CN104788423A - New cystic fibrosis transmembrane conductance regulator inhibitor - Google Patents
New cystic fibrosis transmembrane conductance regulator inhibitor Download PDFInfo
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- CN104788423A CN104788423A CN201510111497.9A CN201510111497A CN104788423A CN 104788423 A CN104788423 A CN 104788423A CN 201510111497 A CN201510111497 A CN 201510111497A CN 104788423 A CN104788423 A CN 104788423A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to amidoimidazole coupled dihydropyridone compounds represented by formula I, and/or medicinal salts thereof, a preparation method of the compounds and/or the medicinal salt a use of the compounds and/or the medicinal salts thereof in the treatment and/or prevention of cystic fibrosis (CF) related hereditary diseases induced by cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation, and a medicinal composition containing the compounds and/or the medicinal salts thereof. In the formula I, R<1> and R<2> are respectively independently selected from H, cyan groups, trifluoromethyl groups, halogens, (C1-C6) straight chain or branched chain alkyl groups, C3-12 alicyclic groups, phenyl groups, other (C5-C10) aryl groups, (C5-C10) heteroaryl groups or (C3-C7) heterocyclic groups.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of dihydropyridone described in claim and connect glyoxaline compound and physiologically acceptable salt thereof, their preparation and they treating and/or preventing the purposes lacked to cystic fibrosis, abnormal intestinal secretion, secretory diarrhea, the dirty disease of polycystic kidney, chronic obstructive pulmonary disease, chronic bronchitis, mucopolysaccharide disease and the congenital bilateral vas deferens increased in the relevant disease of male infertility that (CBAVA) cause.
Technical background
(English is cystic fibrosis transmembraneconductance regulator to cystic fibrosis transmembrane conductance regulator, be abbreviated as CFTR) (English is ATP bindingcassette in conjunction with box to belong to ATP, be abbreviated as ABC) member of translocator superfamily, and abc transport albumen have such as absorb nutritive substance, get rid of toxin, the multiple important biological function such as the cell-cell communication of mediation eukaryote and bacterium.More specifically, CFTR is the gated epithelium chloride channel of ATP that a kind of cAMP activates, be expressed in Mammals air flue, digestive tube (intestines, pancreas etc.) and reproductive tract epithelial top plasma membrane in, this is that chlorion provides approach and critical sites across the motion of top film, participate in the activation of the protein kinase A (PKA) being responsible for salt and fluid transport in multiple organ (comprising lung), and therefore regulate the salt of transepithelial and the transhipment ratio of water, so, in epithelial cell, the normal function of CFTR comprises breathing for maintenance and digests the electrolyte transport being organized in interior whole health is very crucial.The hormone, Toxins,exo-, cholera etc. of such as beta-adrenaline excitant can cause the increase of cAMP, and the phosphorylation of the activation of cAMP dependent kinases and described CFTR chloride channel also causes the opening of chloride channel thus.CFTR chloride channel function and a lot of disease-related, comprise the male infertility etc. that cystic fibrosis (CF), the intestinal secretion extremely increased, secretory diarrhea, the dirty disease of polycystic kidney, chronic obstructive pulmonary disease, chronic bronchitis, mucopolysaccharide disease and congenital bilateral vas deferens disappearance (CBAVA) cause.
CFTR is by about 1480 Amino acid profiles.These amino acid coding forms the tandem repeats in cross-film district, and and then constitutive protein matter, each repeat body comprises 6 transbilayer helixs and 1 nucleotide-binding domain.2 cross-film districts by a large band polarity with multiple phosphorylation site and adjustable (R)-territory be connected, described phosphorylation site is responsible for regulating channel activity and cell transport.
Cystic fibrosis (English is cystic fibrosis, is abbreviated as CF) is a kind of fatal autosomal recessive disease, is one of modal heredopathia in human body, is suddenlyd change cause by cftr gene.Major part CF sudden change shows as the minimizing of cell surface CFTR number of channels or the infringement of channel function (such as gate or conductance suddenly change), or two kinds of situations occur simultaneously.In the U.S., nearly 2,005 centesimal children and up to ten million adults suffer from CF relative disease, also have this recessive genetic disorder patient of similar equal amts in Europe.In the airway epithelial cell of CF patient endogenous expression CFTR sudden change cause the anion secretion of teleblem to reduce, make ion and fluid transport unbalance.The minimizing of anion transport makes the lung mucus accumulation of CF patient increase and the adjoint infected by microbes finally can leading causing death.Except suffering from the disease of respiratory tract aspect, CF patient generally also can suffer from typical gastrointestinal problems and pancreatic insufficiency, if treated not in time, also can cause death.In addition, most of male sex CF patient can not give birth to, and the fertility of women CF patient can reduce.
Although in the past few decades, the effort of modern medicine achieves progress in treatment CF, has made the life-span of CF patient greatly extend, and not yet finds the methods for the treatment of of effective directly target and CFTR again safely up to now.The pathogenesis that people understand cystic fibrosis is further contributed to the decoding of cftr gene, simultaneously for the diagnosis of this disease provides new clue.And the small-molecule drug increasing CFTR channel opener possibility is the potential therapeutic strategy of one for the treatment of CF, many this type of medicines of exploitation will contribute to the solution of CF problem.
Summary of the invention
The invention describes formula I, and/or their pharmacologically acceptable salt
Wherein, R
1and R
2independently be selected from hydrogen, cyano group, trifluoromethyl, halogen, (C separately
1-C
6) straight or branched alkyl, 3-12 unit alicyclic group, phenyl, other (C
5-C
10) aryl, (C
5-C
10) heteroaryl or (C
3-C
7) heterocyclic radical, wherein said heteroaryl or heterocyclic radical have the heteroatoms of 3 O, S or N at the most, and (C
1-C
6) straight or branched alkyl, 3-12 unit alicyclic group, phenyl, other (C
5-C
10) aryl, (C
5-C
10) heteroaryl or (C
3-C
7) heterocyclic radical separately independent sum replaced by 3 substituting groups at the most arbitrarily, described substituting group is selected from-OR ' ,-CF
3,-OCF
3,-SR ' ,-S (O) R ' ,-SO
2r ' ,-SCF
3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH
2)
2n (R ')
2,-OCH
2n (R ')
2,-CON (R ')
2,-(CH
2)
2oR ' ,-CH
2oR ' ,-CH
2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ')
2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH
2)
2n (R ')
2or-CH
2n (R ')
2;
The group that R ' is independently selected from hydrogen separately or replaces arbitrarily, described group is selected from (C
1-C
8) aliphatic group, have that 0-3 to be independently selected from that the 3-8 unit of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or have that 0-5 is independently selected from nitrogen, oxygen can saturated, the fractional saturation of the 8-12 unit of sulfur heteroatom or complete undersaturated bicyclic ring system, or formed together with the atom that connects with them of the R ' of twice appearance have that 0-4 3-12 unit being independently selected from the optional replacement of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or dicyclo.
Preferably, for formula I, wherein R
2for (C
1-C
6) straight or branched alkyl, 3-12 unit alicyclic group, and can be replaced by 3 substituting groups at the most arbitrarily by independent sum separately, described substituting group is selected from-OR ' ,-CF
3,-OCF
3,-SR ' ,-S (O) R ' ,-SO
2r ' ,-SCF
3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH
2)
2n (R ')
2,-OCH
2n (R ')
2,-CON (R ')
2,-(CH
2)
2oR ' ,-CH
2oR ' ,-CH
2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ')
2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH
2)
2n (R ')
2or-CH
2n (R ')
2;
The group that R ' is independently selected from hydrogen separately or replaces arbitrarily, described group is selected from (C
1-C
8) aliphatic group, have that 0-3 to be independently selected from that the 3-8 unit of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or have that 0-5 is independently selected from nitrogen, oxygen can saturated, the fractional saturation of the 8-12 unit of sulfur heteroatom or complete undersaturated bicyclic ring system, or formed together with the atom that connects with them of the R ' of twice appearance have that 0-4 3-12 unit being independently selected from the optional replacement of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or dicyclo.
Preferably, R
1for at the most by the phenyl that 3 substituting groups replace, and substituting group is preferably halogen, R simultaneously
2for (C
1-C
6) straight or branched alkyl.
For R
1substituting group, representational example is as follows,
Asterisk (*) represents that the carbon atom of this key and imidazole ring 4 is connected.
The invention still further relates to and preparing as the formula I of medicine (or medicament) and/or its pharmacologically acceptable salt the purposes prevented and/or treated in the medicine of following disease, be i.e. the male infertility that cystic fibrosis, abnormal intestinal secretion, secretory diarrhea, the dirty disease of polycystic kidney, chronic obstructive pulmonary disease, chronic bronchitis, mucopolysaccharide disease and congenital bilateral vas deferens disappearance (CBAVA) increased cause.
The invention still further relates to pharmaceutical preparation (or pharmaceutical composition), it contains at least one formula I of significant quantity and/or its pharmacologically acceptable salt, the vehicle of physiology tolerance and carrier, and also has other additives and/or other activeconstituentss in due course.Medicine can be Orally administered, such as, with pill, tablet, spraying sheet (lacqueredtablets), coating tablet, granule, hard and soft gelatin capsule, solution, syrup, emulsion, suspensoid or aerosol mixtures form.But, use and also can carry out as follows: per rectum administration, such as, with suppository form; Or parenteral admin, such as, through intravenously, intramuscular or subcutaneous with injection solution or infusion solution, micro-capsule, implant or the form implanting rod; Or through skin or topical, such as, with ointment, solution or tincture form; Or with other administrations, such as with aerosol or form of nasal sprays.
Pharmaceutical preparation of the present invention with itself known and the mode be familiar with by those skilled in the art prepare, except formula I and/or their pharmacologically acceptable salt and/or their prodrug, use pharmaceutically useful inert inorganic and/or organic carrier substances and/or additive.For the preparation of pill, tablet, coating tablet and hard gelatin capsule, such as lactose, W-Gum or derivatives thereof, talcum, stearic acid or its salt etc. may be used.The carrier substance of soft gelatin capsule and suppository has such as fat, wax, semisolid and liquid polyol, natural or sclerosis wet goods.The carrier substance being suitable for preparing solution, such as injection solution or emulsion or syrup has such as water, salt solution, alcohol, glycerine, polyvalent alcohol, sucrose, Nulomoline, glucose, plant wet goods.Be suitable for micro-capsule, implant or implant excellent carrier substance, the multipolymer of such as hydroxyethanoic acid and lactic acid.Pharmaceutical preparation is usually containing the formula I of 0.5 to about 90% weight of having an appointment and/or their pharmacologically acceptable salt and/or their prodrug.Activeconstituents formula I in pharmaceutical preparation and/or the amount of their pharmacologically acceptable salt and/or their prodrug usual about 0.5 to about 1000mg, preferably about 1 are to about 500mg.
Except the activeconstituents of formula I and/or their pharmacologically acceptable salt and carrier substance, pharmaceutical preparation can contain one or more additives, as the reagent of weighting agent, disintegrating agent, tackiness agent, lubricant, wetting agent, stablizer, emulsifying agent, sanitas, sweeting agent, tinting material, correctives, perfume compound, thickening material, thinner, buffer substance, solvent, solubilizing agent, acquisition depot effect, the salt changing osmotic pressure, Drug coating or antioxidant.They also can contain two or more formula I and/or their pharmacologically acceptable salt.When pharmaceutical composition contains two or more formula I, can according to the specific overall pharmacological property of pharmaceutical preparation to the selection of individual compound.Such as, the height potent compound that acting duration is shorter can combine by the long-acting compound lower with effect.With regard to substituting group in formula I is selected, the handiness that allows makes it possible to carry out numerous control to the biology of compound and physicochemical property, can select this kind of required compound thus.In addition, except at least one formula I and/or its pharmacologically acceptable salt, pharmaceutical preparation also can contain one or more other treatments or preventative activeconstituents.
When using formula I, dosage can in grace period and conveniently with doctor known and change, dosage should be suitable for the individual instances of often kind example.It depends on the character of such as applied particular compound, institute's disease therapy and severity, method of application and scheme or what treat is acute or chronic disease or whether prevent.The clinical method that the dosage be applicable to can utilize medical field known is set up.Generally speaking, the per daily dose obtaining results needed in the adult of heavily about 75kg is about 0.01 to about 100mg/kg, preferably about 0.1 to about 50mg/kg, special about 0.1 to about 10mg/kg (in each case with mg/kg batheroom scale).Special in using relatively a large amount of, per daily dose can be divided into some parts, and such as 2,3 or 4 parts are used.Usually, according to individual behavior, may be necessary to depart from described per daily dose up or down.
In addition, formula I can be used as the synthetic intermediate preparing other compounds, particularly other drug activeconstituents, and it such as can be obtained by introducing substituting group or modifying functional group by formula I.
In most of the cases, aftertreatment is carried out to the reaction mixture of the finalization compound containing formula I or intermediate, if necessary, by product by ordinary method purifying well known by persons skilled in the art.Such as, synthesized compound can utilize the method known to carry out purifying as crystallization, chromatogram or reversed-phased high performace liquid chromatographic (RP-HPLC) or based on such as compound size, electric charge or other separation methods hydrophobic.Similarly, the method known such as amino acid sequence analysis, NMR, IR and mass spectroscopy (MS) may be used for characterizing the compounds of this invention.
Therefore, following examples are parts of the present invention, unrestricted the present invention for illustrating.
Should indicate, the modification of non-substantial effect the present invention various embodiment activity is included in the scope of the invention disclosed herein.
Embodiment
The preparation of embodiment: N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 difluorobenzene base)-1H-imidazoles-2-base) cyclopropyl carboxamide
The bromo-1-of the first step: 2-(2,4 difluorobenzene base) ethyl ketone
In the chloroform (100mL) cupric bromide (28.6g, 128.0mmol) being added 1-(2,4 difluorobenzene base) ethyl ketone (10.0g, 64.0mmol) and ethanol (80mL) mixing solutions.Oil bath is heated to 80 DEG C, and insulation reaction about 10 hours.Cross and filter insolubles, add ethyl acetate (200mL), gained mixing solutions uses saturated aqueous common salt (200mL*2) and saturated sodium bisulfite solution (200mL*2) washing successively.Organic phase, through anhydrous sodium sulfate drying, is filtered, is removed solvent under reduced pressure, obtain 13.2g yellow oil, be the bromo-1-of 2-(2,4 difluorobenzene base) ethyl ketone, yield 87.8%.MS:m/z＝235.0、237.0(M+H
+)。
Second step: 2-(2,4 difluorobenzene base) imidazo [1,2-a] pyridine
Pyridine-2-amine (9.5g, 0.1mol) is added in glycol dimethyl ether (200mL) solution of the bromo-1-of 2-(2,4 difluorobenzene base) ethyl ketone (23.5g, 0.1mol).Reaction solution is heated to 100 DEG C of reactions after about 8 hours, removes solvent under reduced pressure.Gained crude product is through mixed solvent (methyl alcohol: the methyl tertiary butyl ether=1:10) recrystallization of methyl alcohol and methyl tertiary butyl ether, precipitation, filtration also vacuum-drying obtain 19.7g white solid, are 2-(2,4 difluorobenzene base) imidazo [1,2-a] pyridine, yield 85.2%.MS:m/z＝232.1(M+H
+)。
The bromo-2-of 3rd step: 3-(2,4 difluorobenzene base) imidazo [1,2-a] pyridine
N-bromo-succinimide (11.6g, 64.9mol) is added in chloroform (200mL) solution of 2-(2,4 difluorobenzene base) imidazo [1,2-a] pyridine (15.0g, 64.9mmol).Reaction solution is heated to 80 DEG C of reactions after about 3 hours, is cooled to room temperature, adds methylene dichloride (200mL).Gained reaction solution saturated sodium bicarbonate solution washing (200mL*3).Organic phase, after anhydrous sodium sulfate drying, is filtered, is removed solvent under reduced pressure, obtain 18.9g white solid, be the bromo-2-of 3-(2,4 difluorobenzene base) imidazo [1,2-a] pyridine, yield 93.9%.MS:m/z＝310.0、312.0(M+H
+)。
4th step: 1-sec-butyl-5-(2-(2,4 difluorobenzene base) imidazo [1,2-a] pyridin-3-yl) pyridine-2 (1H)-one
By sodium carbonate (21.2g, 0.20mol), 1-sec-butyl-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridine-2 (1H)-one (15.2g, 0.055mol), tetra-triphenylphosphine palladium (2.9g, 2.5mmol) add the bromo-2-(2 of 3-successively, 4-difluorophenyl) imidazo [1,2-a] pyridine (15.5g, 0.05mol) tetrahydrofuran (THF) (200mL) solution in.Reaction solution is heated to 85 DEG C of reactions after about 10 hours, is cooled to room temperature.With ethyl acetate (200mL) dilute reaction solution.Gained mixture is with saturated common salt water washing (200mL*3).Merge organic phase, after anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, residuum obtains 12.4g yellow solid through purification by silica gel column chromatography (gradient elution, elutriant is sherwood oil: ethyl acetate=40:1 to 4:1), be 1-sec-butyl-5-(2-(2,4-difluorophenyl) imidazo [1,2-a] pyridin-3-yl) pyridine-2 (1H)-one, yield 65.2%.MS:m/z＝381.2(M+H
+)。
5th step: 5-(2-amino-4-(2,4 difluorobenzene base)-1H-imidazoles-5-base)-1-sec-butyl pyridine-2 (1H)-one
By hydrazine hydrate (55% aqueous solution, 9.8g, 0.1mol) add 1-sec-butyl-5-(2-(2,4-difluorophenyl) imidazo [1,2-a] pyridin-3-yl) pyridine-2 (1H)-one (7.6g, 20.0mmol) ethanol (100mL) solution in.Reaction solution oil bath is heated to reflux and after reacting about 10 hours, is cooled to room temperature.Remove solvent under reduced pressure, residuum ethyl acetate (150mL) is dissolved, and gained solution is with saturated common salt water washing (100mL*2).Organic phase is after anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, residuum obtains 5.2g yellow solid through purification by silica gel column chromatography (elutriant is methylene dichloride: methyl alcohol=40:1), be 5-(2-amino-4-(2,4-difluorophenyl)-1H-imidazoles-5-base)-1-sec-butyl pyridine-2 (1H)-one, yield 75.5%.MS:m/z＝345.1(M+H
+)。
6th step: N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 difluorobenzene base)-1H-imidazoles-2-base) cyclopropyl carboxamide
At 5-(2-amino-4-(2,4-difluorophenyl)-1H-imidazoles-5-base)-1-sec-butyl pyridine-2 (1H)-one (4.0g, N 11.6mmol), in dinethylformamide (60mL) solution, successively add 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (i.e. EDCIHCl, 4.45g, 23.2mmol), N, N-lutidine-4-amine (i.e. DMAP, 0.71g, 5.8mmol), Anhydrous potassium carbonate (3.2g, 23.2mmol) and ethylene-acetic acid (1.5g, 17.4mmol).Under room temperature, reaction is spent the night, and TLC monitoring (sherwood oil: ethyl acetate=1:1) is until react completely.With ethyl acetate (200mL) dilute reaction solution.Gained mixture is with saturated common salt water washing (100mL*3).Organic phase is after anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, residuum is through purification by silica gel column chromatography (gradient elution, elutriant is methylene dichloride: methyl alcohol=100:1 to 6:1) obtain 2.4g faint yellow solid, be N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide, yield 50.2%.MS:m/z＝413.2(M+H
+)。
1H NMR(300MHz,DMSO-d
6)δ:11.70(d,J＝18.6Hz,1H),11.48(s,1H),7.77(d,1H),7.46(d,J＝5.8Hz,2H),7.38-7.14(m,2H),6.37(d,J＝9.2Hz,1H),5.08(t,J＝6.8Hz,1H),1.90(t,J＝6.3Hz,1H),1.39-1.34(m,2H),1.30-1.18(m,3H),1.05-0.97(m,3H),0.85(t,J＝4.6Hz,4H).
The formula I meeting claims all can adopt the synthetic method approximate with above-described embodiment to obtain, and only need change different starting materials.Representational compound is as follows:
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 dichloro benzene base)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-dichlorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-dichlorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 dichloro benzene base)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-dichlorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-dichlorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 difluorobenzene base)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec.-propyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec.-propyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec.-propyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec.-propyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 dichloro benzene base)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec.-propyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-dichlorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec.-propyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-dichlorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec.-propyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec.-propyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec.-propyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec.-propyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 difluorobenzene base)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec.-propyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-sec.-propyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(2-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(3-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(4-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 dichloro benzene base)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-dichlorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-dichlorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(2-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(3-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(4-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 difluorobenzene base)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 dichloro benzene base)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-dichlorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-dichlorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 difluorobenzene base)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-chloro-phenyl-)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 dichloro benzene base)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-dichlorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-dichlorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 difluorobenzene base)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide;
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide.
More how representational compound does not enumerate.
Determination of activity
Formula I and/or their pharmacologically acceptable salt tentatively can carry out active testing according to optical fluorescence membrane potential assay method as CFTR inhibitor.
Measuring principle: it is utilize electronegative fluorescence voltage sensor dyestuff (such as FLIPR membrane potential dyestuff) that membrane potential measures ratio juris, cell is anticipated with testing compound, then on load voltage sensing dyestuff, in conjunction with quencher when sensing dyestuff is outside born of the same parents, after cell depolarization, electronegative dyestuff reassigns to compartment in born of the same parents, discharges thus, cause fluorescence to increase from film impermeable quencher.The change readout (conductance) that functional Δ F508-CFTR gate increases in NIH3T3 cell of membrane potential on FLIPR III is measured using fluorescence plate reader.This fluorescence change changes over direct ratio with the membrane potential caused because of CFTR activity.Can by the fluorimetric detector of suitably outfit as the change of FLIPR (Fluorometric Imaging Plate reader) Real-Time Monitoring fluorescence in 96 or 384-hole microtiter plate.Can detection by quantitative CFTR activity by measuring this mode of membrane potential.
Cell cultures: carry out membrane potential experiment with NIH3T3 Chinese hamster ovary (CHO) cell of stably express Δ F508-CFTR passage.By cell in 37 DEG C, 5%v/vCO
2improve in Eagle substratum (MEM) with maintaining under 100% humidity condition.This culture medium supplemented 8%v/v foetal calf serum, 100 μ g/mL methotrexates and 100U/mL penicillin/streptomycin.Make Growth of Cells at 225cm
2in tissue culture flasks.In order to carry out membrane potential mensuration, by cell with 40,000 cells/well is seeded in the culture plate of 96 pore matrix Jiao Bao quilts, makes it adhere to, and cultivates 48 hours, measure for toughener at 26 DEG C.
Toughener measures: membrane potential screening assay method make use of low chlorine ion (5mM) containing the outer solution of born of the same parents and two-cocoon feeding and adds HTS and measure scheme.It is the damping fluid containing or do not contain testing compound that first time adds, and adds not this Kelin (1-20 μM) after 5 minutes.The maximum chlorine that the program is conducive to activating in response to Δ F508-CFTR flows out.The chlorion that Δ F508-CFTR mediates flows out and causes membrane depolarization, and optional FMP dyestuff is monitored it.
Solution: the outer solution (concentration magnitude is mM) of low chlorine born of the same parents consists of 120 gluconic acid sodium salts, 1.2CaCl
2, 3.3KH
2pO
4, 1.2MgCl
2, 10.0D-glucose, 20.0HEPES, with NaOH adjust pH to 7.4.FMP dyestuff: prepare the outer solution of above-mentioned low chlorine born of the same parents according to working instructions, 10 times of final concentrations, are stored in-20 DEG C with 1mL aliquots containig.
Measuring result: several representational compound utilizes aforesaid method to carry out the detected result (EC of determination of activity
50value) as shown in the table.
Claims (8)
1. formula I, and/or their pharmacologically acceptable salt
Wherein, R
1and R
2independently be selected from hydrogen, cyano group, trifluoromethyl, halogen, (C separately
1-C
6) straight or branched alkyl, 3-12 unit alicyclic group, phenyl, other (C
5-C
10) aryl, (C
5-C
10) heteroaryl or (C
3-C
7) heterocyclic radical, wherein said heteroaryl or heterocyclic radical have the heteroatoms of 3 O, S or N at the most, and (C
1-C
6) straight or branched alkyl, 3-12 unit alicyclic group, phenyl, other (C
5-C
10) aryl, (C
5-C
10) heteroaryl or (C
3-C
7) heterocyclic radical separately independent sum replaced by 3 substituting groups at the most arbitrarily, described substituting group is selected from-OR ' ,-CF
3,-OCF
3,-SR ' ,-S (O) R ' ,-SO
2r ' ,-SCF
3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH
2)
2n (R ')
2,-OCH
2n (R ')
2,-CON (R ')
2,-(CH
2)
2oR ' ,-CH
2oR ' ,-CH
2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ')
2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH
2)
2n (R ')
2or-CH
2n (R ')
2;
The group that R ' is independently selected from hydrogen separately or replaces arbitrarily, described group is selected from (C
1-C
8) aliphatic group, have that 0-3 to be independently selected from that the 3-8 unit of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or have that 0-5 is independently selected from nitrogen, oxygen can saturated, the fractional saturation of the 8-12 unit of sulfur heteroatom or complete undersaturated bicyclic ring system, or formed together with the atom that connects with them of the R ' of twice appearance have that 0-4 3-12 unit being independently selected from the optional replacement of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or dicyclo.
2. according to the formula I of claim 1, wherein R
1for phenyl or other (C
5-C
10) aryl, can be replaced by 3 substituting groups at the most arbitrarily by independent sum separately, described substituting group is selected from-OR ' ,-CF
3,-OCF
3,-SR ' ,-S (O) R ' ,-SO
2r ' ,-SCF
3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH
2)
2n (R ')
2,-OCH
2n (R ')
2,-CON (R ')
2,-(CH
2)
2oR ' ,-CH
2oR ' ,-CH
2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ')
2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH
2)
2n (R ')
2or-CH
2n (R ')
2;
The group that R ' is independently selected from hydrogen separately or replaces arbitrarily, described group is selected from (C
1-C
8) aliphatic group, have that 0-3 to be independently selected from that the 3-8 unit of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or have that 0-5 is independently selected from nitrogen, oxygen can saturated, the fractional saturation of the 8-12 unit of sulfur heteroatom or complete undersaturated bicyclic ring system, or formed together with the atom that connects with them of the R ' of twice appearance have that 0-4 3-12 unit being independently selected from the optional replacement of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or dicyclo.
3. according to the formula I of claim 1, wherein R
2for (C
1-C
6) straight or branched alkyl, 3-12 unit alicyclic group, and can be replaced by 3 substituting groups at the most arbitrarily by independent sum separately, described substituting group is selected from-OR ' ,-CF
3,-OCF
3,-SR ' ,-S (O) R ' ,-SO
2r ' ,-SCF
3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH
2)
2n (R ')
2,-OCH
2n (R ')
2,-CON (R ')
2,-(CH
2)
2oR ' ,-CH
2oR ' ,-CH
2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ')
2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH
2)
2n (R ')
2or-CH
2n (R ')
2;
The group that R ' is independently selected from hydrogen separately or replaces arbitrarily, described group is selected from (C
1-C
8) aliphatic group, have that 0-3 to be independently selected from that the 3-8 unit of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or have that 0-5 is independently selected from nitrogen, oxygen can saturated, the fractional saturation of the 8-12 unit of sulfur heteroatom or complete undersaturated bicyclic ring system, or formed together with the atom that connects with them of the R ' of twice appearance have that 0-4 3-12 unit being independently selected from the optional replacement of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or dicyclo.
4. according to the formula I of claim 1-3, wherein R
1be selected from 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2,4 dichloro benzene base, 2,5-dichlorophenyls, 3,5-dichlorophenyls, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4 difluorobenzene base, 2,5-difluorophenyls or 3,5-difluorophenyl, simultaneously R
2for (C
1-C
6) straight or branched alkyl.
5. at least one formula I in claim 1-4 described in any one and/or its pharmacologically acceptable salt are preparing the purposes in medicine.
6. at least one formula I in claim 1-4 described in any one and/or its pharmacologically acceptable salt are preparing the purposes prevented and/or treated in the medicine of following disease: the male infertility that cystic fibrosis, the intestinal secretion extremely increased, secretory diarrhea, the dirty disease of polycystic kidney, chronic obstructive pulmonary disease, chronic bronchitis, mucopolysaccharide disease and congenital bilateral vas deferens disappearance (CBAVA) cause.
7. the purposes described in claim 6, disease wherein refers to cystic fibrosis.
8. medicine, it includes at least one formula I in the claim 1-4 of effective amount described in any one and/or its pharmacologically acceptable salt, the vehicle of physiology tolerance and carrier, and also has other additives and/or other activeconstituentss in due course.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018041947A1 (en) * | 2016-09-02 | 2018-03-08 | Glaxosmithkline Intellectual Property (No.2) Limited | Imidazole derivatives and their use in the treatment of autoimmune or inflammatory diseases or cancers |
| CN109134431A (en) * | 2018-10-10 | 2019-01-04 | 成都理工大学 | Aminooimidazole as cystic fibrosis transmembrane conductance regulator inhibitor is coupled Pyridione derivatives |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004028480A2 (en) * | 2002-09-30 | 2004-04-08 | The Regents Of The University Of California | Cystic fibrosis transmembrane conductance regulator protein inhibitors and uses thereof |
| WO2008121877A2 (en) * | 2007-04-02 | 2008-10-09 | Institute For Oneworld Health | Cftr inhibitor compounds and uses thereof |
| US20090246137A1 (en) * | 2008-03-31 | 2009-10-01 | Vertex Pharmaceuticals Incorporated | Pyridyl derivatives as cftr modulators |
-
2015
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004028480A2 (en) * | 2002-09-30 | 2004-04-08 | The Regents Of The University Of California | Cystic fibrosis transmembrane conductance regulator protein inhibitors and uses thereof |
| WO2008121877A2 (en) * | 2007-04-02 | 2008-10-09 | Institute For Oneworld Health | Cftr inhibitor compounds and uses thereof |
| US20090246137A1 (en) * | 2008-03-31 | 2009-10-01 | Vertex Pharmaceuticals Incorporated | Pyridyl derivatives as cftr modulators |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018041947A1 (en) * | 2016-09-02 | 2018-03-08 | Glaxosmithkline Intellectual Property (No.2) Limited | Imidazole derivatives and their use in the treatment of autoimmune or inflammatory diseases or cancers |
| CN109134431A (en) * | 2018-10-10 | 2019-01-04 | 成都理工大学 | Aminooimidazole as cystic fibrosis transmembrane conductance regulator inhibitor is coupled Pyridione derivatives |
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