CN104610188B - Itrile group benzene thiazole carboxylic acid amides's compounds containing benzene carbon amidine structure, its preparation and purposes - Google Patents
Itrile group benzene thiazole carboxylic acid amides's compounds containing benzene carbon amidine structure, its preparation and purposes Download PDFInfo
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- CN104610188B CN104610188B CN201510072369.8A CN201510072369A CN104610188B CN 104610188 B CN104610188 B CN 104610188B CN 201510072369 A CN201510072369 A CN 201510072369A CN 104610188 B CN104610188 B CN 104610188B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- QBMRVPDNPTYIGG-UHFFFAOYSA-N S1C(=NC=C1)C(=O)N.C1=CC=CC=C1 Chemical class S1C(=NC=C1)C(=O)N.C1=CC=CC=C1 QBMRVPDNPTYIGG-UHFFFAOYSA-N 0.000 title abstract description 4
- 239000003814 drug Substances 0.000 claims abstract description 11
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 41
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims description 4
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- 229910052708 sodium Inorganic materials 0.000 description 7
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
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- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- QWEWLLNSJDTOKH-UHFFFAOYSA-N 1,3-thiazole-2-carboxamide Chemical class NC(=O)C1=NC=CS1 QWEWLLNSJDTOKH-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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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the drug world relevant to type 2 diabetes mellitus.Specifically, the present invention relates to the double; two target spot inhibitor of a kind of itrile group benzene thiazole carboxylic acid amides class non-saccharide glycoside SGLT2/SGLT1 containing benzene carbon amidine structure, its preparation method and the application in preparing type 2 diabetes mellitus medicine thereof.
Description
Technical field
The present invention relates to the drug world of the treatment of type 2 diabetes mellitus.Specifically, the present invention relates to the double; two target spot inhibitor of the medicative a kind of thiazole carboxylic acid amides class non-saccharide glycoside SGLT2/SGLT1 containing amidine structure of type 2 diabetes mellitus, its preparation method and in purposes pharmaceutically.
Background technology
Diabetes are a kind of metabolic diseases being feature with hyperglycemia.Hyperglycemia is then owing to defect of insulin secretion or its biological agent are 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.The method that there is no radical cure diabetes at present, but diabetes progression suitably can be controlled by multiple treatment means.Mainly include several aspect: the education of diabetics, self-monitoring of blood glucose, Diet Therapy, exercise therapy and Drug therapy.Oral hypoglycaemic medicine is 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 distention, heart disease risk, etc..Therefore the medicine of brand-new action target spot is urgent needs 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, to the contribution of glucose reabsorption in kidney respectively 10% and 90%, in addition SGLT1 is also distributed about in intestinal, the absorption of glucose in responsible intestinal together with GLUT.Suppressing SGLT2 that the glucose in renal tubules can be made can not to be heavily absorbed into blood smoothly and discharge with urine, thus reducing blood sugar concentration, the SGLT2 inhibitor of listing has multiple at present, such as dapagliflozin, canagliflozin and empagliflozin etc..
The inhibitor of these listings is all selective SGLT2 inhibitor, and SGLT1 inhibitory action is very weak.At the initial stage of SGLT2 inhibitor research and development, the selectivity of SGLT2/SGLT1 was considered as once critically important index, because suppressing SGLT1 to be likely in theory cause intestines and stomach side reaction.nullBut research in recent years shows，This theoretic worry it is not necessary that，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 of suppression SGLT2, and this suppression can increase the discharge of glucose in urine in kidney and reduce the absorption of glucose in intestinal, therefore this kind of inhibitor is considered as a kind of brand-new selection controlling blood glucose.
The invention discloses the double; two target spot inhibitor of a kind of itrile group non-glucosides SGLT2/SGLT1 of benzene thiazole carboxylic acid amides's class containing benzene carbon amidine structure, this compound can be used for the medicine of preparation treatment type 2 diabetes mellitus.
Summary of the invention
It is an object of the present invention to provide and a kind of there is the double; two target spot inhibitory activity of good SGLT2/SGLT1, there is the non-glucoside compound of one of Formulas I.
It is a further object to provide the method that preparation has the compound of Formulas I.
It is also another object of the present invention to provide the application in preparation treatment type 2 diabetes mellitus medicine of the compound containing Formulas I.
In conjunction with the purpose of the present invention, present invention is specifically described.
The present invention has the compound of Formulas I and has following structural formula:
Compound of formula I of the present invention is synthesized by following route:
Compound II per uses HCl gas treatment in presence of methyl alcohol, obtains Compound II per I；Compound II per I reacts with amine IV in the presence of a base, obtains the compound V containing amidine structure；Compound V reacts with compound VI, obtains compound VII；Compound VII DCC exist under with compound VIII condensation, obtain compound I.
Compound of formula I of the present invention has the double inhibition effect of SGLT2/SGLT1, can as effective ingredient for preparing the medicine of type 2 diabetes mellitus.The activity of compound of formula I of the present invention is verified by receptor binding assays.
The compound of formula I of the present invention is effective in comparatively wide dosage range.The dosage that such as every day takes, within the scope of 1mg-1000mg/ people, is divided into once or is administered for several times.The actual dosage taking formula I can be determined according to relevant situation by doctor.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that following embodiment is only for illustrating, and it is not intended to limit the present invention.Those skilled in the art all should within the protection domain required by the application 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 II per I
7.55g (100mmol) Compound II per is dissolved in 100mL absolute methanol, slowly passes into dry HCl gas, is substantially saturated to solution, then overnight at room temperature stirring under ice-water bath cooling.Collected by suction solid, ambient temperature in vacuum dries, and obtains white solid, is Compound II per I.
B. the synthesis of compound V-1
12.96g (90mmol) Compound II per I and 8.37g (90mmol) IV-1 is dissolved in the 100mL DMF dried, stir under room temperature, add 12.14g (120mmol) triethylamine, then it is warming up to 80 DEG C of reactions, until TLC checks that reaction completes (usual 3 hours).After having reacted, it is poured in 300mL frozen water after reactant mixture is slightly cold, stirring, use the CH of 100mL × 32Cl2Extracting, merge extraction phase, anhydrous sodium sulfate dries.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and the residue obtained uses column chromatography purification, obtains compound V-1, white solid, ESI-MS, m/z=169 ([M+H]+)。
C. the synthesis of compound VII-1
10.08g (60mmol) compound V-1 and 6.13g (60mmol) compound VI is dissolved in the 50mL THF dried, stir under room temperature, until TLC detects reaction and completes (usual one week).After having reacted, reactant mixture is poured in 200mL frozen water, stirring, uses the CH of 50mL × 32Cl2Extracting, merge extraction phase, anhydrous sodium sulfate dries.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and the residue obtained uses column chromatography purification, obtains compound VII-1, white solid, ESI-MS, m/z=235 ([M+H]+)。
D. the synthesis of compound I-1
7.02g (30mmol) compound VII-1 and 6.90g (30mmol) VIII-1 is dissolved in the 100mL THF dried, stir under room temperature, then add 6.81g (33mmol) N, N'-dicyclohexyl carbodiimide (DCC) and 1.00g4-dimethylamino naphthyridine (DMAP), then stir overnight under room temperature.After having reacted, adding 100mL methyl tertiary butyl ether(MTBE), be stirred for 1 hour, sucking filtration in reactant mixture, filtrate pours in 500mL frozen water, stirring, uses the CH of 100mL × 32Cl2Extracting, merge extraction phase, anhydrous sodium sulfate dries.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and the residue obtained uses column chromatography purification, obtains compound I-1, white solid, ESI-MS, m/z=447 ([M+H]+)。
Embodiment 2-3
With reference to embodiment 1 method, synthesize compound listed in Table.
The suppression to people SGLT2 and people SGLT1 of embodiment 4 Compound ira vitro
Prepared by people's SGLT2 expression vector
Between full length cDNA clone (purchased from GenScript company) (having put HindIII and NotI site at the cDNA two ends) sub-clone of expression people SGLT2 to 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 the restricted enzyme NsiI digestion plasmid containing people SGLT2, so as to linearisation, with agarose gel electrophoresis, linear DNA is purified.With transfection reagent Lipofectamine2000 (Invitrogen company), the DNA after purification proceeded to HEK293 cell (Theracos company of the U.S.).By transfection after cell in the DMEM culture medium containing 10% hyclone 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), culture medium containing purinase element is cultivated, until cell length is to converging state.There is the cell clone of puromycin-resistant by reflecting the methyl-α-D-[U-of SGLT2 activity14C] pyranoside picked-up test screening further (experimental technique is below with describing in detail).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's SGLT1 express cell
PDream2.1 expression vector containing total length people SGLT1cDNA is purchased from GenScript company.Plasmid expands in bacillus coli DH 5 alpha, and this strain culturing is in Luria-Bertani (LB) culture medium containing ampicillin.With QIAGENPlasmidMidi test kit (QIAGEN company) extracting plasmid.Use Lipofectamine2000 transfection reagent, according to the method for workbook, people's SGLT1 expression vector plasmid is proceeded to COS-7 cell (purchased from American Type Tissue Collection).Transfectional cell in the DMEM containing 10%DMSO in-80 DEG C of preservations.
Methyl-α-D-[U-14C] pyranoside picked-up test
Before test, the cell DMEM 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 μ L culture fluid, containing 1 × 105 cell), and in 37 DEG C, 5%CO2 when cultivate 48 hours.Cell with 150 μ L containing sodium buffer (137mMNaCl, 5.4mMKCl, 2.8mMCaCl2, 1.2mMMgCl2, 10mM trishydroxymethylaminomethane/N-2-hydroxyethyl piperazine-N '-ethane sulfonic acid [Tris/Hepes], pH7.2) or without sodium buffer (137mMN-methyl-glucamine, 5.4mMKCl, 2.8mMCaCl2,1.2mMMgCl2,10mMTris/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 (AmershamBiosciences/GEHealthcare) containing sodium or without, in sodium buffer, preparing 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, shaken cultivation 2 hours (SGLT1 analysis) or 1.5 hours (SGLT2 analysis).Cell is by 150 μ L cleaning buffer solution (137mMN-methylglucosamine, 10mMTris/Hepes, pH7.2) wash twice, with TopCount liquid scintillation counter (PerkinElmer company), the picked-up of methyl-α-D-[U-14C] pyranoside is carried out quantitative analysis.Sodium dependency pyranoside intake is the intake obtained with the process containing sodium buffer and deducts the difference (meansigma methods of three wells) processing the intake obtained without sodium buffer.
Shown in the following list of result.
The part of compounds of the present invention is to people SGLT2 and the people SGLT1 IC suppressed50Value
| Compound | IC50(hSGLT2,nM) | IC50(hSGLT1,nM) |
| Dapagliflozin | 1.3 | 1219 |
| Compound I-1 | 7.6 | 15.8 |
| Compound I-2 | 9.4 | 12.2 |
| Compound I-3 | 11.3 | 10.6 |
Above-mentioned IC50Measurement result show, comparing single target spot inhibitor, the compound of the present invention is strong SGLT2 target spot inhibitor and SGLT1 target spot inhibitor simultaneously, it is possible to be used for prepare treatment type 2 diabetes mellitus medicine.
Claims (3)
1. there is the compound of Formulas I structure,
2. the method for the compound of Formulas I described in synthesis claim 1:
Compound II per uses HCl gas treatment in presence of methyl alcohol, obtains Compound II per I；Compound II per I reacts with amine IV in the presence of a base, obtains the compound V containing amidine structure；Compound V reacts with compound VI, obtains compound VII；Compound VII DCC exist under with compound VIII condensation, obtain compound I.
3. the application in preparation treatment type 2 diabetes mellitus medicine of the compound described in claim 1.
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