CN104672207B - The two target spot inhibitor of a kind of nitrothiophene acid amides toluene class and purposes thereof - Google Patents
The two target spot inhibitor of a kind of nitrothiophene acid amides toluene class and purposes thereof Download PDFInfo
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- CN104672207B CN104672207B CN201510076686.7A CN201510076686A CN104672207B CN 104672207 B CN104672207 B CN 104672207B CN 201510076686 A CN201510076686 A CN 201510076686A CN 104672207 B CN104672207 B CN 104672207B
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- sglt2
- nitrothiophene
- sglt1
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- -1 nitrothiophene acid amides toluene class Chemical class 0.000 title abstract description 11
- 239000003112 inhibitor Substances 0.000 title abstract description 9
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 40
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 150000001263 acyl chlorides Chemical class 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims 1
- 108091006269 SLC5A2 Proteins 0.000 abstract description 20
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 abstract description 20
- 108091006277 SLC5A1 Proteins 0.000 abstract description 19
- 102000058090 Sodium-Glucose Transporter 1 Human genes 0.000 abstract description 19
- 238000003756 stirring Methods 0.000 description 14
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
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- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
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- YKXCWZVUWWQSAV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O YKXCWZVUWWQSAV-BTVCFUMJSA-N 0.000 description 1
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 1
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- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
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- 108090001061 Insulin Proteins 0.000 description 1
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- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 102000003673 Symporters Human genes 0.000 description 1
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- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 238000000246 agarose gel electrophoresis Methods 0.000 description 1
- KLOHDWPABZXLGI-YWUHCJSESA-M ampicillin sodium Chemical compound [Na+].C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 KLOHDWPABZXLGI-YWUHCJSESA-M 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
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- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 description 1
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- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 description 1
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Classifications
-
- 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 present invention relates to the pharmaceutical field relevant to diabetes B. Specifically, the present invention relates to the two target spot inhibitor of a kind of nitrothiophene acid amides toluene class SGLT2/SGLT1, its preparation method and in the application prepared in diabetes B medicine.
Description
Technical field
The present invention relates to the pharmaceutical field of the treatment of diabetes B. Specifically, the present invention relates to a kind of nitrothiophene acid amides toluene class SGLT2/SGLT1 that diabetes B is had therapeutic action two target spot inhibitor, its preparation method, and the purposes in pharmacy.
Background technology
The metabolic disease of diabetes to be a kind of taking hyperglycemia be feature. Hyperglycemia is then owing to defect of insulin secretion or its biological action are impaired, or both have concurrently and cause. The hyperglycemia of long-term existence 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 diabetes progression suitably can be controlled by multiple treatment means. Mainly comprise several aspects: the education of diabetic subject, self-monitoring blood sugar, dietetic treatment, exercise therapy and pharmacological agent. Oral hypoglycemic thing by a variety of, such as sulfonylurea, biguanides, thiazolidinediones, glycosidase inhibitor class, etc., but these medicines generally have various different side effect, such 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-glucoselinkedtransporter, SGLT) it is a kind of glucose transporter, there are two kinds of hypotypes and SGLT1 and SGLT2, both all have distribution in renal proximal tubules, the contribution of glucose reabsorption in kidney is respectively 10% and 90%, in addition SGLT1 is also distributed in enteron aisle, is responsible for the absorption of glucose in enteron aisle together with GLUT. Suppressing SGLT2 that the glucose in uriniferous tubules can be made heavily not absorb smoothly to enter blood and discharge with urine, thus reduce blood sugar concentration, the SGLT2 inhibitor of listing has multiple at present, such as dapagliflozin, canagliflozin and empagliflozin etc.
Inhibitor of these listings are all optionally SGLT2 inhibitor, and SGLT1 restraining effect is very weak. At the initial stage of SGLT2 inhibitor research and development, the selectivity of SGLT2/SGLT1 was once considered as very important index, because suppressing SGLT1 may cause intestines and stomach side reaction in theory. But research in recent years shows, this kind worry in theory there is no need, and confirmed (ZambrowiczB by the clinical trial of LX4211, etal.EffectsofLX4211, adualsodium-dependentglucosecotransporters1and2inhibitor, onpostprandialglucose, insulin, glucagon-likepeptide1, andpeptidetyrosineinadose-timingstudyinhealthysubjects, ClinTher., 2013,35 (8), 1162-1173.e8). Owing to SGLT2/SGLT1 inhibitor can suppress SGLT1 further on the basis suppressing SGLT2, and this kind of suppression can increase in kidney the discharge urinating sugar and the absorption reducing glucose in enteron aisle, therefore this kind of inhibitor is considered as the selection of a kind of control blood sugar completely newly.
The present invention discloses the two target spot inhibitor of a kind of nitrothiophene acid amides toluene class SGLT2/SGLT1, and these compounds can be used for preparing the medicine for the treatment of diabetes B.
Summary of the invention
It is an object of the present invention to provide and a kind of there is the two target spot inhibit activities of good SGLT2/SGLT1, there is a kind of non-glucoside compound of formula I structure.
It is a further object to provide the method that preparation has the compound of formula I structure.
It is also another object of the present invention to provide the application of the compound containing formula I structure in preparation treatment diabetes B medicine.
Now content of the present invention is specifically described by object in conjunction with the present invention.
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 I I is changed into the acyl chlorides III of its correspondence; 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.
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.
The 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 of the present invention can be determined 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. Those skilled in the art all should within the protection domain required by the application's claim according to the various changes that the teachings of the present invention is made.
The synthesis of embodiment 1 Compound I
A. the synthesis of compound V
3.46g (20mmol) Compound I I is dissolved in the methylene dichloride of 10mL drying, stirred at ambient temperature, slowly drips the oxalyl chloride adding 3.81g (30mmol) newly distillation, then drips a DMF that adds 2, and then reaction mixture at room temperature stirs and spends the night. Reaction mixture steams dry on a rotary evaporator, then drying 5 minutes in vacuum oil pump, dissolve with 10mL methylene dichloride again, ice-water bath cooling is lower stirs, then slowly drip and add 2.70g (20mmol) IV and 6.07g (60mmol) triethylamine, dropwising 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, it may also be useful to the CH of 50mL �� 32Cl2Extraction, merges extraction phase, successively with 1% dilute hydrochloric acid and salt water washing, and anhydrous sodium sulfate drying. Taking out and filter siccative, filtrate is steamed dry on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound V, white solid, ESI-MS, m/z=291 ([M+H]+)��
B. the synthesis of Compound I
The cyclopentadiene of 2.90g (10mmol) compound V and 1.32g (20mmol) newly distillation is dissolved in 20mL dehydrated alcohol, stir, adding 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, it may also be useful to the CH of 50mL �� 32Cl2Extraction, merges extraction phase, salt water washing, anhydrous sodium sulfate drying. Taking out and filter siccative, filtrate is steamed dry on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains Compound I, white solid, ESI-MS, m/z=339 ([M+H]+)��
The preparation of embodiment 2 reference compound D-1
In order to the outstanding pharmacological effect of the compounds of this invention is described further, the application describes in the present invention
Preparing novel compounds D-1 (not yet open) in research process, its structure is as follows:
Its preparation method is as follows:
A. the synthesis of compound V-1
2.84g (20mmol) Compound I I-1 is dissolved in the methylene dichloride of 10mL drying, stirred at ambient temperature, slowly dripping the oxalyl chloride adding 3.81g (30mmol) newly distillation, then drip a DMF that adds 2, then reaction mixture at room temperature stirs and spends the night. Reaction mixture steams dry on a rotary evaporator, then drying 5 minutes in vacuum oil pump, dissolve with 10mL methylene dichloride again, ice-water bath cooling is lower stirs, then slowly drip and add 2.42g (20mmol) IV p-Aminobenzaldehyde and 6.07g (60mmol) triethylamine, dropwising 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, it may also be useful to the CH of 50mL �� 32Cl2Extraction, merges extraction phase, successively with 1% dilute hydrochloric acid and salt water washing, and anhydrous sodium sulfate drying. Taking out and filter siccative, filtrate is steamed dry on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound V-1, white solid, ESI-MS, m/z=232 ([M+H]+)��
B. the synthesis of Compound D-1
The cyclopentadiene of 2.31g (10mmol) compound V-1 and 1.32g (20mmol) newly distillation is dissolved in 20mL dehydrated alcohol, stir, adding 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, it may also be useful to the CH of 50mL �� 32Cl2Extraction, merges extraction phase, salt water washing, anhydrous sodium sulfate drying. Taking out and filter siccative, filtrate is steamed dry on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains Compound D-1, white solid, ESI-MS, m/z=280 ([M+H]+)��
Embodiment 3 compound is external to the suppression of people SGLT2 and people SGLT1
Prepared by people's SGLT2 expression vector
By full length cDNA clone (purchased from GenScript company) (having put HindIII and NotI site at cDNA two ends) subclone of expression people SGLT2 between HindIII and the NotI 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's SGLT2 stably transfected cell line
Utilize restriction enzyme NsiI to digest the plasmid containing people SGLT2, make it linearizing, with agarose gel electrophoresis, linear DNA is carried out purifying. With transfection reagent Lipofectamine2000 (Invitrogen company), the DNA after purifying 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%CO2After cultivating 24 hours under condition, identical growth medium adds purine mycin (Invitrogen company) continue to cultivate 2 weeks, the cell after screening with puromycin-resistant is inoculated in 96 new orifice plates (one, every hole cell), substratum containing purinase element is cultivated, until cell grows to converging state. The cell clone with puromycin-resistant is by reflecting the methyl-��-D-[U-of SGLT2 activity14C] 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-��-D-[U-14C] pyranoside picked-up test.
Prepared by people's 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 QIAGENPlasmidMidi test kit (QIAGEN company) extracting plasmid. Use Lipofectamine2000 transfection reagent, according to the method for operational manual, people's SGLT1 expression vector plasmid is proceeded to COS-7 cell (purchased from American type culture collection). Transfectional cell in containing the DMEM of 10%DMSO in-80 DEG C of preservations.
Methyl-��-D-[U-14C] pyranoside picked-up test
Before test, the DMEM of cell containing 10%FBS expressing SGLT1 and SGLT2 respectively is inoculated in 96 holes ScintiPlate liquid sudden strain of a muscle plate (PerkinElmer company), and (every hole adds 100 �� L nutrient solutions, containing 1 �� 105 cell), and in 37 DEG C, 5%CO2 when cultivate 48 hours. Cell contains sodium damping fluid (137mMNaCl, 5.4mMKCl, 2.8mMCaCl with 150 �� L2, 1.2mMMgCl2, 10mM Tutofusin tris/N-2-hydroxyethyl piperazine-N '-ethane sulfonic acid [Tris/Hepes], pH7.2) or without sodium damping fluid (137mMN-methyl-glycosamine, 5.4mMKCl, 2.8mMCaCl2,1.2mMMgCl2,10mMTris/Hepes, pH7.2) wash twice. Testing compound is dissolved in containing 25% human plasma and 40 �� Ci/mL methyl-��-D-[U-14C] pyranoside (AmershamBiosciences/GEHealthcare) containing sodium or without, in sodium damping fluid, being prepared into the testing compound solution of a series of suitable concn. The 96 every holes of orifice plate add 50 �� L testing compound solutions, shaking culture 2 hours (SGLT1 analysis) or 1.5 hours (SGLT2 analysis). Cell is with 150 �� L cleaning buffer solution (137mMN-methylglucosamines, 10mMTris/Hepes, pH7.2) wash twice, with TopCount liquid scintillation counter (PerkinElmer company), the picked-up of methyl-��-D-[U-14C] pyranoside is carried out quantitative analysis. Sodium dependency pyranoside intake is the difference (mean value of three wells) subtracting 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 people SGLT2 and people SGLT1 is suppressed by the part of compounds of the present invention50Value
| Compound | IC50(hSGLT2,nM) | IC50(hSGLT1,nM) |
| dapagliflozin | 1.4 | 1339 |
| Reference compound D-1 | 33.8 | 42.7 |
| Compound I | 9.2 | 16.4 |
Above-mentioned IC50Measurement result show, the compound of the present invention is the two target spot inhibitor of strong SGLT2/SGLT1, it is possible to be used for preparing the medicine for the treatment of diabetes B.
Claims (3)
1. the compound with formula I structure,
2. synthesize the method for compound described in claim 1:
Compound I I is changed into the acyl chlorides III of its correspondence; 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. compound described in claim 1 treats the application in diabetes B medicine in preparation.
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| EP0816329A1 (en) * | 1996-06-18 | 1998-01-07 | Hoechst Aktiengesellschaft | Benzoic acid derivatives, process for their preparation and their use for the treatment of diseases |
| CN103649033A (en) * | 2011-05-26 | 2014-03-19 | Tf化学公司 | Family of aryl, heteroaryl, O-aryl and O-heteroaryl carbasugars |
| CN102827122A (en) * | 2011-06-17 | 2012-12-19 | 山东亨利医药科技有限责任公司 | Glucoside derivate |
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