour down at 0 ℃, make it be warmed to room temperature and reach 1 hour, pour in ice-aqueous mixtures then.Isolate organic layer, with dichloromethane extraction water layer secondary (40mL * 2).Organic layer is merged, washes with water, afterwards with saturated brine washing and dry.Collect the solid that forms, with low amounts of water washing and dry (MgSO 4), with the methanesulfonates that obtains thus behind the dried solution evaporation expecting.
4 '-[2-(N, N-diethylamino) ethylamino]-5, the preparation of 7-dihydroxy-6-methoxy flavone.With methanesulfonates 4 '-(2-mesyloxy ethylamino)-5,7-dihydroxy-6-methoxy flavone (442mg, 1mmol), diethylamine (1mL) and anhydrous THF (20mL) heated overnight under refluxing.To react cooling and evaporation, obtain title compound.
6,7-methylene-dioxy-5-hydroxyl-4 '-preparation of methoxyl group-flavone.With Kanzakiflavone-1 or 6,7-methylene-dioxy-5,6 '-dihydroxyflavone (1.49g, 5mmol) [Manchanda, V.P.; Khanna, R.N.Curr.Sci. (1977), 46 (13), 445-6.] and dimethyl sulfate (1.02g, 8mmol) solution in acetone (20mL) exists in Anhydrous potassium carbonate (0.5g) and flows through night next time.Reactant mixture is filtered, and evaporated filtrate obtains the burgundy residue.With residue with up in ethyl acetate and wash with water, afterwards with saturated brine washing, dry (MgSO 4), obtain title compound thus after filtration and the evaporation.
4 '-[2-(N, N-diethylamino) ethyoxyl]-6, the preparation of 7-methylene-dioxy-5-hydroxyl-flavone.With 4 '-[2-(N, N-diethylamino) ethylamino]-5, the preparation method (as mentioned above) of 7-dihydroxy-6-methoxy flavone is similar, by 6,7-methylene-dioxy-5,4 '-the initial preparation title compound of dihydroxyflavone.
4 '-(2,3-dihydroxy-propoxyl group)-5,6, the preparation of 7-trimethoxy flavone.In room temperature, stir under, to 1h (240mg, 0.58mmol) and add in the solution of 0.5N NaOH (3mL) 3-hydroxyl-1,2 epoxy prapane (74mg, 1mmol).This reaction is followed the tracks of with the TLC monitoring.When reaction finishes, be settled out product, collect product and, obtain title compound with silicagel column purification (1% methanol is in ethyl acetate).
2,3-diphenyl-5,6, the preparation of 7-trimethoxy chromone.According to disclosed method (Wu, .J.Med.Chem.1988 such as ESC, 32,183-192), by with ω-phenyl-6-hydroxyl-2,3,4-trimethoxy-1-Phenylethanone. (0.996g, 3.3mmol), benzoyl oxide (6g, 13.3mmol) and sodium benzoate (6.5g, mixture 22.5mmol) is at 180-190 ℃ of following heating preparation in 6 hours title compound.Preparation method (Wu with ω-phenyl resacetophenone, .J.Med.Chem.1987 such as ESC, 30,788-792) similar, ω-phenyl-6-hydroxyl-2,3,4-trimethoxy-1-Phenylethanone. obtains by the following method: anhydrous zinc chloride is added 3,4, in 5-trimethoxy phenol and the benzyl cyanide solution in ethyl acetate, at room temperature in reactant mixture, feed HCl afterwards, then 95-100 ℃ of following water heating.
2,3-diphenyl-5,6, the preparation of 7-trihydroxy chromone.Similar with the preparation method of 1d, make 2,3-diphenyl-5,6,7-trimethoxy chromone and Boron tribromide reacted 30 minutes down in 0 ℃ in dichloromethane, at room temperature reacted then 3 hours, generated title compound.
Embodiment 2
Pharmacology test
The pharmacological activity of The compounds of this invention can be measured in the following illustrative test that provides.
Material and method.Use is from the male Charles River Wistar-Kyoto rat (230-300g) of Japan.Peritoneal injection urethane (1.2g/kg) is with rat anesthesia.Intubate is to help breathing in trachea, and (Harvard Apparatus, South Natick MA) remain on rectal temperature 37 ℃ with the constant temperature blanket.The right common carotid artery intubate and with pressure transducer (P233ID, Statham, Oxnard, CA) be connected to measure phase place pressure (phasic pressure) and mean arterial pressure and heart rate, it is presented at Gould model TA5000 polygraph (Gould, Valley View, OH) on.After operation technique is finished, cardio-vascular parameters was stablized 20 minutes.Behind the record baseline hemodynamic parameter, give animal carrier (DMSO) or noroxylin (5,10 or 20mg/kg, intravenous).Use back 1 hour intravenous of lipopolysaccharide (LPS) and use noroxylin.Giving before carrier or the LPS (i.e. 0 time) and each hour afterwards gets 0.5mL blood to measure the blood plasma level (Shock 14 for Yen, M.H. etc., 60-67,2000) of TNF-α and nitrate (be the indicant of NO formation).Injecting isopyknic saline immediately after each blood drawing is replenished.
Plasma TNF-α measures.Plasma sample (100 μ l) with dilution in 1: 2, is used enzyme-linked immunosorbent assay (ELISA) test kit (Genzyme, Cambridge, MA) measure TNF-α (Yen in duplicate, M.H. etc., Biochem.Biophys.Res.Commun.228:459-466,1996).
Use the chemiluminescence detection superoxide anion.Carrying out peroxide as previously mentioned detects.In brief, aorta is cut into the ring of 5-mm, in containing the Krebs-HEPES buffer of 0.25mmol/L lucigenin, carries out incubation then.With luminescence assays system (microLumate plusLB96V, EG﹠amp; G Berthold) interval with 15 minutes obtains counting under 37 ℃.
Blood plasma nitrate is measured.Carrying out blood plasma nitrate as previously mentioned measures.In brief, for the liquid nitrate reduction is become gas NO, 10 μ l injection is contained 5%VCl 3The collection chamber in.With constant helium flow NO is brought in the NO analyser (Seivers 270B NOA, Seivers Instruments Inc).
Detect iNOS with western blotting.As indicated abovely carry out induction type nitric oxide synthase (iNOS) with western blotting and detect.Used one-level antibody is mouse-anti-iNOS (TrnsductionLaboratoreis) in the experiment.
The mensuration of serum glutamic oxalacetic transaminase (SGOP) and serum glutamic pyruvic transminase (SGTP).Get 10 μ l serum at 0 hour and 6 hours intervals, add on GOP and the GTP slide, place DRI-CHEM3000 (Colorige Tric Analyzer then; FUJIFILM; Tokyo, Japan) in.
Histological research.Obtain the lung regulating liver-QI in (after the administration 8 hours) after the research by the survival mice of each group, these tissues are fixedly carried out histopathological examination with Carson-Millonig solution, at Chen .Lab.Invest.67 such as A. were described in the 175-185 (1992) as in the past.Fixed lung regulating liver-QI is organized in gradient (graded) ethanol dehydration and is embedded in the paraffin.With h and E reagent three microns section statining is used for light microscopy.In preliminary experiment, the pathological characters of accepting the mice of LPS is to have neutrophil cell to soak in the organ of being studied.As the index of tissue injury's order of severity, Histological change is carried out quantitative analysis.This index is that neutrophil cell soaks into index, and it is measured by in the high power field of selecting at random at 10 the neutrophil cell number being counted.This index is represented with mean value standard error of mean (the SEM)/high power field of this 10 number.
Foregoing is illustrative explanation of the present invention, and should not be misinterpreted as is limitation of the present invention.The present invention limits by following claim, also comprises the equivalent of claim.

Claims (57)

1. the chemical compound of formula I:
Wherein:
R 1, R 2And R 3Be independently of one another H, alkyl, alkenyl, alkynyl ,-SO 3H ,-PO 3H 2Or carbohydrate;
Perhaps R 1And R 2Be (CH independently of one another 2) nY and [CH 2CH (OH) CH 2] Y, wherein Y is H, OR 4, NR 5R 6, COOR 4Or OONR 5R 6, R wherein 4, R 5And R 6Be H, alkyl, alkenyl, alkynyl or carbohydrate independently of one another, and R 5And R 6Can form 5 to 7-unit's rings together;
Perhaps R 1And R 2Be heterocycle together;
Perhaps R 2And R 3Be heterocycle together; And
X 1And X 2Be formula independently of one another:
Ar-X 3-T，
Wherein Ar can exist or not exist, and when Ar existed, Ar was phenyl, furyl, thienyl, pyridine radicals, cyclohexyl or benzyl; X wherein 3Be H, C, N, NR ', NR ' R ", NR ' SO 2R ", O or S, condition is that formula I chemical compound is not noroxylin or 5,6,7-trihydroxy-isoflavone, wherein R ' and R " are H, alkyl, alkenyl, alkynyl or carbohydrate independently of one another; Wherein T is (CH 2) nY or [CH 2CH (OH) CH 2] Y, wherein Y is H, OR 4, NR 5R 6, COOR 4Or OONR 5R 6, R wherein 4, R 5And R 6Be H, alkyl, alkenyl, alkynyl or carbohydrate independently of one another; And R 5And R 6Can form 5 to 7-unit's rings together; Or its pharmaceutically useful salt.
2. the chemical compound of claim 1, wherein said alkyl is a low alkyl group.
3. the chemical compound of claim 1, wherein said carbohydrate is monosaccharide, oligosaccharide or polysaccharide or its combination.
4. the chemical compound of claim 1, wherein R 1, R 2And R 3Be independently of one another-SO 3H or-PO 3H 2
5. the chemical compound of claim 1, wherein R 1And R 2Be 5-unit or 6-ring structure together.
6. the chemical compound of claim 1, wherein R 2And R 3Be 5-unit or 6-unit heterocycle together.
7. the chemical compound of claim 1, wherein R 1, R 2And R 3Each is H naturally, and Ar is a phenyl, and X 3Be H.
8. the chemical compound of claim 1, wherein said chemical compound is the salt form of chemical compound.
9. the chemical compound of claim 8, the salt form of wherein said chemical compound is the sodium salt or the potassium salt of chemical compound.
10. the chemical compound of claim 1, wherein said chemical compound is water miscible.
11. the chemical compound of claim 1, wherein said chemical compound be 4 '-(N, N-dimethylamino)-5,6,7-trimethoxy flavone, 4 '-(methylamino)-5,6,7-trimethoxy flavone, 2,3-diphenyl-5,6,7-trimethoxy chromone, 2,3-diphenyl-5,6,7-trihydroxy chromone, 4 '-(sulfonyloxy methyl amino)-5,6,7-trimethoxy flavone or 4 '-(methoxycarbonyl group methoxyl group)-5,6,7-trimethoxy flavone.
12. comprise the pharmaceutical preparation of chemical compound and at least a pharmaceutically useful carrier, diluent or the excipient of claim 1.
13. the pharmaceutical preparation that comprises described chemical compound of claim 12, wherein pharmaceutically useful carrier is an aqueous carrier.
14. treatment and TNF-α excess produce the method for diseases associated, wherein said disease is selected from arthritis, rheumatoid arthritis, segmental enteritis, ulcerative colitis, insulin resistance, multiple sclerosis, organ failure, pulmonary fibrosis and atherosclerosis, and this method comprises the chemical compound of its object of needs being used the claim 1 of effective dose.
15. treatment and superoxide anion base excess produce the method for diseases associated, wherein said disease is selected from Alzheimer, parkinson disease, aging, cancer, myocardial infarction, atherosclerosis, autoimmune disease, radiation injury, edema due to disorder of QI, sunburn, joint disease and oxidative stress, and this method comprises the chemical compound of its object of needs being used the claim 1 of effective dose.
16. the method for treatment septic shock, this method comprises the chemical compound of its object of needs being used the claim 1 of effective dose.
17. the method for treatment inflammation, this method comprise when the chemical compound of right requirement 1 is isoflavone, its object of needs used the chemical compound of the claim 1 of effective dose.
18. the method for treatment organ injury, this method comprises the chemical compound of its object of needs being used the claim 1 of effective dose.
19. the method for claim 18, wherein said organ injury are hepatic injury, injury of lung or injury of kidney or its combination.
20. the method for treatment neurodegenerative disease, wherein said neurodegenerative disease is selected from parkinson disease, Alzheimer, cognitive defect, the loss of memory and apoplexy and combination thereof, and this method comprises the chemical compound of its object of needs being used the claim 1 of effective dose.
21. the method for treatment cancer, this method comprises the chemical compound of its object of needs being used the claim 1 of effective dose.
22. the method for claim 21, wherein said cancer are selected from skin carcinoma, small cell lung cancer, carcinoma of testis, esophageal carcinoma, breast carcinoma, carcinoma of endometrium, ovarian cancer, central nervous system's cancer, hepatocarcinoma, pulmonary carcinoma and carcinoma of prostate and combination thereof.
23. treat cardiopathic method, wherein said heart disease is selected from myocardial ischemia, congestive heart failure and hypertension and combination thereof, this method comprises the chemical compound of its object of needs being used the claim 1 of effective dose.
24. treatment is selected from TNF-α excess and produces, produce the method for the disease of diseases associated, organ injury, arthritis, neurodegenerative disease, cancer and heart disease and combination thereof with superoxide anion base excess, this method comprises uses the pharmaceutical composition that comprises the chemical compound that is selected from following formula for the treatment of effective dose to its object of needs:
Figure A2003801018210004C1
With
Figure A2003801018210005C2
25. the method for claim 24, wherein said organ injury are hepatic injury, injury of lung or injury of kidney or its combination.
26. the method for claim 24, wherein said neurodegenerative disease is selected from parkinson disease, Alzheimer, cognitive defect, the loss of memory and apoplexy and combination thereof.
27. the method for claim 24, wherein said cancer are selected from skin carcinoma, small cell lung cancer, carcinoma of testis, esophageal carcinoma, breast carcinoma, carcinoma of endometrium, ovarian cancer, central nervous system's cancer, hepatocarcinoma, pulmonary carcinoma and carcinoma of prostate and combination thereof.
28. the method for claim 24, wherein said heart disease is selected from myocardial ischemia, myocardial infarction, congestive heart failure and hypertension and combination thereof.
29. the method for claim 24, the pharmaceutical composition that wherein said pharmaceutical composition is oral or parenteral is used.
30. the method for claim 24, wherein said pharmaceutical composition is used to prevent or treatment and TNF-α excess produces, produce relevant disease, septic shock, inflammation, organ injury, neurodegenerative disease, cancer and cardiopathic other therapeutic agent combined administration with superoxide anion base excess with at least a.
31. treatment is selected from TNF-α excess and produces, produce the method for the disease of diseases associated, septic shock, organ injury, neurodegenerative disease, cancer and heart disease and combination thereof with superoxide anion base excess, this method comprises uses the pharmaceutical composition that comprises the formula V compound or pharmaceutically acceptable salt thereof for the treatment of effective dose to its object of needs:
Figure A2003801018210006C1
Wherein:
R 7, R 8And R 9Be independently of one another H, alkyl ,-SO 3H ,-PO 3H 2, carbohydrate or benzyl;
Perhaps R 7And R 8Be heterocycle together;
Perhaps R 8And R 9Be heterocycle together;
X 1Be H, C, NH 2, NHCOCH 3, NO 2Or OR 10, R wherein 10Be H, alkyl, carbohydrate or benzyl,
Condition is to work as Ph-X 1Be positioned at 2-position and R 7, R 8And R 9When being H, alkyl or carbohydrate independently of one another, this chemical compound is not used in the treatment septic shock.
32. the method for claim 31, wherein said alkyl is a low alkyl group.
33. the chemical compound of claim 1, wherein R 1, R 2And R 3Be independently of one another-SO 3H or-PO 3H 2
34. the method for claim 31, wherein said carbohydrate are monosaccharide, oligosaccharide or polysaccharide or its combination.
35. the method for claim 31, wherein R 7And R 8Be heterocycle together.
36. the method for claim 31, wherein R 7And R 8Be 5-ring structure or 6-ring structure together.
37. the method for claim 31, wherein R 8And R 9Be 5-unit or 6-ring structure together.
38. the method for claim 31, wherein X 1Ortho position, a position or para-position at phenyl ring replace.
39. the method for claim 31, wherein said chemical compound is 5,6, the 7-trihydroxy-isoflavone.
40. the method for claim 31, wherein said organ injury are hepatic injury, injury of lung or injury of kidney or its combination.
41. the method for claim 31, wherein said neurodegenerative disease is selected from parkinson disease, Alzheimer, cognitive defect, the loss of memory and apoplexy and combination thereof.
42. the method for claim 31, wherein said cancer are selected from skin carcinoma, small cell lung cancer, carcinoma of testis, esophageal carcinoma, breast carcinoma, carcinoma of endometrium, ovarian cancer, central nervous system's cancer, hepatocarcinoma and carcinoma of prostate and combination thereof.
43. the method for claim 31, wherein said heart disease is selected from myocardial ischemia, myocardial infarction, congestive heart failure and hypertension and combination thereof.
44. the method for claim 31, wherein said pharmaceutical composition is used to prevent or treatment and TNF-α excess produces, produce relevant disease, septic shock, inflammation, organ injury, neurodegenerative disease, cancer and cardiopathic other therapeutic agent combined administration with superoxide anion base excess with at least a.
45. the method for claim 31, the pharmaceutical composition that wherein said pharmaceutical composition is oral or parenteral is used.
46. treatment is selected from TNF-α excess and produces, produce the method for the disease of diseases associated, septic shock, organ injury, neurodegenerative disease, cancer and heart disease and combination thereof with superoxide anion base excess, this method comprise to its object of needs use comprise the treatment effective dose be selected from noroxylin-6-sulfuric ester, noroxylin-6,7-di-sulfate, noroxylin-6-phosphate ester, noroxylin-6,7-bisphosphate, noroxylin-5,6, the pharmaceutical composition of the chemical compound of 7-triguaiacyl phosphate, its sodium and potassium salt derivant and officinal salt thereof.
47. the method for claim 46, wherein said organ injury are hepatic injury, injury of lung or injury of kidney or its combination.
48. the method for claim 46, wherein said neurodegenerative disease is selected from parkinson disease, Alzheimer, cognitive defect, the loss of memory and apoplexy and combination thereof.
49. the method for claim 46, wherein said cancer are selected from skin carcinoma, small cell lung cancer, carcinoma of testis, esophageal carcinoma, breast carcinoma, carcinoma of endometrium, ovarian cancer, central nervous system's cancer, hepatocarcinoma, pulmonary carcinoma and carcinoma of prostate and combination thereof.
50. the method for claim 46, wherein said heart disease is selected from myocardial ischemia, myocardial infarction, congestive heart failure and hypertension and combination thereof.
51. the method for claim 46, wherein said chemical compound are noroxylin-6-sulfuric ester or its sodium or potassium salt derivant.
52. the method for claim 46, wherein said pharmaceutical composition is used to prevent or treatment and TNF-α excess produces, produce relevant disease, septic shock, inflammation, organ injury, neurodegenerative disease, cancer and cardiopathic other therapeutic agent combined administration with superoxide anion base excess with at least a.
53. the method for claim 44, the pharmaceutical composition that wherein said pharmaceutical composition is oral or parenteral is used.
54. treatment is selected from TNF-α excess and produces, produce diseases associated with superoxide anion base excess, inflammation, septic shock, organ injury, neurodegenerative disease, the method of the disease of cancer and heart disease and combination thereof, this method comprise to its object of needs use comprise 4 of treatment effective dose '-(N, the N-dimethylamino)-5,6,7-trimethoxy flavone, 4 '-(methylamino)-5,6,7-trimethoxy flavone, 2,3-diphenyl-5,6,7-trimethoxy chromone, 2,3-diphenyl-5,6,7-trihydroxy chromone, 4 '-(sulfonyloxy methyl amino)-5,6,7-trimethoxy flavone or 4 '-(methoxycarbonyl group methoxyl group)-5,6, the pharmaceutical composition of 7-trimethoxy flavone.
55. comprising, the method for synthetic compound of formula i or its officinal salt, this method make formula (VI) chemical compound:
Figure A2003801018210008C1
R wherein 1, R 2And R 3Be independently of one another H, alkyl, alkenyl, alkynyl ,-SO 3H ,-PO 3H 2Or carbohydrate; Perhaps R 1And R 2Be (CH independently of one another 2) nY and [CH 2CH (OH) CH 2] Y, wherein Y is H, OR 4, NR 5R 6, COOR 4Or OONR 5R 6, R wherein 4, R 5And R 6Be H, alkyl, alkenyl, alkynyl or carbohydrate independently of one another, and R 5And R 6Can form 5 to 7-unit's rings together; Perhaps R 1And R 2Be heterocycle together; Perhaps R 2And R 3Be heterocycle together; With (ArCO) 2O, ArCO 2Na and the reaction of acid sodium salt, wherein Ar as defined above.
56. the method for synthetic compound of formula i or its officinal salt, wherein X 1And X 2Represent Ar-X 3-T, wherein X 3Be H, R 1, R 2And R 3Be H, or R 1And R 2One of be CH 3, this method comprises makes formula VII chemical compound:
Figure A2003801018210009C1
X wherein 1And X 2Represent Ar-X 3-T, wherein X 3Be H,
With aqueous hydrobromic acid (HBr) or Boron tribromide (BBr 3) reaction.
57. comprising, the method for synthetic compound of formula i or its officinal salt, this method make wherein X 1And X 2Represent Ar-X 3-T, wherein X 3-T is OH or NH 2Formula I chemical compound and electrophilic reagent reaction, described electrophilic reagent such as W (CH 2) nY, WCH 2CH (O) CH 2Or HOCH 2CH (O) CH 2, wherein W is that leaving group and Y are H, OR 4, NR 5R 6, COOR 4Or OONR 5R 6, R wherein 4, R 5And R 6Be H, alkyl, alkenyl, alkynyl or carbohydrate independently of one another, and R 5And R 6Can form 5 to 7-unit's rings together.
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CN108164487A (en) * 2017-12-29 2018-06-15 中国医学科学院药用植物研究所海南分所 A kind of extracting method of agalloch eaglewood chromone compounds and its application for treating tumour
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