CN104610017B - One class halogenophenyl propanediol derivative, Preparation Method And The Use - Google Patents
One class halogenophenyl propanediol derivative, Preparation Method And The Use Download PDFInfo
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- CN104610017B CN104610017B CN201510021704.1A CN201510021704A CN104610017B CN 104610017 B CN104610017 B CN 104610017B CN 201510021704 A CN201510021704 A CN 201510021704A CN 104610017 B CN104610017 B CN 104610017B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/40—Halogenated unsaturated alcohols
- C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/60—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by elimination of -OH groups, e.g. by dehydration
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/20—Free hydroxyl or mercaptan
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic System
- C07F1/02—Lithium compounds
Abstract
The present invention relates to the pharmaceutical field relevant to diabetes.Specifically, the present invention relates to II type sodium dependent glucose transhipment (SGLT2) inhibitor of a class halogenophenyl propylene glycol structure, its preparation method and the application in preparation treatment diabetes medicament.
wherein, R
1be selected from halogenic substituent; R
2be selected from C
1-C
5alkyl.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to type ii diabetes.Specifically, the present invention relates to 2 type sodium dependent glucoses transhipment (SGLT2) inhibitor, the preparation method and in purposes pharmaceutically of a class to type ii diabetes medicative halogenophenyl propylene glycol structure.
Background technology
Whole world diabetic subject presents the trend increased gradually, and wherein about the overwhelming majority is type ii diabetes 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 class halogenophenyl propanediol derivative as novel SGLT2 inhibitor, these compounds can be used for the medicine preparing treatment diabetes particularly type ii diabetes.
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 general formula I and pharmaceutically can accept prodrug ester.
Another object of the present invention is to provide preparation and has the compound of general formula I and the method for pharmaceutically acceptable prodrug ester thereof.
Another object of the present invention be to provide compound containing general formula I and pharmaceutically acceptable prodrug ester do the application in treatment diabetes.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has general formula I has following structural formula:
Wherein, R
1be selected from halogenic substituent;
R
2be selected from C
1-C
5alkyl.
Preferred following compound of Formula I,
Wherein, R
1be selected from F, Cl substituting group;
R
2be selected from methyl, ethyl, n-propyl.
More preferably the compound of general formula I has following structure,
Compound of Formula I of the present invention is synthesized by following route:
The process of Compound II per lithium alkylide obtains corresponding lithium aryl III; III and compound IV nucleophilic addition(Adn) obtain V; Compound V sloughs isopropylidene protecting group through selective reduction simultaneously and obtains I; Obtain described lithium aryl and be selected from n-BuLi, sec-BuLi and t-BuLi.Wherein, R
1, R
2definition as previously mentioned.
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.
Compound of 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 compound of Formula I of the present invention is verified by receptor binding assays.
Compound of 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-700mg/ people, is divided into once or administration for several times.The actual dosage taking compound of Formula I of the present invention 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 preparation of embodiment 1I-1
2.92g (10mmol) Compound II per-1 adds in the dry round-bottomed flask of a 100mL, adds the THF of dry magneton one piece and 30mL drying, with the sealing of rubber cork after nitrogen purging.Flask is placed in liquid nitrogen-ethanol and is cooled to-78 DEG C, starts and stirs.The n-BuLi hexane solution of 6.25mL (10mmol) 1.6M is slowly dripped with syringe.After dropwising, continue stirring at this temperature 1 hour.Then drip by syringe the solution that THF that 1.44g (10mmol) compound IV is dissolved in 5mL drying makes.After dropwising, reaction mixture continues stirring 1 hour at such a temperature, is then slowly warming up to room temperature, continues stirring 1 hour.
Reaction mixture is poured in 200mL frozen water, stirs, 100mL × 3 dichloromethane extraction, merges organic phase, saturated common salt water washing, dry (Na
2sO
4).Filtrate evaporate to dryness on a rotary evaporator after suction filtration removing siccative, the resistates obtained, through neutral alumina column column chromatography, obtains product V-1, white solid, ESI-MS, m/z=367 ([M+Na]
+).
1.72g (5mmol) compound V-1 is dissolved in the methylene dichloride of 10mL drying, adds 2.33g (20mmol) Et
3siH, stirs, and slowly drips 1.42g (10mmol) BF under ice-water bath cooling
3et
2o.After dropwising, reaction mixture refluxes under nitrogen protection and spends the night.
Reaction mixture is poured in 200mL frozen water, stirs, 100mL × 3 dichloromethane extraction, merges organic phase, saturated common salt water washing, dry (Na
2sO
4).Filtrate evaporate to dryness on a rotary evaporator after suction filtration removing siccative, the resistates column chromatography purification obtained, obtains product I-1, white solid, ESI-MS, m/z=311 ([M+Na]
+).
The preparation of embodiment 2I-2
3.09g (10mmol) Compound II per-2 adds in the dry round-bottomed flask of a 100mL, adds the THF of dry magneton one piece and 30mL drying, with the sealing of rubber cork after nitrogen purging.Flask is placed in liquid nitrogen-ethanol and is cooled to-78 DEG C, starts and stirs.The sec-BuLi hexane solution of 7.7mL (10mmol) 1.3M is slowly dripped with syringe.After dropwising, continue stirring at this temperature 1 hour.Then drip by syringe the solution that THF that 1.44g (10mmol) compound IV is dissolved in 5mL drying makes.After dropwising, reaction mixture continues stirring 1 hour at such a temperature, is then slowly warming up to room temperature, continues stirring 1 hour.
Reaction mixture is poured in 200mL frozen water, stirs, 100mL × 3 dichloromethane extraction, merges organic phase, saturated common salt water washing, dry (Na
2sO
4).Filtrate evaporate to dryness on a rotary evaporator after suction filtration removing siccative, the resistates obtained, through neutral alumina column column chromatography, obtains product V-2, white solid, ESI-MS, m/z=383 ([M+Na]
+).
1.80g (5mmol) compound V-2 is dissolved in the methylene dichloride of 10mL drying, adds 2.33g (20mmol) Et
3siH, stirs, and slowly drips 1.42g (10mmol) BF under ice-water bath cooling
3et
2o.After dropwising, reaction mixture refluxes under nitrogen protection and spends the night.
Reaction mixture is poured in 200mL frozen water, stirs, 100mL × 3 dichloromethane extraction,
Merge organic phase, saturated common salt water washing, dry (Na
2sO
4).Filtrate evaporate to dryness on a rotary evaporator after suction filtration removing siccative, the resistates column chromatography purification obtained, obtains product I-2, white solid, ESI-MS, m/z=327 ([M+Na]
+).
Embodiment 3-6
With reference to embodiment 1 operation steps, prepare compound listed in Table.
The preparation of embodiment 7 reference compound
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:
2.76g (10mmol) Compound II per-7 adds in the dry round-bottomed flask of a 100mL, adds the THF of dry magneton one piece and 30mL drying, with the sealing of rubber cork after nitrogen purging.Flask is placed in liquid nitrogen-ethanol and is cooled to-78 DEG C, starts and stirs.The sec-BuLi hexane solution of 7.7mL (10mmol) 1.3M is slowly dripped with syringe.After dropwising, continue stirring at this temperature 1 hour.Then drip by syringe the solution that THF that 1.44g (10mmol) compound IV is dissolved in 5mL drying makes.After dropwising, reaction mixture continues stirring 1 hour at such a temperature, is then slowly warming up to room temperature, continues stirring 1 hour.
Reaction mixture is poured in 200mL frozen water, stirs, 100mL × 3 dichloromethane extraction, merges organic phase, saturated common salt water washing, dry (Na
2sO
4).Filtrate evaporate to dryness on a rotary evaporator after suction filtration removing siccative, the resistates obtained, through neutral alumina column column chromatography, obtains product V-7, white solid, ESI-MS, m/z=349 ([M+Na]
+).
1.63g (5mmol) compound V-7 is dissolved in the methylene dichloride of 10mL drying, adds 2.33g (20mmol) Et
3siH, stirs, and slowly drips 1.42g (10mmol) BF under ice-water bath cooling
3et
2o.After dropwising, reaction mixture refluxes under nitrogen protection and spends the night.
Reaction mixture is poured in 200mL frozen water, stirs, 100mL × 3 dichloromethane extraction, merges organic phase, saturated common salt water washing, dry (Na
2sO
4).Filtrate evaporate to dryness on a rotary evaporator after suction filtration removing siccative, the resistates column chromatography purification obtained, obtains product D-1, white solid, ESI-MS, m/z=293 ([M+Na]
+).
Embodiment 8
The IC that compound of the present invention and related compound suppress SGLT2
50value reference literature record method measures.
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 120mMNaCl, 4.7mMKCl, 1.2mMMgCl2,2.2mMCaCl2,10mMHEPESand1mMTris (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 120mMNaCl, 4.7mMKCl, 1.2mMMgCl2,2.2mMCaCl2,10mMHEPES, 1mMTrisand10mM 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 (100mMNaOH) of 20 μ L, then shakes 5 minutes with the speed of 600rpm, and then the Microscint40 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 MicroBetaTrilux 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 number | IC 50(hSGLT2,nM) |
| Reference compound D-1 | 19.5 |
| I-1 | 9.1 |
| I-2 | 10.3 |
| I-3 | 15.8 |
| I-4 | 17.4 |
| I-5 | 13.9 |
| I-6 | 15.2 |
Above-mentioned IC
50measurement result show, compound of the present invention is strong SGLT2 inhibitor, can be used for prepare treatment type ii diabetes medicine.
Claims (2)
1. following compounds,
2. compound described in claim 1 and the pharmaceutically application of acceptable salt in preparation treatment diabetes medicament thereof.
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|---|---|---|---|
| CN201510021704.1A CN104610017B (en) | 2015-01-15 | 2015-01-15 | One class halogenophenyl propanediol derivative, Preparation Method And The Use |
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|---|---|---|---|
| CN201510021704.1A CN104610017B (en) | 2015-01-15 | 2015-01-15 | One class halogenophenyl propanediol derivative, Preparation Method And The Use |
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| CN104610017B true CN104610017B (en) | 2016-01-13 |
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Denomination of invention: Halogenated phenyl propylene glycol derivatives as well as preparation method and application thereof Effective date of registration: 20170816 Granted publication date: 20160113 Pledgee: Guangdong Nanhai Rural Commercial Bank branch branch of Limited by Share Ltd Pledgor: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. Registration number: 2017990000756 |
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Effective date of registration: 20190826 Address after: 526600 Volkswagen Pioneer Park, South Side of Decheng Huanshi Road, Deqing County, Zhaoqing City, Guangdong Province, No. 1207, 1st Building, Second Floor (Residential Reform Business) Patentee after: Zhaoqing Kezhi Automation Equipment Co., Ltd. Address before: Chancheng district has 528000 Taiwan public in Guangdong province Foshan City No. 32 first floor 1636, shop No. 1637 Patentee before: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. |
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