CN101351208A - Reducing cellular cholesterol levels and/or treating or preventing phospholipidosis - Google Patents

Reducing cellular cholesterol levels and/or treating or preventing phospholipidosis Download PDF

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CN101351208A
CN101351208A CNA2006800498805A CN200680049880A CN101351208A CN 101351208 A CN101351208 A CN 101351208A CN A2006800498805 A CNA2006800498805 A CN A2006800498805A CN 200680049880 A CN200680049880 A CN 200680049880A CN 101351208 A CN101351208 A CN 101351208A
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F·马克斯菲尔德
A·索夫
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Cornell Research Foundation Inc
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Abstract

Compounds disclosed herein may be used in disclosed methods for reducing the amount of cholesterol in a cell, for treating a patient suffering from a disorder characterized by cellular accumulation of cholesterol (such as Niemann-Pick Disease Type C or atherosclerosis), and/or for treating or preventing phospholipidosis. In some embodiments, the compounds may include a pyrrolone or triazine moiety.

Description

Reduce cellular cholesterol levels and/or treatment or prevention phospholipidosis
The mutual reference of related application
[001] this application requires the U.S. Provisional Application 60/732 of submission on November 1st, 2005,342, the U.S. Provisional Application of submitting on July 13rd, 2,006 60/807, the U. S. application 11/555 that on October 31st, 269 and 2006 submitted to, 152 priority, wherein this description is included in each application by reference in.
Statement about the federal funding research and development
[002] NIH fund NO.DK27083 provides the part support to the research that obtains the disclosed theme of the application.Therefore, there is certain right in U.S. government to the application's theme.
Background technology
[003] regulating cellular cholesterol levels is essential for correct cell function and growth.An intracellular cholesterol levels is partly regulated by the transportation of cholesterol between various compartments and film.The suitable distribution of the cholesterol between the various cell membrane is very important for many biological functions, as signal transduction and film exchange.Cholesterol levels also can be reconciled to the extracellular receptor of removing cholesterol from cell by transportation.These cholesterol transport mechanism are widely studied, and the defective of adjusting cellular cholesterol levels links together with various diseases.
[004] NP is the lipid storage diseases of a class heredity.Generally acknowledging has 4 types NP: A, B, C and D type.Type A and B are caused by the lipid sphyngomyelin enzymatic activity shortage that the sphingomyelins that can cause in the cell increases, and cause cell death usually.The patient of A type NP often dies from 2 to 4 years old, may survive to later stage in childhood or grows up and suffer from Type B.D type NP (being also referred to as the Nova Scotia mutation) and C type equity, and occur in the descendant in western part, Nova Scotia.
[005] C type NP (NPC) is a kind of recessive hereditary disease, can cause a kind of cholesterol and the abnormal accumulation (1,2) in the cell of many types of other lipids.The most serious symptom is caused by gradual deterioration of neurons, but liver and other peripheral organs also show defective.Though time course can be changed, it is early stage that symptom often occurs in the child, and this disease is fatal at tens years old usually.There are a lot of trials to develop treatment (3-8), but do not have effective Therapeutic Method at present NPC.
[006] mankind have two genes to be associated with the NPC defective, though cutter system is still under study for action really for these protein actives.NCP1 is the memebrane protein of a multispan degree, and endosome or lysosome common and late period are united (9), the degradation of cell device, and the cholesteryl ester (10,11) of cell is brought in hydrolysis into through lipoprotein.NPC1 has the membrane spaning domain of a sterol sensitivity, be similar in endocytoplasmic reticulum to be found can the pair cell cholesterol the variation albumen (12) of reacting.As if this NPC1 albumen helps the bilayer transportation of some hydrophobic molecules, but it does not participate in cholesterol transportation (13-16) directly.NPC2 is a kind of solubility inner chamber albumen, is present in the endosome in late period, and can combined cholesterol (17-19).NPC2 can the free cholesterol of free shuttling to the film of endosome and lysosome restriction in late period, wherein NPC1 obviously outputs to other cell sites at it and has brought into play effect (20).The loss of functional NPC1 or NPC2 cause free cholesterol have late period endosome and/or the endocytosis organelle of lysosome feature in accumulation.These unusual organelles of mentioning herein store organelle (LSOs) for the class lysosome.The LSOs relevant with the related LSOs of NPC and other heritability glycosyl sphingolipids storage disease (often can't metabolism being caused by a kind of specific lipid) is similar; similar part is to store the multiwalled inner verticil that organelle comprises the film bilayer; this bilayer contains cholesterol, sphingomyelins and a large amount of 2-(monoacylglycerol)-phosphate (BMP); be also referred to as molten-two phosphatidic acid (lyso-bisphosphatidic acid; LBPA) (21,22).Therefore, though these diseases from different genetic defectes, but some aspect of cell phenotype is quite similar.
[007] defective of the transportation of cholesterol in NPC of several evidence chain sensings is though the defective of the transportation of other esters also can play a significant role (23).The high-caliber non-esterified cholesterol of NPC cell display abnormality, its accumulation mainly is at LSOs.Cumulative cholesterol can use filipin to detect, and this is a kind of fluorescence detergent (24) that can be combined in the free cholesterol on the film.In wild-type cell, from endosome be transported to the too much cholesterol of cell otherwise be from the cell to born of the same parents outside receptor carry, or by the acyl coenzyme A esterification: cholesterol acyltransferase (ACAT), a kind of enzyme (25) that is positioned on the endoplasmic reticulum.Although free cholesterol has high-load in LSOs, in fact the plasma membrane of cultivating the NPC cell has low cholesterol level (26) and cholesterol to flow out to the defective (27) of the outer receptor of born of the same parents than normal cell.In addition, carry lipoprotein source cholesterol to be used for esterification by ACAT a defective (28,29) is arranged.These features show that cholesterol is deleterious to the NPC cell from endosome outflow in late period.
[008] in the NPC1 gene, find several different gene mutation, among the mankind this corresponding to 95% NPC disease (13,30-33).Dependency between the age of onset of molecular defect and serious symptoms is also indeterminate.The clinical manifestation of NPC disease from adult late-onset or symptom slightly to infant early onset acute symptom (34,35).This shows that other factors in genetic background can partly be improved disease.Equally, cultured cells studies show that the various proteic overexpression that influences the film transportation can reduce the accumulation of cholesterol.Especially, the overexpression (36-38) of little regulation and control guanosine triphosphatase (GTPases), Rab7 and Rab9 has reduced the accumulation of sterol in the fibroblast of cultivating.Because these protein are regulated many aspects of cell membrane transportation, they may not be the good curing targets.But, the influence of the difference of Ren Lei age of onset and exogenous gene overexpression shows that all Drug therapy may develop to improve symptom, even the proteic definite function of NPC is not resumed.
[009] phospholipidosis is a phospholipid has excessive accumulation in bodily tissue a situation.It is relevant with the synthetic and/or metabolic change of phospholipid that the excessive accumulation of phospholipid is considered to.Phospholipidosis can take place when the patient is given with certain medicine.For example, when giving human amiodarone, perhexiline, fluoxetine, gentamycin, can cause phospholipidosis.See M.J.Reasor et al.Exp.Biol.Med.2001,226,825.Because the excessive accumulation of phospholipid is a kind of side effect of some drugs, will be in demand so medicine is induced the compositions of the phospholipidosis that causes and method.
[010] therefore, need regulate the caused treatment of diseases of defective by cellular cholesterol levels to NP and other.Also need to treat or prophylactic agent is induced the method for phospholipidosis.The present invention has satisfied these needs and other related advantages has been arranged.
Summary of the invention
[011] an aspect of of the present present invention relates to chemical compound and the pharmaceutical composition that can be used for reducing cholesterol amount in the cell.In some instances, chemical compound of the present invention comprises a pyrrole ring or triazine part (moiety).Another aspect of the present invention relates to patient's the method that a kind of treatment has the cell accumulation characteristics of cholesterol.In some instances, this invention relates to a kind of treatment C type NP or atherosclerotic method.Another aspect of the present invention relates to a kind of by cellular exposure is reduced the method for cholesterol amount in the cell in a kind of chemical compound of the present invention.In some instances, this method comprises cellular exposure in the chemical compound that contains a pyrrole ring or triazine part.Another aspect of the present invention relates to the method for a kind of treatment or the inductive phospholipidosis of prophylactic agent.
Description of drawings
That [012] Fig. 1 describes is the result of filipin in conjunction with mensuration, and wherein the Chinese hamster ovary celI (CT60) of wild type Chinese hamster ovary celI (TRVb1) and NPC1 saltant is placed in 384 orifice plates and grew 48 hours in the culture medium of routine.Cell is fixed with 1.5%PFA after washing with PBS, dyes with filipin.Utilize the 365DCLP filter to filter the 360/40nm that obtains and excite the image that obtains 10 times of amplifications with 480/40nm emission light in 2 positions in every hole.(A) the painted TRVb1 cell image of filipin; (B) the painted CT60 cell image of filipin.Scale=30 μ M.Utilize average Fei Liping intensity and LSO compartment ratio (Compartment Ratio) to carry out graphical analysis.(C) rectangular histogram of average filipin intensity level; (D) rectangular histogram of LSO compartment ratio value.
That [013] Fig. 2 describes is the result of filipin in conjunction with mensuration, and wherein cell is fixed and the filipin labelling with PFA.(A) 360/40nm that utilizes the automatic fluorescence microscope of Discovery-1 and utilize the filtration of 365DCLP filter to obtain excites the image that obtains 10 times of amplifications with 480/40nm emission light.(B) image after correction shade and the background.(C) high threshold setting is used for identifying the LSO compartment.(D) high threshold setting is used for comprising whole cell compartment.Scale=20 μ M.
[014] Fig. 3 describes be filipin in conjunction with the result who measures, CT60 cell grow overnight and with selecting chemical compound (1-a-13) (B) in screening solution, to handle among solvent (A) or the 10 μ M in growth medium wherein.After hatching in 20 hours, cell is fixed with 1.5%PFA after washing with PBS, dyes with filipin.Obtain the image of 10 times of amplifications.Scale=25 μ M.
[015] Fig. 4 has described the image of filipin dyeing CT60 cell, and this cell is subjected to the influence of some chemical compounds of being added, and they can be induced morphological change and/or increase the intensity of filipin.(A) chemical compound 1-c-1 causes more dispersive fluorescence, and its average filipin intensity does not have significant change.(B) chemical compound 1-c-2 induces compacter LSOs, and filipin intensity does not have significant change.(C) chemical compound 1-c-3 causes in mutant cell and assembles in nuclear week of LSOs and become and disperse more.(D) chemical compound 1-b-4 have thread or the painted filipin intensity of tubulose in cause remarkable increase.Scale=15 μ M.
[016] Fig. 5 has described the chemical constitution (1-a-1,1-a-2,1-a-3,1-a-4,1-a-5,1-a-6,1-a-7,1-a-8,1-a-9,1-a-10,1-a-11,1-a-12,1-a-13 and 1-a-14) of 14 kinds of chemical compounds that obtain from the one-level storehouse.Chemical compound 1-c-2 and 1-c-3 cause morphological change, and chemical compound 1-b-2 causes the increase of filipin intensity, and chemical compound 1-b-4 increase Fei Liping intensity is induced morphological change simultaneously.
[017] Fig. 6 has described the dose response curve (1-a-1,1-a-2,1-a-3,1-a-4,1-a-5,1-a-6,1-a-7,1-a-8,1-a-9,1-a-10,1-a-11,1-a-12,1-a-13 and 1-a-14) of 14 kinds of chemical compounds that obtain from the one-level storehouse.CT60 and CT43 cell kind are in having 384 orifice plates of growth medium.Behind the 24h, add chemical compound to ultimate density 123nM, 370nM, 1.11 μ M, 3.33 μ M and 10 μ M, every concentration 4 holes, cell culture spends the night.Cell is fixed with PFA after washing with PBS, dyes with filipin.This LSO compartment determination of ratio: (A) CT60 cell (average 5 experiments) and (B) CT43 cell (average 3 experiments).Solid line is represented the average of solvent control; Dotted line is represented-3SD.
[018] Fig. 7 has described the cytotoxicity analysis (1-a-1,1-a-2,1-a-3,1-a-4,1-a-5,1-a-6,1-a-7,1-a-8,1-a-9,1-a-10,1-a-11,1-a-12,1-a-13 and 1-a-14) of 14 kinds of chemical compounds that obtain from the one-level storehouse.CT60 and CT43 cell kind are in having 384 orifice plates of growth medium.Behind the 24h, add chemical compound to ultimate density 5,10 and 20 μ M, every concentration 4 holes, cell culture spends the night.The dimethyl sulfoxide of isodose adds in the control wells.Cell is fixed with PFA after washing with PBS, with nuclear staining agent Hoechst33258 dyeing.Utilize the automatic fluorescence microscope of Discovery-1 and utilize the 365DCLP filter to filter the 360/40nm that obtains and excite the image that obtains 4 times of amplifications with 480/40nm emission light.To every porocyte counting, cell quantity reduces the result of percentage ratio compared with the control: (A) CT60 cell (average 4 experiments) and (B) CT43 cell (average 3 experiments).
[019] Fig. 8 describes is the chemical constitution (2-a-1,2-a-3,2-a-8,2-a-9,2-a-12,2-a-13,2-a-15) of 7 kinds of chemical compounds obtaining from the secondary storehouse.
[020] Fig. 9 describes is the influence (2-a-1,2-a-3,2-a-8,2-a-9,2-a-12,2-a-13,2-a-15) of 7 kinds of chemical compounds obtaining from the secondary storehouse.Determining described in dose dependent such as the figure.(A) CT60 cell (average 5 experiments) and (B) CT43 cell (average 3 experiments).Real horizontal line shows the average of solvent control; That dotted line is represented is average-3SD.
What [021] Figure 10 described is the cytotoxicity analysis (2-a-1,2-a-3,2-a-8,2-a-9,2-a-12,2-a-13,2-a-15) of 7 kinds of chemical compounds.Measure the cytotoxicity that selects chemical compound in 7 kinds that from the secondary storehouse, obtain by cell counting and LDH release.For every porocyte counting, according to the cell counting that carries out described in Fig. 7, cell quantity reduces the result of percentage ratio compared with the control: (A) CT60 cell reaches (B) CT43 cell.Measure for the LDH cell toxicant, in 7 kinds of from secondary, obtaining, select chemical compound to exist under the situation, be discharged into the measurement of the cell LDH in the culture medium: (C) CT60 cell, with reference to low (no chemical compound) and high (dissolved cell) contrast.
[022] Figure 11 describes is the influences (2-a-1,2-a-3,2-a-8,2-a-9,2-a-12,2-a-13,2-a-15) at different time of 7 kinds of chemical compounds obtaining from the secondary storehouse.CT60 cell kind is in having 384 orifice plates of growth medium.Behind the 24h, in 4 different hole/concentration, add chemical compound to ultimate density 1.11,3.33 and 10 μ M, and hatched (A) 4 hours, (B) 20 hours, and (C) 48 hours.Cell is fixed with PFA after washing with PBS, dyes with filipin.Utilize the 365DCLP filter to filter the 360/40nm that obtains and excite the image that obtains 10 times of amplifications with 480/40nm emission light in 2 positions in every hole.Measure LSO compartment ratio (average 3 different experiments).Real horizontal line shows the average of solvent control; That dotted line is represented is average-3SD.
[023] Figure 12 describes is 7 kinds of chemical compounds obtaining from the secondary storehouse are handled normal human fibroblasts to U18666A influence (2-a-1,2-a-3,2-a-8,2-a-9,2-a-12,2-a-13,2-a-15).The normal human fibroblast is put into 384 orifice plates of conventional culture medium and grew 24 hours, and cell was handled 4 hours in screening culture medium with chemical compound U18666A (500nM or 250nM) then.Exist down at U18666A then, cell and multiple in select chemical compound (10 μ M) further overnight incubation together.At last, cell is fixed with 1.5%PFA with PBS washing 3 times, washes the back with PBS and dyes with filipin.Utilize Discovery1 microscope 10 times of enlarged images of acquisition and analyze the LSO ratio.Real horizontal line is meant the meansigma methods of the cell that the Ul8666A of each concentration handles, and empty horizontal line shows-3SD.
[024] Figure 13 describes be increase from the effusive cholesterol of 25RA Chinese hamster ovary celI, do not have the NPC sudden change for the parental cell strain of CT60 and CT43 cell strain, described cell is incubated in all cpds of 10 μ M concentration.
The specific embodiment
[025] an aspect of of the present present invention provides the compositions and the method for the level that is used to regulate cellular cholesterol.Compositions of the present invention can be used for treating NP and other and the relevant disease of adjusting cellular cholesterol levels defective.As indicated above, suitably regulating cellular cholesterol levels is necessary for suitable cell function and growth.The influence of chemical compound pair cell cholesterol levels can utilize the filipin combined techniques to measure.
[026] this paper has illustrated a kind of definite automatic screening experiment that can partly reverse the chemical compound of C type NP (NPC) mutant cell phenotype.This method combines based on a kind of fluorescence detergent filipin and free cholesterol.In the cell of undressed sudden change, be to compare a large amount of free cholesterol (42) is arranged with control cells.This free cholesterol with the relevant LSOs of endosome in late period, organelle in be high concentration, but also can comprise protein labeling, they are abundant (47) in the endosome late usually.Molecular defect among the NPC is a sudden change or lacks and one of relevant two the protein N PC1 of endosome in late period and NPC2.These sudden changes cause cholesterol from the defective that late period, endosome effluxed, and cause cholesterol high-caliber accumulation in LSOs.
[027] two kinds of effects of exchanging ganglion cell's cholesterol level that screening test has with the evaluation test chemical compound have been developed.First kind of detection method adopted a kind ofly determines that enough each comprises the filipin-fluorescence intensity threshold value of the image area of cell.Use the method, each cell area can obtain overall filipin fluorescence in each zone.The painted intensity of plasma membrane provides a clear and definite difference that surpasses the cell area of background level.But need second kind of detection, clearly do not distinguish LSO compartment and other cell compartments because be used for determining the threshold value of cell area.Used detected parameters is divided by the pixel count that surpasses more than the threshold value with total fluorescence.The method is the T-CHOL that is used for estimating each cell, and this is approximate based on cell area remains unchanged under various conditions.Though this detection has been considered to provide the mensuration of reliable each cell total cholesterol level, but, obviously diffusion takes place if cell is made a response to a kind of processing or assemble, if or some cholesterol the different abilities in conjunction with filipin is arranged, the possibility of result that detects can be affected.
[028] though this mensuration is not used subcellular fraction information or single cell analysis, it can use the micrometron analysis.At first, microscopic system is the detector of a sensitivity for relative more weak filipin fluorescence.The second, measure each the regional area that only limits to contain cell, it has reduced the contribution of background.The correction of cell density difference when at last, the area that covers with cell provides measurement divided by total fluorescence intensity.
[029] we find, it is useful providing enough saltant that every pixel filipin intensity of the resolving power of wild-type cell is detected as screening.When we adjust the experiment condition that is used to detect, during as cell density and flag condition, adopt this parameter.But it should be noted that, should be noted, because only isolate the CT60 cell from the control cells strain in some cases by a small amount of standard deviation to this.
[030] use LSO compartment ratio detection method, we have obtained wild type to the distinguishing preferably of mutant cell, have wherein used a threshold value to contain area (being the LSOs in the mutant cell) in each zone of heavy label organelle with discriminating.Because the accumulative site of cholesterol is arranged in the NPC cell, the selective measurement in cholesterol storehouse is expected to provide the resolving power of better saltant to wild-type cell.This additional sensitivity is useful in determining section effective ingredient screening test.Coefficient Z ' (46) is the tolerance of the separating capacity of screening test, and LSO compartment ratio detects the Z ' have one 0.61, and relative is that average filipin intensity detection is 0.22.It has been generally acknowledged that the Z ' value greater than 0.5 is enough for screening test.
[031] in first round screening test, we have determined 14 kinds of caused remarkable declines of chemical compound in 10 μ M filipin labellings, comprising produce 3 kinds of chemical compounds that significantly reduce at 123nM.The one-level storehouse is synthetic by 126 kinds of form assemblies.It is effective at 123nM to observe part of compounds, and this shows that the target of some and they in might these chemical compounds has the interaction of high-affinity.
[032] filters out a chemical compound secondary storehouse (high coefficient shows high similarity) with the Tanimoto similarity coefficient in 0.3 to 0.96 scope.Average T animoto similarity coefficient is about 0.75.Screening test adopts and pays attention to avirulence more than the test compounds of low dosage and than the screening in one-level storehouse.Even the dosage of test compounds reduces to 1 μ M from 10 μ M in the detection in secondary storehouse, compare the secondary storehouse with one-level storehouse (0.1%) and still contain the more selected chemical compound of balloon score (0.18%).Therefore, the potential choosing in the object (hits) in a plurality of that be chosen in of chemical drugs causes tangible enrichment in the secondary storehouse.In addition, a lot of chemical compounds of selecting are compared with the chemical compound that first screening obtains bigger curative effect and hypotoxicity are arranged.These 7 kinds of chemical compounds that identify from the secondary storehouse are based on 4 synthetic templates.Chemical compound 2-a-1,2-a-9,2-a-12 and 2-a-13 are based on triazine, and this compounds is the important interest place in the pharmaceutical chemistry field always.See (48-52).
[033] 7 kinds of chemical compounds that are used for further characterizing of selecting from the secondary storehouse roughly can be divided into two groups.Chemical compound 2-a-1,2-a-9,2-a-12 and 2-a-13 (I group) are based on one 1,3, the core of 5 triazines, and this compounds is the important interest place (52-56) in the pharmaceutical chemistry field always.Second group of chemical compound (II group) has the heterocycle core (2-a-3:2-sulfo--1,3-thiazoles alkane-4-ketone derivatives, 2-a-15 comprise pyrroles and the pyrroles-2-ketone that a methine links to each other, and 2-a-8 comprises the 1,3-thiazoles that is connected to pyrazoline by N) of 5 yuan of rings.These two groups of chemical compounds all take place on nuclear a large amount of the replacement, and wherein the triazine of I group mainly has aryl or cyclammonium (or having a diazanyl).Group II also is that aryl replaces, and wherein the characteristics of chemical compound 2-a-3 are the diethyl-amino naphthalenes base section that are connected to an interesting fractional saturation on 2-sulfo--1,3-thiazoles alkane-4-ketone by two keys.Chemical compound 2-a-15 has three aromatic rings in extended conjugation, and chemical compound 2-a-8 combines 6 kinds of different member ring systems, and wherein 5 belong to aromatic.The chemical compound of I group and II group all shows as has molecule high degree of unsaturation, conformational restriction.Their periphery trends towards very hydrophobic, and its center is more hydrophilic.We notice that these characteristics mean that they are a kind of space parents (outer hydrophobic-inner hydrophilic).Though hydrophilic radical (it should be noted that the nitryl group of 2-a-13) is arranged at the edge in some cases, but the part of several hydrogen bonded as one man shows that to the core distribution of these structures these cores can be assisted their specific recognition to the body internal object.
[034] though this mensuration of exploitation is to be used for Chinese hamster ovary celI system, through too small modification, it also should be applicable to analyzes the accumulation of cholesterol in the cell of other types.It is a kind of that to be used for the cumulative detection of cholesterol be useful to NPC but also to other glycolipid storage diseases not only.Though the biochemical basis of these diseases is different, many these diseases cause a similar phenotype, are included in to form the internal membrane volution among the LSOs, and it comprises sphingomyelins, molten-two phosphatidic acid and cholesterol (53,54).This method described herein is not to screen to be used for chemistry only, and can be used for the screening of molecular genetics, suppresses and gene expression as RNAi.Use traditional method, definite minority gene can be proofreaied and correct NPC phenotype (36,38,55) when crossing expression in cell.Our described in this article this screening can be used for the screening of extensive gene expression.
[035] these screening tests have also been determined to strengthen the chemical compound that filipin dyes even surpasses level in the NPC mutant cell.After further study, showing at first can increase the wave band that the more painted chemical compounds of filipin are found in the filipin spectra overlapping and have fluorescence, and therefore, their fluorescence may be the basis that increases fluorescence when detecting.Yet the chemical compound of several non-fluorescence equally also is found the filipin dyeing that can increase the NPC cell.We have found that also some chemical compounds can produce the significant change of the compartment form of enrichment free cholesterol.Particularly, chemical compound 1-c-3 produces a kind of by the big network of the tangible tubulose organelle of filipin labelling.
[036] we also are subject to processing the cholesterol level of cell by a kind of direct chemical method measurement.Most of selected chemical compound all can reduce cellular cholesterol really when screening, though initial 3 kinds of selected chemical compounds do not demonstrate the minimizing cholesterol in a kind of gas chromatographic analysis.Therefore, in some cases, should scrupulous examine the filipin that obtains by chemical analysis independently in conjunction with experimental result.
[037] not by a specific theory constraint, think cholesterol from late period endosome overflow and need several steps.This step of overflowing as transportation in many born of the same parents mainly is (56) of non-vesicle obviously.Infer NPC2 from hydrolysis sterol ester site transportation cholesterol to limitans, play a role (57).Infer that NPC1 and other protein help cholesterol to be transported to the Cytoplasm carrier from limitans.The carrier that these are not determined from the molecule angle as yet is transported to plasma membrane or other organelles (58,59) with cholesterol.Total free cholesterol can be by increasing in endochylema overflowing of receptor outside the born of the same parents in the organelle, and/or by ACAT in the endocytoplasmic reticulum esterification of cholesterol is reduced.Reduce the picked-up of cholesterol or reduce the synthetic minimizing that also can cause cellular cholesterol when hatching with chemical compound.
[038] use the analytical method that is similar to mean intensity and LSO detection, we have measured the minimizing of the lipid BMP that accumulates in the NPC cell.Select chemical compound in the remarkable minimizing (data not shown) that after hatching in 16 hours, does not produce the BMP labelling in obtaining in the secondary storehouse.Several from the secondary storehouse, obtain in select chemical compound to cause the cumulative minimizing of cholesterol of the normal human fibroblasts of handling through U18666A really, thereby cause cholesterol gathering in LSOs.This shows that these chemical compounds do not rely on SCAP sudden change or other properties of the Chinese hamster ovary celI system that is used to screen.
[039] not by a specific theory constraint, the influence of test compound can directly act on LSOs, but has remote-effects equally.For example, Rab4, NPC phenotype (60) can be partly proofreaied and correct in the overexpression of relevant with an endosome classification or endocytosis recovery capsule usually little GTPase.
[040] compounds identified can effectively reduce the cholesterol accumulation to the avirulent concentration of NPC1 cell of cultivating in the screening test.In addition, several chemical compounds (Figure 13) are the amount of cholesterol reducing in normal cell effectively, because they show the effect that promotes that cholesterol overflows in the 25RA Chinese hamster ovary celI.Chemical compound of the present invention also can be used to study the mechanism of cell cholesterol regulating level.For example, chemical compound of the present invention can be modified by photosensitive group and be used for the bonded part of labelling or connect biotin being used for affinity purification.In addition, not by a specific theory constraint, chemical compound of the present invention can reduce cholesterol effectively by the biosynthesis of cellular uptake and/or inhibition cholesterol.
[041] another aspect of the present invention relates to and being used for the treatment of or the method for the inductive phospholipidosis of prophylactic agent.When a kind of pharmaceutical preparation was used to the patient, drug-induced phospholipidosis can be used as a kind of side effect and occurs.For example, following medicine can cause phospholipidosis: ABT-770, AC-3579, amantadine, ambroxol, amikacin, amiodarone, amitriptyline (amitryptilline), AY-9944, azithromycin, Benzoylamide, boxidine, bromhexine, chloreyclizine, chloroquine, chlorphentermine, chlorpromazine, citalopram, cloforex, Clomipramine, clozapine, compound recipe 200-15, cyclizine, DMP-777, erythromycin, fenfluramine, fluoxetine, fluvoxamine, gentamycin, hydroxyzine, IA-3, miboplatin is bright, iprindole, LY281389, maprotiline, meclizine, quinacrine, NE-10064, netilmicin, chlorcyclizine (norchlorcyclizine) falls, dibenzoxin, perhexiline, phentermine, PNU-177864, promazine, promethazine, propranolol, RMl10.393, Sertraline, tamoxifen, thioridazine, tilar ketone, tobramycin, trimeprimine, triparanol, tripelennamine (triperennamine), trospectomycin, cis-H-102/09,1-chlorine amitriptyline (1-chloroamitryptiline) and 4, the female phenol of 4 '-diethylamino ethoxy hexane.See M.J.Reasor et al.Exp.Biol.Med.2001,226,825; M.J.Reasor et al.Expert Opin.Drug Saf.2006,5,567; L ü llmann-Rauch R., Drug-induced Lysosomal Storage Disorders, in L YSOSOMES INB IOLOGY ANDP ATHOLOGY, Vol.6., pp.49-130 (Dingle et al.eds., Amsterdam:North-Holland, 1979); Kodavanti et al.Pharmacol.Rev.1990,42,327; M.J.Reasor.Cationic Amphiphilic Drugs, inC OMPREHENSIVET OXICOLOGY, Vol.8, T OXICOLOGY OF THER ESPIRATORYS YSTEMPp.555-566 (Sipes et al.eds., New York:Elsevier Science, 1997); And Sawada et al.in Toxicol.Sci., 2005,83,282 and Toxicol.Sci.2006,89,554..Multiple medicine with cation lipotropy structure also can cause drug-induced phospholipidosis.This class medicine often by one at least by one under the physiology pH value positively charged uncle's nitrogen or replace hydrophilic region that nitrogen groups forms and one contain can be by the fragrance of the optional replacement of halogen and/or the hydrophobic region of cycloaliphatic group.See M.J.Reasor et al.Exp.Biol.Med.2001,226,825.
[042] is used to determine to cause the method for phospholipidosis chemical compound to be well known in the art.See al.Toxicol.Sci.2005,83,282 as H.Sawada et.Because the phospholipid excessive accumulation is a kind of bad side effect of some drugs, an aspect of of the present present invention relates to a kind of method of inducing phospholipidosis by any compounds for treating among the general formula I-IX described herein that gives the patient treatment effective dose for the treatment of with needs or prophylactic agent.In some cases, patient's drug-induced phospholipidosis is caused by chemical compound U-18666A.In some cases, patient's drug-induced phospholipidosis is by ABT-770, AC-3579, amantadine, ambroxol, amikacin, amiodarone, amitriptyline, AY-9944, azithromycin, Benzoylamide, boxidine, bromhexine, chloreyclizine, chloroquine, chlorphentermine, chlorpromazine, citalopram, cloforex, Clomipramine, clozapine, compound recipe 200-15, cyclizine, DMP-777, erythromycin, fenfluramine, fluoxetine, fluvoxamine, gentamycin, hydroxyzine, IA-3, miboplatin is bright, iprindole, LY281389, maprotiline, meclizine, quinacrine, NE-10064, netilmicin, chlorcyclizine falls, dibenzoxin, perhexiline, phentermine, PNU-177864, promazine, promethazine, propranolol, RMI 10.393, Sertraline, tamoxifen, thioridazine, tilarone, tobramycin, trimeprimine, triparanol, tripelennamine, trospectomycin, cis-H-102/09,1-chlorine amitriptyline and 4, the administration of the female phenol of 4 '-diethylamino ethoxy hexane is caused.In some cases, patient's drug-induced phospholipidosis is caused by the administration of amiodarone, perhexiline, azithromycin, fluoxetine, imipramine, chloreyclizine, tamoxifen or gentamycin.
[043] another aspect of the present invention relates to a kind of method, comprise to a kind of first therapeutic agent of the patient treatment effective dose of needs and second therapeutic agent of treatment effective dose; Wherein, this first therapeutic agent is any chemical compound among the described general formula I-IX of this description; This second therapeutic agent is a kind of anoretics, anti-anginal drug, anti-arrhythmic, antibiotic, anticarcinogen, antidepressants, the estrogen antagonist agent, hydryllin, antilipemic agent, antimalarial agent, antinauseant, antipsychotic, antithrombotic agents, antiviral agent, cholesterol synthetic inhibitor, the diazepine atypical antipsychotic agents, histamine H 1-blocker, matrix metallo-proteinase inhibitor, the neutrophil elastase inhibitor, schistosomicide, succagoga, selective serotonin reuptake inhibitor or the tranquillizer that causes drug-induced phospholipidosis.In some cases, described second therapeutic agent is a kind of antibiotic, arrhythmia, antidepressants, histamine H 1-blocker or the anticarcinogen that causes drug-induced phospholipidosis.
[044] another aspect of the present invention relates to a kind of method for the treatment of the mammalian cell that drug-induced phospholipidosis takes place, comprise to the described general formula I-IX of this description of described cell therapy effective dose in any chemical compound.In some cases, patient's drug-induced phospholipidosis is caused by chemical compound U-18666A.Another aspect of the present invention relates to a kind of method for the treatment of the mammalian cell that drug-induced phospholipidosis takes place, comprise to the described general formula I-IX of this description of described cell therapy effective dose in any chemical compound, wherein drug-induced phospholipidosis to small part is by ABT-770, AC-3579, amantadine, ambroxol, amikacin, amiodarone, amitriptyline, AY-9944, azithromycin, Benzoylamide, boxidine, bromhexine, chloreyclizine, chloroquine, chlorphentermine, chlorpromazine, citalopram, cloforex, Clomipramine, clozapine, compound recipe 200-15, cyclizine, DMP-777, erythromycin, fenfluramine, fluoxetine, fluvoxamine, gentamycin, hydroxyzine, IA-3, miboplatin is bright, iprindole, LY281389, maprotiline, meclizine, quinacrine, NE-10064, netilmicin, chlorcyclizine falls, dibenzoxin, perhexiline, phentermine, PNU-177864, promazine, promethazine, propranolol, RMI 10.393, Sertraline, tamoxifen, thioridazine, tilarone, tobramycin, trimeprimine, triparanol, tripelennamine, trospectomycin, cis-H-102/09,1-chlorine amitriptyline and 4, the administration of the female phenol of 4 '-diethylamino ethoxy hexane is caused.
[045] The preparation of chemical compound of the present invention
[046] Fig. 5 and 8 described chemical compounds are commercially available.Utilize synthetic method known in the art, the represented chemical compound of general formula I-XXXIX can be seen for example J.March by chemical compound shown in Fig. 5 and 8 or other commercially available compound, Advanced Organic Chemistry, McGraw Hill Book Company, New York, (1992,4 ThEdition); Carey, F.A.and Sundberg, R.J.Advanced Organic Chemistry Part B:Reactions and Synthesis, 3 RdEd.; Plenum Press:New York, 1990; And Organic Chemistry 2 NdEd.Ed.Bruice, P.Y.New Jersey:Prentice Hall, 1998.Representational synthetic method also is illustrated below.
[047] by inserting new functional group on the aromatic rings in the chemical compound shown in Fig. 5 and 8 or modifying existing position functional group thereon, can prepare a large amount of chemical compounds.For example, the operation of typical functional group comprises by at FeBr 3Use Br when existing 2Handle aromatic compound and introduce bromine, by at FeBr 3Handle this aromatic compound and introduce acyl group with acid chloride when existing, with the SnCl that is present among the HCl 2Handle nitro-aromatic compound and obtain amino aromatic compound.Other functional group's operations comprise uses Na/NH 3The reduction of aromatic group obtains cycloolefin or compound cycloalkyl according to reaction condition.For example, because Na/NH is used in the influence of carboxylic acid 3Reduction 1-a-13 will optionally obtain cyclohexene derivative.Square case 1.This cyclohexene intermediate can further reduce and obtain a cyclohexyl derivatives.Perhaps, the cyclohexene intermediate can be with a kind of oxidizer treatment to form a kind of epoxide.This carboxylic acid group also can be in the presence of DCC by with alcohol for example methanol or a kind of ester of benzyl alcohol reaction changing into.
Scheme 1:
[048] shown in scheme 2, utilize the palladium coupling technique can be by a large amount of chemical compounds of lactam derivatives intermediate preparation.The palladium coupling reaction has superiority, because they often carry out with high yield and are applicable to various functional groups.In addition, a considerable amount of organo-boranes are known and/or commercially available.In addition, a large amount of aromatic halides and alkenyl halide are commercially available, and they can easily be transformed into the organo-borane raw material that is used for coupling reaction.
Scheme 2:
Figure A20068004988000602
[049] can prepare multiple triaizine compounds with the palladium coupling reaction.Shown in scheme 3, the reaction of commercially available triazine and aryl/hetaryl bromide or iodide can be used to prepare many derivants, and they can be other chemical compounds by above-mentioned aromatic functional group operational transition all.Palladium coupling that it should be noted that the bromide of aryl/hetaryl or iodide also can be used for preparing the various triazine radical hydrazones shown in scheme 4.
Scheme 3:
Figure A20068004988000611
Scheme 4:
Figure A20068004988000612
[050] Method of the present invention
[051] one aspect of the present invention relates to suffering from a kind of method that the patient that is characterized as the cumulative disease of cholesterol cell treats, and this method may further comprise the steps:
[052] give any one chemical compound among the formula I-IX with patient's effective dose of needs, its Chinese style I is expressed as:
Figure A20068004988000621
Wherein,
X be O or-N (R 7)-;
Y be N or-C (R 8)-;
R 1And R 2Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 2And R 3Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces;
R 4Be hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
R 5Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 9=CR 9) n-aryl or-(CR 9=CR 9) n-heteroaryl;
R 6Be H or alkyl; Or R 5And R 6Form a monocycle that can be optionally substituted or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 7Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 1And R 7Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces;
Each R 8And R 9Represent H or alkyl independently; And
N is 1 or 2;
Formula II is expressed as:
Figure A20068004988000622
Wherein,
X be O or-N (R 6)-;
R 1And R 2Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 2And R 3Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces;
R 4Be hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
R 5Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 6Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 1And R 6Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces;
Formula III is expressed as:
Figure A20068004988000631
Wherein,
R 1Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-(C (R 7) 2) n-(CR 7=C (R 7) 2);
R 2Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or alkyl;
R 3Be hydrogen, alkyl ,-CO 2R 8Or-C (O) N (R 7) (R 8); And
R 4With R 5Represent H or alkyl independently; Or R 4With R 5Form a key together;
Each R 6And R 7Represent H or alkyl independently;
Each R 8Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
L be a key ,-C (R 7) 2-or-(CR 7=CR 7)-; And
A 1And A 2Represent independently cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 7=CR 7)-aryl or-(CR 7=CR 7)-heteroaryl;
Formula IV is expressed as:
Figure A20068004988000641
Wherein,
A is cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 3=CR 3)-aryl or-(CR 3=CR 3)-heteroaryl;
R 2Be alkyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 3Represent H or alkyl independently;
R 4Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Formula V is expressed as:
Figure A20068004988000642
Wherein,
X be O ,-N (R 5)-,-N (R 5) C (O)-,-C (O) N (R 5)-,-OC (O)-,-CO 2-or-N (R 5) CO 2-;
Y be O, S or-N (R 5)-;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 2Represent H or alkyl independently, or 2 R 2Formation=O together;
R 3And R 4Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Each R 5Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Formula VI is expressed as:
Figure A20068004988000643
Wherein,
X be O, S or-N (R 4)-;
R 1Be cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-(C (R 5) 2) n-(CR 5=C (R 5) 2);
R 2Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl;
R 3Be H, alkyl, thiazolinyl, aryl or heteroaryl; Or R 2And R 3Form an optional substituted monocycle or dicyclo together, described ring has 0,1 or 2 hetero atom that is selected from O, N and S;
Each R 4With R 5Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Formula VII is expressed as:
Figure A20068004988000651
Wherein,
X is O or S;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-C (O) R 5
R 2Be H or alkyl;
R 3Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl, heteroarylalkyl or optional substituted monocycle or dicyclo, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2
R 5Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl; Or R 5Be one can by any one or a plurality of alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; And
Each R 6Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Formula VIII is expressed as:
Figure A20068004988000652
Wherein,
X is O or S;
R 1, R 3Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently with A;
R 2And R 4Represent H or alkyl independently;
R 5Be a monocycle that can be optionally substituted or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S;
Formula IX is expressed as:
Figure A20068004988000661
Wherein,
X 1Be-OR 5,-SR 5Or-N (R 5) 2
Each X 2Represent independently O, S or-N (R 5)-;
Each R 1Represent independently alkyl, halogen, nitro, cyano group, alkoxyl, thiazolinyl, alkynyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl ,-N (R 5) 2,-OH ,-C (O) R 6,-CO 2R 5Or C (O) N (R 5) 2
R 2And R 4Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be H, alkyl or halogen;
Each R 5Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Each R 6Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; And
N is 0,1,2,3 or 4.
[053] in some embodiments, the present invention relates to aforesaid method, wherein said disease is a C type NP.
[054] in some embodiments, the present invention relates to aforesaid method, wherein said disease is an atherosclerosis.
[055] in some embodiments, the present invention relates to aforesaid method, wherein said disease is a kind of lysosomal storage disease that is caused by sphingolipid or glycosyl sphingolipid metabolism disorder
[056] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula I.
[057] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula I, X be O or-N (R 7)-; Y is N; R 1And R 2Represent alkyl, haloalkyl or aryl independently; R 3It is aryl; Or R 2And R 3Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces; R 4Be hydrogen; R 5Be Heterocyclylalkyl or aryl; R 6Be H or alkyl; Or R 5And R 6Form an optional substituted monocycle or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S; R 7Be hydrogen; Or R 1And R 7Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces.
[058] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula I, and X is-N (R 7)-; Y is N; R 1And R 2It is aryl; R 3It is aryl; Or R 2And R 3Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces; R 4Be hydrogen; R 5Be Heterocyclylalkyl or aryl; R 6Be H or alkyl; Or R 5And R 6Form an optional substituted monocycle or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S; R 7Be hydrogen; Or R 1And R 7Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces.
[059] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula I, and X is-N (R 7)-; Y is-C (R 8)-; R 1And R 2Represent alkyl, assorted alkyl or haloalkyl independently; R 3Be hydrogen, alkyl, assorted alkyl or haloalkyl; R 4Be hydrogen; R 5It is heteroaryl; R 6Be H or alkyl; R 7Be hydrogen, alkyl, assorted alkyl or haloalkyl; R 8Be H or alkyl.
[060] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula II.
[061] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula II, and X is-N (R 7)-; R 1, R 2And R 5Represent aryl or heteroaryl independently; And R 3, R 4And R 6Represent hydrogen or alkyl independently.
[062] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is a kind of chemical compound of formula III.
[063] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is a kind of chemical compound of formula III; R 1, R 2, A 1And A 2Represent aryl or heteroaryl independently; R 3It is hydrogen or alkyl; R 6Be H or alkyl; L is a key.
[064] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is a kind of chemical compound of formula III; R 1Be-(C (R 7) 2) n-(CR 7=C (R 7) 2); R 2It is alkyl; R 3Be alkyl ,-CO 2R 8Or-C (O) N (R 7) (R 8); R 4With R 5Represent H or alkyl independently; Or R 4With R 5Form a key together; Each R 6And R 7Represent H or alkyl independently; Each R 8Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; L be a key ,-C (R 7) 2-or-(CR 7=CR 7)-; And A 1And A 2Represent alkyl or assorted alkyl independently.
[065] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is a kind of chemical compound of formula III, wherein R 1Comprise a hydroxy-acid group; R 1It is the aryl of a carboxylic acid-substituted; R 1It is the phenyl of a carboxylic acid-substituted; And/or R 1It is the phenyl of a carboxylic acid para-orientation;
[066] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula IV.
[067] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula IV; A, R 1And R 4Represent aryl or heteroaryl independently; R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 3=CR 3)-aryl or-(CR 3=CR 3)-heteroaryl; R 2It is alkyl or aryl; Each R 3Represent H or alkyl independently.
[068] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula V.
[069] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula V; X is-C (O) N (R 5)-or-CO 2-; Y is O or S; R 1, R 3And R 4Represent aryl or heteroaryl independently; Each R 2Represent H or alkyl independently, or 2 R 2Formation=O together; R 3And R 4Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Each R 5Represent H, alkyl, aryl or aralkyl independently; And n is 1 or 2.
[070] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VI.
[071] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VI; X is S; R 1Be aryl, heteroaryl or-(C (R 5) 2) n-(CR 5=C (R 5) 2); R 2Be aryl, heteroaryl ,-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl; Each R 5Represent H, alkyl, aryl or aralkyl independently; And n is 1 or 2.
[072] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VI; X is S; R 1Be aryl, R 2Be aryl, R 3Be H or alkyl.
[073] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VI; X is S; R 1Be the phenyl that alkoxyl replaces, R 2Be the phenyl that dialkyl amido replaces, R 3Be H.
[074] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VI; X is S; R 1Be aryl, heteroaryl or-(C (R 5) 2) n-(CR 5=C (R 5) 2); R 2Be-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl; R 3Be H or alkyl; R 2And R 3Form an optional substituted monocycle or dicyclo together, described ring has 0,1 or 2 hetero atom that is selected from O, N and S; Each R 5Represent H, alkyl, aryl or aralkyl independently; And n is 1 or 2.
[075] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VII.
[076] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VII; X is O or S; R 1Be aryl, heteroaryl or-C (O) R 5R 2Be H or alkyl; R 3Be alkyl, heteroaryl or optional substituted monocycle or dicyclo, described ring has 1 or 2 hetero atom that is selected from O, N and S; R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2R 5Be one can by one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; Each R 6Represent H, alkyl, aryl, aralkyl or Heterocyclylalkyl independently.
[077] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VII; X is O or S; R 1Be aryl, heteroaryl or-C (O) R 5R 2Be H or alkyl; R 3Representative R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2R 5Be one can by one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; Each R 6Represent H, alkyl, aryl, aralkyl or Heterocyclylalkyl independently; M is 0,1,2,3 or 4; Each R 7Represent halogen, hydroxyl, amino, carboxyl, nitro, cyano group, alkyl or alkoxyl independently.
[078] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VIII.
[079] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VIII; X is O or S; R 1, R 3Represent aryl or heteroaryl independently with A; R 2And R 4Represent H or alkyl independently; R 5Be an optional substituted monocycle or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S.
[080] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VIII; X is O or S; R 1, R 3Represent aryl or heteroaryl independently with A; R 2And R 4Represent H or alkyl independently; R 5Representative
Figure A20068004988000692
Wherein n is 0,1,2,3 or 4; Each R 7Represent halogen, hydroxyl, amino, carboxyl, nitro, cyano group, alkyl or alkoxyl independently.
[081] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula IX;
[082] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula IX; X 1Be-N (R 5) 2Each X 2Represent O or S independently; Each R 1Represent independently alkyl, halogen, nitro, cyano group, alkoxyl ,-N (R 5) 2,-OH ,-C (O) R 6,-CO 2R 5Or C (O) N (R 5) 2R 2And R 4Represent aryl, heteroaryl, aralkyl or heteroarylalkyl independently; R 3Be H, alkyl or halogen; Each R 5Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Each R 6Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; And n is 0,1,2,3 or 4.
[083] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is
Figure A20068004988000701
Figure A20068004988000711
[084] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is any chemical compound among the formula X-XXXIX as described below.
[085] another aspect of the present invention relates to a kind of method that reduces the amount of the cholesterol in the cell, may further comprise the steps:
[086] with mammiferous cellular exposure in formula I-IX in one of any a kind of chemical compound, its Chinese style I is expressed as:
Figure A20068004988000712
Wherein,
X be O or-N (R 7)-;
Y be N or-C (R 8)-;
R 1And R 2Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl respectively independently;
R 3Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 2And R 3Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces;
R 4Be hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
R 5Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 9=CR 9) n-aryl or-(CR 9=CR 9) n-heteroaryl;
R 6Be H or alkyl; Or R 5And R 6Form a monocycle that can be optionally substituted or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 7Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 1And R 7Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces;
Each R 8And R 9Represent H or alkyl independently; And
N is 1 or 2;
Formula II is expressed as:
Figure A20068004988000721
Wherein,
X be O or-N (R 6)-;
R 1And R 2Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 2And R 3Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces;
R 4Be hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
R 5Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 6Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 1And R 6Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces;
Formula III is expressed as:
Figure A20068004988000722
Wherein,
R 1Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-(C (R 7) 2) n-(CR 7=C (R 7) 2);
R 2Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or alkyl;
R 3Be hydrogen, alkyl ,-CO 2R 8Or-C (O) N (R 7) (R 8);
R 4With R 5Represent H or alkyl independently; Or R 4With R 5Form a key together;
Each R 6And R 7Represent H or alkyl independently;
Each R 8Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
L be a key ,-C (R 7) 2-or-(CR 7=CR 7)-; And
A 1And A 2Represent independently cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 7=CR 7)-aryl or-(CR 7=CR 7)-heteroaryl;
Formula IV is expressed as:
Figure A20068004988000731
Wherein,
A is cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 3=CR 3)-aryl or-(CR 3=CR 3)-heteroaryl;
R 2Be alkyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 3Represent H or alkyl independently;
R 4Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Formula V is expressed as:
Figure A20068004988000732
Wherein,
X be O ,-N (R 5)-,-N (R 5) C (O)-,-C (O) N (R 5)-,-OC (O)-,-CO 2-or-N (R 5) CO 2-;
Y be O, S or-N (R 5)-;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 2Represent H or alkyl independently, or 2 R 2Formation=O together;
R 3And R 4Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Each R 5Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Formula VI is expressed as:
Wherein,
X be O, S or-N (R 4)-;
R 1Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-(C (R 5) 2) n-(CR 5=C (R 5) 2);
R 2Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl;
R 3Be H, alkyl, thiazolinyl, aryl or heteroaryl; Or R 2And R 3Form an optional substituted monocycle or dicyclo together, described ring has 0,1 or 2 hetero atom that is selected from O, N and S;
Each R 4With R 5Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Formula VII is expressed as:
Figure A20068004988000742
Wherein,
X is O or S;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-C (O) R 5
R 2Be H or alkyl;
R 3Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or optional substituted monocycle or dicyclo, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2
R 5Cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl; Or R 5Be one can by one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; And
Each R 6Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Formula VIII is expressed as:
Figure A20068004988000751
Wherein,
X is O or S;
R 1, R 3Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently with A;
R 2And R 4Represent H or alkyl independently;
R 5Be a monocycle that can be optionally substituted or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S;
Formula IX is expressed as:
Figure A20068004988000752
Wherein,
X 1Be-OR 5,-SR 5Or-N (R 5) 2
Each X 2Represent independently O, S or-N (R 5)-;
Each R 1Represent independently alkyl, halogen, nitro, cyano group, alkoxyl, thiazolinyl, alkynyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl ,-N (R 5) 2,-OH ,-C (O) R 6,-CO 2R 5Or C (O) N (R 5) 2
R 2And R 4Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl respectively independently;
R 3Be H, alkyl or halogen;
Each R 5Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Each R 6Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; And
N is 0,1,2,3 or 4.
[087] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound reduces the amount of the cholesterol in the described cell by the discharge that increases cholesterol in the described cell.
[088] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound absorbs the amount that reduces cholesterol by the cholesterol that suppresses described cell.
[089] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is by the synthetic amount that reduces the cholesterol in the described cell of the cholesterol that suppresses described cell.
[090] in some embodiments, the present invention relates to aforesaid method, the esterification of the cholesterol of wherein said chemical compound by promoting described cell reduces the amount of the cholesterol in the described cell.
[091] in some embodiments, the present invention relates to aforesaid method, wherein said cell is a human body cell.
[092] in some embodiments, the present invention relates to aforesaid method, wherein said cell has C type Niemann-pik Er Shi defective.
[093] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula I.
[094] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula I, X be O or-N (R 7)-; Y is N; R 1And R 2Represent alkyl, haloalkyl or aryl independently; R 3It is aryl; Or R 2And R 3Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces; R 4Be hydrogen; R 5Be Heterocyclylalkyl or aryl; R 6Be H or alkyl; Or R 5And R 6Form an optional substituted monocycle or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S; R 7Be hydrogen; Or R 1And R 7Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces.
[095] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula I, and X is-N (R 7)-; Y is N; R 1And R 2It is aryl; R 3It is aryl; Or R 2And R 3Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces; R 4Be hydrogen; R 5Be Heterocyclylalkyl or aryl; R 6Be H or alkyl; Or R 5And R 6Form an optional substituted monocycle or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S; R 7Be hydrogen; Or R 1And R 7Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces.
[096] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula I, and X is-N (R 7)-; Y is-C (R 8)-; R 1And R 2Represent alkyl, assorted alkyl or haloalkyl independently; R 3Be hydrogen, alkyl, assorted alkyl or haloalkyl; R 4Be hydrogen; R 5It is heteroaryl; R 6Be H or alkyl; R 7Be hydrogen, alkyl, assorted alkyl or haloalkyl; R 8Be H or alkyl.
[097] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula II.
[098] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula II, and X is-N (R 7)-; R 1, R 2And R 5Represent aryl or heteroaryl independently; And R 3, R 4And R 6Represent hydrogen or alkyl independently.
[099] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is a kind of chemical compound of formula III.
[0100] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is a kind of chemical compound of formula III; R 1, R 2, A 1And A 2Represent aryl or heteroaryl independently; R 3It is hydrogen or alkyl; R 6Be H or alkyl; L is a key.
[0101] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is a kind of chemical compound of formula III; R 1Be-(C (R 7) 2) n-(CR 7=C (R 7) 2); R 2It is alkyl; R 3Be alkyl ,-CO 2R 8Or-C (O) N (R 7) (R 8); R 4With R 5Represent H or alkyl independently; Or R 4With R 5Form a key together; Each R 6And R 7Represent H or alkyl independently; Each R 8Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; L be a key ,-C (R 7) 2-or-(CR 7=CR 7)-; And A 1And A 2Represent alkyl or assorted alkyl independently.
[0102] in some embodiments, the present invention relates to preceding method, wherein said chemical compound is the chemical compound with formula III, R 1Comprise a hydroxy-acid group; R 1It is the aryl of a carboxylic acid-substituted; R 1It is the phenyl of a carboxylic acid-substituted; And/or R 1It is the phenyl of a carboxylic acid para-orientation.
[0103] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula IV.
[0104] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula IV; A, R 1And R 4Represent aryl or heteroaryl independently; R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 3=CR 3)-aryl or-(CR 3=CR 3)-heteroaryl; R 2It is alkyl or aryl; Each R 3Represent H or alkyl independently.
[0105] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula V.
[0106] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula V; X is-C (O) N (R 5)-or-CO 2-; Y is O or S; R 1, R 3And R 4Represent aryl or heteroaryl independently; Each R 2Represent H or alkyl independently, or 2 R 2Formation=O together; R 3And R 4Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Each R 5Represent H, alkyl, aryl or aralkyl independently; And n is 1 or 2.
[0107] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VI.
[0108] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VI; X is S; R 1Be aryl, heteroaryl or-(C (R 5) 2) n-(CR 5=C (R 5) 2); R 2Be aryl, heteroaryl ,-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl; Each R 5Represent H, alkyl, aryl or aralkyl independently; And n is 1 or 2.
[0109] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VI; X is S; R 1Be aryl, R 2Be aryl, R 3Be H or alkyl.
[0110] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VI; X is S; R 1Be the phenyl that alkoxyl replaces, R 2Be the phenyl that dialkyl amido replaces, R 3Be H.
[0111] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VI; X is S; R 1Be aryl, heteroaryl or-(C (R 5) 2) n-(CR 5=C (R 5) 2); R 2Be-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl; R 3Be H or alkyl; R 2And R 3Form an optional substituted monocycle or dicyclo together, described ring has 0,1 or 2 hetero atom that is selected from O, N and S; Each R 5Represent H, alkyl, aryl or aralkyl independently; And n is 1 or 2.
[0112] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VII.
[0113] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VII; X is O or S; R 1Be aryl, heteroaryl or-C (O) R 5R 2Be H or alkyl; R 3Be alkyl, heteroaryl or optional substituted monocycle or dicyclo, described ring has 1 or 2 hetero atom that is selected from O, N and S; R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2R 5Be one can by one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; Each R 6Represent H, alkyl, aryl, aralkyl or Heterocyclylalkyl independently.
[0114] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VII; X is O or S; R 1Be aryl, heteroaryl or-C (O) R 5R 2Be H or alkyl; R 3Representative
Figure A20068004988000781
R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2R 5Be one can by one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; Each R 6Represent H, alkyl, aryl, aralkyl or Heterocyclylalkyl independently; M is 0,1,2,3 or 4; Each R 7Represent halogen, hydroxyl, amino, carboxyl, nitro, cyano group, alkyl or alkoxyl independently.
[0115] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VIII.
[0116] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VIII; X is O or S; R 1, R 3Represent aryl or heteroaryl independently with A; R 2And R 4Represent H or alkyl independently; R 5Be an optional substituted monocycle or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S.
[0117] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VIII; X is O or S; R 1, R 3Represent aryl or heteroaryl independently with A; R 2And R 4Represent H or alkyl independently; R 5Representative
Figure A20068004988000791
Wherein n is 0,1,2,3 or 4; Each R 7Represent halogen, hydroxyl, amino, carboxyl, nitro, cyano group, alkyl or alkoxyl independently.
[0118] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula IX.
[0119] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula IX; X 1Be-N (R 5) 2Each X 2Represent O or S independently; Each R 1Represent independently alkyl, halogen, nitro, cyano group, alkoxyl ,-N (R 5) 2,-OH ,-C (O) R 6,-CO 2R 5Or C (O) N (R 5) 2R 2And R 4Represent aryl, heteroaryl, aralkyl or heteroarylalkyl respectively independently; R 3Be H, alkyl or halogen; Each R 5Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Each R 6Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; And n is 0,1,2,3 or 4.
[0120] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is
Figure A20068004988000792
Figure A20068004988000801
[0121] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is a kind of chemical compound one of any among the formula X-XXXIX as described below.
[0122] another aspect of the present invention relates to the method for the phospholipidosis that a kind of treatment or prophylactic agent cause, may further comprise the steps:
[0123] give a kind of chemical compound one of any among the formula I-IX with patient's effective dose of needs, its Chinese style I is expressed as:
Figure A20068004988000802
Figure A20068004988000811
Wherein,
X be O or-N (R 7)-;
Y be N or-C (R 8)-;
R 1And R 2Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 2And R 3Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces;
R 4Be hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
R 5Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 9=CR 9) n-aryl or-(CR 9=CR 9) n-heteroaryl;
R 6Be H or alkyl; Or R 5And R 6Form a monocycle that can be optionally substituted or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 7Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 1And R 7Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces;
Each R 8And R 9Represent H or alkyl independently; And
N is 1 or 2;
Formula II is expressed as:
Figure A20068004988000812
Wherein,
X be O or-N (R 6)-;
R 1And R 2Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 2And R 3Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces;
R 4Be hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
R 5Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 6Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 1And R 6Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces;
Formula III is expressed as:
Wherein,
R 1Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-(C (R 7) 2) n-(CR 7=C (R 7) 2);
R 2Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or alkyl;
R 3Be hydrogen, alkyl ,-CO 2R 8Or-C (O) N (R 7) (R 8); And
R 4With R 5Represent H or alkyl independently; Or R 4With R 5Form a key together;
Each R 6And R 7Represent H or alkyl independently;
Each R 8Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
L be a key ,-C (R 7) 2-or-(CR 7=CR 7)-; And
A 1And A 2Represent independently cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 7=CR 7)-aryl or-(CR 7=CR 7)-heteroaryl;
Formula IV is expressed as:
Figure A20068004988000822
Wherein,
A is cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 3=CR 3)-aryl or-(CR 3=CR 3)-heteroaryl;
R 2Be alkyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 3Represent H or alkyl independently;
R 4Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Formula V is expressed as:
Figure A20068004988000831
Wherein,
X be O ,-N (R 5)-,-N (R 5) C (O)-,-C (O) N (R 5)-,-OC (O)-,-CO 2-or-N (R 5) CO 2-;
Y be O, S or-N (R 5)-;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 2Represent H or alkyl independently, or 2 R 2Formation=O together;
R 3And R 4Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Each R 5Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Formula VI is expressed as:
Wherein,
X be O, S or-N (R 4)-;
R 1Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-(C (R 5) 2) n-(CR 5=C (R 5) 2);
R 2Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl;
R 3Be H, alkyl, thiazolinyl, aryl or heteroaryl; Or R 2And R 3Form an optional substituted monocycle or dicyclo together, described ring has 0,1 or 2 hetero atom that is selected from O, N and S;
Each R 4With R 5Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Formula VII is expressed as:
Figure A20068004988000841
Wherein,
X is O or S;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-C (O) R 5
R 2Be H or alkyl;
R 3Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or optional substituted monocycle or dicyclo, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2
R 5Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl; Or R 5Be one can by one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; And
Each R 6Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Formula VIII is expressed as:
Figure A20068004988000842
Wherein,
X is O or S;
R 1, R 3Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently with A;
R 2And R 4Represent H or alkyl independently;
R 5Be a monocycle that can be optionally substituted or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S;
Formula IX is expressed as:
Figure A20068004988000843
Wherein,
X 1Be-OR 5,-SR 5Or-N (R 5) 2
Each X 2Represent independently O, S or-N (R 5)-;
Each R 1Represent independently alkyl, halogen, nitro, cyano group, alkoxyl, thiazolinyl, alkynyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl ,-N (R 5) 2,-OH ,-C (O) R 6,-CO 2R 5Or C (O) N (R 5) 2
R 2And R 4Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be H, alkyl or halogen;
Each R 5Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Each R 6Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; And
N is 0,1,2,3 or 4.
[0124] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula I.
[0125] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula I, X be O or-N (R 7)-; Y is N; R 1And R 2Represent alkyl, haloalkyl or aryl independently; R 3It is aryl; Or R 2And R 3Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces; R 4Be hydrogen; R 5Be Heterocyclylalkyl or aryl; R 6Be H or alkyl; Or R 5And R 6Form an optional substituted monocycle or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S; R 7Be hydrogen; Or R 1And R 7Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces.
[0126] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula I, and X is-N (R 7)-; Y is N; R 1And R 2It is aryl; R 3It is aryl; Or R 2And R 3Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces; R 4Be hydrogen; R 5Be Heterocyclylalkyl or aryl; R 6Be H or alkyl; Or R 5And R 6Form an optional substituted monocycle or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S; R 7Be hydrogen; Or R 1And R 7Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces.
[0127] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula I, and X is-N (R 7)-; Y is-C (R 8)-; R 1And R 2Represent alkyl, assorted alkyl or haloalkyl independently; R 3Be hydrogen, alkyl, assorted alkyl or haloalkyl; R 4Be hydrogen; R 5It is heteroaryl; R 6Be H or alkyl; R 7Be hydrogen, alkyl, assorted alkyl or haloalkyl; R 8Be H or alkyl.
[0128] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula II.
[0129] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula II, and X is-N (R 7)-; R 1, R 2And R 5Represent aryl or heteroaryl independently; And R 3, R 4And R 6Represent hydrogen or alkyl independently.
[0130] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is a kind of chemical compound of formula III.
[0131] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is a kind of chemical compound of formula III; R 1, R 2, A 1And A 2Represent aryl or heteroaryl independently; R 3It is hydrogen or alkyl; R 6Be H or alkyl; L is a key.
[0132] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is a kind of chemical compound of formula III; R 1Be-(C (R 7) 2) n-(CR 7=C (R 7) 2); R 2It is alkyl; R 3Be alkyl ,-CO 2R 8Or-C (O) N (R 7) (R 8); R 4With R 5Represent H or alkyl independently; Or R 4With R 5Form a key together; Each R 6And R 7Represent H or alkyl independently; Each R 8Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; L be a key ,-C (R 7) 2-or-(CR 7=CR 7)-; And A 1And A 2Represent alkyl or assorted alkyl independently.
[0133] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is a kind of chemical compound of formula III; R 1Contain a hydroxy-acid group; R 1It is the aryl of a carboxylic acid-substituted; R 1It is the phenyl of a carboxylic acid-substituted; And/or R 1It is the phenyl of a carboxylic acid para-orientation.
[0134] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula IV.
[0135] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula IV; A, R 1And R 4Represent aryl or heteroaryl independently; R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 3=CR 3)-aryl or-(CR 3=CR 3)-heteroaryl; R 2It is alkyl or aryl; Each R 3Represent H or alkyl independently.
[0136] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula V.
[0137] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula V; X is-C (O) N (R 5)-or-CO 2-; Y is O or S; R 1, R 3And R 4Represent aryl or heteroaryl independently; Each R 2Represent H or alkyl independently, or 2 R 2Formation=O together; R 3And R 4Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Each R 5Represent H, alkyl, aryl or aralkyl independently; And n is 1 or 2;
[0138] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VI.
[0139] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VI; X is S; R 1Be aryl, heteroaryl or-(C (R 5) 2) n-(CR 5=C (R 5) 2); R 2Be aryl, heteroaryl ,-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl; R 3Be H or alkyl; Each R 5Represent H, alkyl, aryl or aralkyl independently; And n is 1 or 2.
[0140] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VI; X is S; R 1Be aryl, R 2Be aryl, R 3Be H or alkyl.
[0141] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VI; X is S; R 1Be the phenyl that alkoxyl replaces, R 2Be the phenyl that dialkyl amido replaces, R 3Be H.
[0142] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VI; X is S; R 1Be aryl, heteroaryl or-(C (R 5) 2) n-(CR 5=C (R 5) 2); R 2Be-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl; R 3Be H or alkyl; R 2And R 3Form an optional substituted monocycle or dicyclo together, described ring has 0,1 or 2 hetero atom that is selected from O, N and S; Each R 5Represent H, alkyl, aryl or aralkyl independently; And n is 1 or 2.
[0143] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VII.
[0144] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VII; X is O or S; R 1Be aryl, heteroaryl or-C (O) R 5R 2Be H or alkyl; R 3Be alkyl, heteroaryl or optional substituted monocycle or dicyclo, described ring has 1 or 2 hetero atom that is selected from O, N and S; R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2R 5Be one can by one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; Each R 6Represent H, alkyl, aryl, aralkyl or Heterocyclylalkyl independently.
[0145] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VII; X is O or S; R 1Be aryl, heteroaryl or-C (O) R 5R 2Be H or alkyl; R 3Representative R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2R 5Be one can by one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; Each R 6Represent H, alkyl, aryl, aralkyl or Heterocyclylalkyl independently; M is 0,1,2,3 or 4; Each R 7Represent halogen, hydroxyl, amino, carboxyl, nitro, cyano group, alkyl or alkoxyl independently.
[0146] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VIII.
[0147] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VIII; X is O or S; R 1, R 3Represent aryl or heteroaryl independently with A; R 2And R 4Represent H or alkyl independently; R 5Be an optional substituted monocycle or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S.
[0148] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula VIII; X is O or S; R 1, R 3Represent aryl or heteroaryl independently with A; R 2And R 4Represent H or alkyl independently; R 5Representative
Figure A20068004988000881
Wherein n is 0,1,2,3 or 4; Each R 7Represent halogen, hydroxyl, amino, carboxyl, nitro, cyano group, alkyl or alkoxyl independently.
[0149] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula IX.
[0150] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is the chemical compound of a kind of formula IX; X 1Be-N (R 5) 2Each X 2Represent O or S independently; Each R 1Represent independently alkyl, halogen, nitro, cyano group, alkoxyl ,-N (R 5) 2,-OH ,-C (O) R 6,-CO 2R 5Or C (O) N (R 5) 2R 2And R 4Represent aryl, heteroaryl, aralkyl or heteroarylalkyl independently; R 3Be H, alkyl or halogen; Each R 5Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Each R 6Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; And n is 0,1,2,3 or 4.
[0151] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is
Figure A20068004988000882
Figure A20068004988000891
[0152] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is a kind of chemical compound one of any among the formula X-XXXIX as described below.
[0153] in some embodiments, the present invention relates to aforesaid method, wherein said chemical compound is
Figure A20068004988000901
[0154] in some embodiments, the present invention relates in the aforesaid method any one, wherein said patient is a mammal.
[0155] in some embodiments, the present invention relates in the aforesaid method any one, wherein said patient is primate, equine species, Canis animals or felid.
[0156] in some embodiments, the present invention relates in the aforesaid method any one, wherein said patient is human.
[0157] Chemical compound of the present invention and compositions
[0158] one aspect of the present invention relates to the chemical compound that a kind of formula X represents:
Figure A20068004988000902
Wherein,
X is OH or N (R 5) 2
Each R 1Represent independently alkyl, halogen, nitro, cyano group, alkoxyl, thiazolinyl, alkynyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl ,-N (R 5) 2,-OH ,-C (O) R 6,-CO 2R 5Or C (O) N (R 5) 2
R 2And R 4Represent cycloalkenyl group, heterocycloalkenyl, aryl, aralkyl, heteroarylalkyl or heteroaryl independently, described heteroaryl has 1 hetero atom that is selected from N, O or S;
R 3Be H, alkyl or halogen;
Each R 5Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Each R 6Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
N is 0,1,2,3 or 4; And
Condition be when X be NH 2The time, R 2And R 4In be not aryl one of at least.
In some embodiments, the present invention relates to aforesaid chemical compound, wherein said X is NH 2And R 2It is aryl.
In some embodiments, the present invention relates to aforesaid chemical compound, wherein said X is NH 2And R 4It is aryl.
[0159] another aspect of the present invention relates to the chemical compound that a kind of formula XI represents:
Figure A20068004988000911
Wherein,
R 1And R 3Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 2And R 4Represent hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Or R 1And R 2Form a 3-8 unit ring together; Or R 3And R 4Form a 3-8 unit ring together;
R 5, R 6, R 7And R 8Represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Or R 5, R 6, R 7And R 8Form one together and be selected from (C by one at least 2-C 6) alkyl, halogen, nitro, cyano group, alkoxyl, thiazolinyl, alkynyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl ,-N (R 9) 2,-OR 9,-C (O) R 9,-CO 2R 9Or C (O) N (R 9) 2The functional group aryl or the heteroaryl that replace; And
Each R 9Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently.
[0160] in some embodiments, the present invention relates to aforesaid chemical compound, wherein R 1And R 2Form 6 yuan of rings.
[0161] in some embodiments, the present invention relates to aforesaid chemical compound, wherein R 3And R 4Form 6 yuan of rings.
[0162] in some embodiments, the present invention relates to aforesaid chemical compound, wherein R 5, R 6, R 7And R 8Form an aromatic rings together.
[0163] another aspect of the present invention relates to the chemical compound that a kind of formula XII represents:
Figure A20068004988000912
Wherein,
X be O, S or-N (R 4)-;
R 1Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
R 2Be cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl;
R 3Be H, alkyl, thiazolinyl, aryl or heteroaryl; Or R 2And R 3Form an optional substituted monocycle or dicyclo together, described ring has 0,1 or 2 hetero atom that is selected from O, N and S;
Each R 4With R 5Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Or the chemical compound represented of a kind of formula XIII:
Figure A20068004988000921
Wherein,
X be O, S or-N (R 7)-;
R 4Be-(C (R 8) 2) n-(CR 8=C (R 8) 2);
R 5Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-(CR 8=C (R 8) 2);
R 6Be H, alkyl, thiazolinyl, aryl or heteroaryl; Or R 5And R 6Form an optional substituted monocycle or dicyclo together, described ring has 0,1 or 2 hetero atom that is selected from O, N and S;
Each R 7And R 8Represent H, alkyl, cycloalkyl or Heterocyclylalkyl, aralkyl or heteroarylalkyl independently; And
N is 1,2,3,4 or 5;
Or the chemical compound represented of a kind of formula XIV:
Wherein,
X be O, S or-N (R 12)-;
R 9Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl ,-aryl-OR 14, heteroaryl, aralkyl or heteroarylalkyl;
R 10Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 13=CR 13)-aryl or-(CR 13=CR 13)-heteroaryl;
R 11Be H, alkyl, thiazolinyl, aryl or heteroaryl;
Each R 12With R 13Represent H, alkyl, aryl or aralkyl independently;
R 14Be assorted alkyl, Heterocyclylalkyl, heteroaryl, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl; And
N is 1,2,3,4 or 5.
[0164] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XIII, wherein X is S and R 4It is pi-allyl.
[0165] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XIII, wherein X is S, R 4Be pi-allyl and R 5Be-(CR 8=C (R 8) 2).
[0166] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XIV, wherein X is S and R 9Be-pi-allyl-OR 14
[0167] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XIV, wherein X is S and R 9Be-pi-allyl-OR 14, R 10Be aryl, and R 11Be H.
[0168] another aspect of the present invention relates to the chemical compound that a kind of formula XIVa represents:
Figure A20068004988000931
Wherein,
X be O, S or-N (R 12)-;
R 9Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl ,-aryl-OR 14, heteroaryl, aralkyl or heteroarylalkyl;
R 10Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 13=CR 13)-aryl or-(CR 13=CR 13)-heteroaryl;
R 11Be H, alkyl, thiazolinyl, aryl or heteroaryl; Or R 10And R 11Form an optional substituted monocycle or dicyclo together, described ring has 0,1 or 2 hetero atom that is selected from O, N and S;
Each R 12With R 13Represent H, alkyl, aryl or aralkyl independently;
N is 1,2,3,4 or 5.
[0169] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XIVa, wherein X is S and R 9It is aryl.
[0170] another aspect of the present invention relates to the chemical compound that a kind of formula XV represents:
Figure A20068004988000932
Wherein,
A is cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 3=CR 3)-aryl or-(CR 3=CR 3)-heteroaryl;
R 2Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 3Represent H or alkyl independently; And
R 4Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Or the chemical compound represented of a kind of formula XVI:
Figure A20068004988000941
Wherein,
A is cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 5Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 7=CR 7)-aryl or-(CR 7=CR 7)-heteroaryl;
R 6It is alkyl or aryl;
Each R 7Represent H or alkyl independently; And
R 8Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Or the chemical compound represented of a kind of formula XVII:
Figure A20068004988000942
Wherein,
A is cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 9Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 11=CR 11)-aryl or-(CR 11=CR 11)-heteroaryl;
R 10It is alkyl or aryl;
Each R 11Represent H or alkyl independently; And
R 12Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl.
[0171] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XVI, wherein A is heteroaryl and R 6It is aryl.
[0172] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XVI, wherein A is a heteroaryl, R 6It is alkyl.
[0173] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XVII, wherein A is a heteroaryl, R 9Be aryl, and R 10It is alkyl.
[0174] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XVII, wherein A is a heteroaryl, R 9Be aryl, and R 10It is aryl.
[0175] another aspect of the present invention relates to the chemical compound that a kind of formula XVIII represents:
Figure A20068004988000951
Wherein,
R 1Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl;
R 2Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl, heteroarylalkyl or alkyl;
R 3Be hydrogen, alkyl ,-CO 2R 8Or-C (O) N (R 7) (R 8);
R 4With R 5Represent H or alkyl independently; Or R 4With R 5Form a key together;
Each R 6And R 7Represent H or alkyl independently;
Each R 8Represent alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
L be a key ,-C (R 7) 2-or-(CR 7=CR 7)-; And
A 1And A 2Represent independently cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 7=CR 7)-aryl or-(CR 7=CR 7)-heteroaryl;
Or the chemical compound represented of a kind of formula XIX:
Wherein,
R 9Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl, heteroarylalkyl or-(C (R 15) 2) n-(CR 15=C (R 15) 2);
R 10It is aryl;
R 11Be hydrogen, alkyl ,-CO 2R 16Or-C (O) N (R 15) (R 16);
R 12With R 13Represent H or alkyl independently; Or R 12With R 13Form a key together;
Each R 14And R 15Represent H or alkyl independently;
Each R 16Represent alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
L be a key ,-C (R 15) 2-or-(CR 15=CR 15)-;
A 3Represent a bivalence cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 15=CR 15)-aryl-or-(CR 15=CR 15)-heteroaryl-; And
A 4Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 15=CR 15)-aryl or-(CR 15=CR 15)-heteroaryl;
Or the chemical compound represented of a kind of formula XX:
Figure A20068004988000961
Wherein,
R 17Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-(C (R 23) 2) n-(CR 23=C (R 23) 2);
R 18It is aryl;
R 19Be hydrogen, alkyl ,-CO 2R 24Or-C (O) N (R 23) (R 24);
R 20With R 21Represent H or alkyl independently; Or R 20With R 21Form a key together;
Each R 22And R 23Represent H or alkyl independently;
Each R 24Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
L be a key ,-C (R 23) 2-or-(CR 23=CR 23)-;
A 5Represent a bivalence cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 23=CR 23)-aryl-or-(CR 23=CR 23)-heteroaryl-; And
A 6Represent cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 23=CR 23)-aryl or-(CR 23=CR 23)-heteroaryl;
Or the chemical compound represented of a kind of formula XXI:
Figure A20068004988000962
Wherein,
R 25Be-(C (R 31) 2) n-(CR 31=C (R 31) 2);
R 26Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
R 27Be hydrogen, alkyl ,-CO 2R 32Or-C (O) N (R 31) (R 32);
R 28With R 29Represent H or alkyl independently; Or R 28With R 29Form a key together;
Each R 30And R 31Represent H or alkyl independently;
Each R 32Represent alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl independently;
L be a key ,-C (R 31) 2-or-(CR 31=CR 31)-; And
A 7And A 8Represent independently cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 31=CR 31)-aryl or-(CR 31=CR 31)-heteroaryl.
[0176] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XVIII, wherein R 1It is aryl.
[0177] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XVIII, wherein R 1Be aryl, and R 4And R 5Form a key together.
[0178] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XVIII, wherein R 1Be aryl, R 4And R 5Form a key together, L is a key, and A 1It is heteroaryl.
[0179] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XVIII, wherein R 1Be aryl, R 4And R 5Form a key together, L is a key, A 1Be heteroaryl, and A 2It is aryl.
[0180] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XVIII, wherein R 1Comprise a hydroxy-acid group; R 1It is the aryl of a carboxylic acid-substituted; R 1It is the phenyl of a carboxylic acid-substituted; And/or R 1It is the phenyl of a carboxylic acid para-orientation.
[0181] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XX, wherein R 17Comprise a hydroxy-acid group; R 17It is the aryl of a carboxylic acid-substituted; R 17It is the phenyl of a carboxylic acid-substituted; And/or R 17It is the phenyl of a carboxylic acid para-orientation.
[0182] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXI, wherein R 25It is aryl.
[0183] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXI, wherein R 25Be aryl, and R 27Be-CO 2R 32
[0184] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXI, wherein R 25Be aryl, R 27Be-CO 2R 32, and A 7It is heteroaryl.
[0185] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXI, wherein R 25Be aryl, R 27Be-CO 2R 32, A 7Be heteroaryl and A 8It is aryl.
[0186] another aspect of the present invention relates to the chemical compound that a kind of formula XXII represents:
Figure A20068004988000971
Wherein,
X be O ,-N (R 5)-,-N (R 5) C (O)-,-C (O) N (R 5)-,-OC (O)-,-CO 2-or-N (R 5) CO 2-;
Y be O, S or-N (R 5)-;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 2Represent H or alkyl independently, or 2 R 2Formation=O together;
R 3Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 4Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Each R 5Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Or the chemical compound represented of a kind of formula XXIII:
Figure A20068004988000981
Wherein,
X be O ,-N (R 10)-,-N (R 10) C (O)-,-C (O) N (R 10)-,-OC (O)-,-CO 2-or-N (R 10) CO 2-;
Y be O, S or-N (R 10)-;
R 6Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 7Represent H or alkyl independently, or 2 R 7Formation=O together;
R 8It is aryl;
R 9Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 10Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Or the chemical compound represented of a kind of formula XXIV:
Wherein,
X be O ,-N (R 15)-,-N (R 15) C (O)-,-C (O) N (R 15)-,-OC (O)-,-CO 2-or-N (R 15) CO 2-;
Y be O, S or-N (R 15)-;
R 11Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 12Represent H or alkyl independently, or 2 R 7Formation=O together;
R 13It is aryl;
R 14Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 15Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5.
[0187] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXII, wherein R 4Be aryl, X is NH, and R 1It is aryl.
[0188] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXIII, wherein R 4Be aryl, X is NH, and R 6It is aryl.
[0189] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXIV, wherein R 13Be aryl, R 14Be aryl, and X is NH.
[0190] another aspect of the present invention relates to the chemical compound that a kind of formula XXV represents:
Wherein,
X is O or S;
R 1Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl, heteroarylalkyl or-C (O) R 5
R 2Be H or alkyl;
R 3Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl, heteroarylalkyl or optional substituted monocycle or dicyclo, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2
R 5Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl; Or R 5Be one can by one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; And
Each R 6Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Or the chemical compound represented of a kind of formula XXVI:
Wherein,
X is O or S;
R 7Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-C (O) R 11
R 8Be H or alkyl;
R 9It is aryl;
R 10Be H, alkyl or-C (O) N (R 12) 2
R 11Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl; Or R 11Be one can by one or more alkyl, halogen ,-OR 12,-N (R 12) 2,-CO 2R 12, C (O) N (R 12) 2, the optional aromatic yl group that replaces of cyano group or nitro; And
Each R 12Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Or the chemical compound represented of a kind of formula XXVII:
Figure A20068004988001001
Wherein,
X is O or S;
R 13Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-C (O) R 17
R 14Be H or alkyl;
R 15It is aryl;
R 16Be H, alkyl ,-CO 2R 18Or-C (O) N (R 18) 2
R 17Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl; And
Each R 18Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Or the chemical compound represented of a kind of formula XXVIII:
Figure A20068004988001002
Wherein,
X is O or S;
R 19Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-C (O) R 23
R 20Be H or alkyl;
R 21Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl, heteroarylalkyl or optional substituted monocycle or dicyclo, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 22Be alkyl ,-CO 2R 6Or-C (O) N (R 6) 2
R 23Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl; Or R 23Be one can by one or more alkyl, halogen ,-OR 18,-N (R 18) 2,-CO 2R 18, C (O) N (R 18) 2, the optional aromatic yl group that replaces of cyano group or nitro; And
Each R 18Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently.
[0191] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXV, wherein X is S, R 1Be-C (O) R 5, R 2Be H, and R 4Be-CO 2R 6
[0192] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXVI, wherein X is S, R 7Be-C (O) R 11, and R 8Be H.
[0193] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXVII, wherein X is S, R 13Be-C (O) R 17, R 14Be H, and R 16Be-CO 2R 18
[0194] another aspect of the present invention relates to the chemical compound that a kind of formula XXIX represents:
Figure A20068004988001011
Wherein,
X is O;
Y is C (R 8)-;
R 1And R 2Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 2And R 3Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces;
R 4Be hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
R 5Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 9=CR 9) n-aryl or-(CR 9=CR 9) n-heteroaryl;
R 6Be H or alkyl; Or R 5And R 6Form a monocycle that can be optionally substituted or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S;
Each R 8And R 9Represent H or alkyl independently; And
N is 1 or 2;
Or the chemical compound represented of a kind of formula XXX:
Figure A20068004988001021
Wherein
X is-N (R 16)-;
Y is-C (R 17)-;
R 10And R 11Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl respectively independently;
R 12Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 11And R 12Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces;
R 13Be H, alkyl, cycloalkyl, aryl or aralkyl;
R 14Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 18=CR 18) n-aryl or-(CR 18=CR 18) n-heteroaryl;
R 15Be H or alkyl; Or R 14And R 15Form a monocycle that can be optionally substituted or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 16Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 10And R 16Forming one together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or the amino optional 3-8 unit ring that replaces;
Each R 17And R 18Represent H or alkyl independently; And
N is 1 or 2.
[0195] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXX, wherein R 16, R 10, R 11And R 12It is aryl.
[0196] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXX, wherein R 16, R 10, R 11And R 12Be aryl, and R 13Be H.
[0197] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXX, wherein R 16, R 10, R 11And R 12Be aryl, R 13Be H, and R 14It is alkyl.
[0198] another aspect of the present invention relates to the chemical compound that a kind of formula XXXI represents:
Figure A20068004988001031
Wherein,
R 1And R 3Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 2And R 4Represent hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Or R 1And R 2Form a 3-8 unit ring together; Or R 3And R 4Form a 3-8 unit ring together; And
Each R 5Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Or the chemical compound represented of a kind of formula XXXII:
Figure A20068004988001032
Wherein,
R 6And R 8Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl respectively independently;
R 7And R 9Represent hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl respectively independently; Or R 6And R 7Form a 3-8 unit ring together; Or R 8And R 9Form a 3-8 unit ring together; And
Each R 10Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aralkyl or heteroarylalkyl independently.
[0199] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXXI, wherein R 1And R 2Form 7 yuan of rings together, and R 3And R 4Form 7 yuan of rings together.
[0200] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXXI, wherein R 1And R 2Form 7 yuan of rings together, R 3And R 4Form 7 yuan of rings together, and R 5It is aryl.
[0201] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXXII, wherein R 1And R 2Form 7 yuan of rings together, R 3And R 4Form 7 yuan of rings together, and R 5It is alkyl.
[0202] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXXI, wherein R 1And R 3It is aryl.
[0203] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXXI, wherein R 1, R 3And R 5It is aryl.
[0204] another aspect of the present invention relates to the chemical compound that a kind of formula XXXIII represents:
Figure A20068004988001041
Wherein,
X is O;
R 1, R 3Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently with A;
R 2And R 4Represent H or alkyl independently;
R 5Be an optional substituted monocycle or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S;
Or the chemical compound represented of a kind of formula XXXIV:
Figure A20068004988001042
Wherein,
X is S;
R 6Represent cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
R 8Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently with A;
R 7And R 9Represent H or alkyl independently;
R 10Be an optional substituted monocycle or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S;
Or the chemical compound represented of a kind of formula XXXV:
Figure A20068004988001051
Wherein,
X is S;
R 11Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently with A;
R 13Represent cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
R 12And R 14Represent H or alkyl independently;
R 15Be an optional substituted monocycle or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S;
Or the chemical compound represented of a kind of formula XXXVI:
Figure A20068004988001052
Wherein,
X is S;
R 16And R 18Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
A represents cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
R 17And R 19Represent H or alkyl independently;
R 20Be an optional substituted monocycle or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S.
[0205] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXXIV, wherein X is O; A is an aryl, R 10Be an optional substituted monocycle or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S, and R 8It is aryl.
[0206] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXXV, wherein X is S; A is an aryl, R 15Be an optional substituted monocycle or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S, and R 11It is aryl.
[0207] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXXVI, wherein X is S; R 20Be an optional substituted monocycle or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S, R 18Be aryl, and R 16It is aryl.
[0208] another aspect of the present invention relates to the chemical compound that a kind of formula XXXVII represents:
Figure A20068004988001053
Wherein,
R 1, R 2And R 3Represent H, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
A represents one can be chosen wantonly the monocycle of replacement or the aryl or the heteroaryl of dicyclo by one or more halogens, alkyl, nitro, amino, aryl, heteroaryl, aralkyl or heteroarylalkyl, cycloalkenyl group or heterocycloalkenyl independently.
[0209] in some embodiments, the present invention relates to aforesaid chemical compound, wherein R 1, R 2And R 3Be H.
[0210] in some embodiments, the present invention relates to aforesaid chemical compound, wherein R 1, R 2And R 3Be H, and A is an aryl that is replaced by amino.
[0211] in some embodiments, the present invention relates to aforesaid chemical compound, wherein R 1, R 2And R 3Be H, and A is an aryl that is replaced by nitro.
[0212] in some embodiments, the present invention relates to aforesaid chemical compound, wherein R 1, R 2And R 3Be H, and A is an aryl that is replaced by halogen.
[0213] another aspect of the present invention relates to the chemical compound that a kind of formula XXXVIII represents:
Figure A20068004988001061
Wherein,
R 1Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 2And R 3Represent hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; And
Each R 4Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aralkyl or heteroarylalkyl independently;
Or the chemical compound represented of a kind of formula XXXIX:
Figure A20068004988001062
Wherein,
R 5Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 6And R 7Represent hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; And
Each R 8Represent H, alkyl, cycloalkyl, aryl, Heterocyclylalkyl, aralkyl or heteroarylalkyl independently.
[0214] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXXVIII, wherein R 1It is haloalkyl.
[0215] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXXVIII, wherein R 1Be haloalkyl, and R 2And R 3It is aryl.
[0216] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXXVIII, wherein R 1Be haloalkyl, R 2And R 3Be aryl, and at least one R 4Be hydrogen.
[0217] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXXIX, wherein R 6And R 7It is aryl.
[0218] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXXIX, wherein R 6And R 7Be aryl, and at least one R 8It is aryl.
[0219] in some embodiments, the present invention relates to the chemical compound of aforesaid formula XXXIX, wherein R 6And R 7Be aryl, a R 8Be aryl, a R 8Be hydrogen.
[0220] another aspect of the present invention relates to a kind of Pharmaceutical composition, and said composition contains a kind of chemical compound one of any among a kind of pharmaceutically acceptable excipient and the general formula X-XXXIX, and wherein general formula X-XXXIX as mentioned above.
[0221] Definition
[0222] for simplicity, more employed terms are collected in herein in description, embodiment and the appending claims.
[0223] term " ACAT " is meant acyl-CoA: cholesterol acyltransferase.
[0224] term " CHO " is meant Chinese hamster ovary.
[0225] term " DMSO " is meant dimethyl sulfoxine;
[0226] term " FBS " is meant hyclone.
[0227] term " GC ", the gas chromatographic analysis that refers to.
[0228] term " HEPES " is meant 4-(2-ethoxy)-1-piperazine ethyl sulfonic acid.
[0229] term " LBPA " is meant molten-two phosphatidic acid (lyso-bis phosphatidic acid).
[0230] low density lipoprotein, LDL that refers to of term " LDL ".
[0231] term " LSO " is meant lysosome storage cell device.
[0232] term " NPC " is meant C type NP.
[0233] term " PBS " is meant phosphate buffer.
[0234] term " PFA " is meant paraformaldehyde.
[0235] term " hetero atom " is known in the field, refers to other any atoms of elements beyond carbon or the hydrogen atom.Illustrative hetero atom comprises boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
[0236] term " alkyl " is known in the field, comprises saturated aliphatic groups, comprises straight chained alkyl, branched alkyl, cycloalkanes (alicyclic ring) base, the cycloalkyl of alkyl replacement and the alkyl of cycloalkyl substituted.In certain embodiments, have an appointment on the straight or branched alkyl main chain 30 or (for example, the C of carbon atom still less 1-C 30Straight chain, C 3-C 30Side chain), perhaps about 20 or still less.Equally, cycloalkyl has about 3-10 carbon atom in its loop configuration, 5,6 or 7 carbon atoms of perhaps having an appointment in loop configuration.
[0237] unless carbon number is had explanation in addition, " low alkyl group " is meant a kind of alkyl as defined above, but has 1 in its backbone structure to about 10 carbon atoms, and perhaps 1 to about 6 carbon atoms.Equally, " low-grade alkenyl " and " low-grade alkynyl " also has similar chain length.
[0238] term " assorted alkyl " is well known in the art, comprise and contain a heteroatomic radical of saturated aliphatic group in the chain at least, comprise and contain a heteroatomic straight chained alkyl in the chain at least, at least contain a heteroatomic branched alkyl in the chain, contain at least one heteroatomic cycloalkanes (alicyclic ring) base in the ring, at least contain the alkyl that contains a heteroatomic cycloalkyl substituted in cycloalkyl that a heteroatomic alkyl replaces and the chain at least in the ring.Term " Heterocyclylalkyl " is meant and contains at least one heteroatomic cycloalkanes (alicyclic ring) base in a kind of ring.
[0239] term " thiazolinyl " and " alkynyl " are well known in the art, are meant the unsaturated aliphatic group that has with length like the alkyls mentioned above, but comprise two keys or triple bond respectively at least.Term " thiazolinyl " and " alkynyl " comprise unsubstituted unsaturated aliphatic group, and contain one or more substituent unsaturated lipid group groups that are selected from halogen, alkyl, alkoxyl, carbonyl and carboxyl.
[0240] term " cycloalkenyl group " is meant a kind of alcyl that has two keys at least.Term " cycloalkenyl group " comprises unsubstituted unsaturated lipid cyclic group, also comprises containing one or more substituent unsaturated lipid cyclic groups that are selected from halogen, alkyl, alkoxyl, carbonyl and carboxyl.
[0241] term " heterocycloalkenyl " is meant that a kind of at least one two key that contain are selected from the heteroatomic alcyl of N, O and S with at least one.Term " heterocycloalkenyl " comprises unsubstituted unsaturated lipid cyclic group, and contains one or more substituent unsaturated lipid cyclic groups that are selected from halogen, alkyl, alkoxyl, carbonyl or carboxyl.
[0242] term " aryl " is well known in the art, refers to 5,6 and 7 yuan of monocyclic aryl, and its ring structure is made of carbon atom, for example benzene, naphthalene, anthracene, pyrene or the like.Aromatic rings can be substituted base and replace in one or more rings site.Represent substituent group comprise halogen, azide, alkyl, aralkyl, thiazolinyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfydryl, imino group, acylamino-, phosphonate group, phosphonous acid ester group, carbonyl, carboxyl, silicyl, ether, alkylthio group, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic radical, aryl or hetero-aromatic ring part (moiety) ,-CF 3,-CN or the like.Term " aryl " also includes the polycyclic system of two or more rings, wherein two or more carbon atoms are that two rings that adjoin (these rings are " condensed ring ") are common, wherein having a ring at least is aromatic rings, for example, other rings can be cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heteroaryl and/or heterocycle.
[0243] term " heteroaryl " is well known in the art, and 1 to 4 heteroatomic 5,6 and 7 yuan of monocyclic aryl, for example pyrroles, furan, thiophene, imidazoles, oxazole, thiazoles, triazole, pyrazoles, pyridine, pyrazine, pyridazine and pyrimidine or the like are arranged in the finger ring.There is heteroatomic aryl also to can be described as " aryl-heterocyclic " or " heteroaromatics " in those ring structures.Aromatic rings can be replaced in one or more rings site by aforesaid substituent group, for example halogen, azide, alkyl, aralkyl, thiazolinyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfydryl, imino group, acylamino-, phosphonate group, phosphonous acid ester group, carbonyl, carboxyl, silicyl, ether, alkylthio group, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic radical, aryl or hetero-aromatic ring part ,-CF 3,-CN or the like.Term " heteroaryl " also includes the polycyclic system of two or more rings, wherein two or more carbon atoms are that two rings that adjoin (these rings are " condensed ring ") are common, wherein having a ring at least is hetero-aromatic ring, for example, other rings can be cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heteroaryl and/or heterocycle.
[0244] the term neighbour,, to being well known in the art, refer to 1 respectively, 2-, 1,3-and 1,4-disubstituted benzenes.For example, 1,2-dimethylbenzene and o-Dimethylbenzene are synonyms.
[0245] term " aralkyl " is well known in the art, refers to the alkyl that a kind of aryl replaces.
[0246] term " heteroarylalkyl " is well known in the art, refers to the alkyl that a kind of heteroaryl replaces.
[0247] term " heterocycle " or " heterocyclic radical " are well known in the art, refer to 3 to about 10 ring structures, and perhaps 3 to about 7 yuan of rings, and its ring structure contains 1 to 4 hetero atom.Heterocycle also can be polycyclic.Heterocyclic radical comprises, for example, thiophene, thianthrene, furan, pyrans, isobenzofuran, .alpha.-5:6-benzopyran, Xanthene phenoxthine, the pyrroles, imidazoles, pyrazoles, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, iso-indoles, indole, indazole, purine, quinolizine, isoquinolin, quinoline, benzodiazine, naphthyridines, quinoxaline, quinazoline, quinazoline, pteridine, carbazole, phenanthridines, acridine, pyrimidine, ferrosin, azophenlyene, phenarsazine, phenothiazine, furazan, phenarsazine, pyrrolidine, oxolane, Tetramethylene sulfide, oxazole, piperidines, piperazine, morpholine, lactone, lactams such as aza cyclo-butanone and pyrrolidone, sultam, sultone or the like.Heterocycle can be replaced in one or more rings site by aforesaid substituent group, described substituent group such as halogen, azide, alkyl, aralkyl, thiazolinyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfydryl, imino group, acylamino-, phosphonate group, phosphonous acid ester group, carbonyl, carboxyl, silicyl, ether, alkylthio group, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic radical, aryl or heteroaromatic part ,-CF 3,-CN or the like.
[0248] term " multi-ring " or " multi-ring base " are well known in the art, (for example refer to two or more rings, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl and/or heterocyclic radical), wherein two or more carbon atoms are public by two rings that adjoin, for example, these rings are " condensed ring ".The ring that links to each other by the non-atom that adjoins is called as " bridge " ring.Polycyclic each ring can be replaced by substituent group as indicated above, described substituent group such as halogen, alkyl, aralkyl, thiazolinyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfydryl, imino group, acylamino-, phosphonate group, phosphonous acid ester group, carbonyl, carboxyl, silicyl, ether, alkylthio group, sulfonyl, ketone, aldehyde, ester, heterocyclic radical, aryl or heteroaromatic part ,-CF 3,-CN or the like.
[0249] term " carbocyclic ring " is well known in the art, refers to a kind of aromatic rings or non-aromatic ring, and each atom in its medium ring is carbon.
[0250] term " nitro " is well known in the art, refers to-NO 2Term " halogen " is well known in the art, refer to-F ,-Cl ,-Br or-I; Term " sulfydryl " is well known in the art, refers to-SH; Term " hydroxyl " is meant-OH.Term " sulfonyl " is well known in the art, refers to-SO 2 -" halogenide " refers to the respective anionic of halogen, and " class halogenide " have Cotton and Wilkinson compile " Advanced Inorganic Chemistry" 560 pages provided definition.
[0251] term " amine " and " amino " are well known in the art, refer to amine unsubstituted and that replace, for example the part that can be represented by following general formula:
Figure A20068004988001101
Wherein, R50, R51 and R52 represent independently of one another hydrogen, alkyl, thiazolinyl ,-(CH 2) m-R61, perhaps the connected N atom of R50 and R51 forms a heterocycle together, has 4 to 8 atoms in this heterocyclic ring structure; R61 represents aryl, cycloalkyl, cycloalkenyl group, heterocycle or multi-ring; M is 0 or one from 1 to 8 a integer.In some embodiments, have only one can be carbonyl among R50 or the R51, for example, R50, R51 and nitrogen constitute acid imide together.In other embodiment, R50 and R51 (alternatively, and R52) be independent separately represent hydrogen, alkyl, thiazolinyl or-(CH 2) m-R61.Therefore, term " alkylamine " comprises amino as defined above, has a substituted or unsubstituted alkyl on this amino, and promptly having one among R50 and the R51 at least is alkyl.
[0252] term " amide groups " is well known in the art, refers to the part that can be represented by following general formula:
Figure A20068004988001102
Wherein, R50 as defined above, R54 represent hydrogen, alkyl, thiazolinyl or-(CH 2) m-R61, wherein m and R61 are as defined above.
[0253] term " amide groups " refers to the amino carbonyl that replaces in this area, comprises the part that can be represented by following general formula:
Figure A20068004988001111
Wherein, R50 and R51 are as defined above.Some embodiment of amide does not comprise the acid imide of potentially unstable among the present invention.
[0254] term " alkylthio group " is meant the alkyl as defined above of a sulfenyl.In some embodiments, " alkylthio group " part representative-S-alkyl ,-the S-thiazolinyl ,-the S-alkynyl and-S-(CH 2) mOne of among-the R61, wherein m and R61 are as defined above.Representational alkylthio group comprises methyl mercapto, ethyl sulfur or the like.
[0255] term " carboxyl " is well known in the art, for example comprises the part that can be represented by following general formula:
Figure A20068004988001112
Wherein, X50 is a key, or represent oxygen or sulfur, R55 and R56 represent hydrogen, alkyl, thiazolinyl ,-(CH 2) m-R61 or a kind of pharmaceutically acceptable salt, R56 represent hydrogen, alkyl, thiazolinyl or-(CH 2) m-R61, wherein m and R61 are as defined above.When X50 is that oxygen and R55 or R56 are not hydrogen, then this general formula representative " ester ".When X50 is an oxygen, and R55 by as above-mentioned the definition, then this part refers to carboxyl at this, especially when R55 was hydrogen, this general formula was represented " carboxylic acid ".When X50 is an oxygen, and R56 is hydrogen, this general formula representative " formic acid ".In general, when the oxygen atom of above-mentioned general formula is replaced by sulfur, this general formula representative " thiocarbonyl ".When X50 is sulfur and R55 or R56 when being not hydrogen, this general formula representative " thioesters ", and X50 is when to be sulfur and R55 be hydrogen, this general formula representative " thiocarboxylic acid ".When X50 is sulfur and R56 when being hydrogen, this general formula representative " bamic acid ".On the other hand, when X50 is a key, and R55 is not when being not hydrogen, above-mentioned general formula representative " ketone group ".When X50 is a key, and R55 is when being hydrogen, above-mentioned general formula representative " aldehyde radical ".
[0256] term " alkoxyl " is well known in the art and refers to a kind of abovementioned alkyl with an oxygen base on it.Typical alkoxyl comprises methoxyl group, ethyoxyl, propoxyl group, tert-butoxy etc." ether " is two Hydrocarbon that linked to each other by an oxygen covalency.Accordingly, the alkyl substituent that can make alkyl become ether is or similar in appearance to alkoxyl, for example can by-O-alkyl ,-the O-thiazolinyl ,-the O-alkynyl ,-O-(CH 2) mRepresentative one of among-the R61, wherein m and R61 are as indicated above.
[0257] term " sulfonate " is well known in the art, and referring to can be by the part of following general formula representative:
Wherein R57 is electron pair, hydrogen, alkyl, cycloalkyl or an aryl.
[0258] term " sulfuric ester " is well known in the art, and referring to can be by the part of following general formula representative:
Figure A20068004988001122
Wherein R57 is as above-mentioned definition.
[0259] term " sulfonamide " is well known in the art, and referring to can be by the part of following general formula representative:
Figure A20068004988001123
Wherein R50 and R56 are as above-mentioned definition.
[0260] term " sulfamoyl " is well known in the art, and referring to can be by the part of following general formula representative:
Figure A20068004988001124
Wherein R50 and R51 are as above-mentioned definition.
[0261] term " sulphonyl " is well known in the art, and referring to can be by the part of following general formula representative:
Wherein R58 is one of following: hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl.
[0262] term " sulfoxide group (sulfoxido) " is well known in the art, and referring to can be by the part of following general formula representative:
Figure A20068004988001126
Wherein R58 is as above-mentioned definition.
[0263] term " phosphoryl " is well known in the art, can be represented by following general formula:
Figure A20068004988001131
Wherein Q50 represents S or O, and R59 represents hydrogen, low alkyl group or aryl.When for example being used for replacing an alkyl, the phosphoryl in the phosphinylidyne alkyl can be by following general formula representative:
Figure A20068004988001132
Wherein Q50 and R59 independently of one another as above-mentioned definition, and Q51 represents O, S or N.When Q50 was S, phosphoryl partly was " thiophosphate ".
[0264] term " phosphoramidite " is well known in the art, can be represented by following general formula:
Wherein Q51, R50, R51 and R59 are as above-mentioned definition.
[0265] term " amido phosphate ester (phosphonamidite) " is well known in the art, can be represented by following general formula:
Figure A20068004988001134
Wherein Q51, R50, R51 and R59 be as above-mentioned definition, and R60 represents low alkyl group or aryl.
[0266] similarly replaces and can be used for the alkenyl or alkynyl that thiazolinyl and alkynyl produce for example amino thiazolinyl, amino alkynyl, acylamino-thiazolinyl, acylamino-alkynyl, imido grpup thiazolinyl, imido grpup alkynyl, sulfo-thiazolinyl, sulfo-alkynyl, carbonyl substituted.
[0267] definition of each expression is as alkyl, m, n or the like, when it occurred once being independent of the definition in its other place in same structure when above in any structure.
[0268] term " selenium alkyl " is well known in the art, is meant the alkyl that a kind of seleno replaces.On the alkyl substituted similarly " selenide " be selected from-selenium-alkyl ,-selenium-thiazolinyl ,-selenium-alkynyl, selenium-(CH 2) mOne of-R61, m and R61 are as above-mentioned definition.
[0269] term triflyl, tosyl, mesyl, nonaflyl are well known in the art and are meant trifluoromethane sulfonyl group, p-toluenesulfonyl, methane sulfonyl, perfluoro butyl sulfonyl respectively.Term triflate, tosylate, mesylate, nonaflate are well known in the art and refer to fluoroform sulfonyl ester, tolysulfonyl ester, sulfonyl methane ester, perfluoro butyl sulfonyl ester functional group respectively and the molecule that contains described group.
[0270] abbreviation Me, Et, Ph, Tf, Nf, Ts and MS represent methylidene, ethyl, phenyl, trifluoromethane sulfonyl group, perfluoro butyl sulfonyl, p-toluenesulfonyl and methane sulfonyl independently.The list of abridging widely that has the use of common skill organic chemist in this area appears at Organic chemistry magazine (Journal of Organic Chemistry)First phase of each volume; This part list appears at a title usually Abbreviation standard listForm in.
[0271] some chemical compound that contains in the component among the present invention may exist particularly how much or stereomeric form.In addition, polymer also may be optically active among the present invention.The present invention has considered all these chemical compounds, comprising cis and transisomer, R-and S-enantiomer, diastereomer, (D)-isomer, (L)-isomer, and their racemic mixture, and combination, this all belongs to scope of invention.Other asymmetric carbon atom may reside in the substituent group, in alkyl.All these isomers and their mixture all comprise in the present invention.
[0272] for example, a kind of if desired The compounds of this invention of specific enantiomeric form, it can prepare by asymmetric synthesis or with the chiral auxiliary derivation, and wherein the diastereomeric mixture that is produced is separated, and auxiliary group is disconnected so that the enantiomer of pure needs to be provided.Perhaps, in molecule, comprise basic functionality such as amino, or under the situation of acidic functionality such as carboxyl, the salt of enantiomer can form by acid or the alkali with suitable optical activity, differentiate this enantiomer by fractional crystallization well known in the art and chromatograph means then, reclaim pure enantiomer subsequently.
Should be understood that [0273] " replacement " or " using ... replace " comprises so implicit condition: this replacement meets the quantivalence that is substituted atom and substituent allowance, and replacing the result is a stable chemical compound, for example it can spontaneously not transform, for example rearrangement, cyclisation, elimination or other reactions.
[0274] term " replacement " also includes the substituent group of all permissions of organic compounds.One widely aspect, that the substituent group of permission comprises is acyclic and cyclic, side chain and organic compounds substituent group non-side chain, isocyclic and heterocyclic, fragrance and non-fragrance.Exemplary substituent comprises for example above-described substituent group of this paper.For suitable organic compound, the substituent group of being allowed has one or more and can be identical or different.For purpose of the present invention, for example nitrogen can have the hydrogen substituent group to hetero atom and/or any organic compound substituent group of allowing as herein described satisfies heteroatomic valence state.The substituent group that the present invention does not wish to be subject to organic compound by any way and allowed.
[0275] the interim substituent group of phrase used herein " blocking group " expression, it protects potential reactive functionality that undesirable chemical conversion does not take place.The example of these blocking groups comprises the esters of carboxylic acid, the monosilane ester of alcohols, the acetal of aldehyde and ketone and ketal.The field of blocking group chemistry existing summary (Greene, T.W.; Wuts, P.G.M.Protective Groups inOrganic Synthesis, 2 NdEd.; Wiley:New York, 1991).The shielded form of The compounds of this invention comprises within the scope of the invention.
[0276] for purpose of the present invention, determining of chemical element is according to the periodic table of elements, the CAS version, Physics and chemical handbook (Handbook of Chemistry and Physics), the 67th edition, 1986-87, interior front cover.
[0277] Pharmaceutical composition
[0278] in yet another aspect, the invention provides pharmaceutically acceptable compositions, wherein comprise one or more chemical compound of treatment effective dose as indicated above, prepare with one or more pharmaceutically acceptable carriers (additive) and/or diluent.As following detailed description, pharmaceutically acceptable compositions of the present invention can be the solid or the liquid form of the special preparation of administration, comprise the form that is suitable for following mode: (1) oral administration, for example, perfusion (aqueous or non-aqueous solution or suspension), tablet, for example be directed to the oral cavity, the absorbing of Sublingual with whole body, bolus, powder, granule, be applicable to the unguentum of tongue; (2) non-through enteral administration, for example through subcutaneous, muscle, vein or epidural space injection, with for example a kind of sterile solution or suspension or slow releasing preparation form; (3) local application administration is for example with cream, ointment or be applied to the controlled release plaster or the spray of skin; (4) intravaginal or drop rectum with drug are for example with suppository, ointment or foamy form; (5) sublingual administration; (6) administration in the eyes; (7) percutaneous dosing; Or (8) nasal-cavity administration.
[0279] be used for herein phrase " treatment effective dose " expression be a kind of chemical compound, material or the amount that contains compound compositions of the present invention, this amount reasonably can be produced ideal curative effect at least one cell subsets of animal under benefited/risk-ratio at one, is applicable to any therapeutic treatment.
[0280] phrase " pharmaceutically acceptable " that herein adopts is meant that chemical compound, new material, composition and/or dosage form are in rational medical judgment scope, be fit to contact with human and animal's tissue, do not have over-drastic toxicity, zest, anaphylactic reaction or other problems or complication, have one reasonably to be benefited/risk-ratio.
[0281] phrase " pharmaceutically acceptable carrier " that is used for herein is meant a kind of pharmaceutically acceptable material, compositions or carrier, for example liquid or solid filler, diluent, excipient, manufacturing adminicle (for example lubricant, Pulvis Talci magnesium, calcium stearate or zinc or stearic acid), or the solvent encapsulating material, be used for target compound is carried or be transported to another organ or body part from an organ or body part.Every kind of carrier must be in some sense with compositions in the compatibility of other compositions are " acceptables ", and harmless to the patient.Some examples of material that can be used as pharmaceutically acceptable carrier comprise: (1) sugar, and as lactose, dextrose plus saccharose; (2) starch is as corn starch and potato starch; (3) cellulose and derivant thereof are as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) Fructus Hordei Germinatus; (6) gelatin; (7) Pulvis Talci; (8) adjuvant is as cocoa butter and suppository wax; (9) oil is as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum sesami, olive oil, Semen Maydis oil and soybean oil; (10) ethylene glycol is as propylene glycol; (11) polyhydric alcohol is as glycerol, sorbitol, mannitol and Polyethylene Glycol; (12) ester is as ethyl oleate and ethyl laurate; (13) agar; (14) buffer agent is as magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) normal saline; (18) ringer's solution; (19) ethanol; (20) pH value buffer; (21) polyester, Merlon and/or poly-anhydride; Other are used for the avirulent compatible substrate of pharmaceutical formulation to reach (22).
[0282] as indicated above, some embodiment of The compounds of this invention can contain a basic functionality, as amino or alkylamino, therefore, can form pharmaceutically acceptable salt with pharmaceutically acceptable acid.Term " pharmaceutically acceptable salt " is meant the avirulent relatively inorganic and organic acid addition salt of The compounds of this invention in this respect.These salt can be in the manufacture process of drug administration carrier and dosage form original position form, or react separately with suitable organic or inorganic acid, thereby and separate this salt and in follow-up purge process, form by the pure compound of a kind of free alkali form of the present invention.Representational salt comprises hydrobromate, hydrochlorate, sulfate, bisulphate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, lauric acid, benzoate, lactate, phosphate, toluene fulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, mesylate, gluceptate, lactobionate, lauryl sulfonate or the like.(for example see Berge et al. (1977) " Pharmaceutical Salts ", J.Pharm.Sci.66:1-19).
[0283] the pharmaceutically acceptable salt class of motif compound comprises the conventional nontoxic salts or the quaternary ammonium salt of these chemical compounds, as from avirulent organic or inorganic acid.For example, these conventional nontoxic salts comprise from the mineral acid example hydrochloric acid, hydrobromic acid, sulphuric acid, sulfamic acid, phosphoric acid, the salt of nitric acid or the like, and from organic acid such as acetic acid, propanoic acid, succinic acid, glycolic, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, Palmic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-anilinesulfonic acid., the 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, the salt of isethionic acid (isothionic) or the like.
[0284] in other cases, chemical compound of the present invention can comprise one or more acidic functionalities, thereby can form pharmaceutically acceptable salt with pharmaceutically acceptable alkali.Term " pharmaceutically acceptable salt " is meant the avirulent relatively inorganic and organic base addition salts of The compounds of this invention in this respect.These salt can original position form in the manufacture process of drug administration carrier and dosage form, or react separately by the pure compound of free acid form of the present invention and suitable alkali and to form, the hydroxide of described alkali such as pharmaceutically acceptable metal cation, carbonate or bicarbonate, ammonia, or pharmaceutically acceptable organic primary, second month in a season or tertiary amine.Representational alkaline or alkaline-earth salts comprises lithium, sodium, potassium, calcium, magnesium, aluminum salt or the like.The representational organic amine that can be used for forming base addition salts comprises ethamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine etc.(for example seeing the article of above-mentioned Berge et al.).
[0285] wetting agent, emulsifying agent and lubricating oil, as sodium lauryl sulphate and magnesium stearate, and coloring agent, releasing agent, coating agent, sweeting agent, flavoring agent and perfume agent, antiseptic and antioxidant also can be present in the compositions of the present invention.
[0286] pharmaceutically acceptable examples of antioxidants comprises: (1) water soluble antioxidant, as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium pyrosulfite, sodium sulfite etc.; (2) oil-soluble inhibitor is as ascorbyl palmitate, dibutyl BHA (BHA), BHT (BHT), lecithin, propyl gallate, alpha-tocopherol or the like; (3) metal-chelator is as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid etc.
[0287] preparation of the present invention comprises those suitable oral cavities, nasal cavity, part (comprising oral cavity and Sublingual), rectum, vagina and/or non-preparation through enteral administration.Said preparation can present with unit dosage forms easily, and can the known any method preparation of pharmaceutical field.The amount with the active component that produces single dosage form of can combining with carrier material will depend on the main body of being treated and concrete administering mode.Can be generally the chemical compound amount of generation therapeutic effect with carrier material in conjunction with the amount of the active component that produces single dosage form.Usually, in 100%, the active component that the scope of this amount will from about 0.1% to about 99%, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.
[0288] in certain embodiments, preparation of the present invention contains a kind of excipient that is selected from cyclodextrin, cellulose, liposome, micelle forming agent such as bile acid, macromolecule carrier such as polyester and poly-anhydride; And a kind of chemical compound of the present invention.In certain embodiments, above-mentioned preparation makes chemical compound of the present invention have the biological effectiveness of per os.
[0289] preparing these preparations or method for compositions comprises a kind of chemical compound of the present invention and carrier and one or more optional attachment component combinations.In general, preparation be by with The compounds of this invention and liquid-carrier or solid carrier in small, broken bits or both equably, combination nearly, carry out formed product then if necessary and make.
[0290] preparation of the present invention that is suitable for oral administration can be with capsule, cachet, pill, tablet, buccal tablet (uses the fragrance base material, normally sucrose and arabic gum or tragakanta), powder, granule, or as a kind of solution or a kind of aqueous or nonaqueous suspension, or as a kind of oil-in-water or water-in-oil type liquid emulsion, or as a kind of red medicine or syrup, or as a kind of lozenge (use inertia base material, as gelatin and glycerol, or sucrose and arabic gum) and/or as forms such as mouth wasses, each all contains a kind of The compounds of this invention of scheduled volume as effective ingredient.Chemical compound of the present invention also can bolus, electuary or paste form administration.
[0291] in the peroral administration solid dosage forms (capsule, tablet, pill, lozenge, powder, granule, trouches etc.) that is used for of the present invention, active component mixes with one or more pharmaceutically acceptable carriers, as sodium citrate or calcium hydrogen phosphate and/or following any: (1) filler or extender, as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binding agent, for example carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and/or arabic gum; (3) diluent is as glycerol; (4) disintegrating agent is as agar, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, some silicate, sodium carbonate; (5) solidify delayer, as paraffin; (6) absorb accelerator, as quarternary ammonium salt compound and surfactant, as poloxamer and sodium lauryl sulphate; (7) wetting agent, for example cetyl alcohol, glyceryl monostearate, non-ionic surface active agent; (8) absorbent is as Kaolin and bentonite; (9) lubricant is as Pulvis Talci, calcium stearate, magnesium stearate, solid polyethylene ethylene glycol, sodium lauryl sulphate, zinc stearate, sodium stearate, stearic acid and composition thereof; (10) coloring agent; And (11) sustained release agent, as crospolyvinylpyrrolidone or ethyl cellulose.As for capsule, tablet and pill, composite medicine may also comprise buffer agent.That a kind of solid composite of similar type also can be filled in is soft, in the hard-shell capsule, use lactose or excipient such as toffee and High molecular weight polyethylene ethylene glycol.
[0292] tablet can be by compacting or mold pressing preparation, optional one or more attachment components that use.Tabletting can be used binding agent (for example gelatin or hydroxypropyl emthylcellulose), lubricant, inert diluent, antiseptic, disintegrating agent (for example primojel or cross-linking sodium carboxymethyl cellulose), surfactant or dispersant preparation.Molded tablet can be on a suitable machine will be through the mixture of the moistening powder compounds of inert liquid diluent and mold pressing and preparing.
[0293] tablet of pharmaceutical composition of the present invention and other solid dosage formss as lozenge, capsule, pill and granule, can be chosen wantonly with sugar-coat and shell and press quarter or preparation, for example known other sugar-coats of casing and pharmaceutical field together.They also can be mixed with can be slowly or sustained release active component wherein, and this is by using hydroxypropyl emthylcellulose that ratio for example changes so that ideal release profiles to be provided, using other polymeric matrixs, liposome and/or microsphere.They can be made into rapid release, for example lyophilization.They can be sterilized, and for example pass through a filter that filters antibacterial, or dissolve in biocide or other sterile injectable medium in the sterilized water, sterilization solid composite form by adding when being about to use.These compositionss also can be chosen wantonly and contain the lucifuge agent, and can be only or preferably in a kind of mode of delay at a part of release of active ingredients of gastrointestinal.The example of operable embedding composition comprises polymer substance and wax.Active component also can be the microcapsule form, if suitable have one or more above-mentioned adjuvants.
[0294] the peroral administration liquid dosage form of chemical compound of the present invention comprises pharmaceutically acceptable Emulsion, microemulsion, solution, suspension, syrup and elixir.Except active component, liquid dosage form can contain this area inert diluent commonly used, for example water or other solvents, solubilizing agent and emulsifying agent, as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (particularly Semen Gossypii, Semen arachidis hypogaeae, Fructus Maydis, Fructus Canarii albi, Semen Ricini and Oleum sesami), glycerol, the fatty acid ester of tetrahydrofurfuryl alcohol, polyethylene glycol and anhydrous sorbitol, and composition thereof.
[0295] except inert diluent, oral composition can also contain adjuvant, as wetting agent, emulsifying agent and suspending agent, sweeting agent, flavouring agent, pigment, antiseptic, spice and antiseptic.
[0296] in the suspension except active component, also can contain suspending agent, for example ethoxylated isostearyl alcohol, sorbitol and polyoxyethylene, sorbitan ester, microcrystalline Cellulose, aluminium hydroxide (aluminium metahydroxide), bentonite, agar and tragakanta partially, and composition thereof.
[0297] drug combination preparation that is used for rectum or vagina of the present invention can be a kind of suppository, it can prepare by one or more chemical compounds of the present invention are mixed with one or more non-irritating adjuvants that are fit to or carrier, described adjuvant or carrier be cocoa butter, Polyethylene Glycol, suppository wax or salicylic acid for example, and at room temperature be solid but under body temperature, be liquid, therefore can be and release of active compounds in rectum or vaginal canal fusion.
[0298] preparation of the present invention that is fit to vagina administration also comprises and contains the be vaginal suppository of suitable carriers, tampon, Emulsion, gel, unguentum, foam or spray agent known in the art.
[0299] dosage form that is used for part or transdermal administration of The compounds of this invention comprises powder, spray, ointment, unguentum, Emulsion, lotion, gel, solution, sticking patch and snuffing agent.Reactive compound can mix with pharmaceutically acceptable carrier under aseptic condition, and uses any antiseptic that may need, buffer or propellant.
[0300] except reactive compound of the present invention, ointment, unguentum, Emulsion and gel can comprise adjuvant, as animal and plant fat, oil, wax, paraffin, starch, tragakanta, cellulose derivative, polypropylene glycol, organosilicon, bentonite, silicic acid, Talcum and zinc oxide, or its mixture.
[0301] except reactive compound of the present invention, powder and spray can comprise adjuvant, as lactose, Talcum, silicic acid, aluminium hydroxide, calcium-silicate and Silon, or the mixture of these materials.Spray can comprise propellant commonly used in addition, as Chlorofluorocarbons (CFCs) and the non-substituted hydrocarbons of volatility, as butane and propane.
[0302] transdermal patch has the additional advantage that the The compounds of this invention of sustained release is provided to human body.This dosage form can be by with this compound dissolution or be distributed in the suitable medium and prepare.Absorption enhancer also can be used to increase the flux that chemical compound passes skin.This flux or by providing a kind of rate controlling membranes to control, or control by chemical compound is distributed in polymeric matrix or the gel.
[0303] ophthalmic preparation, spongaion, powder, solution or the like are also in the scope that the present invention considers.
[0304] is fit to non-pharmaceutical composition of the present invention and comprises one or more chemical compounds of the present invention and one or more pharmaceutically acceptable sterile isotonic aqueous solution or non-aqueous solution, dispersion, suspended substance or emulsion through enteral administration, or can be recovered to the sterilized powder of aseptic injectable solution or dispersion before use, it can contain sugar, alcohols, antioxidant, buffer agent, bithionol, can make the isoosmotic solute of blood of the receptor of preparation and expection, or suspending agent or thickening agent.
[0305] can be used for the suitable water of pharmaceutical composition of the present invention and the example of nonaqueous carrier and comprise water, ethanol, polyhydric alcohol (as glycerol, propylene glycol, Polyethylene Glycol etc.) and suitable mixture thereof, vegetable oil such as olive oil and injectable organic ester such as ethyl oleate.Suitable flowability can be maintained, for example by using coating material such as lecithin, and by keeping granular size required under the dispersion situation, and by using surfactant.
[0306] these compositionss also can contain adjuvant, as antiseptic, wetting agent, emulsifying agent and dispersant.Prophylaxis of microbial can be guaranteed by adopting various antibacteriums and antifungal the effect of motif compound, for example, and butolan, chlorobutanol, phenol sorbic acid etc.It is desirable using isotonic agent in said composition, as sugar, sodium chloride or the like.In addition, the absorption that prolongs the injectable drug form can realize by the medicament that adopts the energy delayed absorption, as aluminum monostearate and gelatin.
[0307] in some cases, for the effect of prolong drug, it is desirable slowing down absorption subcutaneous or the intramuscular injection medicine.The water miscible crystal a little less than this can have by use or the liquid suspension of amorphous materials are realized.The absorbance of medicine depends on its dissolution rate, thereby may depend on crystalline size and crystal form.Perhaps, to absorb be by with medicine dissolution or be dispersed in the oiliness carrier and realize in a kind of delay of medicament forms of parenterai administration.
[0308] injectable storage form is to prepare by forming microcapsule substrate by motif compound in biological degradation polyalcohol such as polylactic acid-poly-Acetic acid, hydroxy-, bimol. cyclic ester.According to the ratio of medicine to polymer, and the character of the concrete polymer that adopts, drug release rate can be controlled.The example of other biodegradable polymer comprises poe and poly-anhydride.Injectable storage form liquid can realize that they and tissue are compatible by medicine is wrapping in liposome or the microemulsion.
[0309] when chemical compound of the present invention be when coming to human and animal's administration as pharmaceutical preparation, they can itself administration, or with a kind of form administration of pharmaceutical composition, for example wherein contain 0.1% to 99% active component and the pharmaceutically acceptable carrier of (more preferably 10% to 30%).
[0310] preparation of the present invention can per os, injection, part or per rectum give.Certainly their form administrations to be fit to every kind of route of administration.For example, they are injected, suck with tablet or capsular form, with form injection, perfusion or the suction of collyrium, ointment, suppository; Lotion or ointment form topical; With the suppository form rectally.Preferred oral administration.
[0311] " non-through enteral administration " of herein using is meant the enteral that is different from other and the administering mode of topical, normally by injection, include but not limited in the vein, intramuscular, intra-arterial, sheath, in the capsule, under interior, subcutaneous, the epidermis of interior, intracardiac, the Intradermal of socket of the eye, intraperitoneal, trachea, under the intraarticular, capsule, subarachnoid space, canalis spinalis is interior and breastbone inner injection and transfusion.
[0312] " the whole body administration " and " peripheral administration " herein used is meant the non-administering mode that directly enters the central nervous system of chemical compound, medicine or other materials, therefore it enters patient's body, and metabolism and other similar process, for example subcutaneous administration take place.
[0313] these chemical compounds that are used for the treatment of can be by any suitable administration route to human and other animals administers, comprise through oral cavity, via intranasal application for example by spraying, per rectum, transvaginal, injection, pond in and local, for example, comprise a cheek and Sublingual by powder, unguentum or drop.
[0314] though the administration route of selecting how, The compounds of this invention and/or pharmaceutical composition of the present invention that hydrated form that can be suitable uses are prepared into pharmaceutically acceptable dosage form by well known to a person skilled in the art conventional method.
[0315] the actual dose level of active component can change in the pharmaceutical composition of the present invention, so that obtain a kind of like this active principle: and the therapeutic response that it can obtain to expect for concrete patient, compositions and administering mode, and to patient's avirulence.
[0316] dosage level of Xuan Zeing will depend on multiple factor, comprise the specific compound that the present invention adopts or the activity of its ester, salt or amide, route of administration, administration time, the drainage or the metabolic rate of the specific compound that adopts, the speed and the degree that absorb, the cycle of treatment, the other drug, chemical compound and/or the material that are used in combination with the specific compound that adopts, by treatment patient's age, sex, body weight, disease, general health and medication history before, and the known similar factor of medical domain.
[0317] doctor of common skill or veterinary are arranged at the effective dose that can easily determine and leave required pharmaceutical composition in this area.For example, doctor or veterinary begin to leave the pharmaceutical composition that contains The compounds of this invention than reaching the low dosage of expection therapeutic effect, and increase dosage gradually, until producing a desired effect.
[0318] in general, suitable dosage every day of The compounds of this invention will be the minimum effective dose that this chemical compound obtains therapeutic effect.Such effective dose generally depends on factor mentioned above.In general, be used for the dosage of The compounds of this invention of people's oral cavity, intravenous injection, Intraventricular and subcutaneous use, when being used for analgesic activity, scope will be from about 0.0001 to about 100 milligrams of per kilogram of body weight every days.
[0319] if desired, effective every day of the dosage of reactive compound can be divided into the divided dose more than 2,3,4,5,6 or 6, and with reasonable time administration respectively at interval, preferred administering mode is to be administered once every day to optional form with unit dose in whole day.
[0320] though chemical compound of the present invention can be individually dosed, preferably will this this chemical compound with the form administration of pharmaceutical preparation (compositions).
[0321] similar with other medicines, chemical compound of the present invention can be mixed with any form that conveniently is used for the mankind or veterinary's administration.
[0322] on the other hand, the invention provides pharmaceutically acceptable compositions, comprising one or more motif compounds as indicated above of treatment effective dose, and one or more pharmaceutically acceptable carrier (additive) and/or diluent of preparation together.As following detailed description, pharmaceutical composition of the present invention can be in particular the administration of solid or liquid form and prepare, comprise and be applicable to following form of medication: (1) oral administration, for example potus (aqueous or non-aqueous solution or suspension), tablet, bolus, powder, granule, be applicable to the unguentum of tongue; (2) non-through enteral administration, for example through subcutaneous, muscle, vein or epidural space injection, for example with the form of sterile solution or suspension; (3) local application for example is applied to cream, ointment or the spray of skin, lung or mucosa; Or (4) intravaginal or drop rectum with drug, for example with suppository, unguentum or form of foam; (5) Sublingual or oral administration; (6) eye drops; (7) percutaneous dosing; Or (8) nasal-cavity administration.
[0323] term " treatment " is intended to also comprise prevention, treatment and cures.
[0324] patient of this treatment of acceptance is the animal of any needs, comprises primate, particularly human and other mammals, and as horse, cattle, pig and sheep; With general poultry and house pet.
[0325] chemical compound of the present invention can with itself or with pharmaceutically acceptable carrier mixing administration, also can be in conjunction with the antibacterials administration, as penicillin, cephalosporins, aminoglycoside and glycopeptide class.Just carry out a kind of like this administration successive, simultaneously and that separate of follow-up administration when therefore, the therapeutic alliance drug effect that is included in the administration for the first time of this reactive compound does not also have complete obiteration.
[0326] reactive compound of the present invention adds preferred realization like this in the animal feed to: prepare a kind of suitable feed pre-mixing material that contains the reactive compound of effective dose, and this premix material is blended in the complete feeding-stuffs.
[0327] or, a kind of semi-finished product concentrate or feed additive of the active component that contains can be sneaked in the feedstuff.The preparation of this premix material and complete feeding-stuffs and administering mode have explanation (as " Applied Animal Nutrition " in handbook, W.H.Freedman and CO., SanFrancisco, U.S.A., 1969 or " Livestock Feeds and Feeding " O and Bbooks, Corvallis, Ore., U.S.A., 1977).
[0328] micelle
[0329] nearest, pharmacy industry has been introduced microemulsion technology to improve the bioavailability of some lipotropys (water-insoluble) medicament.Example comprises Trimetrine (Dordunoo, S.K., et al., Drug Development and Industrial Pharmacy, 17 (12), 1685-1713,1991and REV 5901 (Sheen, P.C., et al., J Pharm Sci 80 (7), 712-714,1991).Except that other business, once through system provides enhanced bioavailability to microemulsion by preferentially directly absorbing lymphsystem, thereby walks around liver, and prevents that this chemical compound is destroyed in the liver and gall circulation.
[0330] in one aspect of the invention, preparation contains the micelle of a kind of chemical compound of the present invention and the formation of at least a parents' carrier, and wherein this micelle has an average diameter less than about 100nm.The preferred micelle that provides has an average diameter less than about 50nm, and the most preferred micelle that provides has an average diameter less than about 30nm, or even less than about 20nm.
[0331] though considers parents' carrier that all are suitable, but at present preferred carrier is still those generally recognized as safe (GRAS) usually generally, and they can solubilising chemical compounds of the present invention and can this chemical compound of emulsifying when contacting with a kind of compound water (as coming across in the human gi-tract) in the later stage.Usually, satisfying HLB (hydrophilic to the lipophilic balance) value that the amphiphilic composition of these requirements has is 2-20, and its structure comprises the straight chain aliphatic atomic group in C-6 to the C-20 scope.For example (glycolized) fatty glyceride and the polypropylene glycol of polyethylene-ethylene glycolization.
[0332] particularly preferred amphipathic carrier is saturated and single unsaturated polyalkylene glycolization (polyethyleneglycolyzed) fatty glyceride, for example obtains in those hydrogenant wholly or in part each vegetable oil.This oil may be advantageously be made up of 3-, the 2-of corresponding fatty acid and list-fatty glyceride and 2-and single macrogol ester, and particularly preferred aliphatic acid composition comprises capric acid 4-10%, capric acid 3-9%, lauric acid 40-50%, myristic acid 14-24%, Palmic acid 4-14% and stearic acid 5-15%.Another kind of useful amphipathic carrier comprises the anhydrous sorbitol and/or the sorbitol of partial esterification, and saturated or monounsaturated fatty acid (class of department series) or corresponding ethyoxyl analog (tween series).
[0333] commercially available parents' carrier is special consideration, comprise glyceryl monostearate series, oleoyl gathers different glycol glyceride, sad certain herbaceous plants with big flowers acid polyethylene glycol glyceride, or lauroglycol is (by French Gattefosse Corporation, Saint Priest produce and market), polyethyleneglycol oleic acid, Polyethylene Glycol-two oleic acid, Polyethylene Glycol-mono laurate and two lauric acids, lecithin, polysorbate80 etc. (by a plurality of U.S. and company's produce and market all over the world).
[0334] polymer
[0335] be suitable for that hydrophilic polymer of the present invention is that those are soluble in water, on the lipid that can be covalently bound forms to a vesicle and be (promptly biocompatible) polymer patient, the avirulence effect in vivo.Suitable polymers comprises Polyethylene Glycol (PEG), polylactic acid (being also referred to as polylactide), polyglycolic acid (being also referred to as poly-Acetic acid, hydroxy-, bimol. cyclic ester), polylactic acid-polyglycolic acid copolymer, polyvinyl alcohol.Preferred polymer is a molecular weight from about 100 or 120 dalton to about 5000 or 10000 dalton at most, more preferably from about 300 dalton to about 5000 dalton.In an especially preferred embodiment, polymer is a molecular weight from about 100 to about 5000 daltonian Polyethylene Glycol, more preferably molecular weight from about 300 to about 5000 dalton.In an especially preferred embodiment, polymer is 750 daltonian Polyethylene Glycol (PEG (750)).Polymer also can be by monomer number definition wherein; Use at least about 3 polymer of monomers in the embodiment preferred of the present invention, for example contain three monomeric PEG polymer (about 150 dalton).
[0336] other are suitable for hydrophilic polymer of the present invention and comprise polyvinylpyrrolidone, Ju Jia oxazoline (polymethoxazoline), Ju Yi oxazoline (polyethyloxazoline), poly-hydroxypropyl MAAm, PMAm, polydimethylacrylamiin, cellulose derivative such as hydroxy methocel or hydroxyethyl-cellulose.
[0337] in certain embodiments, preparation of the present invention comprises a kind of following biocompatible polymer that is selected from: polyamide, Merlon, the polyalkenes polymer, the polymer of acrylic acid and methacrylate, polyethylene polymer, poly-Acetic acid, hydroxy-, bimol. cyclic ester, polysiloxanes, polyurethane and their copolymer, cellulose, polypropylene, polyethylene, polystyrene, the polymer of lactic acid and glycolic, poly-anhydride, poly-(neighbour) ester, poly-(butanoic acid), poly-(valeric acid), poly-(lactide-caprolactone), polysaccharide, protein, hyaluronic acid, polycyanoacrylate, and their blend, mixture or copolymer.
[0338] cyclodextrin
[0339] cyclodextrin is the ring-type oligosaccharide, contains 6,7 or 8 glucose units, is named respectively by alpha, β or γ.The unknown cyclodextrin that is less than 6 glucose units that exists.Glucose unit is by α-1,4-glucoside key connecting.As the result of the chair conformation of a sugar unit, all secondary hydroxyls (at C-2 and C-3) are positioned at a side of ring, and all primary hydroxyls at C-6 are positioned at opposite side.Therefore, outer surface is hydrophilic, makes cyclodextrin have water solublity.In contrast, the inner chamber of cyclodextrin is hydrophobic, because they are arranged with hydrogen atom and the class ether oxygen of C-3 and C-5.These substrate allow it and various relative hydrophobic compound complexations, comprising for example sterid, as 17-(for example, seeing Van Udenet al.Plant Cell Tiss.Org.Cult.38:1-3-113 (1994)).This complexation is interacted by Van der Waals and forming of hydrogen bond and taking place.Generality summary for the cyclodextrin chemical property is seen Wenz, Agnew.Chem.Int.Ed.Engl., 33:803-822 (1994).
[0340] physicochemical properties of cyclodextrin derivative depend on the degree of kind and replacement consumingly.For example, their dissolubility in water from insoluble (for example triacetyl group-beta-cyclodextrin) to 147% solubility (w/v) (G-2-beta-schardinger dextrin-).In addition, they are dissolved in many organic solvents.The character of cyclodextrin makes it possible to control its dissolubility by the dissolubility that increases or reduce various formulation components.
[0341] a lot of cyclodextrin and its preparation method are put down in writing.(U.S. Patent number 3,459,731 is included this paper by reference in) described electric neutrality cyclodextrin such as Parmeter (I) etc. (U.S. Patent number 3,453,259 is included this paper by reference in) and Gramera for example.Other derivants comprise cyclodextrin [Parmeter (II), the U.S. Patent number 3,453 with cationic properties, 257, include this paper by reference in], insoluble crosslinked cyclodextrin (Solms, U.S. Patent number 3,420,788, include this paper by reference in), and the cyclodextrin [Parmeter (III) with anion performance, U.S. Patent number 3,426,011, include this paper by reference in].Wherein in the cyclodextrin with anion performance, carboxylic acid, hypophosphorous acid, phosphorous acid, phosphonic acids, phosphoric acid, phosphonothiolic acid, sulfo-sulfinic acid (thiosulphinic), sulfonic acid are affixed on the cyclodextrin parent [sees above-mentioned Parmeter (III)].In addition, cyclodextrin sulfoalkyl derivant describe by Stella etc.(U.S. Patent number 5,134,127 is included this paper by reference in).
[0342] liposome
[0343] liposome is made up of at least a lipid duplicature, and described duplicature surrounds an aqueous interior compartment.Liposome can characterize by the type and size of film.Little unilamellar vesicle (SUVs) has single film, and diameter range is usually between 0.02 and 0.05 μ m; The big vesicle of monolayer (LUVS) is usually greater than 0.05 μ m.Big vesicle of few layer and multilamellar vesicle have multilayer film, are generally concentric coat, and usually greater than 0.1 μ m.Liposome with non-concentric coat, promptly several less vesicles are wrapped in the bigger vesicle, are called as many vesicles.
[0344] one aspect of the present invention relates to the preparation that contains liposome, and described liposome contains a kind of chemical compound of the present invention, wherein prepares liposome membrane so that the liposome of the load capacity with raising to be provided.As selection or alternative, chemical compound of the present invention can be included in the liposome bilayer of liposome, or is adsorbed on the liposome bilayer of liposome.Chemical compound of the present invention can be assembled with lipid surfactant and deliver in the liposome interior space; In these cases, the liposome membrane of preparation resists the damage effect of activating agent-surfactant aggregates.
[0345] according to a specific embodiments of the present invention, the lipid bilayer of a liposome comprises with the deutero-fat of Polyethylene Glycol (PEG), extend into by the interior space of liposome as the inner surface of PEG chain, and extend into surrounding enviroment from the outside of lipid bilayer from lipid bilayer.
[0346] activating agent that is included in the liposome of the present invention is dissolved form.The aggregation of surfactant and the activating agent emulsion or the micelle of related activity agent (as contain) can be embedded in the interior space of liposome according to the present invention.Surfactant plays a part to disperse and this activating agent of solubilising, and can be selected from any suitable aliphatic, cycloaliphatic or aromatic series surfactant, include but not limited to lysophosphatidylcholine different chain length, biocompatibility (LPCS) (for example from about C.sub.14 to C.sub.20).The fat of polymer-derived also can be used for micelle formationly as PEG-fat, merge because they play inhibition micelle/film, and polymer is added to the CMC that has reduced surfactant in the surfactant molecule and helps micellar formation.The CMC of preferred surfactants is in micro-molar range; The surfactant of higher CMC can be used for preparing the micelle that is embedded in the liposome of the present invention, yet the micellar surface active agent monomer may influence the stable of liposome bilayer, and is a factor of the liposome of an ideal stability of design.
[0347] can prepare by any various technology well known in the art according to liposome of the present invention.See U.S. Patent number the 4th, 235,871; The PCT application WO 96/14057 that announces, the both includes this description by reference in; New RRC, Liposomes:A practicalapproach, IRL Press, Oxford (1990), pages 33-104; Lasic DD, Liposomes from physics to applications, Elsevier Science PublishersBV, Amsterdam, 1993.
[0348] for example, liposome of the present invention can prepare by the deutero-fat of a kind of hydrophilic polymer is diffused in the preformed liposome, in the micelle that preformed liposome is exposed to lipid graft polymers composition, wherein lipid concentration is corresponding to the final mole percent of the needed fat of deriving in the liposome.The liposome that contains hydrophilic polymer also can form by homogenization well known in the art, lipid field aquation or extruding technology.
[0349] in another exemplary preparation method, activating agent at first by ultrasonic dispersing in a kind of LYSO-PHOSPHATIDYLCHOLINE LYSOPC of easy solubilising hydrophobic molecule or the surfactant of other low CMC (fat that comprises polymer graft).The micelle suspended substance of consequent activating agent is used dried fat sample of rehydration subsequently, and this sample contains a kind of polymer graft fat or cholesterol of suitable molar percentage.Lipid and activating agent suspended substance utilize extruding technology well known in the art to form liposome again, and the liposome that obtains are separated by standard column in the solution of parcel never and separate.
[0350] in one aspect of the invention, the liposome of preparation has roughly size uniformly in selected size range.An effective granulation process comprises that the aqueous suspension with liposome is pressed through a series of polycarbonate membranes with selected homogeneous aperture; The aperture of film will be to roughly corresponding to the full-size of the liposome that produces by extruding.See United States Patent (USP) 4,737,323, it includes this description by reference in.
[0351] discharges instrumentality
[0352] release feature of preparation of the present invention depends on the existence of encapsulating material, encapsulated drug concentration and release instrumentality.For example, release can be manipulated to the pH value dependency, for example, use the responsive coating of pH to make it, or just discharge in higher pH value such as the intestinal time at low pH value such as stomach.A kind of enteric coating can be used for preventing discharging and take place, up to just discharging later on by stomach.Multiple coating or the mixture that is wrapped in the cyanamide in the different materials can be used for obtaining preliminary release under one's belt, carry out follow-up release then in intestinal.Release can be handled by introducing salt or pore former, and absorption or medicine that they can improve water discharge by spreading from capsule.The adjuvant that can regulate medicine dissolution also can be used to sustained release speed.Also can add the reagent that increases substrate degradation or from substrate, discharge.They can add in the medicine, as independent being added to (promptly as particle), perhaps are dissolved in the polymer phase jointly according to allied compound.In all situations, amount should be between 0.1 and 30% (w/w polymer).The type of degradation of promoter comprises inorganic salt such as ammonium sulfate and ammonium chloride, organic acid such as citric acid, benzoic acid, ascorbic acid, inorganic base such as sodium carbonate, potassium carbonate, calcium carbonate, zinc carbonate and zinc hydroxide, organic base such as protamine sulfate, spermine, choline, ethanolamine, diethanolamine, triethanolamine and surfactant are as Tween.RTM and Pluronic.RTM.The pore former (being water soluble compound, as inorganic salt and sugar) that can increase the matrix micropores structure adds in the microgranule mode.Scope should be between 1 and 30% (w/w polymer).
[0353] also can handle the absorption of medicine in the time of staying of intestinal by changing particle.This can for example realize in the following manner: with polymer-coated these particles of a kind of mucoadhesive, or it is chosen as encapsulating material.Example comprises that great majority have the polymer of free carboxy, as chitosan, cellulose, polyacrylate (polyacrylate of Shi Yonging is meant the polymer that contains acrylate group and modified acroleic acid ester group herein, as cyanoacrylates and methacrylate) particularly.
[0354] combinatorial library
[0355] motif compound can use the described combination synthetic method of this part to synthesize.The combination of compounds library can be used for active substance or the relevant character of material that screening of medicaments, pesticide or other biological are learned or medical science is relevant.A combinatorial library that is used for the object of the invention is a kind of mixture at chemically relevant chemical compound, and they can be screened jointly for a kind of character of needs; This chemical combination library can be a liquid or covalently bound to solid carrier.The many relevant chemical compounds of preparation can significantly reduce and simplify the quantity of the screening process that need carry out in a single reaction.The screening that is used for suitable biology, medicine, pesticide or physical property can be undertaken by conventional method.
[0356] multiformity in the compound library can be created on various different levels.For example, it is multifarious that the substrate aromatic group that is used for combined method can be that aromatic proton has, for example variation of ring structure, and/or can change with regard to other substituent groups.
[0357] may be used to generate the compound library of the combination of organic molecule in this area multiple technologies.For example, see people's (1995) such as Blondelle Trends Anal.Chem.14:83; The United States Patent (USP) 5,359,115 and 5,362 of Affymax, the United States Patent (USP) 5,288 of 899:Ellman, the open text WO 94/08051 of people's such as 514:Still PCT wherein all includes this description by reference in; People such as Chen (1994) JACS116:2661:Kerr etc. (1993) JACS115:252; PCT open text WO92/10092, WO93/09668 and WO91/07087; The open text WO93/20242 of the PCT of Lerner etc. wherein all includes this description by reference in).Therefore, about 16 to 1,000,000 in addition more the more all cpds storehouse of sample scale of construction level can be synthesized and screen specific activity or character.
[0358] in an exemplary, a kind of various body (diversomers) compound library of replacement can adopt the technology of people's descriptions in the open text WO 94/08051 of PCT such as Still to utilize the theme reaction synthetic, for example be connected on the polymeric beads, for example be positioned on the position of substrate by a hydrolysis or photodissociation group.According to people's such as Still technology, compound library is synthetic on a cover pearl, and each pearl comprises the label of the concrete various body on the cover identification pearl.Be particularly suitable for finding that at one in the embodiment of enzyme inhibitor, pearl can be dispersed on the permeable membrane surface, and various body is by discharging from pearl with the cracking that is connected of pearl.The various body that discharges from each pearl will diffuse through film to measuring the district, will interact with a kind of enzyme sample there.The detailed description of some combined methods provides below.
[0359] A. directly characterize
[0360] the combinatorial chemistry field development trend is the sensitivity of technology for example, and as mass spectrum (MS), it can be used for characterizing the chemical compound of inferior femto mole, and directly determines the chemical constitution of a kind of chemical compound of selecting from the compound library of combination.For example, if compound library is to be provided on the insoluble supported matrix, individual compound can discharge and be characterized by MS from carrier earlier.In other embodiment, as the part of MS sample preparation technology, can be used to from carrier, discharge chemical compound such as the MS technology of MALDI, especially ought be that a kind of labile bond is with connecting this chemical compound and carrier at first.For example, a kind of from the selected pearl of compound library can be a MALDI step by radiation so that from carrier, discharge various body, and should various body ionizing to be used for the MS analysis.
[0361] B. multipin-synthesis
[0362] compound library of subject methods can be taked multicenter compound library form.In simple terms, Geysen and partner (Geysen et al. (1984) PNAS81:3998-4002) introduced a kind of method and be used to generate compound library, it is in the parallel synthetic method that is arranged on the polyacrylic acid grafted polyethylene stitch of microwell plate form by a kind of.This Geysen technology uses multicenter method jede Woche can synthesize and screen thousands of chemical compound, and the chemical compound that connects can be reused in many detections.Some suitable coupling parts (linker moieties) also can be hung up on the stitch, thereby make this chemical compound can be used for the purification evaluation and further estimate (c.f., Bray et al. (1990) from the carrier fracture after synthetic Tetrahedron Lett31:5811-5814; Valerio et al. (1991) Anal Biochem197:168-177; Brayet al. (1991) Tetrahedron Lett32:6163-6166).
[0363] C. separate-connect-combination again
Utilize separately [0364] in a further embodiment ,-connection-bonded again strategy can overlap on the pearl one provide a kind of diversified compound library (for example, to see Houghten (1985) PNAS82:5131-5135; United States Patent (USP) 4,631,211,5,440,016,5,480,971, it includes this description by reference in).In simple terms, as its name suggests, be introduced in each synthesis step of compound library at degeneracy, pearl is divided into independently group, described group number equals to be added in the number of the different substituents of a certain certain location in the compound library, different substituent groups and each reaction pairing, and a storehouse of pearl reorganization becoming is used for next the repetition.
[0365] in one embodiment, separately-connections-bonded again strategy can use the method for similarly at first being developed by Houghten that is called " tea-bag " to carry out, synthetic inside (the Houghten et al. (1986) that occurs in resin-sealed porous polypropylene bag of chemical compound wherein PNAS82:5131-5135).By these sacks are put into suitable reaction solution, substituent group is connected with the resin of load chemical compound, and all common step as the washing and the deprotection of resin, take place in a reactor simultaneously.Synthetic last, each bag comprises single chemical compound.
[0366] D. by the light orientation, can the synthetic combination of compounds of sterically defined parallel chemical storehouse
[0367] the synthetic scheme of a kind of combination, wherein a kind of chemical compound is to identify by its location on a kind of synthetic substrate, but it is synthetic to be called as space orientation.In one embodiment, anabolic process is to control (Dower et al. (1991) by the specific site that the control chemical reagent joins solid phase carrier Annu Rep Med Chem26:271-280; Fodor, S.P.A. (1991) Science251:767; Pirrung et al. (1992) U.S. Patent number 5,143,854 is included this description by reference in; Jacobs et al. (1994) Trends Biotechnol12:19-26).The spatial resolution of illumination imprint lithography provides miniaturization.This technology can be undertaken by the protection/deprotection reaction of use with protection against light sensitivity group.
[0368] main points of this technology are in people such as Gallop (1994) J Med ChemIllustrate among the 37:1233-1251.Prepare a kind of synthetic substrate and be used for connecting, described connection is amino linker or other the photosensitive junctional complex by covalently bound photosensitive nitro veratryl oxygen carbonyl (NVCO) protection.Light is used to optionally activate a specific region that is used to connect of synthetic substrate.Remove the activation that photosensitive blocking group (deprotection) causes the zone selected by light.After the activation, at first be that one group of amino acid analogue is exposed to whole surface, each is loaded with photosensitive protective group group on the amino endways.Connect the zone only occur in the previous steps by light projection.After reaction stops, plate is washed, and this substrate activates the different regions that are used for second member (building block) reaction of protecting by the second cover shelter irradiation.The pattern of shelter and the order of reactant have been determined product and their position.Owing to utilized the illumination imprint lithography in this process, number that can synthetic chemical compound only be subjected to can with the limited in number in the suitable localized synthetic site of resolution this.The site of each chemical compound is accurately as can be known; Therefore, the interaction of it and other molecules can directly be estimated.
[0369] in a kind of chemosynthesis of light projection, product depends on the pattern of illumination and the addition sequence of reactant.By changing the illumination pattern, there is the different test compounds of a lot of covers to synthesize simultaneously; These characteristics cause many different generations of sheltering strategy.
[0370] E. Bian Ma combinatorial library
[0371] in another embodiment, subject methods adopted a compound library of the Mk system that has a kind of coding.The nearest progress of identified activity chemical compound has adopted the multiple chemical directory system that utilizes label from combinatorial library, and these labels are encoded uniquely for a given reactions steps that beadlet experienced (and the structure through inferring that it is entrained).From conceptive, this way imitation phage display storehouse, wherein active in polypeptide expressed, but the structure of active polypeptide is derived from corresponding genomic dna sequence.First coding of synthetic combinatorial libraries utilizes DNA as code.The existing report of various other forms of codings comprises with the biological oligomer coding (for example oligonucleotide and polypeptide) that can check order, and the binary coding that has the non-labelling that checks order that adds.
[0372] 1. with the biological oligomer labelling that can check order
[0373] utilize the principle in the synthetic compound storehouse of oligonucleotide coded combination to be illustrated (Brenner et al. (1992) PNAS 89:5381-5383) in 1992, and an example of this compound library (the Needles et al. (1993) that appears at 1 year PNAS90:10700-10704).Nominally one is 7 7The polypeptide of the combinatorial library of (=823543) has comprised all combinations of Arg, Gln, Phe, Lys, Val, D-Val and Thr (triliteral aminoacid code), wherein each is by a specific dinucleotide coding (being respectively TA, TC, CT, AT, TT, CA and AC), and this storehouse is by a series of alternately polypeptide and the synthetic preparation of oligonucleotide on solid phase carrier of samsara.In this work; the functional group that amine connects on beadlet is different from the synthetic of polypeptide or oligonucleotide especially; this is by hatching beadlet with reagent simultaneously, and described reagent produces OH group that is used for the synthetic protection of oligonucleotide and the NH that is used for the synthetic protection of polypeptide 2(herein, with 1: 20 ratio).After finishing, each label contains 69-mers, and wherein 14 units have code.This compound library and fluorescent-labeled antibody that is connected with beadlet is hatched, and contains cell instrument (FACS) sorting of the strong fluorescigenic antibody beadlet of connection by fluorescence-activation.The DNA label checks order, and predicts synthetic polypeptide by pcr amplification.By these technology, can derive the compound library that is used for subject methods, wherein the oligonucleotide sequence of label is identified this successive composite reaction of concrete beadlet experience, thereby the evaluation of the chemical compound on the beadlet is provided.
[0374] use of label oligonucleotide allows highstrung labeled analysis.Even so, this method needs careful selected marker and compound library member's the alternately orthogonal set of synthetic required blocking group.In addition, the different head of the chemical instability of label, especially phosphate and sugar is connected, and may limit the synthetic reagent that can be used in non-oligomer storehouse and the selection of condition.In preferred embodiments, compound library adopts the connector allow test compounds library member's selective detachment of being used to measure.
[0375] polypeptide also is used as the labelled molecule of combinatorial library.Two kinds of exemplary methods are described in this area, these the two kinds branching connectors that all adopt to be connected on the solid phase, and wherein coding and aglucon chain are to make in turn.At first method (Kerr JM et al. (1993) J Am Chem Soc115:2529-2531), obtaining of synthetic orthogonality is the sour unstable protection and the alkali unstable protection that is used for the chemical compound chain that is used for coding strand by employing.
[0376] (Nikolaiev et al. (1993) in the selectable method of another kind Pept Res6:161-170), adopt the branching connector, make coding unit can both be connected on the resin of identical functional group with test compound.In one embodiment, a kind of connector that ruptures can be placed between branch point and the pearl, thereby the molecule that fracture is discharged contains code and chemical compound (Ptek et al. (1991) Tetrahedron Lett32:3891-3894).In another embodiment, the connector that can rupture can make test compounds optionally separate with pearl, stays code.Back one structure is valuable especially, because it allows the filler test chemical compound, and the interference of the group of not encoding.In this area independently verified this label of example of fracture and peptide library member's sequence analysis and their corresponding labellings can predict the structure of polypeptide accurately.
[0377] 2. the non-labelling that checks order: binary coding
[0378] a kind of form of selectable encoded test compound library has adopted non-check order, electrophoresis labelled molecule (the Ohlmeyer et al. (1993) that is used as a kind of duadic code of a cover PNAS90:10922-10926).Exemplary labelling is the halogenated aromatic alkyl ether, because its trimethylsilyl ethers, it is captured gas chromatogram (ECGC) and detect being less than the micromolar horizontal available electron of millimicro.The variation of alkyl chain length and the character of aromatic halide and position allow the synthetic of at least 40 kinds of such labels, and this can encode 2 on principle 40(for example, reach 10 12) plant different molecules.In initial report (Ohlmeyer et al., as above) but the ortho-nitrophenyl connector by light fracture, label is attached in a kind of peptide library on effective amido of about 1%.When preparation class polypeptide or other contained the compound library of combination of amine molecule, this approach was easily.But, a kind of more general system develops, and it allows the compound library of the in fact any combination of coding.At this, but chemical compound will be connected on the solid phase carrier by the connector of light fracture, and this labelling is to be inserted into (Nestler et al. (1994) on the beadlet substrate by a kind of catechol ether connector by carbene J Org Chem59:4723-4724).This orthogonal combination strategy allows the compound library member selectivity that is used to detect in the solution to break away from, and decodes by ECGC after the label sets oxidation breaks away from.
[0379] though there is the continuous compound library of several amide to adopt the binary coding that the electrophoresis labelling that is connected to amido is arranged in the art, directly connecting these labellings provides bigger versatility to pearl substrate on the structure that can prepare in the coded combination library.Connect by this way, label and their connector are near inertia as beadlet substrate.The compound library of the combination of binary coding reports that wherein the electrophoresis labelling is to be directly connected to solid phase (Ohlmeyer et al. (1995) PNAS92:6027-6031), and for generating the host compound storehouse provide guidance.These two compound libraries are to use orthogonal connection strategy to constitute, and compound library member wherein is connected to solid phase carrier by photosensitive connector, and label is that strong oxidation scission by cross-linking agent is connected.Because the member of compound library can be repeatedly, elute from the solid phase carrier glazing partly, so the member of compound library can be used for multiple detection.Successive smooth eluting also allows a kind of very high-throughout repeated screening strategy: at first, multiple beadlet is placed on 96 hole microwell plates; Secondly, chemical compound is partly separated and be transferred to test board; The 3rd, a kind of melts combine analytic process is determined active hole; The 4th, corresponding independent being rearranged in the new microwell plate of beadlet; The 5th, one reactive compound is identified; The 6th, structure is decoded.
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Embodiment
[0442] now the present invention is carried out generality and describe, by it will more hold with reference to following embodiment Easily be understood, these embodiment are just in order to illustrate some aspect of the present invention and embodiment, and Be not used in restriction the present invention.
[0443] Example 1: filipin is in conjunction with detection
[0444] we have developed and utilize filipin to be used for proofreading and correct phenotype at the NPC of Chinese hamster ovary celI system Determination method, it can be incorporated into NEC, and has been used for the free courage of NPC cell Sterol content visual. Initial screening is carried out in the CT60 cell, and it expresses one Plant the hamster NPC1 albumen of sudden change and the gain of the sudden change of the functional gene among a kind of SCAP (42). The cholesterol that these cells can not derive low-density lipoprotein is from the endosome in late period Transportation is come out, and a large amount of cholesterol accumulates in the LSO compartment. What Figure 1A-B showed is (Figure 1A) and at the CT60 cell (scheme at a kind of contrast Chinese hamster ovary celI strain TRVb1 (45) The image of filipin dyeing 1B). Can find out that CT60 cell contrast cell shows more Many filipin dyeing and the fluorescence in the CT60 cell are to concentrate on circumnuclear organelle In.
[0445] in order to screen, comes with the Discovery-1 micrometron system that 10 times of object lens are arranged Obtain image and by coming correcting background and shade described in the method. Setting two threshold values is used for luxuriant and rich with fragrance In flat dyeing, low threshold value comprises all cells zone, LSOs was strong around high threshold was used for nuclear Strong filipin dyeing. The threshold value of setting is undressed for 32 holes of every block of plate The analysis of 64 images of CT60 cell. Found that same threshold value can be used for a reality Plurality of plates in testing, but threshold value can be different with the experiment that different modes carries out. In low threshold value Development in, we have compared based on the cell image after the threshold value that transmitted light images is arranged, and These threshold values provide the uniformity good with the transmitted light cell boundary.
[0446] as a kind of simple measurement of filipin staining power, we have measured more than the threshold value The filipin intensity of every pixel. Adjust filipin mark (concentration and time) condition to optimize Difference between CT60 cell and the contrast TRVb1 cell. Shown in Fig. 1 C, this letter Single method provides a suitable high level between CT60 cell and the TRVb1 cell Ability to see things in their true light. The characteristic that is used for the method for screening represents (46) with statistical parameter Z ':
Z′＝1-(3σ c++3σ c-)/|μ c+-μ c-|
[0447] σ whereinc+And σc-Standard deviation (SD) and the collection σ of positive and negative control data groupc+And σc-The mean value of positive and negative control. Utilize CT60 thin to TRVb1 It is 0.22 that the Z ' that born of the same parents' average filipin intensity is calculated is worth, and this is considered to do large-scale sieve usually Choosing is unsuitable, because two expections that distribute can be overlapping when a large amount of holes is screened.
[0448] although intensity detection comes in handy, seeming more image information can provide better Wild type is to the difference of NPC cell. For this reason, we have utilized the filipin mark of LSOs Spatial distribution, they concentrate on nuclear near (Figure 1B). We are to these bright gatherings Use the higher threshold value of second. Use an example of these threshold values as shown in Figure 2. Then, We measure total fluorescence intensity (high threshold, Fig. 2 C) of selected LSO divided by in the cell The number of total pixel (low threshold value, Fig. 2 D). As shown in Figure 1, this LSO compartment is measured It is 0.61 ability to see things in their true light that the Z ' that method has provided stronger CT60 contrast control cells is worth.
[0449] use above-mentioned triage techniques, the compound library that we have screened 14956 kinds of compounds adds Be added to cell 16 hours, final concentration is 10 μ M, and every kind of compound uses a hole. Use Before these compounds, Growth of Cells in containing the normal structure culture medium of 10%FBS, Therefore, LSOs has been full of cholesterol (Figure 1B). Use then average filipin intensity inspection Survey and LSO compartment determination method are carried out image to cell and are processed and analyze. Generally speaking, this two Kind of Analysis deterrmination can reduce the similar compound of filipin mark.
The average filipin intensity that obtains the mean value of the cell of [0450] processing from solvent surpasses 3 The hole of SD is further studied. The image in these selected holes is visually can be detected, And if we obtain picture from the second place, the site that shows weak focus (is about total Amount 0.3%) all be not re-started analysis. There is the hole of low cell number to be considered to one Plant toxicity and show, and these cytotoxic compounds do not follow up. We have also studied The low multiplication factor image of the arrangement in the row and column of plate is to seek the mould of cell quantity or brightness Formula, they may show one of mechanical error in automatic moving liquid step. In an example, In 8 plates of a cover, see a kind of bands of a spectrum pattern, and these compounds are asked at definite pipettor Again screened after the topic.
[0451] from this initial screening, we find that 133 kinds of compounds can reduce average filipin Intensity surpasses 3SD, and 23 kinds of compounds can increase average filipin intensity above 3SD. The visual inspection of image also shows the morphology that 19 kinds of compounds can produce in filipin dyeing pattern Change, this does not meet the standard that we reduce average filipin intensity.
[0452] then under initial screening the same terms these 175 kinds of compounds at 10 μ M again by again Screening, difference is that each compound is placed on two holes of every plate and 2 parallel sieves of plate Choosing. Average filipin intensity and LSO ratio value are all measured. From again selecting the screening Getting 14 kinds of compounds can repeatedly reduce filipin dyeing at 10 μ M, and 8 kinds of chemical combination Thing is found repeatedly to increase filipin dyeing. 9 kinds of compounds are found to change filipin Form distributes. Fig. 3 has shown the screen plate in the hole of control wells that solvent is processed and compound treatment Image, shown the filipin dyeing that reduces.
[0453] Fig. 4 has shown that 4 kinds of compounds cause that the morphology of observing by filipin dyeing becomes The effect of changing. These cells have shown rearrangement, this show cholesterol be changed to different between Every, or the form of LSOs itself changes (compound 1-c-3, Fig. 4 C). Compound The impact of 1-b-4 (Fig. 4 D) is very strong, such as the bright whirlpool institute of filipin dyeing Observe. The impact of compound 1-b-4 is similar to the normal human fibroblast, and (data are not aobvious Show), show that the NPC phenotype of this reaction and cell is incoherent. These can increase bright Aobvious filipin dyes and causes the compound of morphological change not advanced in this research The research of one step.
[0454] can reduce by 14 kinds of compounds of filipin mark and cause 2 of great morphological change Plant the structure of compound as shown in Figure 5. Compound 1-c-2 and 1-c-3 cause morphological change, Compound 1-b-2 and 1-b-4 increase filipin intensity.
[0455] for the materials and methods that screens
[0456] material: cell growth medium Hams F12 and hyclone (FBS) available from Invitrogen company (Carlsbad, CA). Every other chemical reagent comprises dimethyl Sulfoxide (DMSO), filipin/paraformaldehyde (PFA) and Hoechst 33258 are available from Sigma Chemicals (St.Louis, MO). Be used for the compound library of screening available from Chemical Diversity, Inc. (San Diego, CA). The Metamorph image analysis software from Molecular Devices Corporation (Downington, PA).
[0457] cell is cultivated: NPC1 clone, CT60 and CT43 are provided by T.Y.Chang ((Dartmouth Medical School, Hanover, NH). These clones are from the parent Continuous cell line 25RA, this is one and contains in SREBP cracking activator protein (SCAP) The Chinese hamster ovary celI strain (42) of gain function sudden change is arranged. CT60 and CT43 Growth of Cells exist In the Hams F12 culture medium, 1% penicillin/streptomycin (PS), 2g/L have wherein been added Glucose, contain the 1.176 grams per liter sodium acid carbonates [culture medium A] of 10%FBS, contain at one 5% CO2Humidified incubator in remain on 37 ℃. In order to screen, contain at 30 μ l CT60 cell among the growth medium A of 10%FBS (650 cells/well) or CT43 are thin Born of the same parents' (700 cells/well) plant respectively flat, transparent at Costar 384 hole black polystyrene In the plate of the tissue culture treated of bottom (Corning, Inc., NY), to be carried out at cell Obtaining～80% during analysis merges.
[0458] normal human fibroblast (GM5659E) has been grown in 1%P/S and 10% Among the MEM of FBS. For microexamination, fibroblast is in normal growth medium In the culture vessel with glass bottom of 35mm or in 384 orifice plates bed board.
[0459] compound adds: the compound in the compound library is formatted, is used in the Rockefeller Screen in the high flux screening instrument of university. Use the compound treatment from chemical libraries behind the bed board Cell 1 day. Use Packard MiniTrakTMThe robot liquid processing system, we are every Kind of compound added 0.1 μ l (5mM is stored among the DMSO) to 25 μ l by culture medium A and 1%FBS and 20mM2-[4-(ethoxy)-1-piperazinyl] ethyl sulfonic acid (HEPES) group Become, among the screening and culturing base S in the polypropylene board at the bottom of the Falcon 384 hole V-types. For Acquisition～10 μ M final concentrations, the premix compound of 23 μ l is assigned to and contains cell and 30 μ l In the plate of culture medium A. For Preliminary screening, 352 kinds of test compounds are added to every block of plate In, all the other 32 holes only add DMSO in contrast. All have added the plate of compound at 37 ℃ Hatch 16h. Utilize then Bio-Tek Elx405 wash the plate machine (Bio-Tek Instruments Inc., Winooski, VT) wash 3 times with pH value 7.4 phosphate buffers (PBS). Clear to each Wash the cycle, be divided into the PBS of 70 μ l, being drawn into then every hole resid vol is 16 μ l. At last, At room temperature cell is fixed 20 minutes with the PFA of 1.5% among the PBS, washes with PBS then More than 3 times.
[0460] fluorescence labeling. For fixed cell, at room temperature in 45 minutes, filipin is added In the PBS to final concentration be 50 μ g/ml, be used for the marked free cholesterol. Cell is used at last PBS washes 3 times, and obtains immediately image behind the mark.
[0461] fluorescence microscope: from Molecular Devices Corporation's The automatic fluorescence microscope of Discovery-1 type is used for obtaining image, and it is equipped with xenon arc lamp (PerkinElmer, CA), Nikon 10X Plan Fluor 0.3NA object lens and Photometrics CoolSnapHQ camera (1392 * 1040 pixels; Roper Scientific, Tucson, AZ). Use has the 60/40nm of a 365DCLP (DiChroic Long Pass) filter to excite Obtain the filipin image with 480/40nm emission filter. Image file is being transferred to one Be stored in the local host computer before the server.
[0462] utilize CRS CataLyst Express robot (Thermo Electron Corp) to incite somebody to action The storeroom of plate slave plate transports. 2 positions obtain image in every hole, and each position is far from the center, hole About 50 μ m use 2 * 2 frames and method, and the time for exposure of each image is 75ms. For First and postsearch screening adopts diverse ways to carry out automatic focusing. In first screening, use Based on focusing and the self-focusing algorithm of MetaMorph of image, every hole is focused and surpasses one The scope of individual ± 150 μ m and each site in every hole are focused the model that surpasses one ± 20 μ m Enclose. Imagery exploitation 8 * 8 frames and the method that are used for focusing on were floated to reduce light by the 15ms time for exposure In vain. For postsearch screening, based on the automatic focus of laser (from Molecular Devices LAF v.2) be used to seek the bottom of plate. Focusing based on image is used for determining plate Side-play amount between bottom and the cell, each position is again focused on and is surpassed 20 μ m then Scope. No matter the method that focuses on, the acquisition time of every plate is 60-75 minute. 696 * 520 Pixel image obtains with every pixel 12 intensity bits. Each pixel in object is 1.25 * 1.2 μ m.
[0463] graphical analysis: the imagery exploitation Metamorph Discovery-1 of filipin staining cell Image analysis software is analyzed. Developed two kinds of different image analysis methods: (1) is flat All filipin intensity detection and (2) LSO compartment ratio detect. At first, in order to proofread and correct shade, By average all images that from a plate, obtains and utilize low pass filter smoothly average Image create an image. Each pixel of image multiply by the average strong of shadow image then The degree, and a pixel of another pixel of the pixel intensity that will obtain thus divided by shadow image. Deduct this in intensity level by measuring the 5th percentile and each pixel from this image Individual value is come background correction from the image of shadow correction. Under the bed board density of using, all districts The territory has at least 5% image-region not have cell. Next, with two different threshold values Be applied to these filipin images. At first, low threshold value being set is used for comprising that all are occupied by cell The zone. Utilize this screening value to make the transmitted light images profile phase one of profile with the cell of cell Cause. The second, by selecting the bright areas of filipin dyeing, set higher threshold value and be used for The pigmented section that becomes clear in CT60 and/or the Ct43 cell, purpose mainly is the nuclear of identification of cell The LSOs of peripheral region. For average filipin strength detection, use separately low threshold value, I Measured low threshold value above total filipin intensity divided by more than the low threshold value in each zone Pixel count. This has provided an average filipin intensity of each cell compartment. For the LSO district The chamber ratio, we have measured selectively in this total filipin intensity more than high threshold of zone Pixel count divided by low threshold value. This has provided the total strong of every cell area LSO filipin The measurement of degree.
Figure A20068004988001401
[0464] by existing the value that obtains in the situation to deposit divided by compound with solvent control in every block of plate The value that in situation, obtains and obtain normalized value. Similarly method is used to analysis of compounds Stay the impact among the LSOs to cause cholesterol with U18666A human body fibroblast.
[0465] immunofluorescence: the CT60 cell grows to 70% melt in the culture dish of cover glass bottom Close. Behind the 24h, add in the cell in the screening and culturing base of the HEPES that contains 20mM Compound (10 μ M). Behind compound treatment 16-22h, cell washs 3 times with PBS, Fix 20 minutes with 3.3%PFA in room temperature. Cell processes 10 with 50mM ammonium chloride then Minute, wash 3 times with PBS. After 0.1% bovine serum albumin(BSA) sealing 20 minutes, cell With the PBS washing, the saponin with 0.05% is thoroughly changed processing and is existed with anti--LBPA (1: 100) Incubated at room 30 minutes (J.Gruenberg, the contribution of Univ.of Geneva). Then thin Born of the same parents clean 3 times with PBS, in sheep anti-mouse igg-Alexa546 (1: 200) and 100 μ g/ml phenanthrene Flat hatching 30 minutes. At last, cell washs 3 times with PBS, and is being furnished with Princeton Instruments (Princeton, NJ) cooling CCD camera and MetaMorph Leica DMIRB microscope (the Leica Mikroscopie of Imaging System software-driven Und Systeme GmbH, Germany) the lower image that obtains. All images obtain to use oil immersion Object lens (25 *, 1.4NA). Alexa 546-Tf utilizes standard rhodamine filter cube Imaging, and filipin be utilize Leica A4 cube to come imaging [(40nm is logical for 360nm Band) exciter filter and 470nm (band of 40nm is logical) emission filter]. Use Metamorph Discovery-1 image analysis software utilizes the graphical analysis that is used for screening to calculate Method is carried out graphical analysis, has and do not exist the compound situation to estimate cholesterol and LBPA Under concentration.
[0466] Example 2: dose dependent detects
[0467] dose dependent: use the identical method used with screening, compound is respectively 4 Test with 10 μ M, 3.33 μ M, 1.11 μ M, 370nM and 123nM in the individual hole. Choosing The required amount of the once-through operation of the compound of selecting is available from Chemical Diversity, and Preparation 10mM liquid storage among the DMSO. 2 times of concentration of preparation compound in the screening and culturing base Secondary storage liquid plate (20 μ M, 6.66 μ M, 2.22 μ M, 740nM and 246nM). For obtaining ultimate density, this secondary storage liquid of 30 μ l is added to every hole and contains containing of 30 μ l Have in the cell of growth medium A of 10%FBS. The final concentration (0.2% of dimethyl sulfoxide (DMSO) V/v) in all holes, be identical. Cell is taped against every hole with 650 cells/well and contains 30 μ l Costar 384 orifice plates of the growth medium A that contains 10%FBS in. Deposit at compound The time hatched 20 hours, cell as described in screening test, is used PFA with after the PBS washing Fixing and dye with filipin. From the dosage that selects compound in 14 kinds of one-level compound library The be determined at CT60 cell of dependence in independently testing done 5 times at least, and be thin at CT43 Born of the same parents do 3 times at least. Select the dose dependent of compound to exist from 7 kinds of secondary compound library The CT60 cell that is determined in the independent experiment is done 3 times at least, does at least 2 at the CT43 cell Inferior.
[0468] in one-time detection, 14 kinds of dosage with selected compound identical during screening detects are anti-Answer in the curve shown in Fig. 6 A-B. Three compounds wherein are at the CT60 cell of 1.1 μ m In reduce the filipin following 3SD of mean value that solvent processes that dyes, same compound treatment Cell is lower than the solvent of 123nM and processes mean value 2SD above (Fig. 6 A). Compound 1-a-14 A uncommon dose-effect curve is arranged, this may with its CDCC phase in high concentration Close. Whether this impact has specificity to CT60 clone in order to detect, and we have also detected These 14 kinds of selected compounds are to the dose response of CT43 cell, and this is to derive from parent cell line The clone of the another kind of NPC1 sudden change of 25RA. Majority of compounds is not located 10 μ M's Patting more than the following 3SD of average is effectively, but under lower concentration the CT43 cell is lost Effect (Fig. 6 B). What is interesting is and notice these 14 kinds of compounds in these two clones The general trend of impact be similarly, although the vague generalization compound is at a given dosage pair The CT60 cell is more effective.
[0469] Example 3: time course detects
[0470] utilizes the method that is similar to dose dependent, measured these compounds 1.11,3.33 Impact with 10 μ M concentration processing 4,20,48h. At first day, the CT60 cell is with 600 In the growth medium of cells/well kind in 3 384 orifice plates. In order to guarantee in the final time Point keeps same cell density, and compound adds in chronological order. After hatching is spent the night, first The compound that is diluted among the culture medium S in the piece plate (time point of 48h) is added in the hole, To reach ultimate density 1.11,3.33 and 10 μ M. Behind the cell seeding 52h, compound is with class Join in second block of plate like mode, and hatch 20h. At last, behind the cell seeding 68h, change Compound joins in the 3rd block of plate in a similar fashion, and hatches 4h. All three plate PBS Wash 3 times, fix and dye with 50 μ g/ml filipins with 1.5%PFA. Every in each experiment 4 holes of one conditioned measurement, to CT60 and CT43 each experiment repeat 3 times (CT43's Data do not show).
[0471] Example 4: toxicity detects
[0472] in order to measure toxicity, we with compound 5,10 and 20 μ M process CT60 and CY43 cell 24 hours. The cell number in every hole is carried out with the control cells of processing with DMSO Contrast (Fig. 7). After hatching 24h, most compounds do not cause cell quantity at 10 μ M Obviously reduce. Compound 1-a-14 causes that at 10 μ M the CT60 cell number reduces 50%, CT43 Leukopenia 80%. Compound 1-a-4,5,6,8 and 13 has part toxicity, this After 24 hours, there is the 20-30% minimizing indicated at 10 μ M cell numbers.
[0473] be used for Cytometric method: using dosage relies on the similar method of detection method, will Parallel four repetitions of compound are with 0 (dimethylsulfoxide solvent control group), 5,10 and 20 μ m Concentration be added to kind in the CT60 and CT43 cell of 384 well culture plates, difference exists Carry out nuclear staining in cell with Hoechst 33258. The final concentration of dimethyl sulfoxide (DMSO) is at Kong Zhongwei 0.2%. For control cells, the dimethyl sulfoxide (DMSO) of isodose adds in the cell. The cell training Supported 24,48 and 72 hours. Behind each time point, washed cell is used 1.5%PFA then Fixing. After cell is washed 3 times with PBS, under the room temperature with 5 μ g/ml Hoechst 33258 (25 Mg/ml DMSO storage liquid) nucleus dyeed 45 minutes in PBS. At last, cell is used PBS washes 3 times, obtains image with Nikon 4X Plan Apo 0.2NA eyepiece. For Hoechst Imaging, we use the filter setting identical with filipin. In every pixel 12 strength ratios The spy, the image of 520 * 696 pixels has been gathered in our every hole. In 13 objects each Pixel is 3.125 * 3.125 μ m. Utilize the Integrated Morphometry of MetaMorph The Analysis function, the monokaryon zone that cell settles the standard with interactive mode by every block of plate (～200 μ m2) count. Measured the standard area of each target that surpasses threshold value Amount, and the total amount of the standard area of each image is used as cell count. Each concentration and Time point calculates with the DMSO contrast and compares the percentage that cell quantity reduces.
[0474] Example 5: gas chromatography determination cholesterol
[0475] effect of selecting compound to reduce cholesterol in determined by the filipin mark 14 kinds is passed through A kind of selectable chemical method measures, and the method comprises the cytolipin of solvent extraction GC separates (43). With the same condition of filler test under, CT60 cell compound Process cell at 10 μ M. FC concentration in the every cell of gas chromatography determination, all income values Compare with the mensuration of average filipin intensity by (table 1). As shown in table 1, choosingization in 14 kinds The major part of compound causes the decline of whole FC relative concentration gentlenesses of cell, and this is with average luxuriant and rich with fragrance It is the same that Li Pingfa measures. From for the first time screening obtain select object that cellular cholesterol is had not Fixed impact; Comprise that some obviously increase the compound of free cholesterol in the cell.
[0476] table 1 by C T 60 cells of average filipin intensity and gas chromatographic detection through being selected from Select CHF content after the compound treatment in 14 kinds in the one-level compound library.
Compound number The mark of average filipin intensity contrast μ g by G C mensuration1The mark of FC/ μ g albumen contrast
  1-a-1   0.87±0.04   1.02±0.03
  1-a-2   0.88±0.04   1.15±0.05
  1-a-3   0.95±0.04   1.27±0.07
  1-a-4   1.01±0.04   0.87±0.07
  1-a-5   0.89±0.04   1.18±0.06
  1-a-6   0.92±0.04   1.37±0.01
  1-a-7   0.89±0.04   1.04±0.13
  1-a-8   0.90±0.04   1.31±0.10
  1-a-9   0.99±0.04   0.86±0.07
  1-a-10   0.96±0.04   1.23±0.08
  1-a-11   0.90±0.04   0.82±0.07
  1-a-12   0.91±0.04   0.73±0.03
  1-a-13   0.97±0.04   1.54±0.11
  1-a-14   1.24±0.04   1.44±0.16
1The FC-CHF
[0477] first day with CT60 or CT43 cell kind in 6 orifice plates. In select compound with The concentration of 10 μ m is added in the cell. Cell was cultivated 24 hours. Use n-hexane: isopropyl alcohol (3: 2 V/V) extract cytolipin. Dry and Eddy diffusion lipid-soluble extract in n-hexane, subsequently Adopt to be marked on the gas chromatograph in the cupreol conduct and separate.
[0478] method: CT60 cell kind is containing Ham ' s F-12/1.176 grams per liter sodium acid carbonate/2 grams In 6 orifice plates of the culture medium of/L glucose/10%FBS. After hatching 24 hours, cell is with 1 Each compound treatment of 0 μ M, culture medium are replaced by and contain Ham ' s F-12/1.176 grams per liter carbon Acid hydrogen sodium/2 gram/L glucose/5.5%FBS/20mM HEPES. Culture medium changes in every hole Change is the similar experiment condition that has and be used for screening for compound after being added in the cell. Warp Cross compound treatment 18h, cell Hank ' s balanced salt solution (HBSS) is washed 2 times. Cell Lipid n-hexane/isopropyl alcohol (3: 2v/v) extract (43), dry and heavy in n-hexane Outstanding, use then following condition to separate at gas chromatograph (GC). A kind of Hewlett Packard gas-chromatography pattern HP 5890 serial II (Palo Alto, CA) are used to separate CHF, its be equipped with flame ionization detector, separation-non-separate syringe and Scribbling thickness is 15 meters * 0.53 mm H P-5 of the 5% phenyl methyl siloxane film of 1.5 μ m Capillary column. Injection temperature maintains 255 ℃, and the furnace temperature isothermal is controlled at 260 ℃, uses Helium with the 30mL/min flow velocity as mobile phase. Use in the cupreol conduct and be marked with correction The loss of lipid in the leaching process comes CHF (FC) is carried out quantitatively.
[0479] Example 6: the screening of secondary compound library
[0480] estimates the secondary storehouse of containing 3962 kinds of compounds. These compounds are with regard to Tanimoto Selected on the basis of the similitude of the chemistry of coefficient (47).
[0481] we have used the method that is similar to the screening of elementary storehouse that these 3962 kinds of compounds are carried out Screening, difference is that compound is at first at 10 μ M and two kinds of concentration screenings of 1 μ M. Every kind of compound is added in the single hole, and 2 positions obtain image and on average become one in every hole Individual value. 2 of the secondary storehouse are screened completely two concentration and carry out. Use average filipin strong Degree and two kinds of methods analyst images of LSO compartment ratio. At 10 μ M, we use a kind of analysis When measuring, method finds that 574 kinds of compounds are lower than contrast 3SD, find during with two kinds of analytical methods 34 kinds of compounds are lower than contrast 3SD. At 1 μ M, we are with having at least a kind of analytical method to send out Existing 202 kinds of compounds are lower than contrast 3SD, and it is right to find during with 2 kinds of methods that 6 kinds of compounds are lower than According to 3SD.
[0482] we choose at random this 202 kinds of compounds, and at 1 μ M, 300nM and 100nM Again screen 2 times. We add compound in each concentration in 4 different holes, and flat Equal measurement results of the image of 2 positions in every hole. By 2 screenings, at 1 μ M, 300 We have obtained each compound totally 8 values by each analytical method nM and 100nM. Whenever We one have 1 μ M's individual analytical method (average filipin intensity and LSO compartment ratio) 10 values (from 2 that screen for the first time and elective 8) and 300nM and 100 8 values of nM. According to these data, we have selected 7 kinds of compounds to do further to analyze, Their chemical constitution as shown in Figure 8.
The dose-effect curve of [0483] 7 kind of selected compound as shown in Figure 9. Data show 4 Individual compound (2-a-8,2-a-9,2-a-12 and 2-a-13) is at the LSO of 370nM compartment Show the minimizing above 3SD in the determination method, and 3 compounds (2-a-8,2-a-9 and 2-a-12) also show the effect that C T 60 cells is lower than solvent control 2SD at 123nM. As from selecting object in the first round, the major part of these compounds also is to the CT43 cell Effectively (Fig. 9 B).
[0484] Example 7: the absorption of low-density lipoprotein
[0485] the CT60 cell optics culture plate special in 96 holes (Corning, Inc., Corning, NY) growing to 70% merges. After 24 hours, cell and DiI-LDL (6mg/ml) and in Select compound (10 μ M) in being added with the screening and culturing base of 20mM HEPES, to hatch. Whenever Plant compound and add in 8 holes, and the dimethyl sulfoxide (DMSO) of equivalent and DiI-LDL adding In the control wells. Through behind the 20h, cell is washed 3 times with PBS, fixes 20 with 1.5%PFA Minute, and with 50 μ g/ml filipins dyeing 45 minutes. Use the Discovery-1 type automatic Fluorescence microscope obtains image 20 times of multiplication factors. Use 535nm/40nm to excite filtration Device and logical the obtaining of 610nm/60nm band that a Chroma 51001bs DiChroic filter is arranged Get the image of DiI-LDL. The acquisition of filipin image is as indicated above. Every hole is 4 positions Point obtains image, and each compound produces 32 images. The background of this DiI-LDL image As indicated above with shadow correction. Set low threshold value and determine the cell face according to the filipin image Long-pending. At last, measure the average DiI-LDL intensity of each cell compartment.
[0486] as shown in table 2, through 20 hours hatch, all were from the secondary storehouse except 2-a-15 In select compound to cause the minimizing of the picked-up of low-density lipoprotein. This will need further Work is determining whether that this is one of some compound primary impact, or no low-density lipoprotein The minimizing of white picked-up is less important for discharging cholesterol from LSOs. Although, as one Point mutation consequence in the SCAP allele, the CT60 cell has part in the SCAP function Damaged, still desired is that cell will come by the expression that reduces ldl receptor increasing Cholesterol is reacted.
[0487] table 2 CT60 cell is through from after selecting compound treatment in 7 kinds of secondary storehouse The absorption of DiI-LDL.
Compound number The cell area mark of DiI intensity/contrast
  2-a-1   0.43±0.01
  2-a-3   0.62±0.01
  2-a-8   0.77±0.01
  2-a-9   0.85±0.01
  2-a-12   0.72±0.01
  2-a-13   0.72±0.01
  2-a-15   1.00±0.01
[0488] cell and DiI-LDL (6 μ g/ml) exist in the situation and cultivate at compound (10 μ M) 20 hours. Described in the measurement such as method of per unit cell area intensity. Numerical value is by normalization Contrast in pairs every cell area intensity of (solvent processing) cell. Numerical value is based on each condition Lower 32 images from 8 holes. ± SEM.
[0489] Example 8: from the toxicity test of the compound in secondary storehouse.
[0490] Figure 10 shows is the toxicity test result who selects compound in from the secondary storehouse 7 kinds. Compound 2-a-12 causes 75% at 20 μ m to two kinds of CT60 and CT43 cell behind the 24h Cell number reduces. Other compounds are with this understanding to only having that cell does not reduce or causes Slight minimizing, and they have reduced filipin dyeing. The Cytotoxic assessment of these compounds To be discharged into LDH in the culture medium by measurement. Shown in Figure 10 C, by this method The CDCC that records shows these compound warps less than the minimizing that is obtained by cell count May slow down the growth of cell after 24 hours and not cause cell death.
[0491] under 1.1,3.3 and 10 μ M concentration, the time course that reduces in the LSO compartment ratio As shown in figure 11. Through 4 hours processing, compound 2-a-3 was in LSO compartment ratio Show the minimizing of a kind of 3SD of surpassing. Through 20 hours, all compounds were shown at 10 μ M Reveal the minimizing of LSO compartment ratio, and several compound at 1.11 and 3.33 μ M is Effectively. After processing in 48 hours, the effect that reduces LSO compartment ratio generally is retained.
[0492] six kinds that are selected from 7 kinds of compounds in secondary storehouse have hypotoxicity, and not only at LSOs In and in whole cell, can both significantly reduce FC. Several effectively dense in these compounds Degree is lower than 0.5 μ M. Table 3 has been summed up these and has been selected the compound with regard to courage from 6 kinds of secondary storehouse Effect and toxic action that sterol reduces.
[0493] table 3 is from 7 kinds of compounds in secondary storehouse summary to the CT60 impact cell
Compound number. Minimum effective dose (LSO measurement) (3SD@20h) Average filipin is measured the mark of@10 μ M dosage contrast   g FC 1The mark of/μ g albumen (GC)@10 μ M dosage contrast The mark of protein content (μ g/ hole) contrast The mark of cell count@10 μ M dosage contrast behind the 24h
  2-a-   1   3.33   μM   0.74±   0.02   0.65±   0.02   0.94   ±0.03   1.00
  2-a-   3   3.33   μM   0.75±   0.01   0.81±   0.03   0.92   ±0.04   1.00
  2-a-   8   123nM   0.74±   0.01   0.76±   0.03   0.94   ±0.04   0.96
  2-a-   9   370nM   0.74±   0.01   0.75±   0.04   0.94   ±0.05   0.90
  2-a-   12   370nM   0.87±   0.01   ---   ---   0.67
  2-a-   13   370nM   0.75±   0.02   0.79±   0.04   0.97   ±0.03   1.00
  2-a-   15   3.33   μM   0.79±   0.01   0.89±   0.03   0.84   ±0.02   0.94
1The FC-CHF
[0494] The CTA of example 9:LDH.
[0495] CDCC that selects compound in is the technical specification LDH according to manufacturer Discharging mensuration kit (Roche Diagnostic GmbH, Penzberg, Germany) surveys Fixed. The CT60 cell with 3500 cells/well kinds in 96 orifice plates (Costar, Corning Inc., Corning, NY) and hatched 24 hours. Use and method like the dose dependent detection type, Parallel 3 dense with 0 (dimethylsulfoxide solvent control group), 5,10 and 20 μ M of compound Degree adds to respectively in the CY60 cell. After processing 24h, take out the tissue of 100 μ l and cultivate Clear liquid, use SpectraMax M2 fluorescence plate reading machine (Molecular Devices Inc., Sunnyvale, CA) measure the LDH activity in 492nm measurement absorbance. Experiment repeats 3 Inferior, therefore obtain the mean value of 9 data points.
[0496] shown in Figure 10 C, the cytotoxicity of measuring by this method is less than cell count The minimizing that records, show these compounds after 24 hours, may slow down cell growth and not Cause cell death.
[0497] Example 10: to the fibroblastic mensuration of normal human.
[0498] all The above results are to come from Chinese hamster ovary celI, and it is prominent except the NPC1 gene is arranged Become a gene mutation that also has among the SCAP. In order to determine whether that this compound may be to other The cell of type is influential, and we process the normal human with compound U18666A and become fiber finer Born of the same parents, it can cause accumulation (the NL Jacobs et that is similar to the cholesterol shown in the NPC clone Al., J Lipid Res.1997Oct; 38 (10): 1973-87). By filipin dyeing (data Show) and LSO compartment ratio method measurement (Figure 12), we find to use 250nM Or 500nM U18666A processes the remarkable increase that cell has caused the cholesterol accumulation. When being used for When in the secondary storehouse, selecting the compound treatment cell, the several filipins that cause in these compounds Dyeing is decline (Figure 12) significantly. Particularly, compound 2-a-1 has caused filipin dyeing Sharply descend.
[0499] Example 11: to the mensuration of 25RACHO cell
[0500] compound 2-a-1, the 2-a-3 of 25RACHO cell and 10 μ M concentration, 2-a-8,2-a-9 Cultivate with 2-a-13. Cell is loaded with3There are or do not exist various chemical combination in the H cholesterol then Following the trail of (chase) in the situation of thing spends the night. Take out extracellular culture medium, measure from cell In the radioactivity that discharges. Dissolved cell then, and measure the radioactivity of still staying in the cell. Data (Figure 13) show these compound promoted cholesterol from the outflow of 25-RA cell, The 25-RA cell is a Chinese hamster ovary celI strain that does not have NP, and it is used for selecting Be used for the CT43 of our above-mentioned screening and the parent cell line of CT60 cell. The 25-RA cell exists Have among the SCAP one damaged, it can change the homeostasis of cholesterol, comprises the increase cholesterol Synthetic.
[0501] Example 12: the inhibition of lysosomal acid lipase enzyme
[0502] some compound disclosed herein can by suppressing lysosomal acid lipase (LAL) Therapeutic action is arranged. Particularly compound 1-a-4,1-a-11,1-a-14,2-a-3,2-a-8,2-a-9, 2-a-13,2-a-15, and in the formula scope that has defined the name compound other Compound can suppress by LAL the hydrolysis of cholesteryl ester.

Claims (149)

1. one kind is used for may further comprise the steps suffering from the method that the patient that is characterized as the cumulative disease of cholesterol cell treats:
Give with one have a treatment of the patient effective dose that needs, one of any chemical compound among the formula I-IX, its Chinese style I is expressed as:
Figure A2006800498800002C1
Wherein,
X be O or-N (R 7)-;
Y be N or-C (R 8)-;
R 1And R 2Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 2And R 3Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces;
R 4Be hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
R 5Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 9=CR 9) n-aryl or-(CR 9=CR 9) n-heteroaryl;
R 6Be H or alkyl; Or R 5With R 6Form a monocycle or the dicyclo that can choose replacement wantonly together, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 7Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 1And R 7Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces;
Each R 8And R 9Represent H or alkyl independently; And
N is 1 or 2;
Formula II is expressed as:
Figure A2006800498800003C1
Wherein,
X be O or-N (R 6)-;
R 1And R 2Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 2And R 3Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces;
R 4Be hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
R 5Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 6Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 1And R 6Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces;
Formula III is expressed as:
Figure A2006800498800003C2
Wherein,
R 1Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-(C (R 7) 2) n-(CR 7=C (R 7) 2);
R 2Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or alkyl;
R 3Be hydrogen, alkyl ,-CO 2R 8Or-C (O) N (R 7) (R 8);
R 4With R 5Represent H or alkyl independently; Or R 4With R 5Form a key together;
Each R 6And R 7Represent H or alkyl independently;
Each R 8Represent alkyl, cycloalkyl, aryl, assorted alkyl, aralkyl or heteroarylalkyl independently;
L be a key ,-C (R 7) 2-or-(CR 7=CR 7)-; And
A 1And A 2Represent independently cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 7=CR 7)-aryl or-(CR 7=CR 7)-heteroaryl;
Formula IV is expressed as:
Figure A2006800498800004C1
Wherein,
A is cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 3=CR 3)-aryl or-(CR 3=CR 3)-heteroaryl;
R 2Be alkyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 3Represent H or alkyl independently; And
R 4Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Formula V is expressed as:
Figure A2006800498800004C2
Wherein,
X be O ,-N (R 5)-,-N (R 5) C (O)-,-C (O) N (R 5)-,-OC (O)-,-CO 2-or-N (R 5) CO 2-;
Y be O, S or-N (R 5)-;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 2Represent H or alkyl independently, or 2 R 2Formation=O together;
R 3And R 4Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Each R 5Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Formula VI is expressed as:
Figure A2006800498800005C1
Wherein,
X be O, S or-N (R 4)-;
R 1Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-(C (R 5) 2) n-(CR 5=C (R 5) 2);
R 2Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl;
R 3Be H, alkyl, thiazolinyl, aryl or heteroaryl; Or R 2And R 3Form an optional substituted monocycle or dicyclo together, described ring has 0,1 or 2 hetero atom that is selected from O, N and S;
Each R 4With R 5Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Formula VII is expressed as:
Figure A2006800498800005C2
Wherein,
X is O or S;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-C (O) R 5
R 2Be H or alkyl;
R 3Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, or an optional dicyclo that replaces, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2
R 5Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl; Or R 5By one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; And
Each R 6Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Formula VIII is expressed as:
Wherein,
X is O or S;
R 1, R 3Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently with A;
R 2And R 4Represent H or alkyl independently;
R 5Be a monocycle or the dicyclo that can choose replacement wantonly, described ring has 1,2 or 3 hetero atom that is selected from O, N and S;
Formula IX is expressed as:
Wherein,
X 1Be-OR 5,-SR 5Or-N (R 5) 2
Each X 2Represent independently O, S or-N (R 5)-;
Each R 1Represent independently alkyl, halogen, nitro, cyano group, alkoxyl, thiazolinyl, alkynyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl ,-N (R 5) 2,-OH ,-C (O) R 6,-CO 2R 5Or C (O) N (R 5) 2
R 2And R 4Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be H, alkyl or halogen;
Each R 5Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Each R 6Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; And
N is 0,1,2,3 or 4.
2. the method described in the claim 1, wherein said disease is a C type NP.
3. the method described in the claim 1, wherein said disease is an atherosclerosis.
4. the method described in the claim 1, wherein said disease is that a lysosome that is caused by sphingolipid or glycosyl sphingolipid metabolism disorder is stored up imbalance.
5. the method described in the claim 1, wherein said chemical compound is the chemical compound of a kind of formula I.
6. the method described in the claim 1, wherein said chemical compound is the chemical compound of a kind of formula I, X be O or-N (R 7)-; Y is N; R 1And R 2Represent alkyl, haloalkyl or aryl independently; R 3It is aryl; Or R 2And R 3Form optional together by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino 3-8 unit ring that replaces; R 4Be hydrogen; R 5Be Heterocyclylalkyl or aryl; R 6Be H or alkyl; Or R 5And R 6Form an optional substituted monocycle or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S; R 7Be hydrogen; Or R 1And R 7Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces.
7. the method described in the claim 1, wherein said chemical compound is the chemical compound of a kind of formula I, X is-N (R 7)-; Y is N; R 1And R 2It is aryl; R 3It is aryl; Or R 2And R 3Form together by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces; R 4Be hydrogen; R 5Be Heterocyclylalkyl or aryl; R 6Be H or alkyl; Or R 5And R 6Form an optional substituted monocycle or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S; And R 7Be hydrogen; Or R 1And R 7Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces.
8. the method described in the claim 1, wherein said chemical compound is the chemical compound of a kind of formula I, X is-N (R 7)-; Y is-C (R 8)-; R 1And R 2Represent alkyl, assorted alkyl independently or for haloalkyl; R 3Be hydrogen, alkyl, assorted alkyl or haloalkyl; R 4Be hydrogen; R 5It is heteroaryl; R 6Be H or alkyl; R 7Be hydrogen, alkyl, assorted alkyl or haloalkyl; And R 8Be H or alkyl.
9. the method described in the claim 1, wherein said chemical compound is the chemical compound of a kind of formula II.
10. the method described in the claim 1, wherein said chemical compound is the chemical compound of a kind of formula II, X is-N (R 6)-; R 1, R 2And R 5Represent aryl or heteroaryl independently; And R 3, R 4And R 6Represent hydrogen or alkyl independently.
11. the method described in the claim 1, wherein said chemical compound are a kind of chemical compounds of formula III.
12. the method described in the claim 1, wherein said chemical compound are a kind of chemical compounds of formula III; R 1, R 2, A 1And A 2Represent aryl or heteroaryl independently; R 3It is hydrogen or alkyl; R 6Be H or alkyl; And L is a key.
13. the method described in the claim 1, wherein said chemical compound are a kind of chemical compounds of formula III; R 1Be-(C (R 7) 2) n-(CR 7=C (R 7) 2); R 2It is alkyl; R 3Be alkyl ,-CO 2R 8Or-C (O) N (R 7) (R 8); R 4With R 5Represent H or alkyl independently; Or R 4With R 5Form a key together; Each R 6And R 7Represent H or alkyl independently; Each R 8Represent alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; L be a key ,-C (R 7) 2-or-(CR 7=CR 7)-; And A 1And A 2Represent aryl or heteroaryl independently.
14. the method described in the claim 1, wherein said chemical compound are the chemical compounds of a kind of formula IV.
15. the method described in the claim 1, wherein said chemical compound are the chemical compounds of a kind of formula IV; A, R 1And R 4Represent aryl or heteroaryl independently; R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 3=CR 3)-aryl or-(CR 3=CR 3)-heteroaryl; R 2It is alkyl or aryl; And each R 3Represent H or alkyl independently.
16. the method described in the claim 1, wherein said chemical compound are the chemical compounds of a kind of formula V.
17. the method described in the claim 1, wherein said chemical compound are the chemical compounds of a kind of formula V; X is-C (O) N (R 5)-or-CO 2-; Y is O or S; R 1, R 3And R 4Represent aryl or heteroaryl independently; Each R 2Represent H or alkyl independently, or 2 R 2Formation=O together; R 3And R 4Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Each R 5Represent H, alkyl, aryl or aralkyl independently; And n is 1 or 2.
18. the method described in the claim 1, wherein said chemical compound are the chemical compounds of a kind of formula VI.
19. the method described in the claim 1, wherein said chemical compound are the chemical compounds of a kind of formula VI; X is S; R 1Be aryl, heteroaryl or-(C (R 5) 2) n-(CR 5=C (R 5) 2); R 2Be aryl, heteroaryl ,-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl; Each R 5Represent H, alkyl, aryl or aralkyl independently; And n is 1 or 2.
20. the method described in the claim 1, wherein said chemical compound are the chemical compounds of a kind of formula VII.
21. the method described in the claim 1, wherein said chemical compound are the chemical compounds of a kind of formula VII; X is O or S; R 1Be aryl, heteroaryl or-C (O) R 5R 2Be H or alkyl; R 3Be aryl, heteroaryl or an optional substituted dicyclo, described ring has 1 or 2 hetero atom that is selected from O, N and S; R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2R 5By one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; Each R 6Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently.
22. the method described in the claim 1, wherein said chemical compound are the chemical compounds of a kind of formula VII; X is O or S; R 1Be aryl, heteroaryl or-C (O) R 5R 2Be H or alkyl; R 3Representative
Figure A2006800498800009C1
R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2R 5Be one by one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; Each R 6Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; M is 0,1,2,3 or 4; Each R 7Represent halogen, hydroxyl, amino, carboxyl, nitro, cyano group, alkyl or alkoxyl independently.
23. the method described in the claim 1, wherein said chemical compound are the chemical compounds of a kind of formula VIII.
24. the method described in the claim 1, wherein said chemical compound are the chemical compounds of a kind of formula VIII; X is O or S; R 1, R 3Represent aryl or heteroaryl independently with A; R 2And R 4Represent H or alkyl independently; R 5Be an optional dicyclo that replaces, described ring has 1,2 or 3 hetero atom that is selected from O, N and S.
25. the method described in the claim 1, wherein said chemical compound are the chemical compounds of a kind of formula VIII; X is O or S; R 1, R 3Represent aryl or heteroaryl independently with A; R 2And R 4Represent H or alkyl independently; R 5Representative
Figure A2006800498800009C2
Wherein n is 0,1,2,3 or 4; Each R 7Represent halogen, hydroxyl, amino, carboxyl, nitro, cyano group, alkyl or alkoxyl independently.
26. the method described in the claim 1, wherein said chemical compound are the chemical compounds of a kind of formula IX.
27. the method described in the claim 1, wherein said chemical compound are the chemical compounds of a kind of formula IX; X 1Be-N (R 5) 2Each X 2Represent O or S independently; Each R 1Represent independently alkyl, halogen, nitro, cyano group, alkoxyl ,-N (R 5) 2,-OH ,-C (O) R 6,-CO 2R 5Or C (O) N (R 5) 2R 2And R 4Represent aryl, heteroaryl, aralkyl or heteroarylalkyl independently; R 3Be H, alkyl or halogen; Each R 5Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Each R 6Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; And n is 0,1,2,3 or 4.
28. the method described in the claim 1, wherein said chemical compound is:
Figure A2006800498800010C1
Figure A2006800498800011C1
29. a method that reduces the cholesterol amount in the cell may further comprise the steps:
Mammalian cell is exposed to chemical compound one of any among the formula I-IX, and its Chinese style I is expressed as:
Figure A2006800498800011C2
Wherein,
X be O or-N (R 7)-;
Y be N or-C (R 8)-;
R 1And R 2Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 2And R 3Form together by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces;
R 4Be hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
R 5Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 9=CR 9) n-aryl or-(CR 9=CR 9) n-heteroaryl;
R 6Be H or alkyl; Or R 5And R 6Form a monocycle that can be optionally substituted or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 7Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 1And R 7Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces;
Each R 8And R 9Represent H or alkyl independently; And
N is 1 or 2;
Formula II is expressed as:
Figure A2006800498800012C1
Wherein,
X be O or-N (R 6)-;
R 1And R 2Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 2And R 3Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces;
R 4Be hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
R 5Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 6Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 1And R 6Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces;
Formula III is expressed as:
Figure A2006800498800013C1
Wherein,
R 1Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-(C (R 7) 2) n-(CR 7=C (R 7) 2);
R 2Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or alkyl;
R 3Be hydrogen, alkyl ,-CO 2R 8Or-C (O) N (R 7) (R 8);
R 4With R 5Represent H or alkyl independently; Or R 4With R 5Form a key together;
Each R 6And R 7Represent H or alkyl independently;
Each R 8Represent alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
L be a key ,-C (R 7) 2-or-(CR 7=CR 7)-; And
A 1And A 2Represent independently cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 7=CR 7)-aryl or-(CR 7=CR 7)-heteroaryl;
Formula IV is expressed as:
Figure A2006800498800013C2
Wherein,
A is cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 3=CR 3)-aryl or-(CR 3=CR 3)-heteroaryl;
R 2Be alkyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 3Represent H or alkyl independently; And
R 4Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Formula V is expressed as:
Figure A2006800498800014C1
Wherein,
X be O ,-N (R 5)-,-N (R 5) C (O)-,-C (O) N (R 5)-,-OC (O)-,-CO 2-or-N (R 5) CO 2-;
Y be O, S or-N (R 5)-;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 2Represent H or alkyl independently, or 2 R 2Formation=O together;
R 3And R 4Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Each R 5Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Formula VI is expressed as:
Figure A2006800498800014C2
Wherein,
X be O, S or-N (R 4)-;
R 1Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-(C (R 5) 2) n-(CR 5=C (R 5) 2);
R 2Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl;
R 3Be H, alkyl, thiazolinyl, aryl or heteroaryl; Or R 2And R 3Form an optional monocycle or a dicyclo that replaces together, described ring has 0,1 or 2 hetero atom that is selected from O, N and S;
Each R 4With R 5Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Formula VII is expressed as:
Figure A2006800498800014C3
Wherein,
X is O or S;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-C (O) R 5
R 2Be H or alkyl;
R 3Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or an optional dicyclo that replaces, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2
R 5Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl; Or R 5Be can by one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; And
Each R 6Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Formula VIII is expressed as:
Figure A2006800498800015C1
Wherein,
X is O or S;
R 1, R 3Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently with A;
R 2And R 4Represent H or alkyl independently;
R 5Be an optional monocycle or a dicyclo that replaces, described ring has 1,2 or 3 hetero atom that is selected from O, N and S;
Formula IX is expressed as:
Figure A2006800498800015C2
Wherein,
X 1Be-OR 5,-SR 5Or-N (R 5) 2
Each X 2Represent independently O, S or-N (R 5)-;
Each R 1Represent independently alkyl, halogen, nitro, cyano group, alkoxyl, thiazolinyl, alkynyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl ,-N (R 5) 2,-OH ,-C (O) R 6,-CO 2R 5Or C (O) N (R 5) 2
R 2And R 4Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be H, alkyl or halogen;
Each R 5Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Each R 6Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; And
N is 0,1,2,3 or 4.
30. the method described in the claim 29, wherein said chemical compound is discharged the amount that reduces the cholesterol in the described cell by the cholesterol that increases from described cell.
31. the method described in the claim 29, wherein said chemical compound absorbs the amount that reduces the cholesterol in the described cell by the cholesterol that suppresses described cell.
32. the method described in the claim 29, wherein said chemical compound is by the synthetic amount that reduces cholesterol of the cholesterol that suppresses described cell.
33. the method described in the claim 29, wherein said chemical compound reduce the amount of the cholesterol in the described cell by the esterification that promotes cholesterol in the described cell.
34. the method described in the claim 29, wherein said cell are people's cells.
35. the method described in the claim 29, wherein said cell have C type Niemann-pik Er Shi defective.
36. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula I.
37. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula I, X be O or-N (R 7)-; Y is N; R 1And R 2Represent alkyl, haloalkyl or aryl independently; R 3It is aryl; Or R 2And R 3Form together by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces; R 4Be hydrogen; R 5Be Heterocyclylalkyl or aryl; R 6Be H or alkyl; Or R 5And R 6Form an optional substituted monocycle or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S; And R 7Be hydrogen; Or R 1And R 7Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces.
38. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula I, X is-N (R 7)-; Y is N; R 1And R 2It is aryl; R 3It is aryl; Or R 2And R 3Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces; R 4Be hydrogen; R 5Be Heterocyclylalkyl or aryl; R 6Be H or alkyl; Or R 5And R 6Form an optional substituted monocycle or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S; And R 7Be hydrogen; Or R 1And R 7Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces.
39. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula I, X be O or-N (R 7)-; Y is-C (R 8)-; R 1And R 2Represent alkyl, assorted alkyl or haloalkyl independently; R 3Be hydrogen, alkyl, assorted alkyl or haloalkyl; R 4Be hydrogen; R 5It is heteroaryl; R 6Be H or alkyl; R 7Be hydrogen, alkyl, assorted alkyl or haloalkyl; And R 8Be H or alkyl.
40. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula II.
41. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula II, X is-N (R 6)-; R 1, R 2And R 5Represent aryl or heteroaryl independently; And R 3, R 4And R 6Represent hydrogen or alkyl independently.
42. the method described in the claim 29, wherein said chemical compound are a kind of chemical compounds of formula III.
43. the method described in the claim 29, wherein said chemical compound are a kind of chemical compounds of formula III; R 1, R 2, A 1And A 2Represent aryl or heteroaryl independently; R 3It is hydrogen or alkyl; R 6Be H or alkyl; And L is a key.
44. the method described in the claim 29, wherein said chemical compound are a kind of chemical compounds of formula III; R 1Be-(C (R 7) 2) n-(CR 7=C (R 7) 2); R 2It is alkyl; R 3Be alkyl ,-CO 2R 8Or-C (O) N (R 7) (R 8); R 4With R 5Represent H or alkyl independently; Or R 4With R 5Form a key together; Each R 6And R 7Represent H or alkyl independently; Each R 8Represent alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; L be a key ,-C (R 7) 2-or-(CR 7=CR 7)-; And A 1And A 2Represent aryl or heteroaryl independently.
45. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula IV.
46. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula IV; A, R 1And R 4Represent aryl or heteroaryl independently; R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 3=CR 3)-aryl or-(CR 3=CR 3)-heteroaryl; R 2It is alkyl or aryl; Each R 3Represent H or alkyl independently.
47. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula V.
48. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula V; X is-C (O) N (R 5)-or-CO 2-; Y is O or S; R 1, R 3And R 4Represent aryl or heteroaryl independently; Each R 2Represent H or alkyl independently, or 2 R 2Formation=O together; R 3And R 4Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Each R 5Represent H, alkyl, aryl or aralkyl independently; And n is 1 or 2.
49. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula VI.
50. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula VI; X is S; R 1Be aryl, heteroaryl or-(C (R 5) 2) n-(CR 5=C (R 5) 2); R 2Be aryl, heteroaryl ,-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl; R 3Be H or alkyl; Each R 5Represent H, alkyl, aryl or aralkyl independently; And n is 1 or 2.
51. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula VII.
52. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula VII; X is O or S; R 1Be aryl, heteroaryl or-C (O) R 5R 2Be H or alkyl; R 3Be aryl, heteroaryl or an optional substituted dicyclo, described ring has 1 or 2 hetero atom that is selected from O, N and S; R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2R 5Be can by one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; And each R 6Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently.
53. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula VII; X is O or S; R 1Be aryl, heteroaryl or-C (O) R 5R 2Be H or alkyl; R 3Representative
Figure A2006800498800019C1
R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2R 5Be can by one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; Each R 6Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; M is 0,1,2,3 or 4; And each R 7Represent halogen, hydroxyl, amino, carboxyl, nitro, cyano group, alkyl or alkoxyl independently.
54. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula VIII.
55. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula VIII; X is O or S; R 1, R 3Represent aryl or heteroaryl independently with A; R 2And R 4Represent H or alkyl independently; And R 5Be an optional substituted dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S.
56. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula VIII; X is O or S; R 1, R 3Represent aryl or heteroaryl independently with A; R 2And R 4Represent H or alkyl independently; R 5Representative
Figure A2006800498800019C2
Wherein n is 0,1,2,3 or 4; And each R 7Represent halogen, hydroxyl, amino, carboxyl, nitro, cyano group, alkyl or alkoxyl independently.
57. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula IX.
58. the method described in the claim 29, wherein said chemical compound are the chemical compounds of a kind of formula IX; X 1Be-N (R 5) 2Each X 2Represent O or S independently; Each R 1Represent independently alkyl, halogen, nitro, cyano group, alkoxyl ,-N (R 5) 2,-OH ,-C (O) R 6,-CO 2R 5Or C (O) N (R 5) 2R 2And R 4Represent aryl, heteroaryl, aralkyl or heteroarylalkyl independently; R 3Be H, alkyl or halogen; Each R 5Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Each R 6Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; And n is 0,1,2,3 or 4.
59. the method described in the claim 29, wherein said chemical compound is:
Figure A2006800498800020C1
60. chemical compound that formula X represents:
Figure A2006800498800021C2
Wherein,
X is OH or N (R 5) 2
Each R 1Represent independently alkyl, halogen, nitro, cyano group, alkoxyl, thiazolinyl, alkynyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl ,-N (R 5) 2,-OH ,-C (O) R 6,-CO 2R 5Or C (O) N (R 5) 2
R 2And R 4Represent cycloalkenyl group, heterocycloalkenyl, aryl, aralkyl, heteroarylalkyl independently, or have 1 the heteroatomic heteroaryl that is selected from N, O or S;
R 3Be H, alkyl or halogen;
Each R 5Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Each R 6Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
N is 0,1,2,3 or 4; And
At X is NH 2The time, R 2And R 4In be not aryl one of at least.
61. chemical compound described in the claim 60, wherein X is NH 2And R 2It is aryl.
62. chemical compound described in the claim 60, wherein X is NH 2And R 4It is aryl.
63. chemical compound that formula XI represents:
Figure A2006800498800022C1
Wherein,
R 1And R 3Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 2And R 4Represent hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Or R 1And R 2Form a 3-8 unit ring together; Or R 3And R 4Form a 3-8 unit ring together;
R 5, R 6, R 7And R 8Represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Or R 5, R 6, R 7And R 8Form at least the aryl or the heteroaryl that are replaced by a functional group together, described functional group is selected from (C 2-C 6) alkyl, halogen, nitro, cyano group, alkoxyl, thiazolinyl, alkynyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl ,-N (R 9) 2,-OR 9,-C (O) R 9,-CO 2R 9Or C (O) N (R 9) 2And
Each R 9Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently.
64. chemical compound described in the claim 63, wherein R 1And R 2Form 6 yuan of rings.
65. chemical compound described in the claim 63, wherein R 3And R 4Form 6 yuan of rings.
66. chemical compound described in the claim 63, wherein R 5, R 6, R 7And R 8Form an aromatic rings together.
67. chemical compound that formula XII represents:
Wherein,
X be O, S or-N (R 4)-;
R 1Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
R 2Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl;
R 3Be H, alkyl, thiazolinyl, aryl or heteroaryl; Or R 2And R 3Form an optional substituted monocycle or dicyclo together, described ring has 0,1 or 2 hetero atom that is selected from O, N and S;
Each R 4With R 5Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Or the chemical compound represented of a kind of formula XIII:
Wherein,
X be O, S or-N (R 7)-;
R 4Be-(C (R 8) 2) n-(CR 8=C (R 8) 2);
R 5Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-(CR 8=C (R 8) 2);
R 6Be H, alkyl, thiazolinyl, aryl or heteroaryl; Or R 5And R 6Form an optional substituted monocycle or dicyclo together, described ring has 0,1 or 2 hetero atom that is selected from O, N and S;
Each R 7With R 8Represent H, alkyl, cycloalkyl or Heterocyclylalkyl, aralkyl or heteroarylalkyl independently; And
N is 1,2,3,4 or 5;
Or the chemical compound represented of a kind of formula XIV:
Figure A2006800498800024C1
Wherein,
X be O, S or-N (R 12)-;
R 9Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl ,-aryl-OR 14, heteroaryl, aralkyl or heteroarylalkyl;
R 10Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 13=CR 13)-aryl or-(CR 13=CR 13)-heteroaryl;
R 11Be H, alkyl, thiazolinyl, aryl or heteroaryl;
Each R 12With R 13Represent H, alkyl, aryl or aralkyl independently;
R 14Be assorted alkyl, Heterocyclylalkyl, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl; And
N is 1,2,3,4 or 5.
68. the chemical compound of the formula XIII described in the claim 67, wherein X is S and R 4It is pi-allyl.
69. the chemical compound of the formula XIII described in the claim 67, wherein X is S, R 4Be pi-allyl and R 5Be-(CR 8=C (R 8) 2).
70. the chemical compound of the formula XIV described in the claim 67, wherein X is S and R 9Be-aryl-OR 14
71. chemical compound that formula XV represents:
Figure A2006800498800024C2
Wherein,
A is cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 3=CR 3)-aryl or-(CR 3=CR 3)-heteroaryl;
R 2Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 3Represent H, alkyl independently; And
R 4Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Or the chemical compound represented of a kind of formula XVI:
Figure A2006800498800025C1
Wherein,
A is cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 5Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 7=CR 7)-aryl or-(CR 7=CR 7)-heteroaryl;
R 6It is alkyl or aryl;
Each R 7Represent H or alkyl independently; And
R 8Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Or the chemical compound represented of a kind of formula XVII:
Figure A2006800498800025C2
Wherein,
A is cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 9Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 11=CR 11)-aryl or-(CR 11=CR 11)-heteroaryl;
R 10It is alkyl or aryl;
Each R 11Represent H or alkyl independently; And
R 12Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl.
72. the chemical compound of the formula XVI described in the claim 71, wherein A is heteroaryl and R 6It is aryl.
73. the chemical compound of the formula XVI described in the claim 71, wherein A is a heteroaryl, R 6It is alkyl.
74. the chemical compound of the formula XVII described in the claim 71, wherein A is a heteroaryl, R 9Be aryl, and R 10It is alkyl.
75. the chemical compound of the formula XVII described in the claim 71, wherein A is a heteroaryl, R 9Be aryl, and R 10It is aryl.
76. chemical compound that formula XVIII represents:
Figure A2006800498800026C1
Wherein,
R 1Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl;
R 2Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl, heteroarylalkyl or alkyl;
R 3Be hydrogen, alkyl ,-CO 2R 8Or-C (O) N (R 7) (R 8);
R 4With R 5Represent H or alkyl independently; Or R 4With R 5Form a key together;
Each R 6And R 7Represent H or alkyl independently;
Each R 8Represent alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
L be a key ,-C (R 7) 2-or-(CR 7=CR 7)-; And
A 1And A 2Represent independently cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 7=CR 7)-aryl or-(CR 7=CR 7)-heteroaryl;
Or the chemical compound represented of a kind of formula XIX:
Figure A2006800498800026C2
Wherein,
R 9Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl, heteroarylalkyl or-(C (R 15) 2) n-(CR 15=C (R 15) 2);
R 10It is aryl;
R 11Be hydrogen, alkyl ,-CO 2R 16Or-C (O) N (R 15) (R 16);
R 12With R 13Represent H or alkyl independently; Or R 12With R 13Form a key together;
Each R 14And R 15Represent H or alkyl independently;
Each R 16Represent alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
L be a key ,-C (R 15) 2-or-(CR 15=CR 15)-;
A 3Represent a bivalence cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 15=CR 15)-aryl-or-(CR 15=CR 15)-heteroaryl-; And
A 4Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 15=CR 15)-aryl or-(CR 15=CR 15)-heteroaryl;
Or the chemical compound represented of a kind of formula XX:
Wherein,
R 17Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-(C (R 23) 2) n-(CR 23=C (R 23) 2);
R 18It is aryl;
R 19Be hydrogen, alkyl ,-CO 2R 24Or-C (O) N (R 23) (R 24);
R 20With R 21Represent H or alkyl independently; Or R 20With R 21Form a key together;
Each R 22And R 23Represent H or alkyl independently;
Each R 24Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
L be a key ,-C (R 23) 2-or-(CR 23=CR 23)-;
A 5Represent a bivalence cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 23=CR 23)-aryl-or-(CR 23=CR 23)-heteroaryl-; And
A 6Represent cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 23=CR 23)-aryl or-(CR 23=CR 23)-heteroaryl;
Or the chemical compound represented of a kind of formula XXI:
Figure A2006800498800027C2
Wherein,
R 25Be-(C (R 31) 2) n-(CR 31=C (R 31) 2);
R 26Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
R 27Be hydrogen, alkyl ,-CO 2R 32Or-C (O) N (R 31) (R 32);
R 28With R 29Represent H or alkyl independently; Or R 28With R 29Form a key together;
Each R 30And R 31Represent H or alkyl independently;
Each R 32Represent alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
L be a key ,-C (R 31) 2-or-(CR 31=CR 31)-; And
A 7And A 8Represent independently cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 31=CR 31)-aryl or-(CR 31=CR 31)-heteroaryl.
77. the chemical compound of the formula XVIII described in the claim 76, wherein R 1It is aryl.
78. the chemical compound of the formula XVIII described in the claim 76, wherein R 1Be aryl, and R 4And R 5Form a key together.
79. the chemical compound of the formula XVIII described in the claim 76, wherein R 1Be aryl, R 4And R 5Form a key together, L is a key, and A 1It is heteroaryl.
80. the chemical compound of the formula XVIII described in the claim 76, wherein R 1Be aryl, R 4And R 5Form a key together, L is a key, A 1Be heteroaryl, and A 2It is aryl.
81. the chemical compound of the formula XXI described in the claim 76, wherein R 25It is pi-allyl.
82. the chemical compound of the formula XXI described in the claim 76, wherein R 25Be pi-allyl, and R 27Be-CO 2R 32
83. the chemical compound of the formula XXI described in the claim 76, wherein R 25Be pi-allyl, R 27Be-CO 2R 32, and A 7It is heteroaryl.
84. the chemical compound of the formula XXI described in the claim 76, wherein R 25Be pi-allyl, R 27Be-CO 2R 32, A 7Be heteroaryl and A 8It is aryl.
85. chemical compound that formula XXII represents:
Figure A2006800498800028C1
Wherein,
X be O ,-N (R 5)-,-N (R 5) C (O)-,-C (O) N (R 5)-,-OC (O)-,-CO 2-or-N (R 5) CO 2-;
Y be O, S or-N (R 5)-;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 2Represent H or alkyl independently, or 2 R 2Formation=O together;
R 3Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
R 4Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 5Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Or the chemical compound represented of a kind of formula XXIII:
Figure A2006800498800029C1
Wherein,
X be O ,-N (R 10)-,-N (R 10) C (O)-,-C (O) N (R 10)-,-OC (O)-,-CO 2-or-N (R 10) CO 2-;
Y be O, S or-N (R 10)-;
R 6Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 7Represent H or alkyl independently, or 2 R 7Formation=O together;
R 8It is aryl;
R 9Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 10Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Or the chemical compound represented of a kind of formula XXIV:
Figure A2006800498800029C2
Wherein,
X be O ,-N (R 15)-,-N (R 15) C (O)-,-C (O) N (R 15)-,-OC (O)-,-CO 2-or-N (R 15) CO 2-;
Y be O, S or-N (R 15)-;
R 11Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 12Represent H or alkyl independently, or 2 R 12Formation=O together;
R 13Represent aryl;
R 14Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, heteroaryl, aryl, aralkyl or heteroarylalkyl;
Each R 15Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
86. the chemical compound of the formula XXII described in the claim 85, wherein R 4Be aryl, X is NH, and R 1It is aryl.
87. the chemical compound of the formula XXIII described in the claim 85, wherein R 9Be aryl, X is NH, and R 6It is aryl.
88. the chemical compound of the formula XXIV described in the claim 85, wherein R 13Be aryl, R 14Be aryl, and X is NH.
89. the chemical compound of a formula XXV representative:
Figure A2006800498800030C1
Wherein,
X is O or S;
R 1Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl, heteroarylalkyl or-C (O) R 5
R 2Be H or alkyl;
R 3Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl, heteroarylalkyl or an optional substituted dicyclo, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2
R 5Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl; Or R 5By one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; And
Each R 6Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Or the chemical compound represented of a kind of formula XXVI:
Figure A2006800498800031C1
Wherein,
X is O or S;
R 7Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-C (O) R 11
R 8Be H or alkyl;
R 9It is aryl;
R 10Be H, alkyl or-C (O) N (R 12) 2
R 11Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl; Or R 11By one or more alkyl, halogen ,-OR 12,-N (R 12) 2,-CO 2R 12, C (O) N (R 12) 2, the optional aromatic yl group that replaces of cyano group or nitro; And
Each R 12Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Or the chemical compound represented of a kind of formula XXVII:
Figure A2006800498800031C2
Wherein,
X is O or S;
R 13Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-C (O) R 17
R 14Be H or alkyl;
R 15It is aryl;
R 16Be H, alkyl ,-CO 2R 18Or-C (O) N (R 18) 2
R 17Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl; And
Each R 18Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Or the chemical compound represented of a kind of formula XXVIII:
Figure A2006800498800031C3
XXVIII
Wherein,
X is O or S;
R 19Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-C (O) R 23
R 20Be H or alkyl;
R 21Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl, heteroarylalkyl or an optional substituted dicyclo, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 22Be alkyl ,-CO 2R 18Or-C (O) N (R 18) 2
R 23Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl; Or R 23Be can by one or more alkyl, halogen ,-OR 18,-N (R 18) 2,-CO 2R 18, C (O) N (R 18) 2, the optional aromatic yl group that replaces of cyano group or nitro; And
Each R 18Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently.
90. the chemical compound of the formula XXV described in the claim 89, wherein X is S, R 1Be-C (O) R 5, R 2Be H, and R 4Be-CO 2R 6
91. the chemical compound of the formula XXVI described in the claim 89, wherein X is S, R 7Be-C (O) R 11, and R 8Be H.
92. the chemical compound of the formula XXVII described in the claim 89, wherein X is S, R 13Be-C (O) R 17, R 14Be H, and R 16Be-CO 2R 18
93. chemical compound that formula XXIX represents:
Figure A2006800498800032C1
Wherein,
X is O;
Y is-C (R 8)-;
R 1And R 2Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 2And R 3Form together by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces;
R 4Be hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
R 5Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 9=CR 9) n-aryl or-(CR 9=CR 9) n-heteroaryl;
R 6Be H or alkyl; Or R 5And R 6Form a monocycle that can be optionally substituted or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S;
Each R 8And R 9Represent H or alkyl independently; And
N is 1 or 2;
Or a kind of chemical compound of representing by formula XXX:
Figure A2006800498800033C1
Wherein,
X is-N (R 16)-;
Y is-C (R 17)-;
R 10And R 11Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 12Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 11And R 12Form together by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces;
R 13Be H, alkyl, cycloalkyl, aryl or aralkyl;
R 14Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, aralkyl, heteroarylalkyl ,-(CR 18=CR 18) n-aryl or-(CR 18=CR 18) n-heteroaryl;
R 15Be H or alkyl; Or R 14And R 15Form monocycle or the dicyclo that can be optionally substituted together, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 16Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 10And R 16Form together by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces;
Each R 17And R 18Represent H or alkyl independently; And
N is 1 or 2.
94. the chemical compound of the formula XXX described in the claim 93, wherein R 16, R 10, R 11And R 12It is alkyl.
95. the chemical compound of the formula XXX described in the claim 93, wherein R 16, R 10, R 11And R 12Be alkyl, and R 13Be H.
96. the chemical compound of the formula XXX described in the claim 93, wherein R 16, R 10, R 11And R 12Be alkyl, R 13Be H, and R 14It is aryl.
97. chemical compound that formula XXXI represents:
Figure A2006800498800034C1
Wherein,
R 1And R 3Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 2And R 4Represent hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Or R 1And R 2Form a 3-8 unit ring together; Or R 3And R 4Form a 3-8 unit ring together; And
R 5Representation ring alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Or the chemical compound represented of a kind of formula XXXII:
Figure A2006800498800034C2
Wherein,
R 6And R 8Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 7And R 9Represent hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Or R 6And R 7Form a 3-8 unit ring together; Or R 8And R 9Form a 3-8 unit ring together; And
R 10Represent H, alkyl, cycloalkyl, heteroaryl, aralkyl or heteroarylalkyl independently.
98. the chemical compound of the formula XXXI described in the claim 97, wherein R 1And R 2Form 7 yuan of rings together, and R 3And R 4Form 7 yuan of rings together.
99. the chemical compound of the formula XXXI described in the claim 97, wherein R 1And R 2Form 7 yuan of rings together, R 3And R 4Form 7 yuan of rings together, and R 5It is aryl.
100. the chemical compound of the formula XXXII described in the claim 97, wherein R 1And R 2Form 7 yuan of rings together, R 3And R 4Form 7 yuan of rings together, and R 5It is alkyl.
101. the chemical compound of the formula XXXI described in the claim 97, wherein R 1And R 3It is aryl.
102. the chemical compound of the formula XXXI described in the claim 97, wherein R 1, R 3, and R 5It is aryl.
103. chemical compound that formula XXXIII represents:
Figure A2006800498800035C1
Wherein,
X is O;
R 1, R 3Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently with A;
R 2And R 4Represent H or alkyl independently;
R 5Be an optional substituted monocycle or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S;
Or the chemical compound represented of a kind of formula XXXIV:
Wherein,
X is S;
R 6Represent cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
R 8Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently with A;
R 7And R 9Represent H or alkyl independently;
R 10Be an optional substituted monocycle or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S;
Or the chemical compound represented of a kind of formula XXXV:
Figure A2006800498800036C1
Wherein,
X is S;
R 11Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently with A;
R 13Represent cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
R 12And R 14Represent H or alkyl independently;
R 15Be an optional substituted monocycle or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S;
Or the chemical compound represented of a kind of formula XXXVI:
Figure A2006800498800036C2
Wherein,
X is S;
R 16And R 18Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
A represents cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl;
R 17And R 19Represent H or alkyl independently;
R 20Be an optional substituted monocycle or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S.
104. the chemical compound of the formula XXXIV described in the claim 103, wherein X is S; A is an aryl, R 10Be a dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S, and R 8It is aryl.
105. the chemical compound of the formula XXXV described in the claim 103, wherein X is S; A is an aryl; R 15Be a dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S, and R 11It is aryl.
106. the chemical compound of the formula XXXVI described in the claim 103, wherein X is S; R 20Be a dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S; R 18Be aryl, and R 16It is aryl.
107. chemical compound that formula XXXVII represents:
Wherein,
R 1, R 2And R 3Represent H, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; And
A is the aryl or the heteroaryl of a monocycle or dicyclo independently, and described aryl or heteroaryl are replaced by halogen, alkyl, nitro, amino, aryl, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyl or Heterocyclylalkyl.
108. chemical compound described in the claim 107, wherein R 1, R 2And R 3Be H.
109. chemical compound described in the claim 107, wherein R 1, R 2And R 3Be H, and A is by an amino monocyclic aryl that replaces.
110. chemical compound described in the claim 107, wherein R 1, R 2And R 3Be H, and A is a monocyclic aryl that is replaced by a nitro.
111. chemical compound described in the claim 107, wherein R 1, R 2And R 3Be H, and A is a monocyclic aryl that is replaced by a halogen.
112. chemical compound that formula XXXVIII represents:
Figure A2006800498800037C2
XXXVIII
Wherein,
R 1Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 2And R 3Represent hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; And
R 4Represent H, alkyl, cycloalkyl, heteroaryl, aralkyl or heteroarylalkyl independently;
Or the chemical compound represented of a kind of formula XXXIX:
Figure A2006800498800038C1
Wherein,
R 5Represent alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 6And R 7Represent hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl respectively independently; And
R 8Represent H, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently.
113. the chemical compound of the formula XXXVIII described in the claim 112, wherein R 1It is haloalkyl.
114. the chemical compound of the formula XXXVIII described in the claim 112, wherein R 1Be haloalkyl, and R 2And R 3It is aryl.
115. the chemical compound of the formula XXXVIII described in the claim 112, wherein R 1Be haloalkyl, R 2And R 3Be aryl, and at least one R 4Be hydrogen.
116. the chemical compound of the formula XXXIX described in the claim 112, wherein R 6And R 7It is aryl.
117. the chemical compound of the formula XXXIX described in the claim 112, wherein R 6And R 7It is aryl; And at least one R 8It is aryl.
118. the chemical compound of the formula XXXIX described in the claim 112, wherein R 6And R 7Be aryl, a R 8Be aryl, a R 8Be hydrogen.
119. a Pharmaceutical composition contains any one the chemical compound in a kind of pharmaceutically acceptable excipient and the claim 60 to 118.
120. the treatment or the method for the inductive phospholipidosis of prophylactic agent may further comprise the steps:
To one have the patient who needs give with a treatment effective dose, formula I one of any chemical compound in the IX, its Chinese style I is expressed as:
Figure A2006800498800039C1
Wherein,
X be O or-N (R 7)-;
Y be N or-C (R 8)-;
R 1And R 2Represent alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 2And R 3Form together by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces;
R 4Be hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
R 5Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 9=CR 9) n-aryl or-(CR 9=CR 9) n-heteroaryl;
R 6Be H or alkyl; Or R 5And R 6Form a monocycle that is optionally substituted or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 7Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 1And R 7Form together by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces;
Each R 8And R 9Represent H or alkyl independently; And
N is 1 or 2;
Formula II is expressed as:
Figure A2006800498800040C1
Wherein,
X be O or-N (R 6)-;
R 1And R 2Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 2And R 3Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces;
R 4Be hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
R 5Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 6Be hydrogen, alkyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl; Or R 1And R 6Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces;
Formula III is expressed as:
Figure A2006800498800040C2
Wherein,
R 1Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-(C (R 7) 2) n-(CR 7=C (R 7) 2);
R 2Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or alkyl;
R 3Be hydrogen, alkyl ,-CO 2R 8Or-C (O) N (R 7) (R 8); And
R 4With R 5Represent H or alkyl independently; Or R 4With R 5Form a key together;
Each R 6And R 7Represent H or alkyl independently;
Each R 8Represent alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
L be a key ,-C (R 7) 2-or-(CR 7=CR 7)-; And
A 1And A 2Represent independently cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 7=CR 7)-aryl or-(CR 7=CR 7)-heteroaryl;
Formula IV is expressed as:
Figure A2006800498800041C1
Wherein,
A is cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 3=CR 3)-aryl or-(CR 3=CR 3)-heteroaryl;
R 2Be alkyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 3Represent H or alkyl independently; And
R 4Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Formula V is expressed as:
Figure A2006800498800041C2
Wherein,
X be O ,-N (R 5)-,-N (R 5) C (O)-,-C (O) N (R 5)-,-OC (O)-,-CO 2-or-N (R 5) CO 2-
Y be O, S or-N (R 5)-;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl;
Each R 2Represent H or alkyl independently, or 2 R 2Formation=O together;
R 3And R 4Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Each R 5Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Formula VI is expressed as:
Figure A2006800498800041C3
VI
Wherein,
X be O, S or-N (R 4)-;
R 1Be cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-(C (R 5) 2) n-(CR 5=C (R 5) 2);
R 2Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl;
R 3Be H, alkyl, thiazolinyl, aryl or heteroaryl; Or R 2And R 3Form an optional substituted monocycle or dicyclo together, described ring has 0,1 or 2 hetero atom that is selected from O, N and S;
Each R 4With R 5Represent H, alkyl, aryl or aralkyl independently; And
N is 1,2,3,4 or 5;
Formula VII is expressed as:
Figure A2006800498800042C1
Wherein,
X is O or S;
R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or-C (O) R 5
R 2Be H or alkyl;
R 3Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or an optional substituted dicyclo, described ring has 1 or 2 hetero atom that is selected from O, N and S;
R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2
R 5Be cycloalkenyl group, heterocycloalkenyl, heteroaryl, aralkyl or heteroarylalkyl; Or R 5By one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; And
Each R 6Represent H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Formula VIII is expressed as:
Figure A2006800498800042C2
Wherein,
X is O or S;
R 1, R 3Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently with A;
R 2And R 4Represent H or alkyl independently;
R 5Be a monocycle that can be optionally substituted or dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S; And
Formula IX is expressed as:
Figure A2006800498800043C1
Wherein,
X 1Be-OR 5,-SR 5Or-N (R 5) 2
Each X 2Represent independently O, S or-N (R 5)-;
Each R 1Represent independently alkyl, halogen, nitro, cyano group, alkoxyl, thiazolinyl, alkynyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl ,-N (R 5) 2,-OH ,-C (O) R 6,-CO 2R 5Or C (O) N (R 5) 2
R 2And R 4Represent cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
R 3Be H, alkyl or halogen;
Each R 5Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently;
Each R 6Represent alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; And
N is 0,1,2,3 or 4.
121. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula I.
122. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula I, X be O or-N (R 7)-; Y is N; R 1And R 2Represent alkyl, haloalkyl or aryl independently; R 3It is aryl; Or R 2And R 3Form together by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces; R 4Be hydrogen; R 5Be Heterocyclylalkyl or aryl; R 6Be H or alkyl; Or R 5And R 6Form an optional substituted monocycle or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S; And R 7Be hydrogen; Or R 1And R 7Form together by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces.
123. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula I, X is-N (R 7)-; Y is N; R 1And R 2It is aryl; R 3It is aryl; Or R 2And R 3Form together by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces; R 4Be hydrogen; R 5Be Heterocyclylalkyl or aryl; R 6Be H or alkyl; Or R 5And R 6Form an optional substituted monocycle or dicyclo together, described ring has 1 or 2 hetero atom that is selected from O, N and S; And R 7Be hydrogen; Or R 1And R 7Forming together can be by one or more alkyl, halogen, hydroxyl, alkoxyl or an amino optional 3-8 unit ring that replaces.
124. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula I, X be O or-N (R 7)-; Y is-C (R 8)-; R 1And R 2Represent alkyl, assorted alkyl or haloalkyl independently; R 3Be hydrogen, alkyl, assorted alkyl or haloalkyl; R 4Be hydrogen; R 5It is heteroaryl; R 6Be H or alkyl; R 7Be hydrogen, alkyl, assorted alkyl or haloalkyl; And R 8Be H or alkyl.
125. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula II.
126. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula II, X is-N (R 6)-; R 1, R 2And R 5Represent aryl or heteroaryl independently; And R 3, R 4And R 6Represent hydrogen or alkyl independently.
127. the method described in the claim 120, wherein said chemical compound are a kind of chemical compounds of formula III.
128. the method described in the claim 120, wherein said chemical compound are a kind of chemical compounds of formula III; R 1, R 2, A 1And A 2Represent aryl or heteroaryl independently; R 3It is hydrogen or alkyl; R 6Be H or alkyl; And L is a key.
129. the method described in the claim 120, wherein said chemical compound are a kind of chemical compounds of formula III; R 1Be-(C (R 7) 2) n-(CR 7=C (R 7) 2); R 2It is alkyl; R 3Be alkyl ,-CO 2R 8Or-C (O) N (R 7) (R 8); R 4With R 5Represent H or alkyl independently; Or R 4With R 5Form a key together; Each R 6And R 7Represent H or alkyl independently; Each R 8Represent alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; L be a key ,-C (R 7) 2-or-(CR 7=CR 7)-; And A 1And A 2Represent alkyl or assorted alkyl independently.
130. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula IV.
131. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula IV; A, R 1And R 4Represent aryl or heteroaryl independently; R 1Be cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl ,-(CR 3=CR 3)-aryl or-(CR 3=CR 3)-heteroaryl; R 2It is alkyl or aryl; And each R 3Represent H or alkyl independently.
132. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula V.
133. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula V; X is-C (O) N (R 5)-or-CO 2-; Y is O or S; R 1, R 3And R 4Represent aryl or heteroaryl independently; Each R 2Represent H or alkyl independently, or 2 R 2Formation=O together; R 3And R 4Representation ring alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Each R 5Represent H, alkyl, aryl or aralkyl independently; And n is 1 or 2.
134. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula VI.
135. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula VI; X is S; R 1Be aryl, heteroaryl or-(C (R 5) 2) n-(CR 5=C (R 5) 2); R 2Be aryl, heteroaryl ,-(CR 5=CR 5)-aryl or-(CR 5=CR 5)-heteroaryl; Each R 5Represent H, alkyl, aryl or aralkyl independently; And n is 1 or 2.
136. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula VII.
137. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula VII; X is O or S; R 1Be aryl, heteroaryl or-C (O) R 5R 2Be H or alkyl; R 3Be aryl, heteroaryl or an optional substituted dicyclo, described ring has 1 or 2 hetero atom that is selected from O, N and S; R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2R 5By one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; And each R 6Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently.
138. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula VII; X is O or S; R 1Be aryl, heteroaryl or-C (O) R 5R 2Be H or alkyl; R 3Representative
Figure A2006800498800046C1
R 4Be H, alkyl ,-CO 2R 6Or-C (O) N (R 6) 2R 5By one or more alkyl, halogen ,-OR 6,-N (R 6) 2,-CO 2R 6, C (O) N (R 6) 2, the optional aromatic yl group that replaces of cyano group or nitro; Each R 6Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; M is 0,1,2,3 or 4; And each R 7Represent halogen, hydroxyl, amino, carboxyl, nitro, cyano group, alkyl or alkoxyl independently.
139. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula VIII.
140. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula VIII; X is O or S; R 1, R 3Represent aryl or heteroaryl independently with A; R 2And R 4Represent H or alkyl independently; And R 5Be an optional substituted dicyclo, described ring has 1,2 or 3 hetero atom that is selected from O, N and S.
141. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula VIII; X is O or S; R 1, R 3Represent aryl or heteroaryl independently with A; R 2And R 4Represent H or alkyl independently; R 5Representative
Figure A2006800498800046C2
Wherein n is 0,1,2,3 or 4; Each R 7Represent halogen, hydroxyl, amino, carboxyl, nitro, cyano group, alkyl or alkoxyl independently.
142. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula IX.
143. the method described in the claim 120, wherein said chemical compound are the chemical compounds of a kind of formula IX; X 1Be-N (R 5) 2Each X 2Represent O or S independently; Each R 1Represent independently alkyl, halogen, nitro, cyano group, alkoxyl ,-N (R 5) 2,-OH ,-C (O) R 6,-CO 2R 5Or C (O) N (R 5) 2R 2And R 4Represent aryl, heteroaryl, aralkyl or heteroarylalkyl independently; R 3Be H, alkyl or halogen; Each R 5Represent H, alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; Each R 6Represent alkyl, cycloalkyl, heterocycle alkane, aryl, heteroaryl, aralkyl or heteroarylalkyl independently; And n is 0,1,2,3 or 4.
144. the method described in the claim 1, wherein said chemical compound is:
Figure A2006800498800047C1
Figure A2006800498800048C1
145. the method described in the claim 120, wherein said patient is a mammal.
146. the method described in the claim 120, wherein said patient is human.
147. the method described in the claim 1,29 or 120, wherein said chemical compound are a kind of chemical compounds of formula III, R 1Comprise a hydroxy-acid group; R 1It is the aryl of a carboxylic acid-substituted; R 1It is the phenyl of a carboxylic acid-substituted; And/or R 1Be the phenyl of a carboxylic acid para-orientation.
148. the chemical compound described in the claim 76, wherein R with formula XVIII 1Comprise a hydroxy-acid group; R 1It is the aryl of a carboxylic acid-substituted; R 1It is the phenyl of a carboxylic acid-substituted; And/or R 1Be the phenyl of a carboxylic acid para-orientation.
149. the chemical compound described in the claim 76, wherein R with formula XX 17Comprise a hydroxy-acid group; R 17It is the aryl of a carboxylic acid-substituted; R 17It is the phenyl of a carboxylic acid-substituted; And/or R 17Be the phenyl of a carboxylic acid para-orientation.
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Cited By (2)

* Cited by examiner, † Cited by third party
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CN105121437A (en) * 2013-03-15 2015-12-02 发现生物医药公司 Coumarin derivatives and methods of use in treating cystic fibrosis, chronic obstructive pulmonary disease, and misfolded protein disorders
CN105246887A (en) * 2013-03-15 2016-01-13 发现生物医药公司 Coumarin derivatives and methods of use in treating hyperproliferative diseases

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105121437A (en) * 2013-03-15 2015-12-02 发现生物医药公司 Coumarin derivatives and methods of use in treating cystic fibrosis, chronic obstructive pulmonary disease, and misfolded protein disorders
CN105246887A (en) * 2013-03-15 2016-01-13 发现生物医药公司 Coumarin derivatives and methods of use in treating hyperproliferative diseases
US9815825B2 (en) 2013-03-15 2017-11-14 Discoverybiomed, Inc. Coumarin derivatives and methods of use in treating cystic fibrosis, chronic obstructive pulmonary disease, and misfolded protein disorders
CN105246887B (en) * 2013-03-15 2018-05-11 发现生物医药公司 Coumarin derivative and the method for treating hyperproliferative disease
CN105121437B (en) * 2013-03-15 2018-12-04 发现生物医药公司 Coumarin derivative and method for treating cystic fibrosis, chronic obstructive pulmonary disease and misfolded protein matter illness
US10369145B2 (en) 2013-03-15 2019-08-06 Discoverybiomed, Inc. Coumarin derivatives and methods of use in treating hyperproliferative diseases

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