CN104788423B - A kind of new cystic fibrosis transmembrane conductance regulator inhibitor - Google Patents

A kind of new cystic fibrosis transmembrane conductance regulator inhibitor Download PDF

Info

Publication number
CN104788423B
CN104788423B CN201510111497.9A CN201510111497A CN104788423B CN 104788423 B CN104788423 B CN 104788423B CN 201510111497 A CN201510111497 A CN 201510111497A CN 104788423 B CN104788423 B CN 104788423B
Authority
CN
China
Prior art keywords
base
imidazoles
dihydropyridine
oxo
cyclopropyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201510111497.9A
Other languages
Chinese (zh)
Other versions
CN104788423A (en
Inventor
周立宏
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chengdu Univeristy of Technology
Original Assignee
Chengdu Univeristy of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chengdu Univeristy of Technology filed Critical Chengdu Univeristy of Technology
Priority to CN201510111497.9A priority Critical patent/CN104788423B/en
Publication of CN104788423A publication Critical patent/CN104788423A/en
Application granted granted Critical
Publication of CN104788423B publication Critical patent/CN104788423B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the amidoimidazole coupling dihydropyridone compounds shown in Formulas I and/or their officinal salt and preparation method thereof, they can be used for treatment and/or prevent cystic fibrosis (CF) the correlated inheritance disease caused due to cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation, and the pharmaceutical composition containing described compound.Wherein, R1It is at most by the phenyl of 3 halogen substiuted, R2For (C1‑C6) straight or branched alkyl.

Description

A kind of new cystic fibrosis transmembrane conductance regulator inhibitor
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of dihydropyridone described in claim even Glyoxaline compound and physiologically acceptable salt thereof, their preparation and they treatment and/or prevention with Cystic fibrosis, abnormal increase intestinal secretion, secretory diarrhea, the dirty disease of polycystic kidney, chronic obstructive pulmonary disease, The male that chronic bronchitis, mucopolysaccharide disease and congenital bilateral deferent duct disappearance (CBAVA) cause is not Educate the purposes in the disease that disease is relevant.
Technical background
(English is cystic fibrosis transmembrane to cystic fibrosis transmembrane conductance regulator Conductance regulator, is abbreviated as CFTR) belonging to ATP, to combine box (English for ATP binding Cassette, is abbreviated as ABC) member of transport protein superfamily, and abc transport albumen has and such as absorbs The multiple important biological functions such as the cell-cell communication of nutrient substance, eliminating toxin, mediation eukaryote and antibacterial. More specifically, CFTR is the ATP gated epithelium chloride channel that a kind of cAMP activates, and is expressed in In the top plasma membrane of mammal air flue, digestive tract (intestinal, pancreas etc.) and reproductive tract epithelial cell, this is chlorine Ion across top film motion provide approach and critical sites, participate in multiple organ (including lung) be responsible for salt and The activation of the protein kinase A (PKA) of fluid transport, and therefore regulate the salt of transepithelial and the transhipment ratio of water, So, in epithelial cell, the normal function of CFTR includes breathing and digestion is organized in interior whole for maintaining The electrolyte transport of individual health is non-the normally off key.The hormone of such as beta-adrenaline excitant, cholera toxin Etc. may result in the increase of cAMP, and the activation of cAMP dependent kinases and described CFTR chloride ion The phosphorylation of passage also thus causes the opening of chloride channel.CFTR chloride channel function and a lot of diseases Relevant, including cystic fibrosis (CF), abnormal increase intestinal secretion, secretory diarrhea, the dirty disease of polycystic kidney, Chronic obstructive pulmonary disease, chronic bronchitis, mucopolysaccharide disease and congenital bilateral deferent duct disappearance (CBAVA) The male infertility etc. caused.
CFTR is by about 1480 Amino acid profiles.These aminoacid 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 across Film district is connected by a big band polarity with multiple phosphorylation site and adjustable (R)-territory, described phosphorus Polyadenylation sites is responsible for regulating channel activity and cell transport.
Cystic fibrosis (English is cystic fibrosis, is abbreviated as CF) is that a kind of fatal autosome is hidden Property disease, be one of modal hereditary in human body, by cftr gene sudden change cause.Major part CF sudden change shows as minimizing or channel function (the such as gate or electricity of cell surface CFTR number of channels Lead sudden change) infringement, or two kinds of situations occur simultaneously.In the U.S., about 2,005 centesimal youngsters Virgin and up to ten million adults suffers from CF relevant disease, also has this recessiveness of similar equal number in Europe Genetic diseases patient.In the airway epithelial cell of CF patient, the CFTR sudden change of endogenous expression causes teleblem Anion secretion reduce, make ion and fluid transport unbalance.The minimizing of anion transport makes the lung of CF patient Mucus accumulation increases and infects with finally may result in the dead microorganism of people.Except suffering from the disease in terms of respiratory tract Disease, CF patient the most also can suffer from typical gastrointestinal problems and pancreatic insufficiency, if treated not in time, Also result in death.Additionally, major part male CF patient can not give birth to, the fertility of women CF patient Can reduce.
Although in the past few decades, the effort of modern medicine achieves progress, in terms for the treatment of CF The life-span making CF patient is greatly prolonged, but the most not yet finds that safety is the most effectively directly targeted and CFTR Therapeutic Method.The decoding of cftr gene is contributed to people and further appreciates that the morbidity machine of cystic fibrosis System, the diagnosis for this disease simultaneously provides new clue.And increase the little molecule of CFTR channel opener probability Medicine is the potential therapeutic strategy of one for the treatment of CF, and these type of medicines of developing will assist in the solution of CF problem more.
Summary of the invention
The present invention describes compound of formula I, and/or their officinal salt
Wherein, R1It is at most by the phenyl of 3 halogen substiuted, R2For (C1-C6) straight or branched alkyl.
Preferably, R1Selected from 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 2,4 dichloro benzene base, 2,5-dichloro-benzenes Base, 3,5-Dichlorobenzene base, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4 difluorobenzene base, 2,5-difluorobenzene Base or 3,5-difluorophenyl, simultaneously R2For (C1-C6) straight or branched alkyl, i.e. for R1For substituent 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 as the compound of formula I of medicine (or medicament) and/or its officinal salt in preparation prevention and / or treat the purposes in the medicine of following disease, i.e. cystic fibrosis, abnormal increase intestinal secretion, secreted Diarrhoea, the dirty disease of polycystic kidney, chronic obstructive pulmonary disease, chronic bronchitis, mucopolysaccharide disease and congenital double The male infertility that side deferent duct disappearance (CBAVA) causes.
The invention still further relates to pharmaceutical preparation (or pharmaceutical composition), it contains at least one Formulas I chemical combination of effective dose Thing and/or its officinal salt, the excipient of physiology's tolerance and carrier, and also have other to add in due course Agent and/or other active component.Medicine can be Orally administered, such as with pill, tablet, spraying sheet (lacquered Tablets), coated tablet, granule, hard and Perle, solution, syrup, Emulsion, suspensoid or aerosol Form of mixtures.But, use and may be carried out as follows: per rectum is administered, such as with suppository form；Or stomach Parenteral administration, such as through intravenous, intramuscular or subcutaneous with injection solution or infusion solution, microcapsule, implant or Implant the form of rod；Or percutaneous or topical, such as with ointment, solution or tincture form；Or with other Administration, such as with aerosol or form of nasal sprays.
The pharmaceutical preparation of the present invention, by known per se and prepare in the way of being known to those skilled in the art, removes Outside compound of formula I and/or their officinal salt and/or their prodrug, use pharmaceutically useful inert inorganic And/or organic carrier substances and/or additive.Preparation for pill, tablet, coated tablet and hard gelatin capsule For, such as lactose, corn starch or derivatives thereof, Talcum, stearic acid or its salt etc. may be used.Soft bright The carrier mass of glue capsule and suppository has such as fat, wax, semisolid and liquid polyol, natural or fixed oil Deng.Be suitable for preparing the carrier mass of solution, such as injection solution or Emulsion or syrup have such as water, saline, Alcohol, glycerol, polyhydric alcohol, sucrose, Nulomoline, glucose, vegetable oil etc..It is suitable for microcapsule, implant Or implant excellent carrier mass, the copolymer of such as glycolic and lactic acid.Pharmaceutical preparation usually contain about 0.5 to The compound of formula I of about 90% weight and/or their officinal salt and/or their prodrug.In pharmaceutical preparation The amount of active component compound of formula I and/or their officinal salt and/or their prodrug normally about 0.5 is to about 1000mg, preferably from about 1 are to about 500mg.
In addition to the active component of Formulas I and/or their officinal salt and carrier mass, pharmaceutical preparation can contain Have one or more additives, as filler, disintegrating agent, binding agent, lubricant, wetting agent, stabilizer, Emulsifying agent, preservative, sweeting agent, coloring agent, correctives, aromatic, thickening agent, diluent, cushion Matter, solvent, solubilizing agent, the reagent of acquisition depot effect, the change salt of osmotic pressure, coating materials or antioxidant. They can also contain two or more compound of formula I and/or their officinal salt.Contain at pharmaceutical composition When having two or more compound of formula I, to the selection of individual compound can according to pharmaceutical preparation specific totally Pharmacological property.Such as, the height potent compound that acting duration is shorter can be relatively low with effect long-acting Compound combines.The motility allowed for substituent group in compound of formula I selects makes it possible to compound Biology and physicochemical properties carry out numerous control, it is possible to select this kind of required compound.Additionally, In addition at least one compound of formula I and/or its officinal salt, pharmaceutical preparation also can be containing one or more its His therapeutic or preventative active component.
When using compound of formula I, dosage can become in grace period and according to known to conventional and doctor Changing, dosage should be suitable for the individual instances of every kind example.It depends on particular compound, the institute such as applied The treatment character of disease and the order of severity, method of application and scheme or treated be acute or chronic disease or Whether prevent.The dosage being suitable for may utilize clinical method known to medical domain and sets up.It is said that in general, Weighing about and obtaining the daily dose of results needed in the adult of 75kg is about 0.01 to about 100mg/kg, preferably from about 0.1 To about 50mg/kg, especially about 0.1 to about 10mg/kg (in each case with mg/kg weighing machine).Exist especially In the case of using relatively large amount, if daily dose can be divided into stem portion, such as 2,3 or 4 parts to use. Generally, according to individual behavior, it may be necessary to deviate described daily dose up or down.
Additionally, compound of formula I can be used as preparing the synthesis of other compounds, particularly other drug active component Intermediate, it can be by compound of formula I such as by introducing substituent group or modifying functional group's acquisition.
In most of the cases, locate after the reactant mixture to the finalization compound containing Formulas I or intermediate is carried out Reason, if it is necessary, by product by conventional method purification well known by persons skilled in the art.Such as, closed The compound become may utilize known to method such as crystallization, chromatograph or reversed phase high-performance liquid chromatography (RP-HPLC) Or be purified based on such as compound size, electric charge or other separation methods hydrophobic.Similarly, know Method such as amino acid sequence analysis, NMR, IR and mass spectrography (MS) may be used for characterize the compounds of this invention.
Therefore, following example are the parts of the present invention, are used for illustrating and the unrestricted present invention.
It should be noted that, the modification of the non-substantial effect present invention various embodiment activity is included in institute herein In the disclosed scope of the invention.
Detailed description of the invention
Embodiment: N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 difluorobenzene base)-1H-imidazoles-2- Base) preparation of cyclopropyl carboxamide
The bromo-1-of the first step: 2-(2,4 difluorobenzene base) ethyl ketone
Copper bromide (28.6g, 128.0mmol) is added 1-(2,4 difluorobenzene base) ethyl ketone (10.0g, 64.0mmol) Chloroform (100mL) and ethanol (80mL) mixed solution in.Oil bath is heated to 80 DEG C, and is incubated anti- Should about 10 hours.Being filtered to remove insoluble matter, add ethyl acetate (200mL), gained mixed solution is successively Wash by saturated aqueous common salt (200mL*2) and saturated sodium bisulfite solution (200mL*2).Organic facies warp Anhydrous sodium sulfate is dried, and filters, removes solvent under reduced pressure, obtain 13.2g yellow oil, be the bromo-1-of 2-(2,4- Difluorophenyl) 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 the bromo-1-of 2-(2,4 difluorobenzene base) ethyl ketone (23.5g, 0.1mol) Glycol dimethyl ether (200mL) solution in.After reactant liquor being heated to 100 DEG C of reactions about 8 hours, Remove solvent under reduced pressure.Gained crude product is through the mixed solvent (methanol: methyl tertbutyl of methanol Yu methyl tertiary butyl ether(MTBE) Ether=1:10) recrystallization, separate out, filter and be vacuum dried and to obtain 19.7g white solid, be 2-(2,4-difluoros Phenyl) imidazo [1,2-a] pyridine, yield 85.2%.MS:m/z=232.1 (M+H+)。
The 3rd bromo-2-of step: 3-(2,4 difluorobenzene base) imidazo [1,2-a] pyridine
N-bromo-succinimide (11.6g, 64.9mol) is added 2-(2,4 difluorobenzene base) imidazo [1,2-a] In chloroform (200mL) solution of pyridine (15.0g, 64.9mmol).Reactant liquor is heated to 80 DEG C instead Room temperature should be cooled to after about 3 hours, add dichloromethane (200mL).Gained reactant liquor unsaturated carbonate Hydrogen sodium solution washing (200mL*3).Organic facies is dried through anhydrous sodium sulfate, filters, removes 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-dioxanes penta Borine-2-base) pyridine-2 (1H)-one (15.2g, 0.055mol), tetra-triphenylphosphine palladium (2.9g, 2.5mmol) It is sequentially added into the tetrahydrochysene furan of the bromo-2-of 3-(2,4 difluorobenzene base) imidazo [1,2-a] pyridine (15.5g, 0.05mol) Mutter in (200mL) solution.After reactant liquor being heated to 85 DEG C of reactions about 10 hours, it is cooled to room temperature. With ethyl acetate (200mL) dilute reaction solution.Gained mixture saturated aqueous common salt washs (200mL*3). Merge organic facies, dried through anhydrous sodium sulfate, filter, remove solvent under reduced pressure, residue is through silica gel column chromatography Purification (gradient elution, eluent is petroleum ether: ethyl acetate=40:1 to 4:1) obtain 12.4g yellow solid, It is 1-sec-butyl-5-(2-(2,4 difluorobenzene base) 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
Hydrazine hydrate (55% aqueous solution, 9.8g, 0.1mol) is added 1-sec-butyl-5-(2-(2,4 difluorobenzene base) miaow Azoles also [1,2-a] pyridin-3-yl) ethanol (100mL) solution of pyridine-2 (1H)-one (7.6g, 20.0mmol) In.After reactant liquor oil bath being heated to backflow and reacting about 10 hours, it is cooled to room temperature.Remove solvent under reduced pressure, Residue ethyl acetate (150mL) is dissolved, and gained solution saturated aqueous common salt washs (100mL*2). Organic facies is dried through anhydrous sodium sulfate, filters, removes solvent under reduced pressure, and residue (is washed through silica gel column chromatography purification De-liquid is dichloromethane: methanol=40:1) obtains 5.2g yellow solid, is 5-(2-amino-4-(2,4 difluorobenzene Base)-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
5-(2-amino-4-(2,4 difluorobenzene base)-1H-imidazoles-5-base)-1-sec-butyl pyridine-2 (1H)-one (4.0g, In DMF (60mL) solution 11.6mmol), successively add 1-ethyl-(3-dimethyl Aminopropyl) phosphinylidyne diimmonium salt hydrochlorate (i.e. EDCI HCl, 4.45g, 23.2mmol), N, N-dimethyl Pyridine-4-amine (i.e. DMAP, 0.71g, 5.8mmol), Anhydrous potassium carbonate (3.2g, 23.2mmol) and Ethylene-acetic acid (1.5g, 17.4mmol).Reacting overnight under room temperature, TLC monitors (petroleum ether: acetic acid second Ester=1:1) until reaction is completely.With ethyl acetate (200mL) dilute reaction solution.Gained mixture is with full With brine It (100mL*3).Organic facies is dried through anhydrous sodium sulfate, filters, removes solvent under reduced pressure, Through silica gel column chromatography purification, (gradient elution, eluent is dichloromethane to residue: methanol=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-difluoros Phenyl)-1H-imidazoles-2-base) cyclopropyl carboxamide, yield 50.2%.MS:m/z=413.2 (M+H+)。
1H NMR(300MHz,DMSO-d6) 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 compound of formula I meeting claims all can use the synthetic method with above-described embodiment approximation to obtain Arrive, only need to change different starting materials.Representational compound is as follows:
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 dichloro benzene base)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-Dichlorobenzene base)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-Dichlorobenzene base)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-difluorophenyl)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-sec-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-difluorophenyl)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 dichloro benzene base)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-Dichlorobenzene base)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-Dichlorobenzene base)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 difluorobenzene base)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-difluorophenyl)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-normal-butyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-difluorophenyl)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 dichloro benzene base)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-Dichlorobenzene base)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-Dichlorobenzene base)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl first Amide；
N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 difluorobenzene base)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-difluorophenyl)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-difluorophenyl)-1H-imidazoles-2-base) ring third Base Methanamide；
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(2-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(3-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(4-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 dichloro benzene base)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-Dichlorobenzene base)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-Dichlorobenzene base)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(2-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(3-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(4-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 difluorobenzene base)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-propyl group-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 dichloro benzene base)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-Dichlorobenzene base)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-Dichlorobenzene base)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 difluorobenzene base)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-ethyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-chlorphenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 dichloro benzene base)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-Dichlorobenzene base)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-Dichlorobenzene base)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(4-fluorophenyl)-1H-imidazoles-2-base) cyclopropyl formyl Amine；
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,4 difluorobenzene base)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(2,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl Methanamide；
N-(5-(1-methyl-6-oxo-1,6-dihydropyridine-3-base)-4-(3,5-difluorophenyl)-1H-imidazoles-2-base) cyclopropyl Methanamide.
More representational compounds do not enumerate.
Determination of activity
Compound of formula I and/or their officinal salt as CFTR inhibitor can tentatively according to optical fluorescence across Transmembrane potential algoscopy carries out active testing.
Measuring principle: the principle of transmembrane potential algoscopy is to utilize electronegative fluorescence voltage sensor dyestuff (such as FLIPR transmembrane potential dyestuff), anticipate cell with testing compound, then on-load voltage sensing dyestuff, passes Infecting material and combine quencher when born of the same parents are outer, after cell depolarization, electronegative dyestuff reassigns to intracellular Compartment, thus discharges from film impermeable quencher, causes fluorescence to increase.FLIPR is measured with fluorescence plate reader On III, transmembrane potential changes the reading increased as functional Δ F508-CFTR gate in NIH3T3 cell Value (conductance).The change of this fluorescence changes over direct ratio with the transmembrane potential caused because of CFTR activity.Permissible By the fluorescence detector such as FLIPR (Fluorometric Imaging Plate reader) of suitably outfit at 96 or 384-hole trace Titer plate is monitored the change of fluorescence in real time.Can detection by quantitative CFTR live by measuring this mode of transmembrane potential Property.
Cell is cultivated: thin with the NIH3T3 Chinese hamster ovary (CHO) stably expressing Δ F508-CFTR passage Born of the same parents carry out transmembrane potential experiment.By cell in 37 DEG C, 5%v/vCO2Improvement is maintained with under 100% damp condition In Eagle culture medium (MEM).This culture media supplemented 8%v/v hyclone, 100 μ g/mL first ammonia butterflies Purine and 100U/mL penicillin/streptomycin.Cell is made to be grown in 225cm2In tissue culture flasks.In order to carry out Transmembrane potential measures, and by cell with 40,000 cells/well is seeded in the 96 coated culture plates of pore matrix glue so that it is Adhere to, cultivate 48 hours at 26 DEG C, measure for reinforcing agent.
Reinforcing agent measures: transmembrane potential Screening test method make use of the low chlorine ion (5mM) containing the outer solution of born of the same parents and Two-cocoon feeding adds HTS and measures scheme.Adding for the first time is the buffer containing or not contain testing compound, 5 points Not this Kelin (1-20 μM) is added after clock.The program is conducive to the maximum in response to Δ F508-CFTR activation Chlorine flows out.The chloride ion of Δ F508-CFTR mediation flows out and causes membrane depolarization, optional FMP dyestuff to enter it Row monitoring.
Solution: the outer solution (concentration magnitude is mM) of low chlorine born of the same parents consists of 120 gluconic acid sodium salts, 1.2CaCl2、 3.3KH2PO4、1.2MgCl2, 10.0D-glucose, 20.0HEPES, with NaOH adjust pH value to 7.4. FMP dyestuff: preparing the outer solution of above-mentioned low chlorine born of the same parents according to operation instructions, 10 times of final concentrations, with 1mL etc. Divide specimen storage in-20 DEG C.
Measurement result: several representational compounds utilize the testing result (EC that said method carries out determination of activity50 Value) as shown in the table.

Claims (5)

1. compound of formula I, and/or their officinal salt
Wherein, R1It is at most by the phenyl of 3 halogen substiuted, R2For (C1-C6) straight or branched alkyl.
2. according to the compound of formula I of claim 1, wherein R1Selected from 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 2,4-dichloro Phenyl, 2,5-Dichlorobenzene base, 3,5-Dichlorobenzene base, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4 difluorobenzene base, 2,5- Difluorophenyl or 3,5-difluorophenyl, simultaneously R2For (C1-C6) straight or branched alkyl.
3. in claim 1 and 2 at least one compound of formula I described in any one and/or its officinal salt preparation prevention and/ Or treat the purposes in the medicine of following disease: cystic fibrosis, abnormal increase intestinal secretion, secretory diarrhea, polycystic kidney Dirty disease, chronic obstructive pulmonary disease, chronic bronchitis, mucopolysaccharide disease and congenital bilateral deferent duct disappearance (CBAVA) The male infertility caused.
4. the purposes described in claim 3, disease therein refers to cystic fibrosis.
5. medicine, it comprises in the claim 1 and 2 of effective dose at least one compound of formula I described in any one and/or it can Pharmaceutical salts, the excipient of physiology's tolerance and carrier, and also have other additives and/or other active component in due course.
CN201510111497.9A 2015-03-13 2015-03-13 A kind of new cystic fibrosis transmembrane conductance regulator inhibitor Expired - Fee Related CN104788423B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510111497.9A CN104788423B (en) 2015-03-13 2015-03-13 A kind of new cystic fibrosis transmembrane conductance regulator inhibitor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510111497.9A CN104788423B (en) 2015-03-13 2015-03-13 A kind of new cystic fibrosis transmembrane conductance regulator inhibitor

Publications (2)

Publication Number Publication Date
CN104788423A CN104788423A (en) 2015-07-22
CN104788423B true CN104788423B (en) 2016-10-26

Family

ID=53553662

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510111497.9A Expired - Fee Related CN104788423B (en) 2015-03-13 2015-03-13 A kind of new cystic fibrosis transmembrane conductance regulator inhibitor

Country Status (1)

Country Link
CN (1) CN104788423B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB201614934D0 (en) * 2016-09-02 2016-10-19 Glaxosmithkline Intellectual Property (No 2) Ltd Chemical compounds
CN109134431B (en) * 2018-10-10 2021-06-04 成都理工大学 Aminoimidazole-coupled pyridone derivatives as cystic fibrosis transmembrane conductance regulator inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
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

Also Published As

Publication number Publication date
CN104788423A (en) 2015-07-22

Similar Documents

Publication Publication Date Title
CN105121432B (en) Heterocycleamide as kinase inhibitor
CN102428084B (en) Compound
CN111511749B (en) Compounds having macrocyclic molecular structures and uses thereof
EP3766882B1 (en) Phthalazine isoxazole alkoxy derivatives, preparation method thereof, pharmaceutical composition and use thereof
EP3177612B1 (en) Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
CN109843858A (en) Certain chemical entities, composition and method
KR101171433B1 (en) Imidazolidinone derivatives
JP2006503010A (en) Some novel imidazopyridines and their use
WO2020078362A1 (en) Imidazole aromatic ring compound, preparation method and uses thereof
CN103596568A (en) Methods and compositions for treating Parkinson disease
EA023574B1 (en) 6-CYCLOBUTYL-1,5-DIHYDROPYRAZOLO[3,4-d]PYRIMIDIN-4-ONE DERIVATIVES AND THEIR USE AS PDE9A INHIBITORS
CN103635230A (en) Proteostasis regulators
CN111655693B (en) Inhibition of transient receptor potential A1 ion channels
JP2021526123A (en) Autotaxin inhibitors and their use
EP3021847B1 (en) Spiroquinoxaline derivatives as inhibitors of non-apoptotic regulated cell-death
CN105073751A (en) Novel substituted imidazoles as casein kinase 1 [delta]/[epsilon] inhibitors
CN105143208A (en) Quinazolines as kinase inhibitors
WO2019011228A1 (en) Imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6h)-one compound and use thereof
CN107987072A (en) Benzazole compounds as CRTH2 inhibitor
CN104788423B (en) A kind of new cystic fibrosis transmembrane conductance regulator inhibitor
KR20020010482A (en) Novel N-triazolylmethyl-piperazine derivatives as neurokinin-receptor antagonists
EP3105207B1 (en) Gpr142 agonist compounds
EP4310080A1 (en) Polymorphic forms of compound and preparation method therefor and application thereof
BR112017016278B1 (en) Use of a compound having btk inhibitory activity or a salt thereof to produce a preventive and/or therapeutic agent for the prevention or treatment of an immune disease
CN110407839B (en) Preparation and application of triazole heterocyclic compound containing heteroaryl amide structure

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20161026

CF01 Termination of patent right due to non-payment of annual fee