CN100356922C - Cystic fibrosis transmembrane conductance regulator protein inhibitors and uses thereof - Google Patents
Cystic fibrosis transmembrane conductance regulator protein inhibitors and uses thereof Download PDFInfo
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- CN100356922C CN100356922C CNB038233665A CN03823366A CN100356922C CN 100356922 C CN100356922 C CN 100356922C CN B038233665 A CNB038233665 A CN B038233665A CN 03823366 A CN03823366 A CN 03823366A CN 100356922 C CN100356922 C CN 100356922C
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Abstract
The invention provides compositions, pharmaceutical preparations and methods for inhibition of cystic fibrosis transmembrane conductance regulator protein (CFTR) that are useful for the study and treatment of CFTR-mediated diseases and conditions. The compositions and pharmaceutical preparations of the invention may comprise one or more thiazolidinone compounds, and may additionally comprise one or more pharmaceutically acceptable carriers, excipients and/or adjuvants. The methods of the invention comprise, in certain embodiments, administering to a patient suffering from a CFTR-mediated disease or condition, an efficacious amount of a thiazolidinone compound. In other embodiments the invention provides methods of inhibiting CFTR that comprise contacting cells in a subject with an effective amount of a thiazolidinone compound. In addition, the invention features a non-human animal model of CFTR-mediated disease which model is produced by administration of a thiazolidinone compound to a non-human animal in an amount sufficient to inhibit CFTR.
Description
Background of invention
Cystic fibrosis transmembrane conductance regulator protein (CFTR) is for being expressed in the epithelial cAMP activation of mammal air flue, intestinal, pancreas and testis chloride channel.CFTR is the Cl that is responsible for the cAMP mediation
-Excretory chloride channel.Can cause the increase of cAMP, the activation and the described CFTR Cl of cAMP dependent kinases such as the hormone of β-adrenal gland's agonist or such as the toxin of cholera toxin
-The phosphorylation of passage, it can cause the opening of this passage.Ca in the cell
2+Increase also can activate different top (apical) membrane channels.The phosphorylation that is caused by Protein kinase C can cause the Cl in the film of top
-Channel opener or close.CFTR mainly is arranged in epithelium, and this is Cl
-Ion is striden the motion of top film and approach and critical sites (key point) is provided and has regulated the transhipment ratio of the salt and the water of transepithelial with this.CFTR chloride channel function comprises some types of cystic fibrosis (CF) and male infertility, multiple cystic kidney disease and secretory diarrhea with disease is relevant more widely.
This heritability fatal disease cystic fibrosis (CF) is caused by the sudden change of CFTR.Observation in human cystic fibrosisization (CF) patient and the CF mouse model shows that CFTR is in intestinal and pancreas fluid transport and have critical function (Grubb et al., 1999, Physiol.Rev.79:S193-S214 in the male genetic; Wong, P.Y., 1997, Mol.Hum.Reprod.4:107-110).It is the morbidity and the cause of death main among the CF that yet the CFTR disappearance can produce airway disorders, its mechanism still unclear (Pilewski et al., 1999, Physiol.Rev.79:S2 1 5-S255).The main difficulty of understanding air flue disease among the CF comprises inappropriate (it manifests few and does not have airway disorders) of CF mouse model, the shortage of CF large animal model and the availability limitations (it does not also damage by chronic infection with by inflammation) of people CF air flue.Do not use high-affinity, CFTR selective depressant to study the pathogenesis of the air flue disease among the CF or generation CF phenotype in the large animal model as yet.
High-affinity CFTR inhibitor is in the treatment of secretory diarrhea and cystic kidney disease and also have clinical effect in the inhibition male genetic.Chemical compound diphenylamines-2-carboxylate (DPC) and 5-nitro-2-(3-phenylpropyl amino) benzoate (NPPB) can suppress CFTR under high concentration, but suppressing activity, it does not have specificity (Cabantchik et al., 1992, Am.J.Physiol.262:C803-C827; McDonough et al., 1994, Neurone 13:623-634; Schultz et al., 1999, Physiol.Rev.79:S109-S144).Best CFTR inhibitor glyburide (glibenclamide) working concentration that is used for electric physiology and the research of other cellular level is>100 μ M (Sheppard et al., 1992, J.Gen.Physiol.100:573-591; Hongre et al, 1994, Pflugers Arch.426:284-287).Yet also suppress other Cl in this concentration glyburide
-Transport agents (transporter) and k
+Passage (Edwards et al., 1993, Br.J.Pharmacol.110:1280-1281; Rabe et al., 1995, Pflugers Arch.429:659-662; Yamazaki et al., 1997, Circ.Res.81:101-109).Effective micromolecular inhibitor of other ion transporter is known, but the micromolecule that specific C FTR suppresses ability that has of secreted disease treatment also do not occur being fit to.
Therefore, animal model and secreted treatment of conditions and the control that needs the CTFR inhibitor compound and use this chemical compound exploitation to be used for CF research and to treat.The present invention has satisfied the requirement of these demands and others and has overcome the defective that exists in the background technology.
Summary of the invention
The invention provides the compositions, pharmaceutical preparation and the method that suppress cystic fibrosis transmembrane conductance regulator protein (CFTR), it can be used for the research and the treatment of the disease mediated and disease of CFRT.Composition medicine preparation of the present invention can comprise one or more thiazolidinone compounds or derivant and can contain one or more drug acceptable carriers, excipient and/or adjuvant in addition.Method of the present invention comprises, in certain embodiments, suffers from the thiazolidinone compound or the derivant of patient's effective dose of the disease mediated or disease of CFTR.In other embodiment, the invention provides the method that suppresses CFTR, it comprises thiazolidinone compound or the derivant contact individual cells of utilizing effective dose.Characteristics of the present invention also are the non-human animal model that CFTR is disease mediated, and this model produces by thiazolidinone compound or the derivant that gives the non-human animal and be enough to suppress CFTR.
From the following detailed description, may be obvious that these and other purpose and advantage of the present invention.
Brief description of drawings
Can more comprehensively understand the present invention with reference to the following drawings, this accompanying drawing only is for illustrative purposes.
Figure 1A is depicted as the triage techniques flow chart that is used to identify the CFTR inhibitor.Can stimulate CFTR by the pluripotency agonist in the epithelial cell of stable transfection, this epithelial cell coexpression human CFTR and have a Cl the biglyyest
-/ I
-The yellow fluorescence protein of sensitive fluorescence (YFP).After adding test compound, contain I by adding
-Solution can be induced I
-Flow into.
Figure 1B is depicted as the triage techniques that utilizes Figure 1A, from the diagram of the fluorescence data of single aperture, has wherein shown contrast (no activator, no test compound), non-active compound respectively, and active CFTR inhibitor compound.
Fig. 1 C is depicted as the CFTR inhibitor chemical constitution of identifying by Figure 1A triage techniques.
Fig. 1 D is depicted as has the chemical constitution that maximum CFTR suppresses active thiazolidinone derivatives ring 2.Complete thiazolidinone derivatives structure is shown in Fig. 1 C.Relative potential energy is: 0.2 (CFTR
Inh-020), 0.3 (CFTR
Inh-029), 1.0 (CFTR
Inh-172), 0.2 (CFTR
Inh-185), 0.1 (CFTR
Inh-214) and 0.1 (CFTR
Inh-236).
Fig. 2 A is depicted as the CFTR inhibitor 3-[(3-trifluoromethyl that utilizes Figure 1A triage techniques) phenyl]-the 5-[(4-carboxy phenyl) methylene]-(this paper refers to CFTR to 2-thioxo-4-thiazolidinone
Inh-172) to the relative fluorescence diagram of a plurality of concentration of time mapping.
Fig. 2 B is depicted as the time course curve of inhibition, shows to add 2 μ M CFTR
Inh-172 backs are at the I of different time CFTR mediation
-The transhipment rate.The figure that inserts is that the time course curve that suppresses to reverse illustrates, and shows 1 μ M CFTR
InhThe I of-172 flushing back different times
-The transhipment rate.Three groups of experimental results are represented with meansigma methods ± standard error.
Fig. 2 C is depicted as the diagram of utilizing different agonist to stimulate back CFTR to suppress, and described agonist comprises benzoflavone and benzimidazolone UC
CFChemical compound (UC
CF-029 (2-(4-pyridine) benzo [h]-4H-.alpha.-5:6-benzopyran (chromen)-4-ketone disulfate) and UC
CF-853 (Galietta et al.2001J.Biol.Chem.276:19723-19728)), genistein (genistein), CPT-cAMP, 8-methoxypsoralen (8-methoxypsoralen) are (8-MPO), 8-Pentamethylene .-1,3-dipropyl xanthine (dipropyxanthine) (CPX) (are 50 μ M) (three groups of experimental results with ± standard error represent).Solid bars shows agonist, and hollow strips shows with 5 μ M CFTR
Inh-172 agonist.
Fig. 3 A is depicted as CFTR
InhThe inhibitory action of short circuit current (short-circuit current) in the permeability FRT cell of-172 couples of expressing human CFTR stimulates CFTR by 100 μ M CPT-cAMP.
Fig. 3 B is depicted as CFTR
Inh-172 (circles) are summed up figure (three groups of experimental results are represented with standard error) with the dosage-inhibitory action data of glyburide (square).
Fig. 3 C is depicted as the CFTR of short circuit current in former (non-permeability) human bronchial epithelial cell of being commissioned to train foster
Inh-172 inhibitory action.In the irrigation solution of top, add inhibitor (left hand view) or in base side and top solution subsequently, add inhibitor (right part of flg).
Fig. 3 D is depicted as the diagram that CFTR expresses the full cell patch pincers of FRT cell, be presented at+80mV (open circles) and-membrane current that 100mV (filled circles) locates to draw.Stimulate CFTR by 5 μ M forskolins (forskolin), add 2 μ M CFT subsequently
Inh-172.
Fig. 3 E is depicted as to be interrupted alternately stimulates (a-c) (alternate stimulation) to produce the diagram of fractionated membrane potential.
Fig. 3 F is depicted as (contrast, open circles) under the base state, forskolin stimulation back (filled circles), reaches adding 0.2 μ M CFTR
InhThe current-voltage relation diagram of~50% inhibitory action (hollow triangle) appears in-172 backs.
Fig. 4 A is depicted as and is being with or without 5 μ M CFTR
InhUTP-(100 μ M) stimulates Ca in-172 airway epithelia cells that detect with the short circuit current analysis when existing
2+Rely on Cl
-The secretion diagram.
Fig. 4 B is depicted as volume-activation Cl that the experiment of full cell patch pincers detects in the FRT cell
-Electric current (hypotonic 250mosM/kg H
2O) diagram.There are being and do not having 5 μ M CFTR
Inh-172 record currents when existing.
Fig. 4 C is depicted as in the 9HTEo-/Dx cell of MDR-1 up-regulated
3H-vincristine (vincristine) accumulation diagram.There are being and do not having verapamil (verapamil) (100 μ M) or CFTR
InhThe interior vincristine of detection cell during-172 (5 μ M) (standard error, n=3).
Fig. 4 D is depicted as and adopts CFTR
Inh-172, diazoxide (diazoxide) (100 μ M) and glyburide (10 μ M) are carried out pancreatic beta cell (INS-1) the membrane potential diagram of extracellular perfusion record.
Fig. 4 E be depicted as the membrane potential that causes by operation shown in Fig. 4 D on average change (Δ mV) diagram (standard error, n=4).
Fig. 5 A is depicted as not to be had (top) and (centre) intraperitoneal injection CFTR is being arranged
InhIsolating mice ileum ring (loop) photo 6 hours time during-172 (150 μ g/kg), behind the 1 μ g cholera toxin intracavitary administration.Saline control (not having cholera toxin, the bottom) shows as a comparison.
Ileum ring weight when Fig. 5 B studies 6 hours that obtain from the 14-16 ring, data are represented (n=6-8 mice) with meansigma methods ± standard error.For non-activity analog, CFTR
Inh4-carboxyl phenyl group in-172 replaced by 3-methoxyl group-4-methoxy-ethylene base phenyl (standard error, every group of 6-8 mice,
*P<0.001, variance analysis).
Fig. 5 C remove when being depicted as after the oral gavage administration 6 hours before the liquid of chamber with remove afterwards between the weight ratio (standard error, every group of 4 mices, p<0.001) of whole small intestinal.
Fig. 5 D is depicted as in isolating rat colon mucosa and adds amiloride and with CFTR after the stimulation of forskolin (20 μ M)
Inh-172 inhibiting short circuit currents.As shown with CFTR
Inh-172 join serous coat, follow by mucomembranous surface (n=4).
Figure 6 shows that
14C-labelling CFTR
Inh-172 synthetic sketch maps.Utilize labelling
14The C bromoacetic acid will as parent material
14C is attached in the thiazolidone nuclear.
Figure 7 shows that rat is through single dose intravenous bullet (bolus) infusion 50 μ Ci
14C labelling CFTR
InhAfter-172, one group of CFTR
Inh-172 pharmacokinetic analysis are figure as a result.Serum radioactivity data are represented (n=3-6 rat) with meansigma methods ± standard error.The corresponding 2 Room models of matched curve (Fitted curve), wherein distribution half-life is 0.14hr again, removes half-life 10.3hr, and maximum serum-concentration is 3.2 μ g/mL, and area under curve is 3.8 μ g.hr/mL, and distribution volume is 1.2L, clearance rate is 99mL/hr.
Figure 8 shows that behind the bullet infusion
14C labelling CFTR
Inh-172 organ scattergram.Result among the figure A is from single dose intravenous bullet infusion 2 μ Ci
14C labelling CFTR
Inh-172 mice is put to death animal in the indicated time, collects organ and carries out
14The analysis of C radioactivity, data with infusion after the fixed time whole organ (except that skeletal muscle with the every gram tissue report)
14The C radioactivity is represented (meansigma methods ± standard error, 4 mices of each time point).Result among the figure B is from giving the bullet infusion 50 μ Ci
14C labelling CFTR
Inh-172 rat, and behind infusion, detected the CFTR of whole organ in 60 minutes
Inh-172 (3 rats).
Figure 9 shows that the mice body fluid and the liver CFTR that detect by thin layer chromatography
InhOne group of photo of-172 metabolic analysis results, this mice is as figure A among Fig. 8
14C labelling CFTR
Inh-172 perfusions.
14C labelling CFTR
Inh-172 standards are 1,3 and 6nCi (left hand view), and 10,30 and 60nCi (right part of flg).Egative film is carried out the radioactive automatic developing of 48 hours (left hand view) and 12 hours (right part of flg).
A picture group that Figure 10 shows that the closed intestinal ring model of mice feature result is shown.Figure A: utilize 200 μ L buffer to carry out the injection of intestinal ring, encircle the detection (meansigma methods ± standard error, 4 mices of each time point) of weight in the indicated time.Insert figure (bottom) for there being and not having CFTR
Inh-172 (20 μ gi.p. (lumbar injection), in the time of n=4) at 30 minutes absorbance %.Inserting figure (top) is CFTR
Inh-172 chemical structural drawing.Figure B: be the inductive humoral selection time graph of cholera toxin in mice closed hoop model.Dotted line shows contrast (saline injection) ring.The data of injection ring (1 μ g cholera toxin/ring) are represented with meansigma methods ± standard error (4-6 mice).
Figure 11 shows that and give CFTR behind the mice cholera toxin
Inh-172 pairs of excretory inhibitory action one picture groups of intestinal juice are shown.Figure A: the amount of body fluid cumulative inhibition in the mice ring model-effect figure.Give the CFTR of mice single dose by intraperitoneal injection
Inh-172, in the weight (meansigma methods ± standard error, each dosage 4-6 mice) of 6 hours detection rings.Dotted line is represented the average weight of the saline injection contrast ring of same mouse.Figure B:CFTR
Inh-172 inhibiting persistence.Give injected in mice 20 μ g CFTR in the specified time that gives the cholera toxin front and back
Inh-172 (i.p.) (each time point 4-6 mice).Figure C: intravenous injection (i.v.) (tail vein, left vertical coordinate) and the oral administration (CFTR among the TPGS
Inh-172, right vertical coordinate) back blood plasma
14C-CFTR
InhThe time graph of-172 radioactivities.Data are represented (4 mices) with the counting of the every μ Ci injection of per minute.Figure D:
14C-CFTR
InhBehind-172 intravenous injections and the oral administration 6 hours,
14C-CFTR
Inh-172 accumulations (4 mices) at the gastro-intestinal digestion organ.Figure E: orally give CFTR
Inh-172 (200 μ g among the TPGS) are to the inhibitory action of the inductive humoral selection of cholera toxin in the mice open loop model.Data with oral raise by force back 6 hours chamber liquid full small intestinal weight ratio before and after removing represent (meansigma methods ± standard error, every group of 4 mices,
*P<0.01).Figure F:CFTR
Inh-172 stride the permeability (meansigma methods ± standard error, 18 inserted sheets (insert)) of Caco-2 cell monolayer, wherein Papp=16 * 10
-6Cm/s.
Figure 12 shows that CFTR in the rat closed hoop model
InhAn inhibiting picture group of-172 pairs of cholera toxins (figure A) and the inductive humoral selection of STa toxin (figure B) is shown.Data are represented (every group of 4 rats) with meansigma methods ± standard error,
*P<0.01.
Figure 13 shows that CFTR in mice ileum (figure A) and the people's colon (figure B)
InhAn inhibiting picture group of the short circuit current that-172 pairs of forskolins and STa toxin stimulate is shown.The STa toxin is as inserting shown in the figure.The result of study of 5 mices of data representation and two cover people tissues.Both sides at tissue add CFTR simultaneously
Inh-172.Amiloride (10 μ M) is present in the solution of top.
Figure 14 shows that CFTR
Inh-172 couples of T84 colon epithelial cell Cl
-One picture group of excretory inhibiting short circuit current analysis is shown.Figure A: data are with the expression of tracing of experiment (every kind condition under 5-12 inserted sheet).Both sides at cellular layer add CFTR simultaneously
Inh-172.The CFTR agonist comprises forskolin (left side), 8-Br-cGMP (centre) and CFTR
ACT-16 (right sides).Figure B:(left side) utilize amphotericin B (250 μ g/mL) to carry out the base side permeation after, the inhibitory action of the short circuit current that CFTRinh-172 stimulates forskolin.Be depicted as the experiment of 6 inserted sheets.(central authorities) are CFTR in permeability and (vs.) non-permeability T84 cell
Inh-172 pairs of forskolins stimulate (circle) and 8-Br-cGMP to stimulate the inhibitory action average magnitude-effect figure (meansigma methods ± standard error, 6-12 inserted sheet) of (triangle) short circuit current.There is high K in (right side)
+Base side solution (68mM) and low Cl
-CFTR in the solution of top
Inh-172 pairs of forskolins stimulate the inhibitory action of short circuit current.Be depicted as 4 experiments.
Before describing the present invention, should understand the present invention and be not limited to described particular, It should change. Should be understood that also term used herein is only for describing the order of particular , be not the purpose in order to limit, because scope of the present invention can only be by appended claim Limit.
Unless other definition is arranged, technology used herein and scientific terminology have the affiliated skill of the present invention The identical meanings that art personnel understand usually. Although with method as herein described and material phase Sihe equivalence Method and material can be used in practice of the present invention and test, but this paper will to preferred method and Material is described. All mentioned publications of this paper are incorporated herein by reference open and retouch State method and/or the material relevant with quoting publication.
Should point out that the singulative in this paper and the claims " a " " an " reaches " the " bag Draw together the described things of plural number, unless there is other clearly to set forth in the literary composition. Therefore, for example " an suppresses Agent " expression comprise the plural number of this inhibitor, and " the cell " comprises technology under this area The expression of the known a kind of and various kinds of cell of personnel and its equivalent, etc.
The publication that the present invention discussed only provides disclosing before the application's submission date, and is incorporated herein by the reference of this paper.Any reference of this paper can not be thought owing to negating that the present invention is early than these publications in invention early.In addition, the date issued that is provided also may be different with the date issued of reality, and this needs respectively to its confirmation.
The definition that this paper adopted is for illustrate former thereby provides, and can not think restriction.Technology used herein and scientific terminology should have with the present invention under the identical meanings of technical staff's common sense.
The detailed description of invention
Basis of the present invention is the discovery of thiazolidinone compound and derivant, and it is the CFTR inhibitor of high-affinity.Below the structure of chemical compound of the present invention and derivant will be described in further detail, and pharmaceutical preparation and using method.
Definition
" cystic fibrosis transmembrane conductance regulator protein disease states mediated or symptom " or " CFTR disease states mediated or symptom " by the activity of cystic fibrosis transmembrane conductance regulator protein (CFTR) (for example refers to, the activity of CFTR in ion transport) any state, disease or the disease that causes, perhaps this state, disease or disease symptoms.Can treat this state, disease, disease or its symptom by the activity that suppresses CFTR, for example, CFTR ion transport inhibitory action.Found that the CFTR activity comprises, for example to the intestinal secretion of various agonist (comprising cholera toxin) reactions (referring to for example, Snyder et al.1982 Bull.World Health Organ.60:605-613; Chao et al.1994 EMBO J.13:1065-1072; Kimberg et al.1971 J.Clin.Invest.50:1218-1230).
For reducing the chemical compound of the ion transport efficient that is caused by CFTR, particularly the chloride ion that is caused by CFTR is transported " CFTR inhibitor " used herein.Preferably, CFTR inhibitor of the present invention is a specific C FTR inhibitor, promptly suppress CFTR active and to the activity of other ion transport agent not significant or opposite effect, for example other chlorine transport agents, potassium transport agents or the like.Preferably, described CFTR inhibitor is a high-affinity CFTR inhibitor, for example, the affinity of CFTR is at least an about micromole, usually about one to five micromole.
Disease in the individuality is contained in " treatment (Treating) " used herein or " treatment (treatment) ", morbid state, the treatment of disease or symptom, wherein said disease, morbid state, disease or symptom are mediated by the CFTR activity, and comprise: (1) prevents described disease, morbid state, or disease, promptly cause the clinical symptoms of disease described in the individuality not made progress, it can expose or tend to suffer from described disease, state, or disease, but also do not experience or show its symptom, (2) suppress disease, state, or disease, promptly stagnate or reduce described disease, morbid state or disease, or the development of its clinical symptoms, or (3) alleviate described disease, morbid state, or disease, promptly cause described disease, morbid state, or disease, or the recovery of its clinical symptoms.
" treatment useful effect dosage " or " effective dose " refer to the dosage of The compounds of this invention, it is with The compounds of this invention during to the mammal of this chemical compound of needs or other individual administrations, to disease, morbid state, disease or symptom, be enough to produce effectively therapeutical effect as defined above by the active mediation of described CFTR.The amount of The compounds of this invention that constitutes " treatment effective dose " is different according to age of described chemical compound, described disease and the order of severity and individuality to be treated, body weight or the like, but those skilled in the art can conventionally determine according to the knowledge of its grasp and according to the disclosure.
Described term " individuality " and " patient " are a member or a plurality of member of any mammal and nonmammalian kind, and it may need pharmaceutical methods of the present invention, compositions and treatment.Individual thus and patient includes but not limited to primates (comprising the people), Canidae, cat family, ungulate (for example, horse, cattle, pig (for example pig (pig)), birds and other individuality.Special concern has the people and the non-human animal (for example domestic animal and performing animal) of commercial value.
" mammal " refers to a member and a plurality of member of any mammal kind, and comprise as example, Canidae; Cat family; Horse; Cattle; Sheep; Rodent or the like and primates, particularly people.Non-human animal model is mammal particularly, and for example primates, murine, Lagomorpha etc. can be used in the experimentation.
Term described herein " unit dosage form " refers to the dispersive single dose unit that is suitable for the humans and animals individuality of physics, composition in the per unit contains the The compounds of this invention of scheduled volume, it calculates according to the dosage that is enough to produce required effect, and contains medicine acceptable diluent, carrier or excipient simultaneously.The description that the unit dosage form that the present invention is new is described according to used specific compound and the pre-effect that produces and in the host pharmacokinetics of every kind of chemical compound determine.
Described term " physiological status " comprises with living deposits the state of cell coupling, for example with the main water environment state of the temperature of the cell coupling of depositing of living, pH, salinity or the like.
" pharmaceutically-acceptable excipients " refers to be used for the excipient of pharmaceutical compositions, it typically is safe, nontoxic, abiotic and is not other unnecessary material, and comprise for animals acceptance and the human pharmaceutically-acceptable excipients.Used " medicine can be accepted excipient " of description of the present invention and claims comprises a kind of and multiple this type of excipient simultaneously.
" medicine can be accepted derivant " of The compounds of this invention used herein comprises salt, ester, enol ether, enol ester, acetal, ketal, ortho esters, hemiacetal, hemiketal, acid, alkali, solvate, hydrate or its prodrug.Those skilled in the art use the preparation method of known this derivatization can easily prepare this derivant.Thus Zhi Bei chemical compound do not contain basic toxic action can be to animal or human's administration, perhaps it is the active or prodrug of pharmacy.
" the acceptable salt of medicine " of The compounds of this invention refers to that medicine can accept and have the required pharmacologically active of parent compound.This salt comprises: (1) acid adds and salt, forms with mineral acid (all example hydrochloric acids, hydrogen bromide, sulphuric acid, nitric acid, phosphoric acid or the like); Or form with organic acid, this organic acid is such as acetic acid, propanoic acid, caproic acid, cyclopentanepropanoiacid acid, hydroxyacetic acid, acetone acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid (Fumaric acid), tartaric acid, citric acid, benzoic acid, 3-(4-hydroxyphenyl) benzoic acid, lauric acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, 1, the 2-ethionic acid, the 2-ethylenehydrinsulfonic acid, benzenesulfonic acid, the 4-chlorobenzenesulfonic acid, the 2-LOMAR PWA EINECS 246-676-2, the 4-toluenesulfinic acid, camphorsulfonic acid, 4-methyl bicyclic [2.2.2] eight-2-thiazolinyl-1-carboxylic acid, glucoheptonic acid, 4,4 '-di-2-ethylhexylphosphine oxide-(3-hydroxyl-2-thiazolinyl-1-carboxylic acid), the 3-phenylpropionic acid, trimethylace tonitric, butylacetic acid, lauryl sulphate acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid or the like; Or (2) acid proton in appearing at parent compound can form salt when being replaced by metal ion (for example alkali metal ion, alkaline earth ion or aluminium ion); Or form salt jointly with organic base (for example ethanolamine, diethanolamine, triethanolamine, tromethane, N-methylglucosamine or the like).
" the acceptable ester of medicine " of The compounds of this invention refers to that medicine can accept and have the required pharmacological activity of described parent compound, and includes but not limited to alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, cycloalkyl and the heterocyclic radical ester of acidic-group (including but not limited to carboxylic acid, phosphoric acid, hypophosphorous acid, sulfonic acid, sulfinic acid and boric acid).
" the acceptable enol ether of medicine " of The compounds of this invention refers to the acceptable enol ether of medicine and has the required pharmacological activity of described parent compound, and include but not limited to the derivant of general formula C=C (OR), wherein R is hydrogen, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, cycloalkyl or heterocyclic radical.
" the acceptable enol ester of medicine " of The compounds of this invention refers to the acceptable enol ester of medicine and has the required pharmacological activity of described parent compound, and include but not limited to general formula C=C (OC (O) R), wherein R is hydrogen, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, cycloalkyl or heterocyclic radical.
" the medicine acceptable solvent or the hydrate " of The compounds of this invention refer to medicine acceptable solvent or hydrate complex and have the required pharmacological activity of described parent compound, and include but not limited to The compounds of this invention and one or more solvents or hydrone or 1 to about 10 kinds or 1 to 2,3 or the complex of 4 kind of solvent or hydrone.
" prodrug " refers to discharge any chemical compound of the reactive precursor chemical compound of general formula (I) at body when prodrug during to the mammalian subject administration.The prodrug of described general formula (I) chemical compound is included in the functional group that hydrolyzable under the physiological condition of standard becomes corresponding carboxyl, hydroxyl, amino or sulfydryl.The example of this functional group includes but not limited to hydroxy ester in general formula (I) chemical compound (for example ethyl ester, methyl ester, benzene methyl derivant) and carbamate (for example, N, N-dimethylamino carbonyl) or the like.Other example comprises the dipeptides of hydroxyl in general formula (I) chemical compound or carboxyl or tripeptide ester or the like.The preparation of this functional compounds is well known in the art.For example, contain the hydroxyl that is attached thereto and (for example, work as X
1, X
2, X
3, Y
1, Y
2Or Y
3During for hydroxyl) general formula (I) chemical compound can handle with carboxylic acid that contains the free carboxyl group end or dipeptides, enzymatic synthesis condition known in the art produces down required esters functional group.Similarly, contain the free carboxyl group that is attached thereto general formula (I) chemical compound can with contain hydroxyl such as serine residue (for example ,-N (H)-C (H) (CH
2OH)-C (O)-) alcohol or tripeptides handle, enzymatic synthesis condition known in the art produces down required esters functional group.In addition, general formula (I) chemical compound that contains the carboxyl ester group that is attached thereto can be handled with different carboxyl ester, generates to have general formula (I) chemical compound that the required function ester group is attached thereto under the transesterification condition.All this functional groups belong to scope of the present invention.
Term used herein " organic group " and " organic radical " refer to any carbon-containing group, comprise alkyl, and it is divided into aliphatic hydrocarbon, cyclic hydrocarbon, aromatic hydrocarbon, its functionalization derivant and/or its various compositionss.Term " aliphatic hydrocarbon " refers to saturated or unsaturated straight or branched alkyl and comprises for example alkyl, thiazolinyl and alkynyl.Term " alkyl " refers to replace or non-replacement, saturated straight chain or branched hydrocarbyl or chain (for example, C
1-C
8) for example comprise methyl, ethyl, isopropyl, t-butyl, heptyl, n-octyl group, dodecyl, octadecyl, amyl group, 2-ethylhexyl or the like.The replacement that is fit to comprises the hydroxyl, sulfydryl, low alkyl group sulfenyl (lower alkylthio), nitro, cyano group, single substituted-amino, single substituted-amino of protection, two substituted-amino, C of amino, halogen, hydroxyl, the protection of carboxyl, amino, the protection of carboxyl, protection
1-C
7Alkoxyl, C
1-C
7Acyl group, C
1-C
7Acyloxy or the like.Term " substituted alkyl " refers to that the alkyl group of above-mentioned definition has been carried out one to three time replacement by the carboxyl of the amino of the hydroxyl of hydroxyl, protection, amino, protection, cyano group, halogen, trifluoromethyl, single substituted-amino, two substituted-amino, lower alkoxy, sulfydryl, low alkyl group sulfenyl, carboxyl, protection or carboxyl, amino and/or hydroxy salt.Be associated as using with the substituent group of assorted aromatic rings, hereinafter Ding Yi term " replacement (cycloalkyl) alkyl " is replaced by listed " substituted alkyl " identical group with " substituted cycloalkyl ".Term " thiazolinyl " refers to have unsaturated, the straight or branched alkyl with one or more carbon-to-carbon double bonds such as vinyl.Term " alkynyl " refers to have unsaturated, the straight or branched alkyl of one or more carbon-to-carbon triple bonds.Term " cyclic group " refers to closed cyclic hydrocarbon radical, and it is divided into alcyl, aromatic radical or heterocyclic radical.Term " alcyl " refers to have the cyclic hydrocarbon radical of similar fatty group." aromatic radical " or " aryl " refers to monocycle or polycyclic aromatic hydrocarbon base, and can comprise one or more hetero atoms, hereinafter it done further definition.Term " heterocycle " refers to closed hydrocarbon, and the one or more atoms in its medium ring are non-carbon (for example, N, O, S etc.) and have hereinafter done further definition.
" organic group " can functionalization or contained the additional functional group relevant with organic group in addition, and such as carboxyl, amino, hydroxyl or the like, it can be protection or unprotected.For example, phrase " alkyl group " should not only comprise pure open chain saturated hydrocarbon alkyl substituent, such as methyl, ethyl, propyl group, t-butyl or the like, but also comprise and contain in addition substituent alkyl substituent well known in the art, described substituent group such as hydroxyl, alkoxyl, sulfydryl, alkyl sulfenyl, alkyl sulfonyl, halogen, cyano group, nitro, amino, carboxyl or the like.Therefore " alkyl group " comprises ether, ester, haloalkyl, 4-nitro alkyl, carboxyalkyl, hydroxy alkyl, sulfoalkyl or the like.
Term " halo group " or " halogen " that this paper replaces use refer to fluorine, chlorine, bromine, iodine group.Preferred halogen is chlorine and fluorine.
Term " haloalkyl " refers to the alkyl group by the above-mentioned definition of one or more halogen atom replacements.Described halogen can be identical or different.Term " dihalo alkyl " refers to that halogen can be identical or different by the abovementioned alkyl group of two halogens replacements.Term " tri haloalkyl " refers to that halogen can be identical or different by the abovementioned alkyl group of three halogens replacements.Term " perhaloalkyl radical " refers to the alkylhalide group group of above-mentioned definition, and wherein each hydrogen atom in the alkyl group is all replaced by halogen atom.Term " perfluoroalkyl " refers to the alkylhalide group group of above-mentioned definition, and each hydrogen atom in the wherein said alkyl group is all by fluorine-based replacement.
Term " cycloalkyl " refers to monocycle, dicyclo or trinucleated saturated rings, and it is for full fully and/or part is unsaturated.The example of this group comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, adamantyl, ring octyl group, suitable-or anti--naphthalane, bicyclo-[2.2.1] seven-2-alkene (bicycle[2,2,1] hept-2-ene), hexamethylene-1-alkynyl, ring penta-1-alkynyl, 1,4-encircles hot diynyl, or the like.
Term " (cycloalkyl) alkyl " refers to that the alkyl group of above-mentioned definition is by an above-mentioned cycloalkyl substituted.The example of this group comprises (cyclohexyl) methyl, 3-(cyclopropyl)-n-propyl group, 5-(Pentamethylene .) hexyl, 6-(adamantyl) hexyl, or the like.
Term " substituted-phenyl " refers in particular to the phenyl group that is replaced by one or more parts; in some instances; replaced by one or two or three parts, it is selected from hydroxyl, cyano group, nitro, sulfydryl, alkyl sulfenyl, trifluoromethyl, the C of halogen, hydroxyl, protection
1-C
7Alkyl, C
1-C
7Alkoxyl, C
1-C
7Acyl group, C
1-C
7The amino of the methylol of the carboxymethyl of the carboxyl of acyloxy, carboxyl, oxygen carboxyl, protection, carboxymethyl, protection, methylol, protection, amino, protection, (the single replacement) amino, (the single replacement) amino of protection, (two replacement) amino, formamido group, the formamido group of protection, N-(C
1-C
6Alkyl) N-(C of formamido group, protection
1-C
6Alkyl) formamido group, N, N-two (C
1-C
6Alkyl) formamido group, trifluoromethyl, N-((C
1-C
6Alkyl) sulphonyl) for example diphenyl or the naphthyl group product of amino, N-(benzene sulfonyl) amino or phenyl, replacement or non-replacement.
The example of term " substituted-phenyl " comprises single or two (halo) phenyl group, for example, and 2-, 3-or 4-chlorphenyl, 2,6-Dichlorobenzene base, 2,5-Dichlorobenzene base, 3,4-Dichlorobenzene base, 2-, 3-or 4-bromophenyl, 3,4-dibromo phenyl, 3-chloro-4-fluorophenyl, 2-, 3-or 4-fluorophenyl or the like; Single or two (hydroxyl) phenyl group, for example 2,3, or 4-hydroxy phenyl, 2, hydroxy derivatives of 4-dihydroxy phenyl and protection thereof or the like; The nitrobenzophenone group for example, 2-, 3-or 4-nitrobenzophenone; The cyano-phenyl group, for example, 2-, 3-or 4-cyano-phenyl; Single or two (alkyl) phenyl for example, 2-, 3-or 4-aminomethyl phenyl, 2,4-3,5-dimethylphenyl, 2-, 3-or 4-(isopropyl) phenyl, 2-3-or 4-ethylphenyl, 2-, 3-or 4-(n-propyl group) phenyl or the like; List or two (alkoxyl) phenyl group, for example, 2,6-Dimethoxyphenyl, 2-, 3-or 4-(isopropoxy) phenyl, 2-, 3-or 4-(t-butoxy) phenyl, 3-ethyoxyl-4-anisyl or the like; 2-, 3-or 4-trifluoromethyl; Mono carboxylic phenyl or dicarboxyl phenyl or (carboxyl of protection) phenyl group, 2-for example, 3-or 4-carboxyl phenyl or 2,4-two (carboxyl of protection) phenyl; Single or two (methylol) phenyl or (methylol of protection) phenyl, 2-for example, 3-or 4-(methylol of protection) phenyl or 3,4-two (methylol) phenyl; Single or two (aminomethyl) phenyl or (aminomethyl of protection) phenyl for example, 2-, 3-or 4-(aminomethyl) phenyl or 2,4-(aminomethyl of protection) phenyl; Or single or two (N-(methanesulfonamido)) phenyl for example, 2-, 3-or 4-(N-(methanesulfonamido)) phenyl.And, the disubstituted phenyl group represented in described term " substituted-phenyl ", wherein said substituent group is different, for example, 3-methyl-4-hydroxy phenyl, 3-chloro-4-hydroxy phenyl, 2-methoxyl group-4-bromophenyl, 4-ethyl-2-hydroxy phenyl, 3-hydroxyl-4-nitrobenzophenone, 2-hydroxyl-4-chlorphenyl or the like.
Term " (substituted-phenyl) alkyl " refers to that a kind of above-mentioned substituted-phenyl group is connected on a kind of abovementioned alkyl group.The example of this group comprises 2-phenyl-1-chloroethyl, 2-(4 '-methoxyphenyl) ethyl, 4-(2 ', 6 '-dihydroxy phenyl)-n-hexyl, 2-(5 '-cyano group-3 '-methoxyphenyl)-n-phenyl, 3-(2 ', 6 '-3,5-dimethylphenyl) propyl group, 4-chloro-3-aminobenzyl, 6-(4 '-methoxyphenyl)-3-carboxyl hexyl, 5-(4 '-aminomethyl phenyl)-3-(aminomethyl) phenyl, 5-phenyl-3-carbonyl amyl group-1-base, (4-hydroxyl naphthyl-2-yl) methyl or the like.
As mentioned above, term " fragrance " or " aryl " refer to five yuan and six-membered carbon ring.Simultaneously as mentioned above, term " heteroaryl " refers to five yuan or hexatomic ring replacing arbitrarily, and it contains 1-4 hetero atom, and for example oxygen, sulfur and/or nitrogen-atoms, particularly nitrogen-atoms can be separately or be connected with oxygen or sulphur atom on encircling.These five yuan or hexatomic ring can be undersaturated fully.
In addition, above-mentioned substituted five-membered or hexatomic ring arbitrarily may at random be fused in five yuan of aromatic series or the hexatomic ring system.For example, described ring can at random be fused to such as in pyridine or triazole system five yuan or the hexatomic ring system, and preferred phenyl ring.
Following member ring systems is the example by heterocycle (no matter replacing or the non-replacement) group of term " heteroaryl " expression: thienyl, furyl, pyrrole radicals, pyrrolidinyl, imidazole radicals isoxazolyl, triazolyl, thiadiazolyl group, the 4-oxadiazole base, tetrazole radical, the thiatriazole base, oxa-triazolyl (oxatriazolyl), pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl oxazinyl, triazine radical, thiadiazine base tetrazolo, 1,5-[b] pyridazinyl and purine radicals, and benzo-fused derivant, for example benzoxazolyl, benzothiazolyl, benzimidazolyl and indyl.
The substituent group of the heteroaryl ring of above-mentioned any replacement is from one to three halogen; trihalomethyl group; amino; the amino of protection; ammonia salt; single substituted-amino; two substituted-aminos; carboxyl; the carboxyl of protection; carboxylate; hydroxyl; the hydroxyl of protection; the salt of oh group; lower alkoxy; sulfydryl; the low alkyl group sulfenyl; alkyl; substituted alkyl; cycloalkyl; substituted cycloalkyl; (cycloalkyl) alkyl; (cycloalkyl) alkyl that replaces; phenyl; substituted-phenyl; phenylalkyl and (phenyl of replacement) alkyl.The substituent group of heteroaryl groups maybe when for trihalomethyl group, is trifluoromethyl, trichloromethyl, trisbromomethyl or three iodomethyls as defined above.During as relevant with above-mentioned heteroaryl ring substituent group, " lower alkoxy " refers to C
1-C
4Alkoxy base, " low alkyl group sulfenyl " refers to C simultaneously
1-C
4Alkyl sulfenyl group.
Term " (the single replacement) amino " refers to that this substituent group is selected from phenyl, substituted-phenyl, alkyl, substituted alkyl, C by a kind of amino of substituent group replacement
1-C
4Acyl group, C
2-C
7Thiazolinyl, C
2-C
7Substituted alkenyl, C
2-C
7Alkynyl, C
7-C
16Alkylaryl, C
7-C
16Substituted alkyl aryl and heteroaryl groups.Described (single replace) amino can contain the content that the group of amido protecting is comprised as term " (the single replacement) amino of protection " in addition.Term " (two replacement) amino " refers to that this substituent group is selected from phenyl, substituted-phenyl, alkyl, substituted alkyl, C by the amino group of two kinds of substituent groups replacements
1-C
7Acyl group, C
2-C
7Thiazolinyl, C
2-C
7Alkynyl, C
7-C
16Alkylaryl, C
7-C
16Substituted alkyl aryl and heteroaryl.These two kinds of substituent groups can be identical or different.
Term " heteroaryl (alkyl) " refers to be replaced on any position by the heteroaryl groups of above-mentioned definition the alkyl group of above-mentioned definition.
" arbitrarily " or " at random " refer to that incident, situation, feature or the element described subsequently can (but unnecessary) take place, and this description comprises example that this incident and situation take place and the example that does not take place thereof.For example, " utilize alkyl group at random singly to replace or disubstituted heterocyclic group " and refer to that described alkyl can (but unnecessary) occur, and this description comprises and utilizes alkyl group that this heterocyclic group is carried out single the replacement or disubstituted state and the state that this heterocyclic group replaced without this alkyl group.
Term " electron withdraw group " refers to that ability that in molecule functional group is drawn to electronics itself is more than if the electron-withdrawing power of hydrogen atom when having occupied position identical in the described molecule.The example of electron withdraw group includes but not limited to, halogen group ,-C (O) R group (wherein R is an alkyl); Carboxylic acid and ester group;-NR
3 +Group (wherein R is alkyl or hydrogen); Azo group; Nitro;-OR and-SR base (wherein R is a hydrogen or alkyl); And the organic group (as herein defined) that contains this type of electron withdraw group, halogenated alkyl group (comprising the whole haloalkyl group) for example, or the like.
Has the same molecular formula but the characteristic of its atomic bonding or order are different or its atoms in space is arranged different chemical compounds and is called " isomers ".Its atoms in space is arranged different isomerss and is called " stereoisomer ".Be not that the enantiomorphous stereoisomer of mirror image is called " diastereomer " mutually, and the enantiomorphous stereoisomer of non-each other stack mirror image is called " enantiomer " mutually.When chemical compound had center of asymmetry, for example, it was combined with four kinds of different groups, and the existence of a pair of stereoisomer is possible.Can utilize the absolute configuration of its center of asymmetry to come the labelling enantiomer, and can utilize the R-of Cahn and Prelog and S-Cahn-Ingold-Prelog sequence rule to describe, perhaps also can be appointed as dextral or left-handed isomer (that is, being divided into the isomer for (+) or (-)) by its molecule rotatory polarization optical plane describes.Chipal compounds can exist with single enantiomer or with the form of its mixture.The mixture that contains described enantiomer equal portions is called " racemic mixture ".
Chemical compound of the present invention can have one or more center of asymmetries; Therefore this chemical compound can be prepared as independently (R)-or (S)-stereoisomer or its mixture.Unless other prompting is arranged, the description of the specific compound in description of the present invention and claims or name should comprise single enantiomer and composition thereof, its racemic modification or other simultaneously.The separation method of stereochemical evaluation and stereoisomer is (referring to for example, " Advanced OrganicChemistry " chapter 4, the 4th edition, J.March, John Wiley and Sons, New York, the discussion in 1992) well known in the art.
General introduction
The invention provides thiazolidone compositions, thiazolidinone derivatives compositions and be used for the method for the inhibition cystic fibrosis transmembrane conductance regulator protein (CFTR) of high affinity, and and research and Therapeutic Method state disease mediated to CFTR.The discovery of theme thiazolidinone compound of the present invention and derivant thereof is to utilize the screening of identifying a large amount of potential candidate compounds that carry out with the analysis of the direct acting CFTR inhibitor of CFTR to realize.Because the multiple CFTR activator that plays a role by different activated channels is included in the research of identifying this motif compound, therefore do not adhere to any particular theory and operator scheme, inhibition chemical compound of the present invention as if by or contiguous CFTR Cl
-Transhipment passage performance inhibitory action.Conduct effectively some 2-thioxo-4-thiazolidinone chemical compound and derivants of CFTR inhibitor have been determined in the screening of 50,000 kinds of different chemical compounds.These chemical compounds and derivant be not with known CFTR agonist and known in the past CFTR inhibitor DPC, NPPB or glyburide (glibenclamide) had chemistry and structural related in the past.The great majority of identifying from screening are CFTR inhibitor Cl in people's air flue cell effectively
-The inhibiting K of electric current
IFor~300nM.Inhibitory action be quick, reversible and CFTR special.
Now the compositions and methods of the invention are done more detailed description
Thiazolidinone compound and derivant
The described thiazolidinone compound and the derivant that are used for the present composition and method comprise five or more polyatomic heterocycle, it comprises nitrogen, at least one sulfur, oxygen or selena atom that phenyl ring replaces, and with bonded one or more carbonyls of heterocycle or thiocarbonyl.More specifically, this theme thiazolidinone compound and derivant can have following general formula (I):
X wherein
1, X
2And X
3Independently be selected from hydrogen, organic group, halogen, nitro, azo group, hydroxyl and sulfydryl; Y
1, Y
2And Y
3Independently be selected from hydrogen, organic group, halogen, nitro, azo group, hydroxyl and sulfydryl; A
1And A
2Independently be selected from oxygen and sulfur, A
3Be selected from sulfur and selenium; And A
4Contain one or more carbon or hetero atom and can exist or not exist; Perhaps its pharmaceutically-acceptable derivative thereof is as single stereoisomer or its mixture.When in this center heterocycle, not having A
4The time, it is a five-membered ring.
In certain embodiments, the described thiazolidinone compound of above-mentioned general formula (I) and derivant comprise general formula (Ia):
X wherein
1, X
2And X
3Independently be selected from hydrogen, organic group, halogen, nitro, azo group, hydroxyl and sulfydryl; Y
1, Y
2And Y
3Independently be selected from hydrogen, organic group, halogen, nitro, azo group, hydroxyl and sulfydryl; And A
1And A
2Independently be selected from oxygen and sulfur.In specific embodiment, X
1Can be electron withdraw group, also can comprise halogenated alkyl group, dihalo alkyl group, tri haloalkyl group (for example, trifluoroalkyl group) and fluorine-based.Y
2Independently be selected from alkyl, hydroxyl, carboxyl, nitro, carbonic ester, carbamate, alkoxyl, alkyl-carbonyl and halogen group, Y
1Independently be selected from hydroxyl and bromo, and Y
3Independently be selected from hydrogen and nitro.
In many embodiments, described thiazolidinone compound of general formula (I) and derivant can comprise the 3-aryl-5-aryl methylene-2-thioxo-4-thiazolidinone of general formula (Ib),
Wherein at least a X
1, X
2And X
3Be electron withdraw group; And Y
1, Y
2And Y
3Independently be selected from hydrogen, alkyl, hydroxyl, carboxyl, nitro, carbonic ester, carbamate, alkoxyl, alkyl-carbonyl and halogen group.In one embodiment, X
1The position at place is selected from 2,3 or 4; Y
2The position is selected from 2,3 or 4; And Y
1And Y
3Can be hydrogen.
Described 3-aryl-5-aryl methylene-2-thioxo-4-thiazolidinone can have general formula (Ic) particularly:
Y wherein
1-Y
3As mentioned above.In one embodiment, the residing position of described trifluoromethyl group is selected from 2,3 or 4; Y
2Residing position is selected from 2,3 or 4; The Y in this embodiment wherein
1And Y
3Can be hydrogen.
In some embodiments of the present invention, thiazolidinone compound of the present invention comprises:
That is phenyl 3-[(3-trifluoromethyl)]-the 5-[(4-nitrobenzophenone) methylene]-2-thioxo-4-thiazolidinone; And
That is phenyl 3-[(3-trifluoromethyl)]-5-[(4-oxygen carboxy phenyl) methylene]-2-thioxo-4-thiazolidinone; And
That is phenyl 3-[(3-trifluoromethyl)]-the 5-[(4-carboxy phenyl) methylene]-2-thioxo-4-thiazolidinone; And
That is, the 3-[(3-trifluoromethyl) phenyl]-5-[(3, the 4-dihydroxy phenyl) methylene]-2-thioxo-4-thiazolidinone; And
That is, the 3-[(3-trifluoromethyl) phenyl]-5-[(3,5-two bromo-4-hydroxy phenyls) methylene]-2-thioxo-4-thiazolidinone; And
That is phenyl 3-[(3-trifluoromethyl)]-5-[(3-bromo-4-hydroxyl-5-nitrobenzophenone) methylene]-2-thioxo-4-thiazolidinone.Selectively, the trifluoromethyl group in any above-mentioned chemical compound can be in 2 or 4 of phenyl ring.
Medication preparation
The present invention also provides the medication preparation of above-mentioned motif compound.This motif compound can be formed the various preparations of the various route of administration of being used for the treatment of property administration.More particularly, The compounds of this invention is by becoming pharmaceutical composition by prescription with the drug acceptable carrier that is fit to, diluent, excipient and/or adjuvant combination, also but prescription becomes the preparation of solid, semisolid, liquid or gaseous form, for example tablet, capsule, powder, granule, ointment, solution, suppository, injection, inhalant and aerosol.Preferably, described preparation does not contain can detected DMSO (dimethyl sulfoxide), its be not non local, intestinal outer and intestinal in medicine acceptable carrier, diluent, excipient or the adjuvant of administration.Described preparation can be oral by comprising, in the oral cavity, rectum, non-intestinal, intraperitoneal, Intradermal, transdermal, trachea or the like different route of administration to individuality or patient's administration of this medicine of needs.
In one embodiment, topical (for example transdermal administration) is useful.Local administration preparation can be the form of transdermal subsides, suppository, paste, lotion, unguentum, colloid or the like.Topical formulations can comprise one or more penetrating agent, thickening agent, diluent, emulsifying agent, dispersant or bonding agent.When described compound becomes transdermal when transmission, described chemical compound can with penetration enhancers prescription or together use together with it.Penetration enhancers (penetration enhancers) comprises chemosmosis reinforcing agent and physics penetration enhancers, can promote that described chemical compound transmits by skin, and also alternately is called " penetration enhancers (permeation enhancers) ".The penetration enhancers of physics for example comprises, such as the electrophoretic techniques of iontherapy, ultransonic application (or " phonophoresis ") or the like.The chemosmosis reinforcing agent be before compound administration, simultaneously or the reagent of administration at once after the administration, it can increase the particularly cuticular permeability of skin, provides this medicine percutaneous enhanced osmotic effect.
The chemical compound that is used for strengthening cutaneous permeability comprises: sulfoxide, dimethyl sulfoxide (DMSO) and decyl methyl sulfoxide (C
10MSO); Ether, such as TC, ten oxyethylene groups-vaccenic acid ether (dekaoxyethylene-oleylether), and TC; Surfactant is such as sodium laurate, sodium lauryl sulphate, cetrimonium bromide, benzalkonium chloride, poloxamer (Poloxamer) (231,182,184), tween (20,40,60,80) and lecithin; 1-substituted nitrogen heterocyclic cycloheptane-2-ketone, particularly 1-N-lauryl azepan-2-ketone; Alcohol is such as ethanol, propanol, capryl alcohol, benzyl alcohol or the like; Vaseline is such as oil frozen glue (ore deposit ester), mineral oil (liquid petrolatum) or the like; Fatty acid is such as C
8-C
22With other fatty acid (for example, isostearic acid, sad, oleic acid, lauric acid, valeric acid); C
8-C
22Aliphatic alcohol (for example, oily enol, lauryl alcohol); C
8-C
22The lower alkyl esters (for example, ethyl oleate, isopropyl myristate, butyl stearate, methyl laurate, isopropyl myristate, isopropyl palmitate, methylpropionate, ethyl oleate) of fatty acid and other fatty acid; C
8-C
22The monoglyceride of fatty acid (for example, dodecyl monoglyceride); Tetrahydrofurfuryl alcohol polyethylene glycol ether; 2-(2-ethoxy ethoxy) ethanol; Diethylene glycol monomethyl ether; The alkyl aryl ether of polyethylene oxide; Polyethylene oxidation monomethyl ether; Polyethylene cacodyl oxide base ether; C
6-C
8The connection lower alkyl esters of diacid (for example ethanedioic acid diisopropyl ester); Ethyl acetate; Acetoacetic ester; Its polyhydric alcohol and ester are such as propyleneglycoles, ethylene glycol, glycerol, butanediol, polyethylene glycol and single dodecoic acid polyethylene glycol ester; Amine and other nitrogen-containing compound, for example carbamide, dimethyl acetylamide (DMA), dimethyl formamide (DMF), 2-Pyrrolidone, N-alkyl pyrrolidone (for example 1-Methyl-2-Pyrrolidone); Ethanolamine, diethanolamine and triethanolamine; Terpenes; Alkane ketone (alkanones) and organic acid, particularly salicylic acid and Salicylate, citric acid and succinic acid.Other chemistry and physics penetration enhancers be Transdermal Delivery of Drugs for example, A.F.Kydonieus (ED) 1987 CRL Press; Percutaneous Penetration Enhancers, eds.Smith et al. (CRC Press, 1995); Lenneruas et al., J Pharm Pharmacol 2002; 54 (4): 499-508; Karande et al., Pharm Res 2002; 19 (5): 655-60; Vaddi et al., J Pharm Sci 2002 July; 91 (7): 1639-51; Ventura et al., J Drug Target 2001; 9 (5): 379-93; Shokri et al., Int J Pharm 2001; 228 (1-2): 99-107; Suzuki etal., Biol Pharm Bull 2001; 24 (6): 698-700; Alberti et al., J Control Release2001; 71 (3): 319-27; Goldstein et al., Urology 2001; 57 (2): 301-5; Kiijavainen et al., Eur J Pharm Sci 2000; 10 (2): 97-102; And Tenjarla et al., Int J Pharm 1999; 192 (2): described in the 147-58.
When described chemical compound and chemosmosis reinforcing agent prescription, described penetration enhancers is selected from dosage described chemical compound coupling and that transmit by individual's skin with the described chemical compound of satisfied promotion and exists, and for example is used for the transmission of this chemical compound to systemic circulation.In one embodiment, described chemical compound and penetration enhancers rather than DMSO prescription.
In one embodiment, described chemical compound provides in the medicine transmission patch, for example saturating mucosa and transdermal patch, and can with the penetration enhancers prescription.Substrate (this substrate provides slow release described chemical compound, gets final product sustained release) that described patch generally includes supporting layer (it is impermeable to chemical compound with other formulation components), contact with the one side of described supporting layer and adhesive layer (it is positioned at the identical side of described supporting layer with described substrate).Described substrate may be selected to be and is fit to route of administration, and can be and for example can be polymeric or hydrosol substrate.
In pharmaceutical preparation, motif compound of the present invention can its pharmaceutically-acceptable derivative thereof form administration, salt for example, and perhaps it can be single or uses with the form of suitable associating and combination with the other medicines reactive compound.Following method and excipient only are example rather than any limitation of the invention.
For oral formulations, described motif compound can be single or prepares tablet, powder, granule and capsule with the additive combination that is fit to, for example, and with the additive of routine, such as lactose, mannitol, corn starch or potato starch; With bonding agent, such as crystalline cellulose, cellulose derivative, arabic gum, corn starch or gelatin; With disintegrating agent, such as corn starch, potato starch or sodium carboxymethyl cellulose; With lubricant, such as Talcum or magnesium stearate; As needs, with diluent, buffer agent, wetting agent, antiseptic and flavoring agent combination.Useful especially is that the prescription of described theme thiazolidinone compound and buffer agent can provide the effect of described chemical compound to the protection of the gastric acid environment of low pH.The precipitation of described chemical compound in the time of also can preferably providing a kind of intestinal bag to be avoided by stomach.
Motif compound of the present invention can pass through its dissolving in water solublity or water-insoluble solution (such as plant or other similar oil, synthctic fat acid glyceride, high-grade aliphatic ester or third rare ethylene glycol), suspension or emulsifying prescription in ejection preparation; And if desired, can make up with the additive (such as solubilizing agent, isotonic agent, suspending agent, emulsifying agent, stabilizing agent agent antiseptic) of routine.Useful especially solubilizing agent comprises vitamin E TPGS (d-alpha-tocopherol polyethylene glycol 1000 succinates), cyclodextrin or the like.
Chemical compound of the present invention can be used in aerosol formulation and passes through inhalation.But chemical compound prescription of the present invention is in the acceptable cast charge such as dichlorodifluoromethane, propane, nitrogen or the like of pressure (aerosol substrate).
In addition, described motif compound can be by being mixed and made into suppository with multiple alkali (such as emulsifying alkali or water-soluble alkali).Chemical compound of the present invention can carry out rectally by suppository, described suppository can comprise the excipient such as cocoa ester, Polyethylene Glycol and polyethylene glycol, and it dissolves under body temperature, and at room temperature solidifies.
The unit dosage forms of oral or rectally can be provided, for example syrup, elixir, suspension, every kind of dosage unit wherein, for example teaspoonful, a soupspoon capacity, tablet or suppository contain the compositions predetermined close of (containing one or more inhibitor).Simultaneously, the injection or the unit dosage forms of intravenous administration can comprise that being dissolved in sterilized water, normal saline or other medicines can accept described inhibitor in the liquid composite of carrier.
According to morbid state individual and that treated, and route of administration, described motif compound is with μ g-10mg/kg body weight dosed administration every day 0.1 for example.Because the common effectiveness of therapeutical effect is very different for different mammals, show as in the people dosage usually less than rat 20,30 or even 40 times (per unit body weight), therefore described dosage range is wider.Similarly, the form of administration is also bigger to the influence of dosage.The inventor finds that the inductive intestinal juice secretion of cholera toxin can be by the blocking-up of the single dose intraperitoneal administration of about 10-20 microgram, about 10 times of effective doses that are higher than rat in the mice.Therefore for example oral dose can be about 10 times of injected dose.Higher dosage can be used for topical routes.
Common dosage form can be the solution that is suitable for intravenous administration; Tablet is taken in 2-6 time every day, or takes in the time-controlled release capsule once contain higher proportion content active component or tablet or the like every day.Capsule material by being dissolved in different pH value, utilize capsule that osmotic pressure slowly discharges or can obtain described time-controlled-release function by other any known sustained release means.
For the application of subject methods, described motif compound can comprise CFTR inhibitor prescription with the other medicines active agent.
Be used for medicine of the present invention and can accept excipient, such as excipient (vehicles), adjuvant, carrier or diluent, the public can easily obtain.In addition, the acceptable auxiliary substance of medicine such as pH regulator agent and buffering reagent, osmotic pressure regulator, stabilizing agent, wetting agent or the like, also is that the public obtains easily.
Will be understood by those skilled in the art that the order of severity of the function according to specific compound, described symptom and the sensitivity that described individuality has side effects, can change dosage level.The described technical staff in this area utilizes various means can easily determine the preferred dose of given chemical compound.
The invention provides the medicine box of the unit dosage forms that contains described motif compound, be generally oral or injection type.In this medicine box, except that containing described unit dosage forms, this container should comprise describes described medicine in the purposes of the interested pathologic state of treatment institute with follow the informedness package insert of effect.Preferred chemical compound and unit dose are above described.
Belong to the morbid state that CFTR inhibitor of the present invention is treated
CFTR inhibitor disclosed herein can be used for the treatment of CFTR disease states mediated, promptly, by CFTR activity (for example, the CFTR activity in the ion transport) any morbid state, disease or the disease that causes or the symptom of this morbid state, disease or morbid state.This morbid state, disease or disease or its symptom are suitable for and treat by the CFTR activity inhibition, for example the inhibitory action of CFTR ion transport.
In one embodiment, CFTR inhibitor of the present invention is used for the treatment of the relevant morbid state of the unusual intestinal secretion that increases, particularly acute unusual increase intestinal secretion.Disclosed the effect of CFTR activity in intestinal secretion, this intestinal secretion be to various agonist comprise cholera toxin reaction (referring to for example, Snyder et al.1982 Bull.World Health Organ.60:605-613; Chaoet al.1994 EMBO J. 13:1065-1072; Kimberg et al.1971 J. Clin.Invest.50:1218-1230).Therefore CFTR inhibitor of the present invention can reduce the intestinal juice secretion thus by the effective dose administration that suppresses the CFTR transhipment.
Therefore, the CFTR inhibitor can be used for the treatment of intestinal anaphylaxis condition of illness and diarrhoea, particularly secretory diarrhea.In developing country, secretory diarrhea is the most important reason of infant death, and 500 numbers of dying (Gabriel et al., 1994 Science 266:107-109) of dieing ten thousand deaths are arranged every year approximately.Some researchs comprise the research of using the CF mice, show that CFTR is intestinal chloride ion (and therefore forming liquid) excretory final general channels (Snyder et al., 1982, the Bull.World HealthOrgan.60:605-613 to various agonist reactions; Chao et al., 1994 EMBO.J.13:1065-1072; With Kimberget al., 1971, J.Clin.Invest.50:1218-1230).The present invention uses mice intestinal juice secretion model to show, the CFTR inhibitory action that produces that is administered systemically of the described inhibitor of non-toxic dosage can have been blocked the inductive intestinal juice secretion of cholera toxin (seeing embodiment) effectively.
Can use the diarrhoea of CFTR inhibitor for treating of the present invention to produce owing to being exposed to various pathogen and preparation, it includes but not limited to cholera toxin (Vibrio cholera), escherichia coli E.coli (particularly enterotoxigenic (ETEC)), Shigella (Shigella), Salmonella (Salmonella), Campylobacter (Campylobacter), difficult clostridium (Clostridiurra difficile), parasite (for example, Giardia (Giardia), Endamoeba (Entamoeba histolytica), cryptosporidiosis (Cryptosporidiosis), Cyclosporae (Cyclospora)), diarrhea virus (for example rotavirus), sitotoxin, the enterotoxin that maybe can produce the intestinal secretion of the increase that is mediated by CFTR exposes.
Other diarrhoea comprises that AIDS follows diarrhoea (for example, the relevant diarrhoea of AIDS) and inflammatory gastrointestinal disorder, for example ulcerative colitis, inflammatory bowel (IBD), Crohn ' s disease or the like.Report is arranged, and intestinal inflammation can change the expression of three kinds of main intestinal salt transhipment mediation agent and can produce the diarrhoea of ulcerative colitis, and it is simultaneously by increasing transepithelial Cl
-Secretion and the NaCl that suppresses epithelium absorb and produce (referring to for example, Lohi et al., 2002, Am.J. Physiol.Gastrointest.Liver Physiol.283 (3): G567-75).
CFTR inhibitor of the present invention also can be used for such as the dirty treatment of diseases of polycystic kidney, and finds to can be used as the male sterility medicine by the CFTR activity that suppresses testis.
CFTR inhibitor of the present invention also can be used in the screening of large animal model (for example, Spira etal., 1981, the described Rabbit Model of Infect.Immun.32:739-747).In addition, also can further detect the characteristic of CFTR inhibitor of the present invention to the excremental analysis of stool of using vibrio cholera alive (Vibrio cholerae) to produce.
The non-human animal model of CFTR defective and people organize models
CFTR inhibitor of the present invention also can be used for producing the non-human animal model of disease, wherein said disease relevant with the CFTR function of reduction (for example, the ion transport of reduction).Ever-increasing evidence shows at CFTR and lacks among the patient that particularly in the patient who is subjected to cystic fibrosis (CF) effect, liquid that the air flue submucosal gland produces and macromole hyposecretion can cause the damage of mucomembranous cilium and antibacterial removing function; Yet, be limited to the serious ill air flue (Jayaraman et al.2001 Proc.Natl.Acad.Sci.USA 98:8119-8123) that in lung transplantation, obtains in the functional study of people's air flue gland.Acute CFTR inhibitory action makes the effect of mensuration CFTR in water, salt and the macromole secretion of submucosal gland mediation become possibility.High-affinity CFTR inhibitor can produce pharmacology's creature that anthropomorphic dummy CFTR lacks the non-human animal model of (for example anthropomorphic dummy CF phenotype).Particularly, find large animal model (for example CF) that CFTR lacks illustrate the CF airway disorders begin with process in pathophysiological mechanism, and the therapeutic effect of estimating CF for example screens the special-purpose in the candidate agent of CFTR defective or its symptom treatment.
In air flue and disorder of pancreas and male sterility, can illustrate the inhibitory action of CFTR ion transport.For example, the CFTR passage inhibitory action in described lung and air flue can influence the mucus accumulation that airway surface liquid produces, and its further obstructing airway also seriously accumulates on the lung wall, provides the basic environment of infection takes place, thereby has caused chronic lung disease.This identical situation can occur in the pancreas, and wherein the mucus of Dui Jiing has been destroyed the exocrine function of pancreas and stoped essential food preparation enzyme to enter intestinal.
Can produce non-human animal model by the administration that can effectively reduce the active CFTR inhibitor of CFTR ion transport dosage.Useful especially is the purposes of CFTR inhibitor of the present invention in inducing non-human animal's cystic fibrosis (CF) phenotype.The administration that effectively suppresses the CFTR inhibitor dosage of CFTR receptor in lung for example can be simulated the CFTR that finds and be lacked in CF.The route of administration of CFTR inhibitor has as above been done detailed description.According to employed non-human animal, described motif compound is 50-500 μ g/kg body weight for example, and every day, 1 to 3 time dosage provided intraperitoneal, subcutaneous or other approach to produce inhuman animal model.Oral dose can be higher than described intraperitoneal or subcutaneous administration dosage about 10 times.
The non-human animal model of CFTR relevant disease can be as the model of the relevant morbid state of any CFTR activity suitable and that reduce.This morbid state comprises and the relevant disease of CFTR sudden change that this sudden change can produce the unusual of epithelium ion and transhipment.These can further upset relevant with the removing of air flue and other mucous epithelium and pipeline epithelium mucomembranous cilium unusually.By in the non-human animal, inducing CFTR to lack phenotype,, the morbid state that pharmacology's mould is built sends out property chronic pancreatitis (idiopathic chronic pancreatitis), deferent duct defective (vas deferens defects), slight pneumonopathy, asthma or the like but including but not limited to cystic fibrosis (comprising atypia CF), spy.The disease relevant with CFTR loss function summary is referring to for example, Noone et al.Respir Res 2 328-332 (2001).The non-human animal model that the CFTR inhibitor produces also can be used as the model (for example, antibacterial, virus and fungus, particularly respiratory tract infection) that CFTR lacks infected by microbes in the individuality.In a useful especially embodiment, CFTR inhibitor of the present invention is used for the pharmacology and induces cystic fibrosis (CF) phenotype.
The animal that is suitable for producing animal model of the present invention comprises any animal, mammal particularly, for example non-human primates (for example, monkey, chimpanzee, gorilla or the like), Rodents (for example, rat, mice, gerbil jird, hamster, ferret or the like), Lagomorpha, pig (swine) (for example pig (pig), miniature pig (miniature pig)), horse, Canidae, cat family or the like.To larger animal is interested especially.
Described CFTR inhibitor also can be organized with isolating people and contact the ex vivo treatment that produces disease and use (ex vivo) model at body.This tissue can contact with the active CFTR inhibitor of CFTR dosage in the described tissue of effective reduction, and they can be less to 15 minutes or nearly 2 hours or longer.Interested people's tissue includes but not limited to lung (comprising trachea and air flue), liver, pancreas, testis or the like.The tissue of handling at inhibitor can carry out physiology, biochemistry, genomics or other and study and identify the significant new treatment target molecule of the pathophysiology of disease.For example the chorista from people's lung CF can be exposed to the inhibitor that is enough to induce described CF phenotype, and can carry out this research and identify the significant new treatment target molecule of CF Pathophysiology.
Synthesizing of The compounds of this invention
According to those skilled in the art's known method or with US 5,326, the disclosed similarity method of 770 and US6,380,186 (they all quote the reference as this), or with the following stated method similar methods, can prepare chemical compound of the present invention.
Should be understood that in the following description the substituent group of described general formula and/or the combination of variant only allow when its structure produces stable compound.
This area described technical staff also can understand, and has only the functional group of intermediate compound may need to protect by stable blocking group in the step of the following stated.This functional group comprises hydroxyl, amino, sulfydryl and carboxylic acid.The blocking group that hydroxyl is fit to comprises trialkylsilkl or dialkyl group silicyl (for example, t-butyl dimetylsilyl, t-butyl diphenyl silicyl or trimethyl silyl), THP trtrahydropyranyl, benzyl or the like.Suitable blocking group for amino, amidino groups and guanidine radicals comprises t-butoxy carbonyl, benzyloxycarbonyl or the like.The blocking group that is fit to for sulfydryl comprises-C (O)-R (wherein R is alkyl, aryl or aryl alkyl), p-methoxy-benzyl, trityl or the like.The blocking group that is fit to for carboxylic acid comprises Arrcostab, aryl ester or aralkyl ester.
The routine techniques known and as described herein according to the described technical staff in this area can add or remove blocking group.
The purposes of blocking group is referring to Theodora W.Greene, Peter G.M.Wuts, Protective groups in Organic Synthesis (1999), 3rd Ed., the detailed description among the Wiley-Interscience.Described blocking group can be the polymer resin such as Wang resin or 2-chloro trityl chlorination resin.
Those skilled in the art also can understand; although the protection derivant of this general formula (I) chemical compound as mentioned above (for example; described in the general introduction and thiazolidinone compound and derivant of this paper); may not have so pharmacological activity, but they can to the mammal administration and subsequently in vivo metabolism form the chemical compound with pharmacological activity of the present invention.Therefore this derivant is called " prodrug ".The prodrug of all general formulas (I) all within the scope of the invention.
Following reaction scheme has shown the method for preparing The compounds of this invention.Should be understood that those skilled in the art can prepare chemical compound of the present invention according to similar methods with according to the described technical staff's known method in this area.Usually, from such as the source of Aldrich or according to the known source of described technical staff, this area synthetic obtain starting ingredient (referring to for example, Smith and March, March ' s Advanced Organic Chemistry:Reactions, Mechanisms, andStructure, 5
ThEdition (Wiley Interscience, New York)).In addition, can be according to the described technical staff's known method in this area with various substituted radicals (for example, the X of The compounds of this invention
1, X
2, X
3, Y
1, Y
2And Y
3Deng) be connected on described starting ingredient, intermediate species and/or the end-product.
In following reaction scheme, R represents the alkyl or aryl alkyl, the halogen atom of W representative such as Cl, Br or I.
Following reaction scheme 1 is at the preparation of general formula (1) chemical compound, and it is the chemical compound (for example, described in the general introduction and thiazolidinone compound and derivant of this paper) of the invention described above, wherein A
4Do not exist, and A
1, A
2, A
3, X
1, X
2, X
3, Y
1, Y
2And Y
3(for example, described in the general introduction and thiazolidinone compound and derivant of this paper) as mentioned above.
Usually, at first by general formula (a) chemical compound and equivalent such as the alkali of NaOH prepared in reaction general formula (1) chemical compound at room temperature.To be dissolved in suitable adding in the reactant mixture subsequently such as the general formula in the solvent of THF (b) chemical compound.Then with the reactant mixture stir about that produced 1 hour-Yue 24 hours.Again a kind of acid such as HCl is added in this reactant mixture.Then with the reactant mixture stir about that produced 1 hour-Yue 24 hours.Separation by routine separates from this reactant mixture with the chemical compound of purification technique with general formula (c).Under the Knoevenagel of routine condensation condition, subsequently this general formula (c) chemical compound and the reaction of general formula (d) chemical compound are produced required general formula (1) product.
Selectively, can prepare general formula (1) chemical compound, wherein A according to following reaction scheme 2
1, A
2, A
3, Y
1, Y
2And Y
3(for example, described in the general introduction and thiazolidinone compound and derivant of this paper) as mentioned above, and W is a halogen:
Usually, at first by under the Knoevenagel of routine condensation condition, for example in glacial acetic acid, ethanol and other appropriate solvent of the piperidines that contains catalytic amount, under refluxad, general formula (e) chemical compound and the reaction of general formula (f) chemical compound are produced general formula (1) chemical compound.Separation by routine subsequently separates general formula (g) chemical compound with purification technique from this reactant mixture.Then under the Ullmann of standard condensation condition, for example elevated temperature and Cu and Cu
2Under the existence of O or CuO, produce required general formula (1) product with general formula (h) compound treatment general formula (g) chemical compound.
Selectively, prepare general formula (1) chemical compound, wherein A according to following reaction scheme 3
1, A
2, A
3, Y
1, Y
2And Y
3(for example, described in the general introduction and thiazolidinone compound and derivant of this paper) as mentioned above, and W is a halogen.
In this reaction scheme, the first step produces the chemical compound of general formula (c) for Ullmann condensation between general formula (e) chemical compound and general formula (h) chemical compound, and itself and general formula (d) chemical compound carry out the Knoevenagel condensation and produce required general formula (1) product subsequently.
Can buy or according to method well known in the art or utilize F.C.Brown et.al., J.Am.Chem.Soc., 78,384-388 (1956) from different chemical supplier; R.E.Strube, OrganicSynthesis, CV 4,6; K.S.Markley and E.E.Reid, J.Am.Chem.Soc., 52, the initial compounds of the synthetic described general formula (e) of disclosed similarity method among the 2137-2141 (all these documents are all quoted reference as this paper at this).
With above-mentioned similar methods, the 3-[(3-trifluoromethyl) phenyl]-the 5-[(4-carboxyl phenyl) methylene]-(this paper refers to CFTR to 2-thioxo-4-thiazolidinone
Inh-172) (referring to Fig. 1 C) and the analog that contains diverse location trifluoromethyl and carboxyl substituent are (referring to for example, Fig. 1 D) synthetic is by with 2-sulfo--3-[a-trifluoromethyl-4-phenyl]-4-thiazolidone (a=2,3 or 4) carries out the Knoevenagel condensation with b-carbonyl benzaldehyde (b=2,3 or 4) in the presence of piperidines finishes.Filter this precipitation, use washing with alcohol, drying, recrystallization produces bright yellow crystal (70-85% yield) for 2-3 time from ethanol.By
1H-NMR verifies structure.Prove that by thin layer chromatography and HPLC its purity is>99%.
Embodiment
Provide following embodiment and how to prepare and use complete disclosure and description of the present invention for those skilled in the art provide, rather than the restriction of present inventor's invention scope, and be not that the following experiment of expression is all experiments or has only carried out these experiments.Guarantee accurately for employed data (for example, dosage, temperature or the like) as far as possible, but some experimental erroies and depart from and should take into account.Unless other explanation is arranged, ratio is that part by weight, molecular weight are that mean molecule quantity, temperature are represented with Celsius temperature, and pressure is atmospheric pressure or near atmospheric pressure.
Synthesizing of The compounds of this invention by following indefiniteness embodiment example.
Synthetic embodiment
The 3-[(3-trifluoromethyl) phenyl]-the 5-[(4-carboxy phenyl) methylene]-2-thioxo-4-thiazolidinone synthetic
A. stir down, in 30 minutes to 3-trifluro toluidine (trifluromethylanilne) (1.6g, 10mmol) and triethylamine (1g, dropwise add in ethyl acetate 10mmol) (10mL) solution Carbon bisulfide (0.8g, 10mmol).Carry out an about half when adding step, begin slight exothermic reaction, can control easily by using the ice bath that is interrupted.After stirring is spent the night, filter the ether washing precipitation that deep yellow viscous solution is also used 50mL, air drying, the light yellow dithiocarbamate solid of acquisition 3g (89%), m.p.92-95 ℃ (dec.).
B. stir chloracetic acid sodium (with chloracetic acid (0.064g, 0.46mmol) NaHCO of adding 0.6mL
3Solution prepares among the pH 8-9) and be cooled to 5-10 ℃, in 10 minutes, add dithiocarbamate (0.3g, 0.9mmol).Continue to stir and be warmed up to ambient temperature up to this flask.After stirring 2 hours, solution is cooled to 10 ℃ also uses the concentrated hydrochloric acid acidify, and this reactant mixture is heated to 90-95 ℃, 30 minutes.Filter the precipitation produced, wash with water and recrystallization produces 2-sulfo--3-(3-trifluoromethyl)-4-thiazolidone of 0.103g from ethanol luminescent crystal, yield 83%, m.p.177-178 ℃,
1H NMR (300MHz, CDCl
3): δ 4.18 (s, 2H, CH
2), 7.40 (d, 1H, phenyl, J=8.0Hz), 7.48 (s, 1H, phenyl), 7.64 (t, 1H, phenyl, J=8.0Hz), 7.72 (d, 1H, phenyl, J=7.6Hz) ppm.
C. (0.1g is 0.36mmol) with 4-carboxyl benzaldehyde (0.054g, the mixture of dehydrated alcohol 0.36mmol) (1mL) and piperidines (1) 30 minutes for 2-sulfo--3-(3-the trifluoromethyl)-4-thiazolidone of the above-mentioned acquisition of backflow under stirring.Filter yellow mercury oxide, use washing with alcohol, dry and from the solid target compound of yellow crystal of ethyl alcohol recrystallization generation 0.108g (73%), m.p.:180-182 ℃,
1H NMR (300MHz, DMSO-d
6): δ 7.78 (d, 2H, carboxy phenyl, J=8.2Hz), 7.80-8.00 (m, 5H, trifluoromethyl and CH), 8.07 (d, 2H, carboxyl phenyl, J=8.31Hz), 13.20 (s, 1H, COOH, alternative D
2O) ppm.
D. use and above-mentioned similar methods, prepare following chemical compound:
The 3-[(3-trifluoromethyl) phenyl]-5-[(3-carboxyl-4-hydroxy phenyl) methylene]-2-thioxo-4-thiazolidinone;
The 3-[(3-trifluoromethyl) phenyl]-5-[(3,4,5-trihydroxy phenyl) methylene]-2-thioxo-4-thiazolidinone;
The 3-[(3-trifluoromethyl) phenyl]-5-[(2,3,4-trihydroxy phenyl) methylene]-2-thioxo-4-thiazolidinone;
3-[(3-trifluoromethyl-4-fluorine) phenyl]-5-[(3-carboxyl-4-hydroxy phenyl) methylene]-2-thioxo-4-thiazolidinone; And
3-[(4-fluoro-3-trifluoromethyl) phenyl]-the 5-[(4-carboxyl phenyl) methylene]-2-thioxo-4-thiazolidinone.
Following material and method are used for the following examples.
Cell strain, mice and chemical compound
According to reporting in the past that (Galietta et al.2001 J.Biol.Chem.276:19723-19728) produced Fischer rat thyroid (FRT) cell and the halogen indicator YFP-H148Q of coexpression human wild type CFTR.Density with 20,000 cells in every hole is deceived cell inoculation in the wall platelet (Corning Costar) in 96 holes of the Coon ' s improvement F12 culture fluid that contains 5% hyclone, 2mM L-glutaminate, 100U/mL penicillin and 100 μ g/mL streptomycins.In inoculation back 48 hours, to analyze, this moment, cell was just for merging monolayer (every hole-40,000 cell).
Utilize different collect from ChemBridge (San Diego, 50,000 kinds of medicine sample chemical compounds CA) carry out initial screening, this chemical compound obtains with the 10mM storage solutions form among the DMSO and be diluted to 100mM in 96 hole platelet.To (SanDiego, the structure-activity of analog CA) is analyzed available from ChemBridge and ChemDiv.
Wild type and cystic fibrosis (Δ F508 homozygote mutant) mice is by University ofCalifornia, and the CF animal feeding center of San Francisco (UCSF) (Animal Core facility) raises.Authorize zoopery by UCSF zooscopy committee (Committee on Animal Research).
Obtain T84 and Caco-2 cell from UCSF cell culture center.With the T84 cell culture in 1: 1 blended DMEM that contains 5% hyclone, 100U/mL penicillin, 100 μ g/mL streptomycins and Hams F12 culture fluid and be seeded among the Snapwell inserts (Corning Costar), at (the 5%O of humidity
2/ 95%CO
2) atmosphere, 37 ℃ of cultured cells.The inoculation back was used cell in 10-14 days.The Caco-2 cell culture in the DMEM that contains 10 hyclones, 1% non essential amino acid, 100U/mL penicillin, 100 μ g/mL streptomycins, is cultivated on Snapwell inserts.21-24 days use cells after inoculation.The wild-type mice of CD1 genetic background such as above-mentioned raising.Male Wistar rat (200-250g) is available from the Jackson laboratory.By zooscopy committology zoopery.Obtained fresh people's colonic segment at that time and transferred in the ice-cold saline in that excision is operating, used in back 1 hour in excision.
Forskolin, 8-bromine cGMP, amiloride (amiloride), cholera toxin and STa toxin available from Sigma Chemical Co. (St.Louis, MO).CFTR
ACT~16 from ChemBridge (SanDiego, CA).
The screening step
Utilize the screening system (Beckman) of customization to analyze, this system contains 3-meter mechanical hand, CO
2Incubator, dull and stereotyped lotion device, liquid handling platform (liquid handling workstation), bar code reader, the platform of uncapping (delidding station) and two FluoStar fluorescence plate count device (BMG Labtechnologies, Offenburg, Germany), (500 ± 10nm) excite and HQ535/30M (535 ± 15nm) emission filters (Chroma) for two syringe pumps of every outfit and HQ500/20X.SAMI version 3.3 softwares (Beckman) that utilization improves at two plate count devices assemble robot system.User software writes VBA (Visual Basic forApplications) and calculates baseline deduction, standardization fluorescence gradient (fluorescence slopes) (providing the halogenide rate of influx) from the data file that stores.
By at described incubator (37 ℃, 90% humidity, 5%CO
2) in load the 40-60 piece and contain 96 orifice plates of FRT cell, in conveyer belt, load 96 orifice plates and the disposable plastic suction pipet head that contains test compound, set up described analysis.For beginning to analyze, to 3 times (300uL/ washs) of each aperture washing in 96 orifice plates at every turn, stay 50 μ LPBS with PBS.Add the CFTR-activation cocktail (5 μ M forskolins, 100 μ M IBMX, the PBS liquid of 25 μ M celery flavin) of 10 μ L, after 5 minutes, add the final concentration that a kind of test compound (the 1mM DMSO solution of 0.5 μ L) obtains 10 μ M to every hole.After 10 minutes, 96 orifice plates are transferred to the plate count device carry out fluorescence analysis.By continuous record fluorescence (every some 200ms) 2 seconds (baseline), and adding fast (<0.5s) 160 μ L isosmolar PBS (137mM Cl wherein
-By I
-Replacement) write down again 12 seconds after, analyze the I of the CFTR-mediation in every hole respectively
-Transhipment.
[cAMP] and oxicity analysis in the cell
The analysis of [cAMP] and phosphatase was as reported (Galietta et al.2001 J. Biol.Chem.276:19723-19728) in the past.Utilize dihydro rhodamine (dihydrorhodamine) method to cultivate 24 hours post-evaluation cytotoxic effects with 0-1000 μ M inhibitor at cell.Utilize serum chemistry and analysis of Hematology Changes (UCSF clinical laboratory) to estimate the toxic action of animal in the inhibitor injection back of mice being carried out intraperitoneal 0-100ug/kg every day in the time of the 5th day.
The MDR-1 activity
By detecting in immortal people's tracheal cell strain 9HTEo-/Dx
3The H-vincristine is accumulated and is estimated the MDR-1 activity, wherein endogenous MDR-1 up-regulated (Rasola et al.1994 J. Biol.Chem.269:1432-1436) in the selection that increases doxorubicin concentration.With cell inoculation (200,000 cells/every hole) in 24 hole platelets.After 48 hours, with containing (unit is mM): 130 NaCl, 2KCl, 1 KH
2PO
4, 2 CaCl
2, 2 MgCl
2, 10 Na-Hepes (pH 7.3) and 10 glucoses the solution washing cell, and with containing
3H-vincristine (0.7 μ M; 1 μ Ci/mL) 200 μ l same solution were hatched 1 hour at 37 ℃.Also use 0.25M NaOH cracking three times with ice-cold solution washing cell.Measure the content of vincristine by scinticounting.
Utilize CFTR to express the FRT cell and carry out the short circuit current test
The Snapwell inserted sheet (Snapwell inserts) that will contain the FRT cell of expressing CFTR or human bronchial epithelial cell is packed in the Ussing tank systems.For the FRT cell, be full of half groove with the 75mMNaCl of 5mL and 75mM gluconic acid sodium salt (top) and 150mM NaCl (substrate) (pH 7.3), and come that with 250 μ g/mL amphotericin Bs basement membrane is carried out permeability and handle (Galiettaet al.2001 J. Biol.Chem.276:19723-19728).Mapping bronchial epithelial cell and T84 cell, two and half grooves all contain the Krebs bicarbonate solution.With air (FRT cell) or contain 5%CO
2Air (bronchus and T84 cell) double groove continuous charge and remain on 37 ℃.(World Precision Instruments, Sarasota Florida) utilize Ag/AgCl electrode and 1M KCl agar bridge to come the continuous record short circuit current by DVC-1000 voltage patch-clamp.
Cl
-The patch clamp analysis of channel activity
Detect membrane current with complete cyto-architectural form.For record Cl
-Passage, used extracellular (bath) solution contains (unit is mM): 150 NaCl, 1 CaCl
2, 1 MgCl
2, 10 glucoses, 10 mannitols, 10 TES (pH 7.4), and (pipet) solution contains in the cell: 120 CsCl, 1MgCl
2, 10 TEA-Cl, 0.5 EGTA, 1 Mg-ATP, 10 Hepes (pH 7.3).In the solution of described extracellular, CFTR is activated with forskolin (5 μ M).Monitoring film transduction right-100 and+time course of 80mV alternate voltages pulse reaction.In the time of determining, interrupt experiments produce current-voltage relation (potential pulse with the increasing degree of 20mV from-100 increase to+100mV).The responsive Cl of capacity
-(extracellular NaCl is reduced to 120 NaCl to passage by the hypisotonic solution activation; 250mosM/kg).Activate the responsive Cl-passage of calcium in the human bronchial epithelial cell by in the solution of described extracellular, adding 100 μ M UTP.
The responsive K of ATP
+The patch clamp analysis of passage
The membrane potential of record pancreatic beta cell strain INS-1, wherein used extracellular (bath) solution contains (unit is mM): 130 NaCl, 2 KCl, 1 KH
2PO
4, 2 CaCl
2, 2 MgCl
2, 10 Na-Hepes (pH 7.3) and 10 glucoses.Used pipet contains (unit is mM): 140 KCl, 1 CaCl
2, 2mM MgCl
2, 10 EGTA, 0.5 MgATP, 10 K-Hepes (pH 7.3).After obtaining full cellularity, amplifier is transformed into current clamp (current-clamp) pattern.
Intestinal juice secretion and short circuit current
In 3 analyses of pro-, detected accumulation of fluid (the Oi et al.2002 Proc.Natl.Acad.Sci.USA 99:3042-3046 in the ileum ring; Gorbach et al.1971 J. Clin.Invest.50:881-889).The mice (or Δ F508 homozygote mice) (Mus 8-10 in age week, body weight 25-35g) that CD1 genetic background will be arranged after hungry 24 hours by lumbar injection Ke Taming (chlore-ammonia ketone, 40mg/kg) and xylazine (8mg/kg) anaesthetize.In operation, use heating cushion to make body temperature maintain 36 ℃-38 ℃.Adopt little abdominal incision to expose small intestinal and by sewing up the closed ileum ring (length 20-30mm) that separates nearly caecum.Separately come ring is injected with 100 μ L PBS or the PBS that contains cholera toxin (1 μ g).In some experiments, described inhibitor (150 μ g/kg) is by the intraperitoneal injection administration.Utilize to sew up and close abdominal incision and mice is revived from anesthesia.In the time of 6 hours,, from the abdominal cavity, take out intestinal ring, detection ring length and weight after removing mesentery and connective tissue with this mouse anesthesia.
In the adult mice secretory diarrhea model of sealing, utilize orogastric feeding syringe needle mouse stomach (gavage) to be dissolved in cholera toxin (10 μ g) (or giving buffer separately) (the Richardson et al.1986 Infect.Immun.54:522-528 of 7% bicarbonate buffer of 0.1mL; Gabriel et al.1999 Am J.Physiol.276:G58-G63).Four experimental grouies are: matched group (giving buffer separately), cholera processed group, cholera processing+inhibitor group (irritating preceding 2 minutes lumbar injection 150 μ g/kg of stomach) and independent inhibitor group.After 6 hours,, from the abdominal cavity, take out small intestinal (from the pylorus to the caecum) and peel off continuous mesentery and connective tissue mice euthanasia.Intestinal is weighed, vertically cut open subsequently and remove liquid in the chamber (by blotting) and weighing once more.Remove the intestinal anharmonic ratio value of front and back according to liquid in the chamber and calculate accumulation of fluid.For the detection of short circuit current, separate the colon bar of rat, separate by passivity and peel off Musclar layer, put into Ussing groove (area 0.7cm
2), be incubated in the oxygenate bicarbonate Ringers solution that contains 10 μ M indometacin (indomethacin).By adding amiloride (10 μ M), follow-up adding inhibitor suppresses Na to use forskolin (20 μ M) to stimulate also subsequently
+Electric current then detects short circuit current.
14The CFTR of C-labelling
InhSynthetic (Fig. 6) of-172
By in 30 minutes to the 3-5-trifluoromethylaniline (1.6g that stirs, 10mM) and triethylamine (1g, (0.8g 10mM) comes synthetic mesophase product 2-sulfo--3-(3-trifluoromethyl)-4-thiazolidone to drip Carbon bisulfide in ethyl acetate 10mM) (10mL) solution.Utilize ice bath to prevent to react overheated.After stirring is spent the night, filter the viscous solution of buff and wash the gained precipitation, obtain the light yellow dithiocar-bamate solid (92 °-95 ℃ of fusing points) of 3g (yield 89%) with air drying with the 50mL ether.Stir Br-
14The C-sodium acetate is (by Br-
14C-acetic acid prepares (Amersham), 55mCi/mmol, 64mg, is 0.46mM in 0.6mL water, utilizes NaHCO
3Regulate pH 8-9) and be cooled to 5 °-10 ℃, add in 10 minutes dithiocar-bamate (0.3g, 0.9mM).Lasting stirring makes this flask be raised to room temperature simultaneously.After 2 hours, described solution is cooled to 10 ℃,, and is heated to 90 °-95 ℃ maintenances 30 minutes with dense HCl acidify.Filter resulting precipitation, wash with water and from ethanol recrystallize obtain the required glossiness crystalline product of 103mg (yield 83%), m.D.177 °-178 ℃; Specific activity (
14C) 55mCi/mmol;
1H NMR (300MHz, CDCl
3): δ 4.18 (s, 2H, CH
2), 7.40 (d, 1H, phenyl, J=8.0Hz), 7.48 (s, 1H, phenyl), 7.64 (t, 1H, phenyl, J=8.0Hz), 7.72 (d, 1H, phenyl, J=7.6Hz) ppm.
For 2-sulfo--3-(3-trifluoromethyl)-5-[4-carboxyl phenyl methylene]-the 4-thiazolidone (
14C-5) (
14C-CFTR
Inh-172) synthetic, will be dissolved in 2-sulfo--3-(3-trifluoromethyl)-4-thiazolidone in the dehydrated alcohol (
14C-5) (100mg, 0.36mM) (54mg, 0.36mM) mixture and piperidines refluxed 30 minutes with the 4-carboxyl benzaldehyde.Filter the yellow mercury oxide of gained, with washing with alcohol, drying and from ethanol recrystallize obtain the yellow crystals of 108mg (yield 73%), m.p.180 °-182 ℃; Specific activity (
14C) 54mCi/mmol;
1H NMR (300MHz, DMSO-d
6): δ 7.78 (d, 2H, carboxyl phenyl, J=8.2Hz), 7.80-8.00 (m, 5H, trifluoromethyl and CH), 8.07 (d, 2H, carboxyl phenyl, J=8.31Hz), 13.20 (s, 1H, COOH, D
2The O exchange) ppm.Recrystallization by repeatedly make purity reach>99.9%.
Pharmacokinetic
To be dissolved among the PBS (being titrated to pH 7.4) that contains 3%DMSO with NaOH
14C-CFTR
Inh-172 (50 μ Ci) bolus (bolus) arrived rat (male Sprague-Dawley rat, 360-420 gram) by the jugular vein intubate intravenously administrable of reserving in 1 minute.Collect blood in the specific time from jugular vein.Use the multi-functional scintillation counter of LS-6500 (Multi-PurposeScintillation Counter, Beckman) by scinticounting (Scintiverse SE, Fisher, CA) measure blood plasma (by with whole blood with 14,000g separated in centrifugal 10 minutes) in
14The C-radioactivity.Utilize WinNonLin software (Pharsight) to carry out pharmacokinetic analysis.After collecting last blood/tissue sample, put to death rat with excessive pentobarbital.All animal operations obtain the permission of UCSF zooscopy committee.
Tissue distribution and removing research
Will
14C-CFTR
Inh-172 (2 μ Ci) bolus in 1 minute by be administered in the tail cava vein mice (male CD1 mice, 30-35g).Put to death mice at 5,30,120 and 240 minutes.Exteriorize, weigh and in distilled water (10-50 volume %), grind.Measure radioactivity and be expressed as the total of every organ by homogenate (25-50 μ L) being carried out scinticounting
14C-radioactivity (or be every gram tissue to skeletal muscle).In the identical moment, collect blood, urine and bile (from gallbladder and duodenum), detect
14The C-radioactivity also is expressed as the form of every mL liquid.
14C-CFTR
InhRemove research by collecting urine and feces in first 24 hours after-172 administrations.Through with pharmacokinetic in carried out tissue distribution research in the rat of identical processing.
The inhibitor metabolic analysis
On silica plate, by adopting ethyl acetate: hexane: the thin layer chromatography of methanol (1: 1: 0.1) dicyandiamide solution dissolves, and it obtains rf~0.5 for original inhibitor with the aliquot point of body fluid (blood plasma, urine, bile) and liver homogenate.Use Hyperfilm (Amersham) to carry out radioactive automatic developing with Transcreen LE amplification system (Kodak).Include in all plates
14The CFTR of C-labelling
Inh-172 standards.
Short circuit current detects (embodiment 7)
For cell research, the Snapwell inserted sheet (Snapwell inserts) that will contain the T84 cell monolayer put into the Ussing tank systems (Navicyte, Harvard Apparatus, Holliston, MA).With containing (unit is mM) NaCl 120, NaHCO
325, KH
2PO
43.3, K
2HPO
40.8, MgCl
21.2, CaCl
21.2, the Krebs-bicarbonate solution of glucose 10 (remaining on 37 ℃) is full of half groove, and feeds 5%CO continuously
2/ 95%O
2Gas.High K
+Buffer contains (unit is mM) NaCl 65, KCl 67.5, KH
2PO
41.5, CaCl
21, MgCl
20.5, HEPES 10, glucose 10.Low Cl
-Buffer contains (unit is mM) gluconic acid sodium salt 120, KH
2PO
43.3, K
2HPO
40.8, MgCl
21.2, CaCl
21.2, HEPES 10, glucose 10 (remaining on 37 ℃), and bubbling air continuously.For the intracolic detection of mice, come anesthetized mice by intraperitoneal injection ketamine (40mg/kg) and xylazine (8mg/kg).Take out ileum,, cut along mesenteric line, and put into little Ussing groove (area 0.7cm with ice-cold Krebs buffer washing
2, World PrecisionInstruments, Sarasota, FL).For the detection of people's intestinal, peel off the Musclar layer of colonic segment and put into above-mentioned groove by the passivity separation.Be full of half groove with the oxygenate Ringers bicarbonate solution that contains 10 μ M indometacin.Utilize Ag/AgCl electrode and 1M KCl agar bridge record short circuit current with DVC-1000 voltage clamp (World Precision Instruments).As described below agonist/inhibitor is added half groove.
In mice and the rat model at body intestinal juice secretion (embodiment 5 and 7)
Do not give food 24 hours to mice (Mus 8-10 in age week, a body weight 25-35g) feedwater with CD1 genetic background.Use heating cushion that body temperature is maintained 36 ℃-38 ℃ with the said method anesthetized mice and at intra-operative.Adopt little abdominal incision to expose small intestinal, and utilize and sew up the closed ileum ring (length 20-30mm) that separates nearly caecum.With the independent PBS of 100 μ L or contain PBS (1 μ g) the injection intestinal ring of cholera toxin.In some experiments, the specific time point before or after the cholera toxin injection carries out CFTR by lumbar injection
Inh-172 (0-200 μ g) administration.Close abdominal incision and mice is revived from anesthesia with stitching.In the time of 6 hours, anesthetized mice takes out the intestinal ring from the abdominal cavity,
Detection ring length and weight after removing mesentery and connective tissue.
For the liquid secretion that detects rat closed hoop model midgut toxin-induced, with pentobarbital sodium (45mg/kg) anesthesia male Wistar rat (body weight 200-250g).Separate intestinal ring (40-60mm) and with 300 independent μ L PBS or contain cholera toxin (10 μ g) or the PBS of STa toxin (0.1 μ g) injects.In some experiments, after cholera toxin or the administration of STa toxin, give CFTR by intraperitoneal injection
Inh-172 (200 μ g).Detection ring length and weight when 3 hours (STa) or 6 hours (cholera toxin).
CFTR
InhIn the research of-172 oral administration, use the open loop mouse model, wherein use orogastric feeding syringe needle to mice with 7% independent bicarbonate buffer or cholera toxin (1 μ g is dissolved in 7% bicarbonate buffer) and and CFTR
Inh-172 (200 μ g among the vitamin E TPGS are referring to as follows) are irritated stomach together.After 6 hours, from the abdominal cavity, take out small intestinal (from the pylorus to the caecum) and peel off related mesentery and connective tissue.This small intestinal of weighing, and vertically dig to open and remove chamber liquid, weigh once more with the accumulation of quantitative liquid.
The Caco-2 permeability is analyzed
The Caco-2 cell culture is reached 400-600 Ω cm on the porous inserted sheet
-1Impedance.For transhipment research, replace culture fluid with isopyknic Hank ' s buffer salt solution (HBSS), this solution contains 15mM glucose and 25mM HEPES (pH 7.3).After 1 hour, in last groove, add CFTR
Inh-172 (25 μ M) and at 37 ℃ of soft swing plates.(reception) groove takes out 50 μ L solution the end of from the specific time, absorbs (385nm) by UV and detects CFTR
Inh-172 concentration.Apparent permeability (Papp) calculates by following formula: Papp=dC/dTX (Vr/AC0), wherein dC/dT is CFTR in the receiving slit
InhAdvancing the speed of-172 concentration, Vr is the volume of receiving slit, A is the monolayer surface area, and C0 is the CFTR in the donor groove
Inh-172 initial concentrations.
The research of pharmacokinetics and oral administration biaavailability
Utilize Hal that mice is carried out of short duration anesthesia, and will be dissolved in vitamin E TPGS (d-alpha-tocopherol cetomacrogol 1000 succinate, 0.5%w/v) CFTR
Inh-172 are dissolved in the TPGS water slurry of 10%w/v)
14C labelling-CFTR
Inh-172 (12 μ Ci) per os is irritated stomach and is given mice.As a comparison, other mice gives by tail venoclysis intravenous
14C-CFTR
Inh-172 (2 μ Ci).Collecting blood at specific time point detects in the blood plasma
14The C radioactivity.In the time of 6 hours, put to death mice and exteriorize with excessive pentobarbital and be used for detecting the radioactivity of homogenate.
Biology, embodiment 1
The screening of CFTR inhibitor
The Preliminary screening art designs of identifying The compounds of this invention is to interact by direct CFTR-inhibitor to identify CFTR Cl
-The transduction inhibitor.Shown in the flow process of Figure 1A, be combined in CFTR-by the activation cocktail that contains forskolin, IBMX and celery flavin (apigenin) and express the pre-CFTR of stimulation in the FRT cell.Make and to identify to inhibitor that this inhibitor is directly blocked CFTR Cl by number of mechanisms activation CFTR (cAMP raises, phosphodiesterase suppresses and directly CFTR combination)
-Transporting pathway and not other in the disabling signal approach close on step.FRT cell coexpression yellow fluorescence protein is the Cl on basis
-/ I
-Induction apparatus, its provide the quantitative fluorescence sense analysis that suppresses effect (referring to for example, Jayaraman et al., 2000, J.Biol.Chem.275:6047-6050; Galiettaet al., 2001, Am.J.J.Physiol.281:C1734-C1742.).After pre-stimulation of CFTR and chemical compound adding, make cell be in introversive I
-In the gradient to order about I
-Interior stream also produces the fluorescence that reduces.Every kind of analysis comprises two seconds baseline fluorescence of record, contains I in quick the adding subsequently
-Solution after carry out 12 seconds continuous fluorescence record.Use full-automatic high flux screening equipment respectively in 96 orifice plate patterns detectable concentration be the chemical compound (referring to following embodiment 2) of 10 μ M.
Figure 1B is depicted as relative YFP fluorescence that the analytical method of utilizing Figure 1A obtains 50, the 000 chemical compound Preliminary screening representative curve to the time mapping.According to I
-The slope that adds back fluorescence reduction carries out quantitative analysis, and 49,993 chemical compounds are to I
-The kinetics of interior stream does not have significant effect (<10% slope reduces).The negative slope of seven kinds of chemical compounds has reduction (10-52%) by a small margin, and nearly all this compounds has similar structural core, and this core constitutes (Fig. 1 C) by the 2-thioxo-4-thiazolidinone heterocycle of phenylmethylene that has replacement and phenyl moiety.Screen and identify the most effective CFTR inhibitor surpassing 250 kinds of analog with thiazolidone core texture subsequently.
Fig. 1 D shows that the most effective thiazolidone CFTR inhibitor of identifying in the screening is the 3-[(3-trifluoromethyl) phenyl]-the 5-[(4-carboxyl phenyl) methylene]-(this paper is called CFTR to 2-thioxo-4-thiazolidinone
Inh-172), and five kinds have the analog that remarkable inhibition is renderd a service.Therefore following compounds is accredited as the CFTR inhibitor: the phenyl 3-[(3-trifluoromethyl)]-the 5-[(4-carboxyl phenyl) methylene]-2-thioxo-4-thiazolidinone (CFTR
Inh-172); The 3-[(3-trifluoromethyl) phenyl]-the 5-[(4-nitrobenzophenone) methylene]-2-thioxo-4-thiazolidinone (CFTR
Inh-020); The 3-[(3-trifluoromethyl) phenyl]-5-[(4-oxo carboxyl phenyl) methylene]-2-thioxo-4-thiazolidinone (CFTR
Inh-029); The 3-[(3-trifluoromethyl) phenyl]-5-[(3, the 4-dihydroxy phenyl) methylene]-2-thioxo-4-thiazolidinone (CFTR
Inh-1 85), the 3-[(3-trifluoromethyl) phenyl]-5-[(3,5-two bromos-4-hydroxy phenyl) methylene]-2-thioxo-4-thiazolidinone (CFTR
Inh-214) and the 3-[(3-trifluoromethyl) phenyl]-5-[(3-bromo-4-hydroxyl-5-nitrobenzophenone) methylene]-2-thioxo-4-thiazolidinone (CFTR
Inh-236).The most effective CFTR inhibitor comprises one or more electron withdraw groups, electron withdraw group or polar substituent on 3-trifluoromethyl group on for example above-mentioned ring 1 and the ring 2.Choose CFTR
Inh-172 are further analyzed.Relative effectivenes is: 0.2 (CFTR
Inh-020), 0.3 (CFTR
Inh-029), 1.0 (CFTR
Inh-172), 0.2 (CFTR
Inh-185), 0.1 (CFTR
Inh-214) and 0.1 (CFTR
Inh-236).
CFTR has been synthesized in the effect of the position on ring for check trifluoromethyl and carboxyl substituent
Inh8 kinds of analog of-172 wherein are transferred to described substituent group each unique location on ring 1 (trifluoromethyl) and ring 2 (carboxyls).With CFTR
Inh-172 relatively (render a service 1.0), the 3-[(a-trifluoromethyl) phenyl]-the 5-[(b-carboxyl phenyl) methylene]-the relative inhibition of 2-thioxo-4-thiazolidinone analog renders a service and is: 0.69 (a=2, b=2), (0.70 2,3), 0.66 (2,4), 0.74 (3,2), (0.90 3,3), 0.67 (4,2), (0.64 4,3) and 0.56 (4,4).
Biology, embodiment 2
CFTR
Inh-172 characteristic
The given dose of theme thiazolidinone compound can utilize the fluorimetry shown in Figure 1A to measure as mentioned above to the inhibition level of CFTR.Fig. 2 A is depicted as with the CFTR of relative YFP fluorescence to time representation
Inh-172 dosage-inhibition data.This thiazolidinone compound can be observed significant CFTR inhibitory action when 0.3-0.6 μ M concentration.Fig. 2 B shows CFTR
Inh-172 inhibitory action (being shown as the image of the relative transport velocity of adding or washing back to the time) was at~10 minutes (t
1/2Be 4 minutes) finish, and after washing with t
1/2Be by~5 minutes take a turn for the worse (illustration).Transport velocity shows CFTR shown in Fig. 2 C relatively
Inh-172 can suppress to be activated by the CFTR that the multiple agonist that is not included in the used activation cocktail combination of initial screening causes effectively.These agonist comprise genistein (genistein), CPT-cAMP, CPX, 8-MPO and powerful benzo cornel ketone (benzoflavone) CFTR activator UC
CF-029 (2-(4-pyridine) benzo [h] 4H-.alpha.-5:6-benzopyran-4-ketone disulfate) and benzimidazolone (benzimidazolone) CFTR activator UC
CF-853 (referring to Galietta, et al., 2001, J Biol.Chem.276:19723-19728).
Also carry out electric Physiological Experiment and set up CFTR
Inh-172 inhibition effectiveness and specificity.Fig. 3 A is depicted as CFTR
Inh-172 couples of CFTR express quick, the dose-dependent inhibitory action of the short circuit current in the FRT cell, wherein with CFTR
Inh-172 join in the solution of hatching the apical cell surface.Fig. 3 B has shown the CFTR that detects under the same conditions
Inh-172 (K
d~300nM, Hill coefficient~1) and glyburide (K
d~200 μ M) mean dose-inhibition relation.
Found that this thiazolidone is at the cell (primary culture that comprises T84 cell and human bronchial epithelial cell) of natural expression wild type CFTR and express and have similar inhibition in the transfection FRT cell of G551D-CFTR and Δ F508-CFTR and render a service (low temperature is proofreaied and correct back (lowtemperature correction)).For the research in the bronchus cell, block Na with amiloride
+Passage makes reference current depend on CFTR to a great extent.Behind the maximum activation of CPT-cAMP CFTR, use CFTR from tip side
Inh-172 have suppressed short circuit current (Fig. 3 C, left side) consumingly.When add fashionable CFTR from base side
Inh-172 also can suppress short circuit current (Fig. 3 C, right side).
Shown in Fig. 3 D, in CFTR-expression FRT cell, detected full cell membrane electric current.Stimulate with 5 μ M forskolins, can produce membrane current (total membrane capacitance 21 ± 3pF) of 381 ± 47pA/pF (n=4) at+100mV.As to desired this current-voltage relation of pure CFTR electric current being linear (Fig. 3 F).With 2 μ M CFTR
Inh-172 carry out the extracellular perfusion, and electric current is reduced rapidly, show the CFTR inhibitory action that non-voltage relies on.Utilize the CFTR of low concentration
Inh-172 (0.2 μ M) obtain~50% inhibitory action proof carrier frequency channel break shortage voltage-dependent (Fig. 3 F).
Also detected CFTR
Inh-172 pairs of inhibiting specificitys of CFTR.To two kinds of non-CFTRCl
-Passage is studied.The CFTR of 5 μ M concentration
Inh-172 can not suppress the Ca in the polar human bronchial epithelial cell
2+Activatory Cl-secretion, this secretion adds UTP (100 μ M) generation (Fig. 4 A) by hatching on the top in the solution.There is being and do not having CFTR
Inh-172 short circuit currents that exist maximum down UTP to rely on are respectively 9.9 ± 0.5 μ A/cm
2With 10.0 ± 0.2 μ A/cm
2(standard error, n=4).The CFTR of 5 μ M
Inh-172 can not block and carry out the extracellular with 250 mosM/kg hypisotonic solutions and be poured in the activatory Cl of the capacity that causes in the FRT cell
-Electric current (Fig. 4 B).
To the CFTR congener, ATP has carried out detecting (Rasola et al.1994J.Biol.Chem.269:1432-1436) in conjunction with the activity of cascade transduced element (ATP-binding cassette transpoter) MDR-1 (multi-drug resistance albumen-1) in crossing the 9HTEo-/Dx cell of expressing MDR-1.MDR-1 inhibitor verapamil (verapamil, 100 μ M) can make the accumulation of vincristine rise strongly, and its active medicine with the MDR-1 mediation is discharged oppositely relevant (Fig. 4 C).CFTR
InhTherefore the accumulation that-172 (5 μ M) do not influence vincristine does not suppress MDR-1.
Another kind of CFTR congener is sulphur urea (sulphonylurea) receptor (SUR), and it regulates the responsive K of ATP
+The activity of passage (K-ATP passage) (Aguilar-Bryan and Bryan 1999 Endocr.Rev.20:101-135).SUR1 expresses in pancreatic beta cell, and its may command membrane potential and insulin discharge.As glyburide, the sulphur urea causes that by the depolarization of blocking-up K-ATP passage and film insulin discharges (and hypoglycemic reaction).For determining CFTR
InhWhether-172 also block the K-ATP passage, and the membrane potential of pancreas in rat β cell strain INS-1 has been carried out detecting (Fig. 4 D, Fig. 4 E).Relative with the bigger film depolarization that glyburide causes, CFTR
Inh-172 (2 and 5 μ M) can not make the membrane potential depolarization.The CFTR of 5 μ M
Inh-172 can cause less hyperpolarization, and it is significantly less than the hyperpolarization that K-ATP channel activator diazoxide (diazoxide, 100 μ M) causes.Studies show that of other, the CFTR of 5 μ M
Inh-172 can not block aquaporin (AQP1), carbamide transport factor (UT-B), Na
+/ H
+Exchange factor (NHE3) and Cl
-/ HCO
3 -Exchange factor (AE1).
Further the analysis showed that the CFTR of 5 μ M
Inh-172 cAMP that can not influence cell produce or phosphatase activity.In the FRT cell, basic cAMP content is the every hole of 225 ± 22fmol/, and it stimulates at 20 μ M forskolins can increase to every hole of 1290 ± 190fmol/ (not having inhibitor) and 1140 ± 50 (+CFTR in back 30 minutes
Inh-172) (n=3).As judge CFTR after under the concentration of height to 100 μ M 24 hours with the analysis of dihydro rhodamine
Inh-172 pairs of FRT cells do not have toxicity.In mice, intraperitoneal injection every day 1000 μ g/kg CFTR
Inh-172 did not cause tangible toxicity totally in 7 days.Not minimizing of the picked-up of food and water, serum electrolyte concentration, glucose, liver function index, serum creatinine, amylase and hematocrit do not change.In addition, the CFTR of the big whole-body dose of single
Inh-172 (10 mg/kg) do not cause tangible toxicity.
Biology, embodiment 3
Render a service at body
Utilization is to the excretory two kinds of analyses of the inductive intestinal juice of cholera toxin, and in isolating intestinal by the short circuit current analysis to CFTR
Inh-172 effectiveness has carried out trying in body examination.In first kind of analysis, set up a series of small intestinal closed hoop at body, and the chamber of (alternate) ring has at interval been injected with a spot of saline or the saline that contains cholera toxin.Measure the accumulation of fluid in the chamber after 6 hours.Shown in Fig. 5 A, in the ring that cholera toxin is handled, tangible accumulation of fluid and expansion are arranged, and contiguous contrast (saline) ring remains sky.Single gives CFTR before the perfusion cholera toxin
Inh-172 (150 μ g/kg, intraperitoneal) can effectively prevent the accumulation of fluid in the intestinal ring that described toxin handles.
The data of a series of these experiments are summed up shown in Fig. 5 B.CFTR
Inh-172 make liquid secretion obviously be reduced to level in the saline control ring, and wherein nonactive thiazolidone analog can not suppress liquid secretion.As indicated in the data (Gabriel et al.1994 Science 266:107-109) in the past, the intestinal ring from homozygote Δ F508-CFTR mice that cholera toxin is handled also remains empty, show that CFTR has participated in the intestinal juice secretion.In second kind of analysis, by oral cholera toxin administration (10 μ g) and the CFTR of system
InhThe intestinal juice secretion is induced in-172 administrations.After 6 hours,, whole small intestinal detected tangible accumulation of fluid by being weighed.As shown, CFTR
Inh-172 administrations can obviously reduce the accumulation of intestinal juice, and the intestinal anharmonic ratio value of available chamber liquid before and after shifting out come quantification (Fig. 5 C).
Fig. 5 D has shown CFTR
Inh-172 pairs of inhibitory action of striding the short circuit current of complete rat colon mucosa.Suppress Na with amiloride
+Behind the electric current, forskolin can make short circuit current rise rapidly.With CFTR
Inh-172 is much bigger when joining in serous coat (serosal) solution to the inhibitory action ratio of short circuit current when joining in the mucosa solution, and the loss that this may be when arriving colon epithelial cell by remaining submucous tissue is relevant.In mucosa solution, add 5 μ M CFTR separately
Inh-172 can reduce>80% short circuit current.These results provide CFTR
Inh-172 in intestinal to CFTR Cl
-The electric physiology evidence that passage is inhibited.
Biology, embodiment 4
Pharmacokinetic analysis
Pour at the single dose intravenous
14The CFTR of C labelling
InhBehind-172 bolus, by to serum
14The series of carrying out the C radioactivity detects and has finished the pharmacokinetic analysis of rat.Dabbling inhibitor total amount (400 μ g ,~1mg/kg) can be effective as the diarrhea medicine of rat.Fig. 7 shows serum
14C radioactivity kinetics and two-compartment model coincide better, and have the distribution volume of 1.2L and the AUC (area under curve) of 3.8 μ ghr/mL.Half-life is 0.14hr (distributing again) and 10.3hr (removing).After the administration 72 hours in blood plasma, or in liver or kidney homogenate, do not detect in 14 days after the administration
14The CFT of C labelling
Inh-172.
Behind single dose intravenous perfusion bolus, can determine according to the radioactivity of organ homogenate and body fluid
14The CFTR of C labelling
Inh-172 tissue distribution.Among Fig. 8, figure A has summed up CFTR
Inh-172 perfusion backs specified time points is in the major organs of mice
14C distributes.At first in liver and kidney, observe in 5 minutes
14The C radioactivity, and reduce in time.In brain, heart, skeletal muscle or testis, almost do not find radioactivity.In later time point (30-240 minute),
14The C radioactivity is accumulated in intestinal.Among Fig. 3, figure B is presented at behind the intravenous perfusion bolus 60 minutes and detects in rat
14The analogous organs of C radioactivity distribute, and almost do not have radioactivity in brain, heart and skeletal muscle.In some experiments, in perfusion
14The CFTR of C-labelling
Inh-172 (50 μ Ci) back was put to death rat on the 10th day.
For determining CFTR
Inh-172 in kidney, liver and intestinal cumulative mechanism, detected in serum, urine and the bile
14The C radioactivity.In 2 hours after the perfusion, the mean urinary radioactivity of mice is 4.2 ± 1.2 * 10
5Cpm/mL.Urine and blood
14C radioactivity ratio is at 5-7: 1 scope, ratio~(1550mOsm is than 310mOsm) compared in 5: 1, showed CFTR with the mole osmotic pressure of urine and serum
Inh-172 are removed by kidney by glomerular filtration, and absorb or secretion without renal tubules.
14The roughly the same CFTR that supported of the kinetics that the C radioactivity reduces in serum, urine and nephridial tissue
Inh-172 kidney purge mechanisms of removing (data not shown).According to
14The C radioactivity in liver rapidly accumulation and subsequently in intestinal cumulative observed result studied CFTR
Inh-172 in bile cumulative probability.After to the mice administration 60 minutes, in the bile
14C radioactivity intensity is in the blood~9 times.For determining the CFTR in the bile
InhThe-172nd, being excreted in the feces still is to turn back in the circulation, in perfusion 24 hours behind the radiolabeled inhibitor urine and the feces of mice is collected.In urine, find 93 ± 3% excretory radioactivity, supported to utilize the renal excretion of enterohepatic circulation to be main mechanism.
For determining that in organ and body fluid detected 14C radioactivity is the corresponding complete CFTRinh-172 or the CFTRinh-172 of corresponding chemical modification, urine, serum and bile sample and the liver homogenate supernatant by centrifugal preparation are carried out thin layer chromatography and radioactive automatic developing.Figure 9 shows that the single speckle of rf~0.5 of the original CFTRinh-172 that corresponding bolus perfusion gives.The radioactive automatic developing of body fluid and organ homogenate shows single speckle at same rf place, show the chemical modification that CFTRinh-172 does not take place.
By spectrophotometric pH titration determination CFTR
Inh-172 for pKa be 5.5 weak acid.Under physiological pH ,~1% CFTR
Inh-172 exist with the nonionic acid with low polarity and high membrane permeability.CFTR in the above-mentioned cell model
Inh-172 are shown the feasibility of oral bioavailability preparation by quick picked-up, but are essential for avoiding precipitating the influence that prevents low gastric acid pH.The result who draws from these pharmacokinetics researchs shows, CFTR in rodent
Inh-172 remove by kidney and to be got rid of lentamente and chemical modification and CFTR do not take place
Inh-172 concentrate in bile and are accumulated in the intestinal.CFTR
Inh-172 can not obviously cross over blood brain barrier, and seldom find CFTR
Inh-172 accumulate in comprising other vitals of heart, lung, skeletal muscle and testis.CFTR
InhIt is useful that-172 slow kidney removing, intestinal accumulation and the characteristic that does not almost have blood brain barrier to permeate are used for anti-diarrhea agents.
Biology, embodiment 5
CFTR
Inh-172 inhibiting dosage effect and persistent period
The purpose of present embodiment is with above-mentioned and intraperitoneal injection single dose CFTR
InhThe relevant observed result of-172 effect expands in the closed intestinal ring model of mice and suppresses the liquid secretion effect that cholera toxin stimulates.Especially, the purpose of present embodiment is to detect to keep CFTR
Inh-172 inhibiting dose-effect relationships and the apparent half-life.
At first, thus measure the feature that intestinal ring Liquid Absorption and excretory kinetics are determined mouse model.For carrying out Absorption Study, 200 μ L PBS are expelled to independently the intestinal ring after, detect intestinal ring content liquid at specific time point.Among Figure 10, figure A is presented at~the quick Liquid Absorption that has 25 minutes the time 50% liquid to keep.Relatively (among Figure 10, scheme the illustration of A) with matched group, (20 μ g) carries out CFTR with the excretory dosage of the inductive intestinal juice of strong inhibition cholera toxin
Inh-172 intraperitoneal administration can not change the speed (detecting) of Liquid Absorption in the time of 30 minutes.For the research secretion, the intestinal ring is injected with cholera toxin (1 μ g is dissolved in 0.1mL PBS).Among Figure 10, figure B is presented at that liquid secretion slowly starts in 6 hours, this consistent (Gorbach et al.J.Clin.Invest.1971 50-881-889 with the research in rodent model in the past; Oi et al.Proc.Natl.Acad.Sci.USA 200299:3042-3046).The fast Absorption of liquid in intestinal shows under the normal condition, if secretion is blocked, cumulative liquid can be by fast Absorption in the enteric cavity of activation secretion back, indication in addition after giving cholera toxin the CFTR inhibitory action can prevent the accumulation of liquid effectively.
Among Figure 11, figure A has summed up CFTR in the mice
InhThe result of-172 docs-effects research wherein carries out the administration of single dose inhibitor immediately by lumbar injection after closed intestinal ring being carried out the cholera toxin perfusion.As viewed in the ring of non-cholera toxin injection, basic intestinal juice content (dotted line) is near zero.CFTR
InhThe inhibition of the accumulation of fluid in the intestinal ring of-172 pairs of cholera toxins injection can reach~and 90%, at~5 μ gCFTR
InhThe inhibitory action of-172 (150 μ g/kg) is 50%.In described docs-effect research, remove the CFTR of the single dose 20 μ g of the different time before and after the cholera toxin administration
InhOutside-172 administrations, the inhibiting persistent period is detected.Among Figure 11, figure B is presented at cholera toxin administration front and back and gave CFTR in 3 hours
InhAccumulation of fluid in-172 pairs of chambeies has significant inhibitory effect.But there was not significant inhibitory effect in preceding 6 hours in the cholera toxin administration.Consider 6 hour persistent period of cholera toxin load study, CFTR
Inh-172 inhibiting lasting t
1/2Be~9-10 hour.
Biology, embodiment 6
CFTR
Inh-172 oral administration biaavailability
Be test orally give CFTR
Inh-172 diarrhea effect, in mice to CFTR
Inh-172 pharmacokinetics is measured, and to CFTR
Inh-172 the Caco-2 monolayer transhipment of striding detects.Because CFTR
Inh-172 are nonpolar relatively weak acid (pKa 5.5), and it may precipitate under one's belt, so utilize two kinds of reagent-vitamin E TPGS and cyclodextrin that are commonly used to solubilising oral administration medicine to realize oral administration.Utilize
14The CFTR of C labelling
Inh-172 detect.
Among Figure 11, figure C has shown behind oral and intravenous administration
14C-CFTR
Inh-172 pharmacokineticss in mice.Intravenous administration produces higher initial serum-concentration, and it reduced (tissue distributes again) in~30 minutes, and the serum radioactivity is lower after just oral, arrives peaking at~60-90 minute, begins reduction subsequently.Among Figure 11, when figure D has summed up behind the oral and intravenously administrable 6 hours
14C-CFTR
Inh-172 organ distributes, and being presented in gastrointestinal tract and liver and the kidney has accumulation.
14The C radioactivity in bile than concentrated in the serum~10 times, and in feces, almost do not have radioactivity to drain (in 24 hours<10% total drainage radioactivity), show that enterohepatic circulation has promoted CFTR
Inh-172 accumulations in intestinal.Oral CFTR
Inh-172 administrations are compared (tissue/serum content at 4-6 hour) and are shown CFTR in the TPGS preparation with intravenous administration
Inh-172 oral administration biaavailabilities are 15-20%.
Among Figure 11, figure F shows CFTR
Inh-172 show linear increasing in striding the Caco-2 monolayer, derive thus CFTR
Inh-172 permeability coefficient is 16 * 10
-6Cm/s.This value is included in that (for example, pindolol (pindolol) is 36 * 10 in the span that various oral administration medicines are set up
-6Cm/s, sildenafil are 48 * 10
-6Cm/s) (Stenberg et al. J.Med.Chem. 200144:1927-1937.
Biology, embodiment 7
The inhibitory action of the liquid secretion of cGMP-and cAMP-mediation
Utilization is measured CFTR at body rat intestine ring model
InhThe inhibition effect of the liquid secretion of-172 couples of cGMP-and cAMP-mediation, and test CFTR
Inh-172 effects in alternate animal model.Guanyl (guanylyl) cyclase C receptor is expressed in the enterocyte (enterocytes) of rat, makes combination of STa toxin and cytoplasm cGMP raise (Mann et al.Biochem Biophys Rescommun 1997 239:463-466).Have been found that the STa toxin can cause liquid secretion (Cohen et al.Am J Physiol 1989 257:G118-123) after 3 hours in rat ileum.To the effective dosage of mice (600 μ g/kg) time, CFTR
Inh-172 can prevent the inductive liquid secretion of cholera toxin in the rat intestine ring (among Figure 12, figure A).For the liquid secretion of STa toxin-induced, with STa toxin (0.1 μ g is dissolved in 300 μ L PBS) the intestinal ring is injected, and after 3 hours detection ring weight.Among Figure 12, figure B shows CFTR
Inh-172 suppressed~75% intestinal juice secretion.
In mice and human intestinal epithelial's sheet, detected short circuit current, to estimate CFTR
InhThe inhibitory action of-172 pairs of transepithelial ion secretions.Among Figure 13, figure A has shown that forskolin or STa toxin (illustration) stimulate back CFTR
InhThe dosage of the short circuit current in-172 pairs of mice ileums relies on inhibitory action.To the chlorine secretion of cAMP and cGMP dependence, the CFTR of~5 μ M
Inh-172 all have 50% inhibitory action.Among Figure 12, figure B is presented at CFTR in people's colon
Inh-172 pairs of short circuit currents have similar inhibition to render a service.
Unfavorable observed result is CFTR
InhThe apparent inhibition of-172 pairs of intestinal short circuit currents (2-5 μ M) is renderd a service and is lower than the result who finds at the electrophysiologic study that several cell strains that comprise CFTR expression FRT cell (0.2-0.5 μ M) and Calu-3 cell (0.5 μ M) are carried out basically.There are several explanations to consider to this species diversity, comprise cell type difference, reach the CFTR of the enterocyte in the complete intestinal
Inh-172 limited, (inner negative cell electromotive force has reduced [CFTR in the cell in the membrane potential effect
Inh-172]), and ATP and CFTR
Inh-172 competition effect.
The short circuit current detection that the T84 colon epithelial cell carries out is analyzed this phenomenon.Shown in the experiment of the representativeness among Figure 14, figure A shows the CFTR chlorine transduction direct agonist CFTR that passes through cAMP agonist forskolin (left side), cell permeability cGMP analog 8-Br-cGMP (central authorities) or identified by high flux screening
ActAfter-16 stimulations ,~3 μ M CFTR
InhShort circuit current in-172 pairs of non-permeability T84 cell monolayers produces 50% inhibitory action.For measuring CFTR
Inh-172 render a service to weaken whether need complete cell relatively in the T84 cell, after carry out permeabilityization with amphotericin B pair cell basement membrane, and at Cl
-Gradient exists under (producing detectable electric current) short circuit current is detected.Among Figure 14, CFTR after figure B (left side) the demonstration permeabilityization
InhThe inhibition usefulness of-172 pairs of short circuit currents increases substantially.Figure 14 has summed up the docs-effect data, and figure B (central authorities) shows after the cell permeabilityization CFTR to from~3 to 0.3 μ M
InhThe apparent KI of-172 inhibitory action descends.Be test CFTR
Inh-172 usefulness in intact cell descend whether (to reduce [CFTR outside the cytoplasm pair cell by the negative membrane potential in inside
Inh-172]) cause, using high K
+Substrate has been carried out the short circuit current detection to the T84 cell after hatching the solution depolarization.Among Figure 14, figure C is presented at the CFTR that increases in the unpolarized cell
Inh-172 usefulness (KI~0.3 μ M) are recovered, and show that the cell membrane electromotive force is to CFTR
InhPlay a significant role in-172 usefulness.
According to above data, can infer that thiazolidine compound of the present invention is (with CFTR
Inh-172 for representative) to by having the diarrhea effect in the relevant diarrhoea of the enterotoxin secretion inducing diarrhoea, Traveller ' s and the AIDS complication that cause such as the product of the vibrio cholera (Vibrio cholerae) in escherichia coli (E.coli) and cholera enterotoxin (enterotoxogenic) organism.The CFTR inhibitory action can be used for by the attached treatment of the bacterial diarrheal of intestinal invasive such as clostruidium and Salmonella kind; Yet the CFTR inhibitory action can not reduce the mucosa injury that is produced by these organisms.Similarly, can not expect that the basic pathology that the CFTR inhibitory action can be corrected in the inflammatory bowel disease changes, but can reduce the secretory volume of intestinal juice body.Evidence suggests that recently the liquid secretion that is caused by the viral diarrhea such as rotavirus can have such as Ca
2+Mediation Cl
-Other mechanism of passage participates in, although the effect of CFTR in liquid secretion is still unclear, therefore can use The compounds of this invention to test in the animal model that is fit to.
To sum up, thiazolidone CFTR blocker CFTR
Inh-172 prevent cAMP and the inductive ion/liquid secretion of cGMP and do not influence intestinal juice and absorb in rodent and people's intestinal.Pharmacology that it is good and living features are used for the further diarrhea of exploitation and are laid a good foundation.
Though the present invention is described with reference to specific embodiment, it be appreciated for those skilled in the art that under the condition that does not depart from true spirit of the present invention and scope, can make various changes and carry out the equivalence replacement it.In addition, for adapting to particular environment, material, material compositions, process, process steps, can make various modifications according to target of the present invention, spirit and scope.All such modifications should be included in the appended claims scope of the present invention.
Claims (46)
1. general formula (Ic) chemical compound that form single with it or blended stereoisomer exists or the acceptable salt of its medicine purposes in preparing the medicine for the treatment of the individuality of suffering from the cystic fibrosis transmembrane conductance regulator protein disease states mediated, described morbid state is treated described general formula (Ic) chemical compound by the ion transport that suppresses the cystic fibrosis transmembrane conductance regulator mediation:
Y wherein
1, Y
2And Y
3Be independently selected from hydrogen, carbonic ester, carboxyl, halogen, nitro and hydroxyl.
2. purposes as claimed in claim 1, wherein said morbid state are the unusual intestinal secretion that increases.
3. purposes as claimed in claim 2, wherein said morbid state are secretory diarrhea.
4. purposes as claimed in claim 1, wherein said morbid state are the dirty disease of polycystic kidney.
5. purposes as claimed in claim 1, wherein said general formula (Ic) chemical compound is selected from:
The 3-[(3-trifluoromethyl) phenyl]-the 5-[(4-carboxyl phenyl) methylene]-2-thioxo-4-thiazolidinone.
6. purposes as claimed in claim 1, the trifluoromethyl in the wherein said general formula (Ic) is positioned at 2,3 or 4 of connected described phenyl.
7. purposes as claimed in claim 1, wherein said Y
2Be selected from hydroxyl, carboxyl, nitro, carbonic ester and halogen group.
8. purposes as claimed in claim 6, the trifluoromethyl in the wherein said general formula (Ic) is positioned at 3 of described phenyl.
9. purposes as claimed in claim 1, wherein said Y
2Be oh group.
10. purposes as claimed in claim 9, wherein said Y
1Be oh group.
11. purposes as claimed in claim 9, wherein said Y
1Be bromine.
12. purposes as claimed in claim 9, wherein said Y
3Be nitro.
14. general formula (Ic) chemical compound or the acceptable salt of its medicine that exist with its single or blended stereoisomer form suppress the purposes in the active medicine of cystic fibrosis transmembrane conductance regulator protein in the described cell, described general formula (Ic) chemical compound in preparation by the contact individual cells:
Y wherein
1, Y
2And Y
3Be independently selected from hydrogen, carbonic ester, carboxyl, halogen, nitro and hydroxyl.
15. purposes as claimed in claim 14, wherein said general formula (Ic) chemical compound is:
The 3-[(3-trifluoromethyl) phenyl]-the 5-[(4-carboxyl phenyl) methylene]-2-thioxo-4-thiazolidinone.
16. purposes as claimed in claim 14, the trifluoromethyl in its formula of (Ic) is positioned at 2,3 or 4 of connected described phenyl.
17. purposes as claimed in claim 14, the trifluoromethyl in its formula of (Ic) is positioned at 3 of described phenyl.
18. purposes as claimed in claim 14, wherein Y
2Be selected from hydroxyl, carboxyl, nitro, carbonic ester and halogen group.
19. purposes as claimed in claim 14, wherein Y
2Be oh group.
20. purposes as claimed in claim 19, wherein Y
1Be hydroxyl.
21. purposes as claimed in claim 19, wherein Y
1Be bromine.
22. purposes as claimed in claim 19, wherein Y
3Be nitro.
24. purposes as claimed in claim 14, wherein said medicine is ingestible.
25. purposes as claimed in claim 14, wherein said medicine further comprises the medicine acceptable carrier.
Suppress the cytocyst fibrosis 26. exsomatize in analyzing and stride the active method of film conduction regulating factor protein, comprise to be enough to suppress general formula (Ic) chemical compound or the acceptable salt of its medicine and the described cells contacting dosage, that form single with it or blended stereoisomer exists of cystic fibrosis transmembrane conductance regulator ion transport in the described cell, described general formula (Ic) chemical compound:
Y wherein
1, Y
2And Y
3Be independently selected from hydrogen, carbonic ester, carboxyl, halogen, nitro and hydroxyl.
27. general formula (Ic) chemical compound that exists with its single or blended stereoisomer form or the acceptable salt of its medicine are used for producing the purposes of the medicine of non-human animal's cystic fibrosis phenotype, described general formula (Ic) chemical compound in preparation:
Y wherein
1, Y
2And Y
3Be independently selected from hydrogen, carbonic ester, carboxyl, halogen, nitro and hydroxyl.
28.3-[(3-phenyl trifluoromethyl)]-the 5-[(4-carboxyl phenyl) methylene]-2-thioxo-4-thiazolidinone suffers from purposes in the medicine of the morbid state individuality relevant with the ion transport of the unusual increase that is caused by cystic fibrosis transmembrane conductance regulator in preparation treatment.
29. as purposes as described in the claim 28, the cystic fibrosis transmembrane conductance regulator ion transport of wherein said unusual increase is relevant with diarrhoea.
30. purposes as claimed in claim 29, wherein said diarrhoea are secretory diarrhea.
31. purposes as claimed in claim 28, wherein said morbid state are the dirty disease of polycystic kidney.
32. one kind contains thiazolidinone compound, and drug acceptable carrier, medicine can accept diluent and medicine and can accept at least a pharmaceutical composition in the excipient, described thiazolidinone compound is independently selected from:
The 3-[(3-trifluoromethyl) phenyl]-the 5-[(4-nitrobenzophenone) methylene]-2-thioxo-4-thiazolidinone;
The 3-[(3-trifluoromethyl) phenyl]-5-[(4-oxygen carboxyl phenyl) methylene]-2-thioxo-4-thiazolidinone;
The 3-[(3-trifluoromethyl) phenyl]-the 5-[(4-carboxyl phenyl) methylene]-2-thioxo-4-thiazolidinone;
The 3-[(3-trifluoromethyl) phenyl]-5-[(3, the 4-dihydroxy phenyl) methylene]-2-thioxo-4-thiazolidinone;
The 3-[(3-trifluoromethyl) phenyl]-5-[(3,5-two bromo-4-hydroxy phenyls) methylene]-2-thioxo-4-thiazolidinone; And
The 3-[(3-trifluoromethyl) phenyl]-5-[(3-bromo-4-hydroxyl-5-nitrobenzophenone) methylene]-2-thioxo-4-thiazolidinone.
33. as compositions as described in the claim 32, wherein said compositions does not contain can detected dimethyl sulfoxide.
34. contain general formula (Ic) chemical compound or the acceptable salt of its medicine that exist with its single or blended stereoisomer form, and drug acceptable carrier, medicine can be accepted diluent and medicine and can accept at least a pharmaceutical composition in the excipient:
Y wherein
1, Y
2And Y
3Be independently selected from hydrogen, carbonic ester, carboxyl, halogen, nitro and hydroxyl.
35. compositions as claimed in claim 34, the trifluoromethyl in its formula of (Ic) is positioned at 2,3 or 4 of connected described phenyl.
36. compositions as claimed in claim 34, wherein Y
2Be selected from hydroxyl, carboxyl, nitro, carbonic ester and halogen group.
37. compositions as claimed in claim 34, the trifluoromethyl in its formula of (Ic) is positioned at 3 of described phenyl.
38. compositions as claimed in claim 34, wherein Y
2Be oh group.
39. compositions as claimed in claim 38, wherein Y
1Be hydroxyl.
40. compositions as claimed in claim 38, wherein Y
1Be bromine.
41. compositions as claimed in claim 40, wherein Y
3Be nitro.
42. as compositions as described in the claim 34, wherein said compositions does not contain can detected dimethyl sulfoxide.
43. the purposes in the medicine of the described compositions of claim 32 cystic fibrosis transmembrane conductance regulator defective in preparation generation non-human animal, wherein the cystic fibrosis transmembrane conductance regulator ion transport is suppressed.
44. purposes as claimed in claim 43, wherein said animal are mammal or birds.
45. purposes as claimed in claim 44, wherein said mammal are non-human primates, Rodents or ungulate class.
46. purposes as claimed in claim 43, wherein said animal has the phenotype similar to cystic fibrosis.
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US10/262,573 US20040063695A1 (en) | 2002-09-30 | 2002-09-30 | Cystic fibrosis transmembrane conductance regulator protein inhibitors and uses thereof |
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US60/480,253 | 2003-06-20 |
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AR092857A1 (en) | 2012-07-16 | 2015-05-06 | Vertex Pharma | PHARMACEUTICAL COMPOSITIONS OF (R) -1- (2,2-DIFLUOROBENZO [D] [1,3] DIOXOL-5-IL) -N- (1- (2,3-DIHYDROXIPROPIL) -6-FLUORO-2- ( 1-HYDROXI-2-METHYLPROPAN-2-IL) -1H-INDOL-5-IL) CYCLOPROPANCARBOXAMIDE AND ADMINISTRATION OF THE SAME |
SI2914248T2 (en) | 2012-11-02 | 2023-12-29 | Vertex Pharmaceuticals Incorporated, | Pharmaceutical compositions for the treatment of cftr mediated diseases |
FR2999191B1 (en) | 2012-12-12 | 2016-02-05 | Lesaffre & Cie | PROBIOTIC STRAINS FOR THE TREATMENT AND / OR PREVENTION OF DIARRHEA |
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Non-Patent Citations (1)
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Synthesis and Fungitoxicity of Some5-Substituted-3-Polynitrophenyl Rhodanines. GUPTA et al.J.Indian Chem.Soc. 1978 * |
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AU2003277162B2 (en) | 2009-07-16 |
EA200500583A1 (en) | 2005-12-29 |
MXPA05003366A (en) | 2005-10-05 |
WO2004028480A3 (en) | 2004-07-01 |
EA009847B1 (en) | 2008-04-28 |
BR0314943A (en) | 2005-08-02 |
WO2004028480A2 (en) | 2004-04-08 |
NZ538809A (en) | 2008-06-30 |
JP2006503853A (en) | 2006-02-02 |
EP1549321A4 (en) | 2007-05-23 |
CN1684686A (en) | 2005-10-19 |
AU2003277162A1 (en) | 2004-04-19 |
CA2500498A1 (en) | 2004-04-08 |
EP1549321A2 (en) | 2005-07-06 |
KR20050061501A (en) | 2005-06-22 |
JP4977319B2 (en) | 2012-07-18 |
AU2003277162C1 (en) | 2009-12-24 |
PL376147A1 (en) | 2005-12-27 |
AP2005003292A0 (en) | 2005-06-30 |
CA2500498C (en) | 2012-08-21 |
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