CN109134431A - Aminooimidazole as cystic fibrosis transmembrane conductance regulator inhibitor is coupled Pyridione derivatives - Google Patents
Aminooimidazole as cystic fibrosis transmembrane conductance regulator inhibitor is coupled Pyridione derivatives Download PDFInfo
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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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
- C07D401/14—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 three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
The present invention relates to aminooimidazoles shown in Formulas I to be coupled pyridine compounds and/or their officinal salt and preparation method thereof, they can be used for treating and/or preventing cystic fibrosis (CF) correlated inheritance disease as caused by cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation, and the pharmaceutical composition containing the compound.Wherein, R C3Or C4Or C5Or C6Or C7Or C8Naphthenic base, C3Or C4Or C5Or C6Or C7Or C8Azacycloalkyl, C3Or C4Or C5Or C6Or C7Or C8Oxacycloalkyl, morpholinyl, piperazinyl, nitrogen are by the alkyl-substituted piperazinyl of linear chain or branched chain C1 or C2 or C3 or C4 or C5.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to be coupled pyridine to a kind of aminooimidazole described in claim
Ketone compounds and its physiologically acceptable salt, their preparation and they treat and/or prevent with cystic fibrosis,
Abnormal increased intestinal secretion, secretory diarrhea, the dirty disease of polycystic kindey, chronic obstructive pulmonary disease, chronic bronchitis, glutinous hyperglycemia
And the purposes in the relevant disease of male sterility caused by congenital bilateral vas deferens missing (CBAVA).
Technical background
(English is cysticfibrosistransmembrane to cystic fibrosis transmembrane conductance regulator
Conductanceregulator is abbreviated as CFTR) belonging to ATP combination box, (English is ATPbindingcassette, is abbreviated as
ABC) the member of transport protein superfamily, and abc transport albumen has such as absorption nutriment, excludes toxin, mediates eukaryon
A variety of important biological functions such as biology and the cell-cell communication of bacterium.More specifically, CFTR is a kind of ATP of cAMP activation
Gated epithelium chloride channel is expressed in the top of mammal air flue, alimentary canal (intestines, pancreas etc.) and reproduction tract epithelial cell
In portion's plasma membrane, this provides approach and critical sites for across the top film movement of chloride ion, participates in bearing in multiple organs (including lung)
Blame the activation of the protein kinase A (PKA) of salt and fluid transport, and therefore adjust the salt of transepithelial and the transhipment ratio of water, institute
With, in epithelial cell, the electrolysis of entire body of the normal function of CFTR for maintenance including breathing and digesting tissue
Matter transhipment is very crucial.Hormone, cholera toxin of beta-adrenaline excitant etc. can lead to the increase of cAMP, and
Thus the phosphorylation of the activation of cAMP dependent kinases and the CFTR chloride channel simultaneously causes opening for chloride channel
It puts.CFTR chloride channel function is related to many diseases, including cystic fibrosis (CF), abnormal increased intestinal secretion, secretion
Property diarrhea, the dirty disease of polycystic kindey, chronic obstructive pulmonary disease, chronic bronchitis, glutinous hyperglycemia and congenital bilateral vas deferens
Lack male sterility caused by (CBAVA) etc..
CFTR is by about 1480 Amino acid profiles.These amino acid encodings form the tandem repeats of transmembrane region, and in turn
Constitutive protein matter, each repeat body include 6 transbilayer helixes and 1 nucleotide-binding domain.2 transmembrane regions have more by one
The big band polarity of a phosphorylation site and adjustable (R)-domain is connected, the phosphorylation site be responsible for adjusting channel activity with
Cell transport.
Cystic fibrosis (English is cysticfibrosis, is abbreviated as CF) is a kind of fatal autosomal recessive disease
Disease is one of most common genetic disease in human body, is caused by cftr gene mutation.Most of CF mutation shows as cell
The reduction of surface C FTR number of channels or the damage of channel function (for example perhaps conductance is mutated gate) or two kinds of situations are same
Shi Fasheng.In the U.S., about 2,005 centesimal children and up to ten million adults suffer from CF related disease, in Europe
Also there is this recessive genetic disorder patient of almost identical quantity.Endogenous expression in the airway epithelial cell of CF patient
CFTR mutation causes the anion secretion of teleblem to reduce, and keeps ion and fluid transport unbalance.The reduction of anion transport suffers from CF
The lung mucus accumulation of person increases and with the microorganism infection that finally can lead to people's death.In addition to the disease in terms of respiratory tract
Disease, CF patient generally can also suffer from typical gastrointestinal problems and pancreatic insufficiency, if be not treated in time, also result in dead
It dies.In addition, most of male CF patient cannot give birth to, the fertility of women CF patient can be reduced.
Although in the past few decades, the effort of modern medicine achieves progress in terms for the treatment of CF, suffer from CF
The service life of person greatly prolongs, but not yet finds safety so far and be effectively directly targeted the treatment method with CFTR.It is right
The decoding of cftr gene facilitates the pathogenesis that people further appreciate that cystic fibrosis, while providing for the diagnosis of the disease
New clue.And the small-molecule drug for increasing CFTR channel opener possibility is a kind of potential treatment strategy for treating CF, opens more
Sending out drug such will be helpful to the solution of CF problem.
Summary of the invention
Elaborated in ZL201510111497.9 we research and develop at initial stage aminooimidazole coupling pyridinone cystic fibrosis across
The part research achievement of film conductance regulator inhibitor.Initially we are only to group (the mainly substituted benzene on imidazoles 4
Base) and 5 upper pyridone nitrogen-atoms on substituent groups (mainly straight chain or straight chained alkyl) synthesized and screened.Activity
Measurement display, imidazoles 4 be on difluorophenyl and 5 pyridone nitrogen-atoms when being isopropyl, and bioactivity is higher, after
Continuous work, we start to synthesize and screen for the imidazoles 2 upper groups being connected with amide groups carbon atom, and current work
Make the alicyclic group for only considering screening 3-8 member, while including part azepine and oxa- alicyclic group.Institute specific as follows
It states.
The present invention describes compound of formula I and/or their officinal salt
Wherein, R C3Or C4Or C5Or C6Or C7Or C8Naphthenic base, C3Or C4Or C5Or C6Or C7Or C8Azacycloalkyl, C3
Or C4Or C5Or C6Or C7Or C8Oxacycloalkyl, morpholinyl, piperazinyl, nitrogen are by linear chain or branched chain C1 or C2 or C3 or C4 or C5 alkane
The piperazinyl that base replaces.
I.e. for R substituent, representative structural formula is as follows,
Asterisk (*) indicates that the key is connected with the amide groups carbon atom on imidazole ring 2.
The invention further relates to be used as drug (or medicament) compound of formula I and/or its officinal salt preparation prevention and/
Or the purposes in the drug of the following disease for the treatment of, i.e. cystic fibrosis, abnormal increased intestinal secretion, secretory diarrhea, polycystic kindey
Dirty disease, chronic obstructive pulmonary disease, chronic bronchitis, glutinous hyperglycemia and congenital bilateral vas deferens missing (CBAVA) are led
The male sterility of cause.
The invention further relates to pharmaceutical preparation (or pharmaceutical composition), containing a effective amount of at least one compound of formula I and/
Or the excipient and carrier of its officinal salt, physiology tolerance, and there are also other additives and/or other activity in due course
Ingredient.Drug can be administered orally, such as with pill, tablet, spraying piece (lacquered tablets), coating tablet, particle
Agent, hard and Perle, solution, syrup, emulsion, suspension or aerosol mixtures form.But application can also as follows into
Row: per rectum administration, such as with suppository form；Or parenteral, such as through it is intravenous, intramuscular or subcutaneously with inject solution or
It is transfused solution, micro-capsule, implant or the form for being implanted into stick；Or percutaneous or local administration, such as with ointment, solution or tincture shape
Formula；Or it is administered with other approach, for example with aerosol or form of nasal sprays.
Pharmaceutical preparation of the invention is prepared in a manner of known per se and be known to those skilled in the art, in addition to formula
Outside Compound I and/or their officinal salt and/or their prodrug, pharmaceutical inert inorganic and/or organic carrier are used
Substance and/or additive.For the preparation of pill, tablet, coating tablet and hard gelatin capsule, may use such as lactose,
Cornstarch or derivatives thereof, talcum, stearic acid or its salt etc..The carrier mass of Perle and suppository have for example fat,
Wax, semisolid and liquid polyol, natural or fixed oil etc..It is suitable for preparing solution, for example injects solution or emulsion or syrup
The carrier mass of agent has such as water, salt water, alcohol, glycerol, polyalcohol, sucrose, inverted sugar, glucose, vegetable oil.It is suitable for
Micro-capsule, implant or the carrier mass for being implanted into stick, such as the copolymer of glycolic acid and lactic acid.Pharmaceutical preparation usually contains 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 activity at
The amount normally about 0.5 of compounds of formula I and/or their officinal salt and/or their prodrug is to about 1000mg, preferably from about 1
To about 500mg.
Other than the active constituent of Formulas I and/or their officinal salt and carrier mass, pharmaceutical preparation can contain one kind
Or multiple additives, such as filler, disintegrating agent, adhesive, lubricant, wetting agent, stabilizer, emulsifier, preservative, sweet taste
Agent, colorant, corrigent, aromatic, thickener, diluent, buffer substance, solvent, solubilizer, the examination for obtaining depot effect
Agent, salt, coating agent or the antioxidant for changing osmotic pressure.They can also containing two or more compound of formula I and/or they
Officinal salt.It, can be according to medicine to the selection of individual compound when pharmaceutical composition contains two or more compound of formula I
The specific overall pharmacological property of object preparation.For example, the shorter height potent compound of acting duration can with effect compared with
Low long-acting compound combination.Permitted flexibility makes it possible to compound for substituent group selection in compound of formula I
Biology and physicochemical properties carry out numerous controls, thus, it is possible to select it is this kind of needed for compound.In addition, in addition at least one
Outside kind compound of formula I and/or its officinal salt, pharmaceutical preparation can also contain one or more other therapeutic or preventative work
Property ingredient.
When using compound of formula I, dosage can change, agent in grace period and according to conventional with known to doctor
Amount should be suitable for the individual instances of every kind example.It depends on for example applied particular compound, the property of treated disease
With severity, method of application and scheme or whether that is treated be acute or chronic disease or prevented.Suitable agent
Amount can be established using clinical method known to medical domain.In general, result needed for being obtained in the adult for weighing about 75kg
Daily dose 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 (at every kind
In the case of with mg/kg batheroom scale).Especially in the case where applying relatively large amount, if daily dose can be divided into stem portion, such as 2,
The application of 3 or 4 parts.In general, according to individual behavior, it may be necessary to deviate the daily dose upward or downward.
In addition, compound of formula I can be used as preparing among the synthesis of other compounds, particularly other drugs active constituent
Body can for example be obtained by introducing substituent group or modification functional group by compound of formula I.
In most cases, the reaction mixture of the final compound containing Formulas I or intermediate is post-processed, such as
It is necessary to purify product by conventional method well known by persons skilled in the art to fruit.For example, synthesized compound is available
Well known method such as crystallization, chromatography or reversed-phased high performace liquid chromatographic (RP-HPLC) or based on such as compound size, charge or
Other hydrophobic separation methods are purified.Similarly, well known method such as amino acid sequence analysis, NMR, IR and mass spectrography
(MS) can be used for characterizing the compounds of this invention.
Therefore, following embodiment is a part of the invention, is not intended to limit the present invention for illustrating.
It should be intended that, the active modification of the various embodiments of the non-substantial effect present invention is included in disclosed herein
The scope of the invention in.
Specific embodiment
Embodiment: 4- sec-butyl-N- (4- (2,4 difluorobenzene base) -5- (1- isopropyl -6- oxo -1,6- dihydropyridine -
3- yl) -1H- imidazoles -2- base) piperazine -1- formamide (compound number 1) preparation
Step 1: the bromo- 1- of 2- (2,4 difluorobenzene base) ethyl ketone
1- (2,4- difluorophenyl) ethyl ketone (10.0g, 64.0mmol) is added in copper bromide (28.6g, 128.0mmol)
In chloroform (100mL) and ethyl alcohol (80mL) mixed solution.Oil bath heating is to 80 DEG C, and insulation reaction about 10 hours.It is filtered to remove
Insoluble matter is added ethyl acetate (200mL), and gained mixed solution successively uses saturated salt solution (200mL*2) and saturation sulfurous
Acid sodium solution (200mL*2) washing.Organic phase is dried over anhydrous sodium sulfate, and filtering, evaporating solvent under reduced pressure obtains 13.2g yellow oil
The bromo- 1- of shape object, as 2- (2,4- difluorophenyl) ethyl ketone, yield 87.8%.MS:m/z=235.0,237.0 (M+H+)。
Step 2: 2- (2,4 difluorobenzene base) imidazo [1,2-a] pyrimidine
The bromo- 1- of 2- (2,4- difluorophenyl) ethyl ketone (23.5g, 0.1mol) is added in pyridine -2- amine (9.5g, 0.1mol)
Glycol dimethyl ether (200mL) solution in.After reaction solution is heated to 100 DEG C of reactions about 8 hours, evaporating solvent under reduced pressure.Institute
Mixed solvent (methanol: methyl tertiary butyl ether(MTBE)=1:10) recrystallization of the crude product through methanol and methyl tertiary butyl ether(MTBE) is obtained, is precipitated, filtering
And it is dried in vacuo to obtain 19.7g white solid, and as 2- (2,4- difluorophenyl) imidazo [1,2-a] pyrimidine, yield 85.2%.
MS:m/z=232.1 (M+H+)。
Step 3: the bromo- 2- of 3- (2,4 difluorobenzene base) imidazo [1,2-a] pyrimidine
2- (2,4- difluorophenyl) imidazo [1,2-a] pyrrole is added in N- bromo-succinimide (11.6g, 64.9mol)
In chloroform (200mL) solution of pyridine (15.0g, 64.9mmol).After reaction solution is heated to 80 DEG C of reactions about 3 hours, it is cooled to
Room temperature is added methylene chloride (200mL).Gained reaction solution washs (200mL*3) with saturated sodium bicarbonate solution.Organic phase is through nothing
After aqueous sodium persulfate is dry, filtering, evaporating solvent under reduced pressure obtains 18.9g white solid, the bromo- 2- of as 3- (2,4- difluorophenyl) miaow
Azoles simultaneously [1,2-a] pyrimidine, yield 93.9%.MS:m/z=310.0,312.0 (M+H+)。
Step 4: 5- (2- (2,4 difluorobenzene base) imidazo [1,2-a] pyrimidin-3-yl) -1- isopropyl pyridine -2 (1H) -
Ketone
By sodium carbonate (21.2g, 0.20mol), 1- isopropyl -5- (4,4,5,5- tetramethyls -1,3, penta boron of 2- dioxane
Alkane -2- base) pyridine -2 (1H) -one (14.5g, 0.055mol), tetra-triphenylphosphine palladium (2.9g, 2.5mmol) sequentially add 3-
In tetrahydrofuran (200mL) solution of bromo- 2- (2,4- difluorophenyl) imidazo [1,2-a] pyrimidine (15.5g, 0.05mol).
After reaction solution is 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 is with saturated common salt water washing (200mL*3).Merge organic phase, after being dried over anhydrous sodium sulfate, filtering is removed under reduced pressure molten
Agent, residue be purified by silica gel column chromatography (gradient elution, eluent are petroleum ether: ethyl acetate=40:1 to 4:1) 12.7g
Yellow solid, as 5- (2- (2,4- difluorophenyl) imidazo [1,2-a] pyrimidin-3-yl) -1- isopropyl pyridine -2 (1H) -
Ketone, yield 69.3%.MS:m/z=367.1 (M+H+)。
Step 5: 5- (2- amino -4- (2,4 difluorobenzene base) -1H- imidazoles -5- base) -1 isopropyl pyridine -2 (1H) -one
5- (2- (2,4- difluorophenyl) imidazo [1,2-a] is added in hydrazine hydrate (55% aqueous solution, 9.8g, 0.1mol)
Pyrimidin-3-yl) -1- isopropyl pyridine -2 (1H) -one (7.3g, 20.0mmol) ethyl alcohol (100mL) solution in.By reaction solution oil
Bath is heated to after flowing back and reacting about 10 hours, is cooled to room temperature.Evaporating solvent under reduced pressure, residue is with ethyl acetate (150mL)
Dissolution, acquired solution is with saturated common salt water washing (100mL*2).After organic phase is dried over anhydrous sodium sulfate, filtering is removed under reduced pressure
Solvent, residue are purified by silica gel column chromatography (eluent is methylene chloride: methanol=40:1) and obtain 5.5g yellow solid, as 5-
(2- amino -4- (2,4- difluorophenyl) -1H- imidazoles -5- base) -1- isopropyl pyridine -2 (1H) -one, yield 83.2%.MS:m/
Z=331.1 (M+H+).Step 6: 4- sec-butyl-N- (4- (2,4 difluorobenzene base) -5- (1- isopropyl -6- oxo -1,6- two
Pyridinium hydroxide -3- base) -1H- imidazoles -2- base) piperazine -1- formamide (compound number 1)
In 5- (2- amino -4- (2,4 difluorobenzene base) -1H- imidazoles -5- base) -1- isopropyl pyridine -2 (1H) -one
In n,N-Dimethylformamide (60mL) solution of (3.8g, 11.6mmol), 1- ethyl-(3- dimethylamino third is successively added
Base) phosphinylidyne diimmonium salt hydrochlorate (i.e. EDCIHCl, 4.45g, 23.2mmol), N, N- lutidines -4- amine (i.e. DMAP,
0.71g, 5.8mmol), Anhydrous potassium carbonate (3.2g, 23.2mmol) and 4- sec-butyl piperazine -1- formic acid (3.2g,
17.4mmol).Overnight, TLC monitors (petroleum ether: ethyl acetate=1:1) until the reaction is complete for reaction at room temperature.With acetic acid second
Ester (200mL) dilute reaction solution.Gained mixture is with saturated common salt water washing (100mL*3).Organic phase is dry through anhydrous sodium sulfate
After dry, filtering, evaporating solvent under reduced pressure, residue is purified by silica gel column chromatography that (gradient elution, eluent are methylene chloride: methanol
=50:1 to 5:1) obtains 3.1g yellow solid, as 4- sec-butyl-N- (4- (2,4- difluorophenyl) -5- (1- isopropyl -6- oxygen
Generation -1,6- dihydropyridine -3- base) -1H- imidazoles -2- base) piperazine -1- formamide, yield 53.6%.MS:m/z=499.3 (M
+H+)。
1HNMR(400MHz,DMSO-d6)δ:10.06(s,1H),8.76(s,1H),7.78(d,1H),7.19(d,1H),
7.05(d,1H),6.92(s,1H),6.51(d,1H),4.49-4.43(m,1H),3.33-3.24(m,4H),2.94-2.85
(m,4H),2.69-2.63(m,1H),1.52-1.44(m,8H),1.11(d,3H),0.89(t,3H).
The compound of formula I for meeting claims can be used to be obtained with the approximate synthetic method of above-described embodiment, only
Different starting materials need to be changed.Representational compound see the table below:
More representational compounds are not listed one by one.
Determination of activity
Compound of formula I and/or their officinal salt can be tentatively according to optical fluorescence membrane potentials as CFTR inhibitor
Measuring method carries out active testing.
Measuring principle: the principle of membrane potential measuring method be using negatively charged fluorescence voltage sensor dyestuff (such as
FLIPR film potential dyestuff), cell is pre-processed with untested compound, then on-load voltage senses dyestuff, senses dyestuff extracellular
When combine quencher, after cell depolarization, negatively charged dyestuff reassigns to compartment intracellular, thus quenches from film is impermeable
It goes out and discharges in agent, fluorescence is caused to increase.Using the change of membrane potential on fluorescence plate reader measurement FLIPR III as NIH3T3
Functionality Δ F508-CFTR gates increased readout (conductance) in cell.This fluorescence change with because of CFTR activity caused by
The change of membrane potential is directly proportional.It can be existed by the fluorescence detector such as FLIPR (Fluorometric Imaging Plate reader) being suitably equipped with
The change of real-time monitoring fluorescence in the microtiter plate of the hole 96 or 384-.It can quantitative detection by measurement this mode of membrane potential
CFTR activity.
Cell culture: film is carried out with NIH3T3 Chinese hamster ovary (CHO) cell for stablizing the expression channel Δ F508-CFTR
Potential Examination.By cell in 37 DEG C, 5%v/vCO2Eagle culture medium (MEM) is improved with maintaining under 100% damp condition
In.The culture medium supplements 8%v/v fetal calf serum, 100 μ g/mL methotrexate (MTX)s and 100U/mL penicillin/streptomycin.Make thin
Intracellular growth is in 225cm2In tissue culture flasks.In order to carry out film potential measurement, cell is seeded in 96 holes with 40,000 cells/wells
In the coated culture plate of matrigel, make its adherency, cultivated 48 hours at 26 DEG C, is measured for reinforcing agent.
Reinforcing agent measurement: low chlorine ion (5mM) and two-cocoon feeding containing extracellular solution is utilized in film potential the screening test method
HTS is added to measure scheme.Addition is the buffer for containing or not contain untested compound for the first time, adds not this Kelin after five minutes
(1-20μM).The program is conducive to the maximum chlorine outflow activated in response to Δ F508-CFTR.Δ F508-CFTR mediate chlorine from
Subflow goes out to lead to membrane depolarization, and optional FMP dyestuff is monitored it.Solution: the low extracellular solution of chlorine (concentration magnitude is mM) group
As 120 gluconic acid sodium salts, 1.2CaCl2、3.3KH2PO4、 1.2MgCl2, 10.0D- glucose, 20.0HEPES, with NaOH tune pH
It is worth to 7.4.
FMP dyestuff: the above-mentioned extracellular solution of low chlorine, 10 times of final concentrations, with the storage of 1mL aliquot are prepared according to operation instructions
It is stored in -20 DEG C.
Measurement result: the representational compound in part carries out the testing result (EC of determination of activity using the above method50
Value) it is as shown in the table.
。
Claims (5)
1. compound of formula I and/or their officinal salt
Wherein, R C3Or C4Or C5Or C6Or C7Or C8Naphthenic base, C3Or C4Or C5Or C6Or C7Or C8Azacycloalkyl, C3Or C4Or
C5Or C6Or C7Or C8Oxacycloalkyl, morpholinyl, piperazinyl, nitrogen are taken by linear chain or branched chain C1 or C2 or C3 or C4 or C5 alkyl
The piperazinyl in generation.
2. at least one compound of formula I described in claim 1 and/or its officinal salt are preparing cystic fibrosis transmembrane biography
Lead the purposes in regulatory factor inhibitor class drug.
3. at least one compound of formula I described in any one of claim 1 and 2 and/or its officinal salt prevent in preparation
And/or the purposes in the drug of the following disease for the treatment of: cystic fibrosis, abnormal increased intestinal secretion, secretory diarrhea, polycystic kindey
Dirty disease, chronic obstructive pulmonary disease, chronic bronchitis, glutinous hyperglycemia and congenital bilateral vas deferens missing (CBAVA) are led
The male sterility of cause.
4. purposes described in claim 3, disease therein refers to cystic fibrosis.
5. drug, it includes described in any one of a effective amount of claim 1 and 2 at least one compound of formula I and/or its
Officinal salt, physiology tolerance excipient and carrier, and in due course there are also other additives and/or other activity at
Point.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1370557B1 (en) * | 2001-03-09 | 2005-11-16 | Pfizer Products Inc. | Benzimidazole anti-inflammatory compounds |
| CN101087605A (en) * | 2004-12-24 | 2007-12-12 | 贝林格尔·英格海姆国际有限公司 | Indolidone derivatives for the treatment or prevention of fibrotic diseases |
| CN104788423A (en) * | 2015-03-13 | 2015-07-22 | 成都理工大学 | New cystic fibrosis transmembrane conductance regulator inhibitor |
-
2018
- 2018-10-10 CN CN201811176336.8A patent/CN109134431B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1370557B1 (en) * | 2001-03-09 | 2005-11-16 | Pfizer Products Inc. | Benzimidazole anti-inflammatory compounds |
| CN101087605A (en) * | 2004-12-24 | 2007-12-12 | 贝林格尔·英格海姆国际有限公司 | Indolidone derivatives for the treatment or prevention of fibrotic diseases |
| CN104788423A (en) * | 2015-03-13 | 2015-07-22 | 成都理工大学 | New cystic fibrosis transmembrane conductance regulator inhibitor |
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