CN106632235A - Methoxyphenyl thiophene amide structure-containing double-target inhibitors and use thereof - Google Patents
Methoxyphenyl thiophene amide structure-containing double-target inhibitors and use thereof Download PDFInfo
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- CN106632235A CN106632235A CN201611194360.5A CN201611194360A CN106632235A CN 106632235 A CN106632235 A CN 106632235A CN 201611194360 A CN201611194360 A CN 201611194360A CN 106632235 A CN106632235 A CN 106632235A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention relates to the field of medicines related to type 2 diabetes, and particularly relates to methoxyphenyl thiophene amide structure-containing SGLT2/SGLT1 (sodium-glucose linked transporter 2/sodium-glucose linked transporter 1) double-target inhibitors, as well as a preparation method and application thereof to preparation of a medicament for type 2 diabetes. A structural formula is shown in the description, wherein X is selected from a halogen substituent.
Description
Technical field
The present invention relates to the drug world of the treatment of diabetes B.Specifically, the present invention relates to have to diabetes B
The double target spot inhibitor of the SGLT2/SGLT1 of one class thiophene-carboxamides containing anisyl class formation of therapeutic action, its preparation method, with
And in purposes pharmaceutically.
Background technology
Diabetes are a kind of metabolic diseases being characterized with hyperglycaemia.Hyperglycaemia be then due to defect of insulin secretion or
Its biological agent is damaged, or both have concurrently and cause.Long-standing hyperglycaemia during diabetes, cause various tissues, particularly eye,
Kidney, heart, blood vessel, chronic lesion, the dysfunction of nerve.The method that there is no radical cure diabetes at present, but by various treatments
Means can carry out suitable control to diabetes progression.Mainly include several aspects：The education of diabetic, self-monitoring blood
Sugar, dietary therapy, exercise therapy and drug therapy.Oral hypoglycaemic medicine is by many kinds, such as sulfonylurea, biguanides, thiazole
Alkane diones, glycosidase inhibitor class, etc., but these medicines generally have a variety of side effects, such as hepatotoxicity,
Hypoglycemia, abdominal distension, heart disease risk, etc..Therefore the medicine of brand-new action target spot is clinically active demand.
Sodium-glucose co-transporters body (sodium-glucose linked transporter, SGLT) is a kind of glucose
Transport protein, there is two kinds of hypotype i.e. SGLT1 and SGLT2, and both are distributed in renal proximal tubules, to glucose in kidney
Re-absorbed contribution is respectively 10% and 90%, and in addition SGLT1 is also distributed about in enteron aisle, is responsible in enteron aisle together with GLUT
The absorption of glucose.Suppress SGLT2 that the glucose in renal tubule can be prevented to enter blood from smooth reabsorption and discharge with urine,
So as to reduce blood sugar concentration, at present the SGLT2 inhibitor of listing has multiple, such as dapagliflozin, canagliflozin and
Empagliflozin etc..
The inhibitor of these listings is selective SGLT2 inhibitor, very weak to SGLT1 inhibitory action.In SGLT2 suppressions
At the initial stage of preparation research and development, the selectivity of SGLT2/SGLT1 was considered as once critically important index, because suppressing SGLT1 resonable
By may above cause intestines and stomach side reaction.But research in recent years shows, it is this it is theoretic worry it is not necessary that, and
(Zambrowicz B, et al.Effects of LX4211, a dual are confirmed by the clinical testing of LX4211
sodium-dependent glucose cotransporters 1and 2inhibitor,on postprandial
glucose,insulin,glucagon-like peptide 1,and peptide tyrosine in a dose-timing
study in healthy subjects,Clin Ther.,2013,35(8),1162-1173.e8).Due to SGLT2/SGLT1
Inhibitor can further suppress SGLT1 on the basis of SGLT2 is suppressed, and this suppression can increase the row of glucose in urine in kidney
Go out and reduce the absorption of glucose in enteron aisle, therefore this kind of inhibitor is considered as a kind of selection of brand-new control blood sugar.
The invention discloses the double target spot inhibitor of the SGLT2/SGLT1 of class thiophene-carboxamides containing an anisyl class formation, this
A little compounds can be used to prepare the medicine for the treatment of diabetes B.
The content of the invention
It is an object of the present invention to provide it is a kind of with the double target spot inhibitory activity of good SGLT2/SGLT1, with logical
The non-glucoside compound of one class of Formulas I.
It is a further object to provide preparing the method with compounds of formula I.
It is also another object of the present invention to provide containing compounds of formula I in terms for the treatment of diabetes B medicine is prepared
Application.
Present invention is specifically described in conjunction with the purpose of the present invention.
The present invention has following structural formula with compounds of formula I：
Wherein, X is selected from halogenic substituent.
It is preferred that the compound of below general formula I has following structure,
Compound of Formula I of the present invention is synthesized by following route：
Compound II is changed into its corresponding acyl chlorides III；Acyl chlorides III reacts in the presence of a base with compound IV, is changed
Compound V；There is condensation reaction in compound V, obtain compound I with cyclopentadiene in the presence of a base；Wherein X institutes as defined above
State.
Compound of Formula I of the present invention has the double inhibition effect of SGLT2/SGLT1, can be used for as active ingredient
Prepare the medicine of diabetes B.The activity of compound of Formula I of the present invention is verified by receptor binding assays
's.
The compound of Formula I of the present invention is effective in comparatively wide dosage range.The dosage for example taken daily is about
In the range of 1mg-1000mg/ people, it is divided into and once or is for several times administered.The dosage for actually taking compound of Formula I of the present invention can be by
Doctor determines according to relevant situation.
Specific embodiment
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only for
Illustrate, and be not intended to limit the present invention.The various change that those skilled in the art's training centre of the invention is made all should
Within the protection domain required by the application claim.
The synthesis of the compound I-1 of embodiment 1
A. the synthesis of compound V-1
4.68g (20mmol) compound II-1 is dissolved in the dichloromethane of 10mL dryings, is stirred under room temperature, is slowly added dropwise
The oxalyl chloride of 3.81g (30mmol) newly distillations, is then added dropwise 2 and drips DMF, and then reactant mixture is stirred at room temperature overnight.Instead
Answer mixture to be evaporated on a rotary evaporator, be then dried 5 minutes in vacuum oil pump, then with the dissolving of 10mL dichloromethane, ice
The lower stirring of water-bath cooling, is then slowly added dropwise 3.10g (20mmol) IV-1 and 6.07g (60mmol) triethylamines, after completion of dropping
Reactant mixture is stirred at room temperature overnight, and TLC checks that reaction is completed.After the completion of reaction, toward reactant mixture 100mL is poured into
In frozen water, stirring, using the CH of 50mL × 32Cl2Extraction, merges extraction phase, anhydrous successively with 1% watery hydrochloric acid and salt water washing
Sodium sulphate is dried.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and the residue for obtaining is purified using column chromatography,
Obtain compound V-1, white solid, ESI-MS, m/z=372 ([M+H]+)。
B. the synthesis of compound I-1
The cyclopentadiene of 3.71g (10mmol) compound V-1 and 1.32g (20mmol) newly distillation is dissolved in 20mL absolute ethyl alcohols
In, stirring adds 3.40g (50mmol) solid sodium ethanol, continues to be stirred overnight under room temperature, and TLC checks that reaction is completed.Reaction is mixed
Compound is poured into 100mL frozen water, stirring, using the CH of 50mL × 32Cl2Extraction, merges extraction phase, salt water washing, anhydrous sulphur
Sour sodium is dried.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and the residue for obtaining is purified using column chromatography, is obtained
To compound I-1, white solid, ESI-MS, m/z=420 ([M+H]+)。
Embodiment 2-4
With reference to the operating procedure of embodiment 1, compound listed in Table is synthesized.
Suppression of the Compound ira vitro of embodiment 5 to people SGLT2 and people SGLT1
It is prepared by people SGLT2 expression vectors
The full length cDNA clone (being purchased from GenScript companies) of expression people SGLT2 (Hind III have been put at cDNA two ends
With Not I sites) be subcloned to pEAK15 expression vectors (Theracos companies of the U.S.) Hind III and Not I site it
Between.The method of the clone's digestion with restriction enzyme containing target gene determines.
It is prepared by people SGLT2 stably transfected cell lines
Using restriction enzyme Nsi I plasmids of the digestion containing someone SGLT2, it is allowed to linearize, with Ago-Gel electricity
Swimming is purified to linear DNA.With transfection reagent Lipofectamine2000 (Invitrogen companies) by DNA after purification
Proceed to HEK293 cells (Theracos companies of the U.S.).By the cell after transfection in the DMEM culture mediums containing 10% hyclone
In 37 DEG C, 5%CO2Under the conditions of culture 24 hours after, in identical growth medium add purine mycin (Invitrogen is public
Department) continue to cultivate 2 weeks, the cell with puromycin-resistant after screening is inoculated in 96 new orifice plates (per one, hole
Cell), cultivate in the culture medium containing purinase element, until cell length is to converging state.With the thin of puromycin-resistant
Methyl-α-D- [the U- that born of the same parents clone passes through reflection SGLT2 activity14C] (experimental technique exists the further screening of pyranoside intake test
Hereinafter it is described in detail).The cell clone with highest signal to noise ratio is selected to be used for follow-up methyl-α-D- [U-14C] pyranoside takes the photograph
Take test.
It is prepared by people SGLT1 expression cells
PDream2.1 expression vectors containing total length people SGLT1cDNA are purchased from GenScript companies.Plasmid is in large intestine bar
Expanded in bacterium DH5 α, the strain culturing is in the Luria-Bertani containing ampicillin (LB) culture medium.With
QIAGEN Plasmid Midi kits (QIAGEN companies) extracts plasmid.With the transfection reagents of Lipofectamine 2000, press
People's SGLT1 expression vector plasmids are proceeded into COS-7 cells (purchased from American Type Tissue Culture according to the method for operation manual
The heart).Transfectional cell is in the DMEM containing 10%DMSO in -80 DEG C of preservations.
Methyl-α-D- [U-14C] pyranoside intake test
Before test, the cell that SGLT1 and SGLT2 is expressed respectively is inoculated in into 96 holes with the DMEM containing 10%FBS
ScintiPlate liquid dodges plate (PerkinElmer companies) (100 μ L nutrient solutions being added per hole, containing 1 × 105 cell), and in 37
DEG C, cultivate 48 hours under the conditions of 5%CO2.Cell is with 150 μ L buffer solutions containing sodium (137mM NaCl, 5.4mM KCl, 2.8mM
CaCl2, 1.2mM MgCl2, 10mM trishydroxymethylaminomethanes/N-2- hydroxyethyl piperazine-N '-ethane sulfonic acid [Tris/Hepes],
PH7.2) or without sodium buffer solution (137mM N- methyl-glucamines, 5.4mM KCl, 2.8mM CaCl2,1.2mM MgCl2,
10mM Tris/Hepes, pH7.2) wash twice.Testing compound is dissolved in containing 25% human plasma and 40 μ Ci/mL methyl-α-D-
[U-14C] pyranoside (Amersham Biosciences/GE Healthcare) containing sodium or without sodium buffer solution in, be prepared into
A series of testing compound solution of suitable concns.96 orifice plates add 50 μ L testing compound solutions, shaken cultivation 2 hours per hole
(SGLT1 analyses) or 1.5 hours (SGLT2 analyses).Cell is with 150 μ L cleaning buffer solutions (137mM N-METHYL-ALPHA-L-GLUCOSAMINEs, 10mM
Tris/Hepes, pH7.2) wash twice, with TopCount liquid scintillation counters (Perkin Elmer companies) to methyl-α-D- [U-
14C] pyranoside intake carry out quantitative analysis.Sodium dependence pyranoside intake as processes what is obtained with buffer solution containing sodium
Intake deducts the difference (mean value of three wells) of the intake obtained without the process of sodium buffer solution.
As a result as shown in following table：
The IC that the part of compounds of the present invention suppresses to people SGLT2 and people SGLT150Value
| Compound | IC50(hSGLT2,nM) | IC50(hSGLT1,nM) |
| dapagliflozin | 1.4 | 1339 |
| The compound of embodiment 1 | 6.3 | 18.5 |
| The compound of embodiment 2 | 6.8 | 16.1 |
| The compound of embodiment 3 | 8.1 | 22.7 |
| The compound of embodiment 4 | 11.4 | 25.9 |
Above-mentioned IC50Measurement result show that the compound of the present invention is the double target spot inhibitor of strong SGLT2/SGLT1, can
For preparing the medicine for the treatment of diabetes B.
Claims (4)
1. there is the compound of general formula I,
Wherein, X is selected from halogenic substituent.
2. compound of Formula I defined in claim 1, selected from following compounds,
3. the arbitrary defined method for belonging to compounds of formula I of claim 1-2 is synthesized：
Compound II is changed into its corresponding acyl chlorides III；Acyl chlorides III reacts in the presence of a base with compound IV, obtains compound
V；There is condensation reaction in compound V, obtain compound I with cyclopentadiene in the presence of a base；The wherein definition of X such as claim 1-
2 is arbitrary described.
4. application of the compound of Formula I defined in one of claim 1-2 in terms for the treatment of diabetes B medicine is prepared.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611194360.5A CN106632235A (en) | 2015-02-11 | 2015-02-11 | Methoxyphenyl thiophene amide structure-containing double-target inhibitors and use thereof |
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|---|---|---|---|
| CN201611194360.5A CN106632235A (en) | 2015-02-11 | 2015-02-11 | Methoxyphenyl thiophene amide structure-containing double-target inhibitors and use thereof |
| CN201510076733.8A CN104693171A (en) | 2015-02-11 | 2015-02-11 | Methoxyphenyl-containing thiophene amide structured double-target-point inhibitor and use thereof |
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| CN201510076733.8A Pending CN104693171A (en) | 2015-02-11 | 2015-02-11 | Methoxyphenyl-containing thiophene amide structured double-target-point inhibitor and use thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101287728A (en) * | 2005-08-17 | 2008-10-15 | 先灵公司 | Novel high affinity thiophene-based and furan-based kinase ligands |
| CN101479254A (en) * | 2006-06-29 | 2009-07-08 | 大正制药株式会社 | C-phenyl 1-thioglucitol compound |
| CN101959515A (en) * | 2008-02-25 | 2011-01-26 | 默克专利有限公司 | Glucokinase activators |
-
2015
- 2015-02-11 CN CN201611194360.5A patent/CN106632235A/en active Pending
- 2015-02-11 CN CN201510076733.8A patent/CN104693171A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101287728A (en) * | 2005-08-17 | 2008-10-15 | 先灵公司 | Novel high affinity thiophene-based and furan-based kinase ligands |
| CN101479254A (en) * | 2006-06-29 | 2009-07-08 | 大正制药株式会社 | C-phenyl 1-thioglucitol compound |
| CN101959515A (en) * | 2008-02-25 | 2011-01-26 | 默克专利有限公司 | Glucokinase activators |
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