CN104725346A - Cyano-substituted double-target inhibitors containing methoxybenzene thiophene amide and application thereof - Google Patents

Cyano-substituted double-target inhibitors containing methoxybenzene thiophene amide and application thereof Download PDF

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Publication number
CN104725346A
CN104725346A CN201510075166.4A CN201510075166A CN104725346A CN 104725346 A CN104725346 A CN 104725346A CN 201510075166 A CN201510075166 A CN 201510075166A CN 104725346 A CN104725346 A CN 104725346A
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compound
sglt2
application
sglt1
cyano
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Chinese (zh)
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蔡子洋
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Foshan Saiweisi Pharmaceutical Technology Co Ltd
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Foshan Saiweisi Pharmaceutical Technology Co Ltd
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Priority to CN201510075166.4A priority Critical patent/CN104725346A/en
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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

Abstract

The invention relates to the field of medicines related to type II diabetes mellitus and in particular relates to cyano-substituted SGLT (sodium glucose linked transporter)2/SGLT1 double-target inhibitors containing methoxybenzene thiophene amide, a preparation method of the inhibitors and an application of the inhibitors to preparation of medicines related to type II diabetes mellitus. A structure of the inhibitors is shown in a formula I in the specification.

Description

Two target spot inhibitor of the methoxy benzene thiophene-carboxamides class that a kind of itrile group replaces and uses thereof
Technical field
The present invention relates to the pharmaceutical field of the treatment of diabetes B.Specifically, the present invention relates to the medicative a kind of itrile group of diabetes B replace containing methoxyphenyl thiophene-carboxamides class SGLT2/SGLT1 two target spot inhibitor, its preparation method, and in purposes pharmaceutically.
Background technology
The metabolic disease of diabetes to be a kind of with hyperglycemia be feature.Hyperglycemia be then due to defect of insulin secretion or its biological action impaired, or both have concurrently and cause.Long-standing hyperglycemia during diabetes, causes various tissue, particularly eye, kidney, heart, blood vessel, neural chronic lesion, dysfunction.There is no the method for radical cure diabetes at present, but suitably can be controlled diabetes progression by multiple treatment means.Mainly comprise several aspect: the education of diabetic subject, self-monitoring of blood glucose, dietetic treatment, exercise therapy and pharmacological agent.Oral hypoglycaemic medicine by a variety of, as sulfonylurea, biguanides, thiazolidinediones, glycosidase inhibitor class, etc., but these medicines generally have various different side effect, as hepatotoxicity, hypoglycemia, abdominal distension, heart disease risk, etc.Therefore the medicine of brand-new action target spot is active demand clinically.
Sodium-glucose co-transporters body (sodium-glucose linked transporter, SGLT) be a kind of glucose transporter, there are two kinds of hypotypes and SGLT1 and SGLT2, both all have distribution in renal proximal tubules, 10% and 90% are respectively to the contribution of glucose reabsorption in kidney, in addition SGLT1 is also distributed in enteron aisle, is responsible for the absorption of glucose in enteron aisle together with GLUT.Suppress SGLT2 that the glucose in uriniferous tubules can be made heavily not absorb smoothly enter blood and discharge with urine, thus reduce blood sugar concentration, the SGLT2 inhibitor of listing at present has multiple, as dapagliflozin, canagliflozin and empagliflozin etc.
Inhibitor of these listings are all optionally SGLT2 inhibitor, very weak to SGLT1 restraining effect.At the initial stage of SGLT2 inhibitor research and development, the selectivity of SGLT2/SGLT1 was once considered to very important index, because suppress SGLT1 may cause intestines and stomach side reaction in theory.But research in recent years shows, this theoretic worry there is no need, and confirm by the clinical trial of LX4211 (Zambrowicz B, et al.Effects of LX4211, a dual 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).Because SGLT2/SGLT1 inhibitor can suppress SGLT1 further on the basis suppressing SGLT2, and this suppression can increase the discharge of glucose in urine in kidney and reduce the absorption of glucose in enteron aisle, therefore this kind of inhibitor is considered to a kind of selection of control blood sugar completely newly.
What the invention discloses the replacement of a kind of itrile group contains the two target spot inhibitor of methoxyphenyl thiophene-carboxamides class SGLT2/SGLT1, and these compounds can be used for the medicine preparing treatment diabetes B.
Summary of the invention
An object of the present invention is to provide and a kind of there is the two target spot inhibit activities of good SGLT2/SGLT1, there is the non-glucoside compound of a class of formula I.
Another object of the present invention is to provide the method that preparation has the compound of formula I.
Another object of the present invention is to provide the application of compound in preparation treatment diabetes B medicine containing formula I.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has formula I has following structural formula:
Formula I of the present invention is synthesized by following route:
Compound II per changes the acyl chlorides III of its correspondence into; Acyl chlorides III reacts with compound IV in the presence of a base, obtains compound V; Compound V in the presence of a base with cyclopentadiene generation condensation reaction, obtain Compound I; Wherein the definition of X as previously mentioned.
Formula I of the present invention has the double inhibition effect of SGLT2/SGLT1, can be used as the medicine of effective constituent for the preparation of diabetes B.The activity of formula I of the present invention is verified by receptor binding assays.
Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-1000mg/ people, is divided into once or administration for several times.The actual dosage taking formula I can be decided according to relevant situation by doctor.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
the synthesis of embodiment 1 Compound I
A. the synthesis of compound V
4.68g (20mmol) Compound II per is dissolved in the methylene dichloride of 10mL drying, stirred at ambient temperature, and slowly drip the oxalyl chloride of 3.81g (30mmol) newly distillation, then drip 2 DMF, then reaction mixture at room temperature stirs and spends the night.Reaction mixture is evaporate to dryness on a rotary evaporator, then in vacuum oil pump dry 5 minutes, dissolve with 10mL methylene dichloride again, ice-water bath cooling is lower stirs, then slowly drip 2.92g (20mmol) IV and 6.07g (60mmol) triethylamine, dropwise rear reaction mixture at room temperature to stir and spend the night, TLC checks that reaction completes.After having reacted, pour in 100mL frozen water toward reaction mixture, stir, use the CH of 50mL × 3 2cl 2extraction, merges extraction phase, uses 1% dilute hydrochloric acid and salt water washing successively, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound V, white solid, ESI-MS, m/z=363 ([M+H] +).
B. the synthesis of Compound I
The cyclopentadiene of 3.62g (10mmol) compound V-1 and 1.32g (20mmol) newly distillation is dissolved in 20mL dehydrated alcohol, stir, add 3.40g (50mmol) solid sodium ethanol, continue stirring and spend the night under room temperature, TLC checks that reaction completes.Reaction mixture pours in 100mL frozen water, stirs, and uses the CH of 50mL × 3 2cl 2extraction, merges extraction phase, salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains Compound I, white solid, ESI-MS, m/z=411 ([M+H] +).
the preparation of embodiment 2 reference compound D-1
In order to further illustrate the outstanding pharmacological effect of the compounds of this invention, the application describes and prepare novel compounds D-1 (not yet open) in research process of the present invention, and its structure is as follows:
Compound D-1
Its preparation method is as follows:
A. the synthesis of compound V-1
4.08g (20mmol) Compound II per-1 is dissolved in the methylene dichloride of 10mL drying, stirred at ambient temperature, slowly drip the oxalyl chloride of 3.81g (30mmol) newly distillation, then drip 2 DMF, then reaction mixture at room temperature stirs and spends the night.Reaction mixture is evaporate to dryness on a rotary evaporator, then in vacuum oil pump dry 5 minutes, dissolve with 10mL methylene dichloride again, ice-water bath cooling is lower stirs, then slowly drip 2.42g (20 mmol) IV p-Aminobenzaldehyde and 6.07g (60mmol) triethylamine, dropwise rear reaction mixture at room temperature to stir and spend the night, TLC checks that reaction completes.After having reacted, pour in 100mL frozen water toward reaction mixture, stir, use the CH of 50mL × 3 2cl 2extraction, merges extraction phase, uses 1% dilute hydrochloric acid and salt water washing successively, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound V-1, white solid, ESI-MS, m/z=308 ([M+H] +).
B. the synthesis of Compound D-1
The cyclopentadiene of 3.07g (10mmol) compound V-1 and 1.32g (20mmol) newly distillation is dissolved in 20mL dehydrated alcohol, stir, add 3.40g (50mmol) solid sodium ethanol, continue stirring and spend the night under room temperature, TLC checks that reaction completes.Reaction mixture pours in 100mL frozen water, stirs, and uses the CH of 50mL × 3 2cl 2extraction, merges extraction phase, salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains Compound D-1, white solid, ESI-MS, m/z=356 ([M+H] +).
embodiment 3 Compound ira vitro is to the suppression of people SGLT2 and people SGLT1
Prepared by people SGLT2 expression vector
To full length cDNA clone (purchased from GenScript company) (having put Hind III and Not I site at the cDNA two ends) subclone of people SGLT2 be expressed between the Hind III and Not I site of pEAK15 expression vector (Theracos company of the U.S.).The method of the clone's digestion with restriction enzyme containing target gene is determined.
Prepared by people SGLT2 stably transfected cell line
Utilize restriction enzyme Nsi I to digest the plasmid containing people SGLT2, make it linearizing, with agarose gel electrophoresis, purifying is carried out to linear DNA.With transfection reagent Lipofectamine2000 (Invitrogen company), the DNA after purifying is proceeded to HEK293 cell (Theracos company of the U.S.).By the cell after transfection containing 10% foetal calf serum DMEM substratum in 37 DEG C, 5%CO 2cultivate under condition after 24 hours, in identical growth medium, add purine mycin (Invitrogen company) continue cultivation 2 weeks, the cell after screening with puromycin-resistant is inoculated in (one, every hole cell) in 96 new orifice plates, cultivate in the substratum containing purinase element, until cell grows to converging state.There is the methyl-α-D-[U-of cell clone by reflection SGLT2 activity of puromycin-resistant 14c] pyranoside picked-up test screening (experimental technique has detailed description hereinafter) further.Select the cell clone with highest signal to noise ratio for follow-up methyl-α-D-[U- 14c] pyranoside picked-up test.
Prepared by people SGLT1 express cell
PDream2.1 expression vector containing total length people SGLT1cDNA is purchased from GenScript company.Plasmid increases in bacillus coli DH 5 alpha, and this strain culturing is in Luria-Bertani (LB) substratum containing penbritin.With QIAGEN Plasmid Midi test kit (QIAGEN company) extracting plasmid.With Lipofectamine 2000 transfection reagent, according to the method for operational manual, people SGLT1 expression vector plasmid is proceeded to COS-7 cell (purchased from American Type Tissue Collection).Transfectional cell in containing the DMEM of 10%DMSO in-80 DEG C of preservations.
Methyl-α-D-[U- 14c] pyranoside picked-up test
Before test, the DMEM of cell containing 10%FBS expressing SGLT1 and SGLT2 is respectively inoculated in 96 holes ScintiPlate liquid sudden strain of a muscle plate (PerkinElmer company), and (every hole adds 100 μ L nutrient solutions, containing 1 × 105 cell), and in 37 DEG C, cultivate 48 hours under 5%CO2 condition.Cell 150 μ L contain sodium damping fluid (137mM NaCl, 5.4mM KCl, 2.8mM CaCl 2, 1.2mM MgCl 210mM Tutofusin tris/N-2-hydroxyethyl piperazine-N '-ethane sulfonic acid [Tris/Hepes], pH7.2) or without sodium damping fluid (137mM N-methyl-glucamine, 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 in sodium damping fluid, be prepared into the testing compound solution of a series of suitable concn.The 96 every holes of orifice plate add 50 μ L testing compound solutions, shaking culture 2 hours (SGLT1 analysis) or 1.5 hours (SGLT2 analysis).Cell 150 μ L cleaning buffer solution (137mM N-METHYL-ALPHA-L-GLUCOSAMINEs, 10mM Tris/Hepes, pH7.2) wash twice, with TopCount liquid scintillation counter (Perkin Elmer company), quantitative analysis is carried out to the picked-up of methyl-α-D-[U-14C] pyranoside.Sodium dependency pyranoside intake is the difference (mean value of three wells) deducting the intake obtained without the process of sodium damping fluid by the intake obtained containing the process of sodium damping fluid.
Shown in the following list of result:
The IC that part of compounds of the present invention suppresses people SGLT2 and people SGLT1 50value
Compound IC 50(hSGLT2,nM) IC 50(hSGLT1,nM)
dapagliflozin 1.4 1339
Reference compound D-1 41.6 35.1
The compounds of this invention I 13.8 11.7
Above-mentioned IC 50measurement result show, compound of the present invention is the two target spot inhibitor of strong SGLT2/SGLT1, can be used for preparing the medicine for the treatment of diabetes B.

Claims (3)

1. there is the compound of formula I structure,
2. synthesize the method for compound described in claim 1:
Compound II per changes the acyl chlorides III of its correspondence into; Acyl chlorides III reacts with compound IV in the presence of a base, obtains compound V; Compound V in the presence of a base with cyclopentadiene generation condensation reaction, obtain Compound I.
3. the application of compound described in claim 1 in preparation treatment diabetes B medicine.
CN201510075166.4A 2015-02-11 2015-02-11 Cyano-substituted double-target inhibitors containing methoxybenzene thiophene amide and application thereof Pending CN104725346A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004002948A1 (en) * 2001-05-16 2004-01-08 Mitsubishi Pharma Corporation Amide compound and medicinal use thereof
WO2006081389A1 (en) * 2005-01-25 2006-08-03 Synta Pharmaceuticals Corp. Thiophene compounds for inflammation and immune-related uses
WO2014013181A1 (en) * 2012-07-20 2014-01-23 Metabrain Research Thiophene derivatives used in the treatment of diabetes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004002948A1 (en) * 2001-05-16 2004-01-08 Mitsubishi Pharma Corporation Amide compound and medicinal use thereof
WO2006081389A1 (en) * 2005-01-25 2006-08-03 Synta Pharmaceuticals Corp. Thiophene compounds for inflammation and immune-related uses
WO2014013181A1 (en) * 2012-07-20 2014-01-23 Metabrain Research Thiophene derivatives used in the treatment of diabetes

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