CN104497074A - Compound with acrylonitrile group and nitrobenzene-O-glucoside structure and application - Google Patents
Compound with acrylonitrile group and nitrobenzene-O-glucoside structure and application Download PDFInfo
- Publication number
- CN104497074A CN104497074A CN201510021054.0A CN201510021054A CN104497074A CN 104497074 A CN104497074 A CN 104497074A CN 201510021054 A CN201510021054 A CN 201510021054A CN 104497074 A CN104497074 A CN 104497074A
- Authority
- CN
- China
- Prior art keywords
- compound
- acid
- obtains
- application
- sglt2
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims description 36
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical group C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 title abstract description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 229940002612 prodrug Drugs 0.000 claims description 5
- 239000000651 prodrug Substances 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 150000001263 acyl chlorides Chemical class 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 238000010306 acid treatment Methods 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 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 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- 238000003756 stirring Methods 0.000 description 22
- 238000001035 drying Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012267 brine Substances 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 235000001727 glucose Nutrition 0.000 description 5
- 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 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 2
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 210000005252 bulbus oculi Anatomy 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000002304 glucoses Chemical class 0.000 description 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- ZYSNFDOACZTZRR-UHFFFAOYSA-N COC(c(cc1[N+]([O-])=O)ccc1OC(C(C1O)O)OC(CO)C1O)=C(C#N)C#N Chemical compound COC(c(cc1[N+]([O-])=O)ccc1OC(C(C1O)O)OC(CO)C1O)=C(C#N)C#N ZYSNFDOACZTZRR-UHFFFAOYSA-N 0.000 description 1
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- 229940126902 Phlorizin Drugs 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Chemical class 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 150000002303 glucose derivatives Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical class CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- IOUVKUPGCMBWBT-UHFFFAOYSA-N phloridzosid Natural products OC1C(O)C(O)C(CO)OC1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 IOUVKUPGCMBWBT-UHFFFAOYSA-N 0.000 description 1
- IOUVKUPGCMBWBT-GHRYLNIYSA-N phlorizin Chemical compound O[C@@H]1[C@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 IOUVKUPGCMBWBT-GHRYLNIYSA-N 0.000 description 1
- 235000019139 phlorizin Nutrition 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Steroid Compounds (AREA)
Abstract
The invention relates to the field of drugs related to diabetes, in particular to a sodium-glucose co-transporter-2 (SGLT2) inhibitor with the acrylonitrile group and the nitrobenzene-O-glucoside structure, a preparation method of the inhibitor and the application of the inhibitor in preparation of drugs for diabetes. Please see the structural formula of the inhibitor in the specification.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to diabetes B.Specifically, the present invention relates to a kind of to medicative 2 type sodium dependent glucoses transhipment (SGLT2) inhibitor containing acrylonitrile group and oil of mirbane O-glucoside structure of diabetes B, preparation method and in purposes pharmaceutically.
Background technology
Whole world diabetic subject presents the trend increased gradually, and wherein about the overwhelming majority is diabetes B patient.Sulfonylurea, N1,N1-Dimethylbiguanide class, thiazolidinediones, alpha-glucosidase inhibitor class, dipeptidyl peptidase-iv inhibitor class and trypsin class medicine is mainly contained at present at the antidiabetic medicine of Clinical practice.These medicines have good therapeutic action, but long-term treatment exists comparatively severe side effect, and owing to there is resistance, in some cases in time drug combination be all difficult to the blood sugar controlling patient.
2 type sodium dependent glucoses transhipment (SGLT2) are the novel targets of the treatment diabetes of discovered in recent years.SGLT2 is mainly distributed in renal proximal tubules, and its effect absorbs the glucose in urine, and returns it in blood, therefore suppresses that SGLT2's just can reduce the concentration of glucose in blood.When SGLT2 function is suppressed, more glucose will be secreted from urine, this glucose level that will contribute to diabetic subject and keep correct.
Chinese patent CN200610093189.9 discloses the compound of having structure as SGLT2 inhibitor:
Wherein, A is O, S, NH, (CH
2)
n, n=0-3.
Chinese patent CN200380110040.1 discloses the compound of having structure as SGLT2 inhibitor:
Wherein, A is covalent linkage, O, S, NH, (CH
2)
n, n=1-3.
The invention discloses a kind of containing vinyl cyanide and oil of mirbane O-glucoside analog derivative as novel SGLT2 inhibitor, these compounds can be used for preparing the medicine for the treatment of diabetes particularly diabetes B.
Summary of the invention
An object of the present invention is the shortcoming and defect overcoming prior art, provide one to have excellent activity, there is the compound of formula I and pharmaceutically can accept prodrug ester.
Another object of the present invention is to provide preparation and has the compound of formula I and the method for pharmaceutically acceptable prodrug ester thereof.Another object is to provide the compound containing formula I and the application in treatment diabetes thereof.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 CH
3oCH
2group (MOM) is protected, and obtains III; Compound III changes corresponding acyl chlorides IV into; Compound V with after NaH process and IV react, finally use Me
2sO
4be obtained by reacting VI; VI acid treatment obtains VII; VII and VIII is obtained by reacting IX; IX deacetylate obtains I; The described reagent being converted into acyl chlorides comprises SOCl
2, PCl
3, PCl
5(COCl)
2; Described acid is selected from mineral acid and following organic acid, methylsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichoroacetic acid(TCA).
The pharmaceutically acceptable prodrug ester of formula I of the present invention, comprises the ester that any one or more hydroxyl in molecule and ethanoyl, pivaloyl group, various phosphoryl, formamyl, alkoxyl formyl etc. are formed.
Formula I of the present invention has the restraining effect of SGLT2, can be used as the medicine of effective constituent for the preparation of diabetes aspect.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-300mg/ 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.These situations comprise: the physical state of patient, route of administration, age, body weight, individual reaction to medicine, the severity etc. of symptom.
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 preparation of embodiment 1 Compound I
18.3g (100mmol) Compound II per and 12.08g (150mmol) CH
3oCH
2cl (MOMCl) is dissolved in the DMF of 250mL drying, stirs, adds 55.28g (400mmol) solid K
2cO
3, then at N
2lower stirring is spent the night, and TLC detection reaction completes.Be poured into after reaction mixture is slightly cold in 1000mL frozen water, under stirring, regulate pH=2 with concentrated hydrochloric acid, 200mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is III, faint yellow solid, ESI-MS, m/z=226 [M-H]
-, for next step reaction.
Above-mentioned III is dissolved in the methylene dichloride of 100mL drying, and ice-water bath cooling is lower stirs, and slowly drips 12.69g (100mmol) SOCl
2, at a low price, drip DMF, then a room temperature for overnight.Reaction mixture is evaporate to dryness on a rotary evaporator, and the resistates obtained is IV, white solid, for next step reaction.
3.30g (50mmol) the third two eyeball (V) is dissolved in the THF of 100mL drying, ice-water bath cooling is lower stirs, slowly add 4.80g (120mmol, 60%) NaH, after adding, more slowly add 10.03g (50mmol) IV and be dissolved in the solution that 10mL THF makes.Dropwise rear continuation stirring 1 hour, then drip 7.57g (60mmol) methyl-sulfate, dropwise rear room temperature for overnight.Reaction mixture is poured in 500mL frozen water, under stirring, regulates pH=5 with concentrated hydrochloric acid, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is VI, column chromatography purification, obtains sterling VI, white solid, ESI-MS, m/z=290 [M+H]
+.
8.67g (30mmol) compound VI-1 is dissolved in 100mL MeOH, and ice-water bath cooling is lower stirs, and slowly drip 0.5mL concentrated hydrochloric acid, stirred at ambient temperature 3 hours, reaction completes.Reaction mixture is poured in 500mL frozen water, stirs, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is VII, column chromatography purification, obtain sterling VII, white solid, ESI-MS, m/z=246 [M+H]
+.
4.52g (20mmol) compound VI I and 12.34g (30mmol) compound VI II is dissolved in 50mL methylene dichloride, stir, slowly add the solution be made up of 0.80g (20mmol) NaOH and 10mL water, then add 1g tetra-n-butyl ammonium bromide again.Room temperature for overnight.TLC checks that reaction completes.Reaction mixture is poured in 500mL frozen water, stirs, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is IX, column chromatography purification, obtain sterling IX, white solid, ESI-MS, m/z=576 [M+H]
+.
5.75g (10mmol) Compound I X is dissolved in the 30mL MeOH containing 0.6g MeONa, then stirred at ambient temperature 3 hours, and reaction completes.Then add the storng-acid cation exchange resin of 5g drying, room temperature for overnight.Suction filtration, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained is positive empty dry, obtains Compound I, white solid, ESI-MS, m/z=408 [M+H]
+.
The preparation of embodiment 2 reference compound D-1
In order to further illustrate the drug effect of the compounds of this invention, this invention describes not yet open and being all the Compound D-1 of the applicant's design.
Its preparation method is as follows:
13.8g (100mmol) Compound II per-2 and 12.08g (150mmol) CH
3oCH
2cl (MOMCl) is dissolved in the DMF of 250mL drying, stirs, adds 55.28g (400mmol) solid K
2cO
3, then at N
2lower stirring is spent the night, and TLC detection reaction completes.Be poured into after reaction mixture is slightly cold in 1000mL frozen water, under stirring, pH=2 is regulated, 200mL × 3 dichloromethane extraction, brine It with concentrated hydrochloric acid, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is III-2, faint yellow solid, ESI-MS, m/z=181 [M-H]
-, for next step reaction.
Above-mentioned III-2 is dissolved in the methylene dichloride of 100mL drying, and ice-water bath cooling is lower stirs, and slowly drips 12.69g (100mmol) SOCl
2, at a low price, drip DMF, then a room temperature for overnight.Reaction mixture is evaporate to dryness on a rotary evaporator, and the resistates obtained is IV-2, white solid, for next step reaction.
3.30g (50mmol) the third two eyeball (V) is dissolved in the THF of 100mL drying, ice-water bath cooling is lower stirs, slowly add 4.80g (120mmol, 60%) NaH, after adding, more slowly add 10.03g (50mmol) IV-2 and be dissolved in the solution that 10mL THF makes.Dropwise rear continuation stirring 1 hour, then drip 7.57g (60mmol) methyl-sulfate, dropwise rear room temperature for overnight.Reaction mixture is poured in 500mL frozen water, under stirring, regulates pH=5 with concentrated hydrochloric acid, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is VI-2, column chromatography purification, obtains sterling VI-2, white solid, ESI-MS, m/z=245 [M+H]
+.
7.32g (30mmol) compound VI-2 is dissolved in 100mL MeOH, and ice-water bath cooling is lower stirs, and slowly drip 0.5mL concentrated hydrochloric acid, stirred at ambient temperature 3 hours, reaction completes.Reaction mixture is poured in 500mL frozen water, stirs, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is VII-2, column chromatography purification, obtain sterling VII-2, white solid, ESI-MS, m/z=201 [M+H]
+.
4.00g (20mmol) compound VI I-2 and 12.34g (30mmol) compound VI II is dissolved in 50mL methylene dichloride, stir, slowly add the solution be made up of 0.80g (20mmol) NaOH and 10mL water, then add 1g tetra-n-butyl ammonium bromide again.Room temperature for overnight.TLC checks that reaction completes.Reaction mixture is poured in 500mL frozen water, stirs, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is IX-2, column chromatography purification, obtain sterling IX-2, white solid, ESI-MS, m/z=531 [M+H]
+.
5.30g (10mmol) Compound I X-2 is dissolved in the 30mL MeOH containing 0.6g MeONa, then stirred at ambient temperature 3 hours, and reaction completes.Then add the storng-acid cation exchange resin of 5g drying, room temperature for overnight.Suction filtration, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained is positive empty dry, obtains D-1, white solid, ESI-MS, m/z=363 [M+H]
+.
Embodiment 3
The IC that compound of the present invention and related compound suppress SGLT2
50the method that value reference literature is recorded measures (Meng, W.et al, J.Med.Chem., 2008,51,1145-1149).
The carrier using the Chinese hamster ovary celI of stably express humanization SGLT2 to analyze as transhipment, uses the substrate that [14C]-α-D-methyl glucoside ([14C]-AMG) analyzes as transhipment.By stably express, the Chinese hamster ovary celI of humanization SGLT2 is inoculated on 96 orifice plates, and 12 hours are hatched at 37 DEG C, every hole by the KRH-Na+ washing lotion of 200 μ L (containing 120mM NaCl, 4.7mM KCl, 1.2mM MgCl2,2.2mM CaCl2,10mM HEPES and 1mM Tris (pH=7.4)) wash 3 times, then the KRH-Na+ washing lotion containing testing compound or blank is added in every hole, each testing compound arranges 10 concentration, and last each hole adds the washing lotion that 100 μ L contain [14C]-AMG (10 μ Ci/mL).96 orifice plates hatch 1 hour subsequently at 37 DEG C, then every hole adds the ice-cold stop buffer of 100 μ L (containing 120mM NaCl, 4.7mM KCl, 1.2mM MgCl2,2.2mM CaCl2,10mM HEPES, 1mM Tris and 10mM phlorizin (pH=7.4)), 5 times are washed again subsequently, each every hole 100 μ L with this stop buffer.Every Kong Zhongzai adds the ice-cold cytolysate (100mM NaOH) of 20 μ L, then shakes 5 minutes with the speed of 600rpm, and then Microscint 40 liquid adding 80 μ L in every hole dodges liquid, then shakes 5 minutes with the speed of 600rpm.Finally, this 96 orifice plate is at the upper counting of MicroBeta Trilux liquid scintillation counter (PerkinElmer).Response curve use experience four parameter model measures 503nhibiting concentration, is expressed as IC50.Shown in the following list of result.
Part of compounds of the present invention is to the IC of SGLT2
50value
| Compound | IC 50(hSGLT2,nM) |
| Compound I | 12.8 |
| Reference compound D-1 | 26.1 |
Above-mentioned IC
50measurement result show, compound of the present invention is strong SGLT2 inhibitor, can be used for prepare treatment diabetes B medicine.
Claims (3)
1. there is compound and the pharmaceutically acceptable prodrug ester thereof of formula I structure,
2. synthesize the method for compound described in claim 1:
Compound II per CH
3oCH
2radical protection, obtains III; Compound III changes corresponding acyl chlorides IV into; Compound V with after NaH process and IV react, finally use Me
2sO
4be obtained by reacting VI; VI acid treatment obtains VII; VII and VIII is obtained by reacting IX; IX deacetylate obtains I; The described reagent being converted into acyl chlorides is selected from SOCl
2, PCl
3, PCl
5(COCl)
2; Described acid is selected from methylsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichoroacetic acid(TCA).
3. compound described in claim 1 and pharmaceutically acceptable salt and the application of prodrug ester in preparation treatment diabetes medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510021054.0A CN104497074A (en) | 2015-01-15 | 2015-01-15 | Compound with acrylonitrile group and nitrobenzene-O-glucoside structure and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510021054.0A CN104497074A (en) | 2015-01-15 | 2015-01-15 | Compound with acrylonitrile group and nitrobenzene-O-glucoside structure and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104497074A true CN104497074A (en) | 2015-04-08 |
Family
ID=52938543
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510021054.0A Pending CN104497074A (en) | 2015-01-15 | 2015-01-15 | Compound with acrylonitrile group and nitrobenzene-O-glucoside structure and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104497074A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1377363A (en) * | 1999-08-31 | 2002-10-30 | 橘生药品工业株式会社 | Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof |
| CN1437608A (en) * | 2000-03-30 | 2003-08-20 | 布里斯托尔-迈尔斯斯奎布公司 | O-aryl glucoside SGL T2 inhibitors and method |
| US20110269700A1 (en) * | 2008-09-19 | 2011-11-03 | Novartis Ag | Glucoside derivatives and uses thereof |
| CN102510867A (en) * | 2009-10-20 | 2012-06-20 | 诺瓦提斯公司 | Glycoside derivative and uses thereof |
-
2015
- 2015-01-15 CN CN201510021054.0A patent/CN104497074A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1377363A (en) * | 1999-08-31 | 2002-10-30 | 橘生药品工业株式会社 | Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof |
| CN1437608A (en) * | 2000-03-30 | 2003-08-20 | 布里斯托尔-迈尔斯斯奎布公司 | O-aryl glucoside SGL T2 inhibitors and method |
| US20110269700A1 (en) * | 2008-09-19 | 2011-11-03 | Novartis Ag | Glucoside derivatives and uses thereof |
| CN102510867A (en) * | 2009-10-20 | 2012-06-20 | 诺瓦提斯公司 | Glycoside derivative and uses thereof |
Non-Patent Citations (4)
| Title |
|---|
| ADITYA KULKARNI，等: "1,3-Disubstituted-4-Aminopyrazolo [3, 4-d]Pyrimidines, a New Class of Potent Inhibitors for Phospholipase D", 《CHEM BIOL DRUG DES》 * |
| BETH APSEL，等: "Targeted polypharmacology：discovery of dual inhibitors of tyrosine and phosphoinositide kinases", 《NATURE CHEMICAL BIOLOGY》 * |
| RINA HEROWATI，等: "Molecular Docking Studies of Chemical Constituents of Tinospora cordifolia on Glycogen Phosphorylase", 《PROCEDIA CHEMISTRY》 * |
| 邵华，等: "含反式环己烷结构的C-葡萄糖苷类SGLT2 抑制剂的设计、合成与降血糖活性研究", 《有机化学》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104530152A (en) | Compound containing acrylonitrile base and trifluoro methoxyphenyl O-galactoside structure and application | |
| CN104497072A (en) | Derivative containing acrylonitrile and benzene halide O-glucoside structures and preparation method and application thereof | |
| CN104497074A (en) | Compound with acrylonitrile group and nitrobenzene-O-glucoside structure and application | |
| CN104497071A (en) | Compound with acrylonitrile group and cyanobenzene-O-glucoside structure and application | |
| CN104478960A (en) | Compound containing acrylonitrile-based and benzotrifluoride-based O-glucoside structure and application | |
| CN104478961A (en) | Benzene O-glucoside structure derivative with acrylonitrile and amino group and preparation method and application thereof | |
| CN104497073A (en) | Derivative containing acrylonitrile and benzene halide O-glucoside structures and preparation method and application thereof | |
| CN104478964A (en) | Benzene O-glucoside derivative with acrylonitrile structure and preparation method and application thereof | |
| SG172979A1 (en) | Compound having tumor-resident property | |
| CN104530149A (en) | Halogen-substituted phenyl group double-O-glucoside derivant, and preparation method and application thereof | |
| CN104447905A (en) | Derivative containing nitrobenzene and bis-O-glucoside and preparation method and application of derivative | |
| CN104530150A (en) | Compound with amino benzene and diosgenin-diglucoside structure and preparation method and application thereof | |
| CN104497070A (en) | Compound with trifluoromethyl-S-glucoside and application | |
| CN104478963A (en) | Compound containing nitrile-based benzene S-glucoside structure and application of compound | |
| CN104478959A (en) | Compound with nitrile group biphenyl double-glucoside structure and preparation method and application thereof | |
| CN104447906A (en) | Alcoxyl phenyl group diosgenin-diglucoside derivative and preparation method and application thereof | |
| CN104478956A (en) | Phenyl double O-glucoside derivative and preparation method and application thereof | |
| CN104497068A (en) | Compound with trifluoromethoxybenzene-S-glucoside structure and application thereof | |
| CN104530151A (en) | Compound containing nitrobenzene S-glucoside structure and application thereof | |
| CN104478957A (en) | Derivative containing nitrile-based benzene and bis-O-glucoside, preparation method thereof and application | |
| CN104447907A (en) | Compound containing nitro biphenyl diosgenin-diglucoside structure and preparation method and application thereof | |
| CN104497069A (en) | Amido phenyl S-glucoside derivative, preparation method and use thereof | |
| CN104530153A (en) | One category of phenyl S-glucoside derivatives, preparation method of phenyl-class S-glucoside derivatives and application of phenyl-class S-glucoside derivatives in medicament | |
| CN104478962A (en) | Class of halogenated phenyl group S-glucoside derivative and preparation method and application of class of halogenated phenyl group S-glucoside derivative | |
| CN104478675B (en) | One class contains derivative and the purposes of alkoxyphenyl radical and fluoroform phenyl propylene glycol structure |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150408 |
|
| RJ01 | Rejection of invention patent application after publication |