CN106749002A - A kind of glucokinase activators containing nitroquinoline structure and application thereof - Google Patents
A kind of glucokinase activators containing nitroquinoline structure and application thereof Download PDFInfo
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- CN106749002A CN106749002A CN201611134620.XA CN201611134620A CN106749002A CN 106749002 A CN106749002 A CN 106749002A CN 201611134620 A CN201611134620 A CN 201611134620A CN 106749002 A CN106749002 A CN 106749002A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen 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
- C07D215/18—Halogen atoms or nitro radicals
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Abstract
The present invention relates to the drug field related to diabetes B.Specifically, the present invention relates to a kind of glucokinase activators containing nitroquinoline structure, its preparation method and the application in diabetes B medicine is prepared.
Description
Technical field
The present invention relates to the drug field of the treatment of diabetes B.More particularly, it relates to diabetes B
Glucokinase activators, its preparation method of a kind of medicative quinoline structure containing nitro substitution, and in pharmacy
On purposes.
Background technology
Diabetes include a series of syndromes, it is characterized by body can not produce enough insulin or normally use pancreas islet
Element.Most diabetic can clinically be divided into insulin-dependent diabetes mellitus (IDDM) or non-insulin-depending type sugar
Urine is sick (NIDDM).Almost all kinds of diabetes all result from insulin secretion and blood level and reduce or organize to pancreas islet
Reaction reduction (insulin resistance) of element, this hormone generally opposite with insulin action (female mouthful glucagons) level is raised
It is relevant.The abnormal conditions make carbohydrate, lipid and protein metabolism change.The syndrome is masked as hyperglycemia,
Other complication may include angiocardiopathy, retinopathy, DPN, ephrosis, skin disease and gastroparesis.
The main target for treating every kind of this illness is to reduce and control blood sugar level.In IDD
(IDDM) in, the reduction of hyperglycaemia can reduce generation (the Diabetes Control and of the adjoint complication of many IDDM
Complications Trial Research Group,New England J.Med.,1993,329,977-986).For example,
Tightly control the blood sugar level can to make machine nethike embrane disease, ephrosis and the neuropathy of each IDDM patient by the insulin therapy of high intensity
The generation of change reduces more than 50%.The discovery collectively shows that control blood with the pathology similitude seen in IDDM and NIDDM
Sugar level can produce similar benefit (American Diabetes Association, Diabetes in NIDDM patient
Care,1998,21,S88-90)。
The method of several treatment hyperglycemias is had attempted to.Type i diabetes patient receives insulin.In type ii diabetes
In patient, pancreas can excreting insulin, but its amount is not enough to overcome the insulin resistance disease of inherence.Give medicine such as diformazan double
Lonely, glitazone can at least partly relax political affairs insulin resistance, but the medicine can not promote insulin secretion.According to display, some are used
Sulphonylurea therapy can promote insulin secretion by influenceing ion channel, but, it is not by such drug-induced insulin
Glucose dependency or even glucose-sensitive, it is this to treat the wind that actually increase obvious hypoglycemia
Danger.DPP-IV inhibitor, such as GLP or GLP analogs (such as Exedin), can promote cAMP thin in β by incretin mechanism
Secreted in born of the same parents, giving this medicine can promote insulin to be discharged with glucose-dependent fashion.But, even if effective using this
Treatment, or being difficult the tight blood sugar level for controlling NIDMM patient complies with the guidance side that America Diabetes are assisted, club is recommended
Pin.Hence it is highly desirable to the novel method for the treatment of of glycemic control can be carried out fully.
The possible method of glycemic control include improve glucose from the clearance rate in blood and accelerate glucose stock or
This rate for utilizing.Glucose enters most cells by specific transport protein, and wherein glucose is catalyzed by hexokinase
Reaction in be phosphorylated to form G-6-P.In cell, G-6-P has one of several destiny：Pass through
Glycolytic pathway is degraded, and is converted into Tangyuan County, or be oxidized by pentose phosphate pathway.
Glucokinase (GK) is one of the mammal hexokinase of four types (hexokinase IV), in glucostasis
In play an important role.Glucokinase is predominantly located in liver and pancreatic beta cell, wherein expressed have several types
Glucokinase：Due to different montage modes, the type is different in the sequence of the non-terminal amino acids of 15N, but their enzymatic property
It is essentially identical.Glucokinase is also in the neuron expression of hypothalamus.
(1, II, III) different from the enzymatic activity of other three kinds of hexokinases, they just reach in below concentration of glucose 1mM
To saturation, and glucokinase is 8mM to the Km of glucose, and it is close to physiological glucose level (5mM).Therefore, compared with
Under LG level, compared with liver, glucose quickly in brain, muscle and other external application tissues using passing through one by one
Hexose is converted rather than glucokinase.Under glucose level higher, (GLPP water such as after the meal or during overnutrition
It is flat to exceed 10-15mM), the glucose metabolism of glucokinase mediation is accelerated in liver and pancreas.Additionally, hexose swashs
Enzyme I, II and III are suppressed by the G-6-P of high concentration, glucose utilization rate reduction, even and if in high-caliber grape
Under sugared phosphoric acid, glucokinase may proceed to be catalyzed the utilization of glucose.
In the tissue of expression glucokinase, it plays very important effect in glucose uptake and application：In β
In cell, the required signal of the generation insulin releasing of G-6-P, glucose-phosphoric acid is used as being satiated with food in hypothalamus
Signal simultaneously may promote the secretion of incretin, in liver, the glucose -6- phosphorus generated by glucokinase enzyme effect
Acid is used as the mechanism by saving as glycosuria treatment excessive glucose.In liver cell and pancreatic beta-cell, glucokinase is urged
The glucose phosphorylation of change act as the rate limit reaction of glycolysis.In liver, glucokinase determines glucose uptake
With the speed of Glycogen synthesis, it is also considered to be material necessary to the various glucose-sensitive genes of regulation.In liver and pancreas
In dirty β cells, glucokinase can limit the speed of glucose utilization, therefore it is regulation from β cells secrete insulins and liver
The main component of the glycogen storage in dirty.And control what the element secretion of political affairs island and control glycogen storage exactly diabetes were lacked.It is right
Theoretical significance of the glucokinase in diabetes is supported in the genetic group of NIDDM animal models and the research of genetic manipulation.
Glucokinase sports the relatively low activity form of kinases for teenager's youth occurs the cause of patients with type Ⅰ DM.Conversely, glucose
The people of kinase activation mutation is not susceptible to suffer from hyperglycemia, and increases the secretion of insulin and carry out response glucose tolerance examination (glucose
challenge)(Gloyn,A.L,et al.,Diabetes,2003,52,2433-2440；Glaser,B.,et al.,New
England J.Med,1998,338,226-230).Equally, reported that NIDDM patient has abnormal LG kinases
Activity.Additionally, mistake of the glucokinase in the diet type (dietary) or genotype (genetic) animal model of diabetes
Degree expression can prevent, mitigate or reverse the process of the pathological state in the disease.Due to the reason, pharmaceuticals industry is being sought at oneself
Ask can activating glucokinase compound.
Substituted carbamovl, the miscellaneous benzyl ammonia first look down base of substitution, the phenylcarbamoyl of substitution and substituted
Heteroaryl carboxamides based compound has been disclosed as glucokinase activators.Referring to：WO 03/000267、WO 03/
015774、WO 04/045614、WO 04/046139、WO 05/04480、WO 05/054200、WO 05/054233、WO 05/
044801、WO 05/056530、WO 03/080585、WO 04/076420、WO 04/081001、WO 04/063194、WO
04/050645、WO 03/055482、WO 04/002481、WO 05/066145、WO 04/072031、WO 04/072066、WO
00/058293、WO 03/095438、WO 01144216、WO011083465、WO 01/083478、WO 01/085706、WO
01/085707、WO02/008209、WO 02/014312、WO 02/046173、WO 02/048106、WO03/095438、WO
04/031179 and WO 04/052869.The compound can reduce the Km of glucose and/or increase the V of glucokinasemax.Due to
Not yet have the glucokinase activators of list marketing at present, thus still need it is a series of can be by under relatively low activator concentration
The Km of glucose is suitably reduced to the glucokinase activators of 2-5mM.
The invention discloses a kind of glucokinase activators of the quinoline structure containing nitro substitution, the compound can be used for
Prepare the medicine for the treatment of diabetes B.
The content of the invention
It is an object of the present invention to provide a kind of glucokinase activators of the excellent activity with Formulas I.
Method it is a further object to provide the compound with Formulas I is prepared.
It is also another object of the present invention to provide the compound containing Formulas I is as active ingredient and its is treating 2 type glycosurias
Application in terms of disease.
Present invention is specifically described in conjunction with the purpose of the present invention.
Compound of the present invention with Formulas I has following structural formula：
Compound of formula I of the present invention is synthesized by following route：
Compound II obtains its corresponding aryl lithium III by n-BuLi treatment；Catalysis of the III in BFEE
There is addition reaction in lower and (R) -3- chloro- 1,2- expoxy propane, obtain compound IV；Compound V and acid anhydrides Ac2O reactions are obtained
VIA, VIA are processed using ammoniacal liquor or methylamine etc. and are obtained compound VI；Compound IV and VI react in alkaline environment, obtain
To VII；Compound VII obtains product I using oxidizing.
Compound of formula I of the present invention has glucokinase enzyme activation effect, can be used to prepare 2 types sugar as active ingredient
Urinate the medicine of disease.The activity of compound of formula I of the present invention is verified by receptor binding assays.
Compound of formula I of the invention is effective in comparatively wide dosage range.The dosage for example taken daily about exists
In the range of 1mg-1000mg/ people, it is divided into and once or is for several times administered.The dosage for actually taking formula I can be by doctor
Determined according to relevant situation.
Specific embodiment
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only for
Illustrate, and be not intended to limit the present invention.The various change that those skilled in the art's training centre of the invention is made all should
Within the protection domain required by the application claim.
The synthesis of the compound I of embodiment 1
A. the synthesis of compound IV
100mL dry round-bottomed flask in 2.53g (10mmol) compounds II is dissolved in the dry THF of 20mL, it is cold
But to -78 DEG C, the THF solution of the n-BuLi of 6.25mL (10mmol) 1.6M, completion of dropping are slowly added dropwise by syringe for stirring
Afterwards, reactant mixture continues stirring 1 hour at such a temperature.1.42g (10mmol) boron trifluoride second is slowly added dropwise with syringe
Ether, is then slowly added dropwise 0.93g (10mmol) (R) chloro- 1,2- expoxy propane of -3- and is dissolved in the dry THF of 2mL be made molten again
Liquid, after completion of dropping, reactant mixture is stirred at room temperature 5 hours, and TLC display reactions are completed.It is mixed toward reaction after the completion of reaction
Compound is poured into 100mL frozen water, stirring, uses the CH of 50mL × 32Cl2Extraction, merges extraction phase, uses salt water washing, anhydrous
Sodium sulphate is dried.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and the residue for obtaining is purified using column chromatography,
Obtain compound IV, white solid, ESI-MS, m/z=267 ([M+H]+)。
B. the synthesis of compound VI
1.39g (10mmol) compounds V is dissolved in 10mL acetic anhydride, 0.3g anhydrous sodium acetates is added, under nitrogen protection
Backflow 3 hours, TLC checks that reaction is completed.After the completion of reaction, in pouring into 100mL frozen water toward reactant mixture, stir 3 hours,
Use the CH of 50mL × 32Cl2Extraction, merges extraction phase, and saturation NaHCO is used successively3Solution and salt water washing, anhydrous sodium sulfate are done
It is dry.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and the residue for obtaining is dissolved in 20mL absolute ethyl alcohols, adds
Concentrated ammonia liquor 5mL, flows back 5 minutes.During mixture pours into 100mL frozen water after cooling, stir 3 hours, use 50mL × 3
CH2Cl2Extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is in rotary evaporation
It is evaporated on instrument, the residue for obtaining is purified using column chromatography, obtains compound VI, white solid, ESI-MS, m/z=182 ([M+
H]+)。
C. the synthesis of compound VII
1.33g (5mmol) compound IV-1 and 0.91g (5mmol) VI-1 is dissolved in the dry DMF of 20mL, is added
2.07g (15mmol) potash solid, is then stirred overnight at room temperature, and TLC checks that reaction is completed.After the completion of reaction, toward reaction
Mixture is poured into 100mL frozen water, stirring, uses the CH of 50mL × 32Cl2Extraction, merges extraction phase, and salt water washing is anhydrous
Sodium sulphate is dried.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and the residue for obtaining is purified using column chromatography,
Obtain compound VII, white solid, ESI-MS, m/z=412 ([M+H]+)。
D. the synthesis of compound I
1.64g (4mmol) compounds VII-1 is dissolved in 15mL CH2Cl2In, stir at room temperature, add 3.45g
(20mmol) metachloroperbenzoic acid (mCPBA), after reactant mixture is stirred at room temperature 1 hour, temperature rising reflux 3 hours, TLC
Check that reaction is completed.After the completion of reaction, in pouring into 100mL frozen water toward reactant mixture, stirring uses the CH of 50mL × 32Cl2
Extraction, merges extraction phase, and saturated sodium bicarbonate solution and salt water washing, anhydrous sodium sulfate drying are used successively.Suction filtration removes dry
Drying prescription, filtrate is evaporated on a rotary evaporator, and the residue for obtaining is purified using column chromatography, obtains compound I, white solid,
ESI-MS, m/z=444 ([M+H]+)。
The synthesis of the reference compound D-1 of embodiment 2
A. the synthesis of compound IV-2
100mL dry round-bottomed flask in 2.06g (10mmol) compounds II-2 is dissolved in the dry THF of 20mL,
- 78 DEG C are cooled to, the THF solution of the n-BuLi of 6.25mL (10mmol) 1.6M is slowly added dropwise by syringe for stirring, drips
Bi Hou, reactant mixture continues stirring 1 hour at such a temperature.1.42g (10mmol) boron trifluoride is slowly added dropwise with syringe
Ether, is then slowly added dropwise 0.93g (10mmol) (R) chloro- 1,2- expoxy propane of -3- and is dissolved in the dry THF of 2mL what is be made again
Solution, after completion of dropping, reactant mixture is stirred at room temperature 5 hours, and TLC display reactions are completed.After the completion of reaction, toward reaction
Mixture is poured into 100mL frozen water, stirring, uses the CH of 50mL × 32Cl2Extraction, merges extraction phase, uses salt water washing, nothing
Aqueous sodium persulfate is dried.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and the residue for obtaining is pure using column chromatography
Change, obtain compound IV-2, white solid, ESI-MS, m/z=222 ([M+H]+)。
B. the synthesis of compound VI
1.25g (10mmol) compounds V is dissolved in 10mL acetic anhydride, 0.3g anhydrous sodium acetates is added, under nitrogen protection
Backflow 3 hours, TLC checks that reaction is completed.After the completion of reaction, in pouring into 100mL frozen water toward reactant mixture, stir 3 hours,
Use the CH of 50mL × 32Cl2Extraction, merges extraction phase, and saturation NaHCO is used successively3Solution and salt water washing, anhydrous sodium sulfate are done
It is dry.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and the residue for obtaining is dissolved in 20mL absolute ethyl alcohols, adds
Concentrated ammonia liquor 5mL, flows back 5 minutes.During mixture pours into 100mL frozen water after cooling, stir 3 hours, use 50mL × 3
CH2Cl2Extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is in rotary evaporation
It is evaporated on instrument, the residue for obtaining is purified using column chromatography, obtains compound VI, white solid, ESI-MS, m/z=168 ([M+
H]+)。
C. the synthesis of compound VII-2
1.11g (5mmol) compound IV-2 and 0.84g (5mmol) VI is dissolved in the dry DMF of 20mL, 2.07g is added
(15mmol) potash solid, is then stirred overnight at room temperature, and TLC checks that reaction is completed.After the completion of reaction, toward reactant mixture
Pour into 100mL frozen water, stirring uses the CH of 50mL × 32Cl2Extraction, merges extraction phase, salt water washing, anhydrous sodium sulfate
Dry.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and the residue for obtaining is purified using column chromatography, is changed
Compound VII-2, white solid, ESI-MS, m/z=353 ([M+H]+)。
D. the synthesis of compound D-1
1.41g (4mmol) compounds VII-2 is dissolved in 15mL CH2Cl2In, stir at room temperature, add 3.45g
(20mmol) metachloroperbenzoic acid (mCPBA), after reactant mixture is stirred at room temperature 1 hour, temperature rising reflux 3 hours, TLC
Check that reaction is completed.After the completion of reaction, in pouring into 100mL frozen water toward reactant mixture, stirring uses the CH of 50mL × 32Cl2
Extraction, merges extraction phase, and saturated sodium bicarbonate solution and salt water washing, anhydrous sodium sulfate drying are used successively.Suction filtration removes dry
Drying prescription, filtrate is evaporated on a rotary evaporator, and the residue for obtaining is purified using column chromatography, obtains compound D-1, and white is solid
Body, ESI-MS, m/z=420 ([M+H]+)。
Activation of the Compound ira vitro of embodiment 3 to glucokinase
Extracorporeal glucose kinases is tested
The external activity of glucokinase activators of the invention is evaluated in two independent tests：Use EC50Survey
Try to evaluate effect of each compound under fixed, physiology related concentrations glucose, and in fixed, near saturation
If the glucose S under the compound of (possibility) concentration0.5Test to evaluate its Vm and S for glucose0.5Effect.For every
The individual test, glucokinase by the test system containing NAD+ and the coupling of G 6 PD,
Estimated in the increase of 340nm monitoring traps.Test at 30 DEG C, using thermostatically controlled ELIASA (absorbance
Plate reader) and transparent, 96 holes, flat, XPS (Costar 3695, Coming) carry out.Each 50 μ L is tested
Mixture contains 10mM K+MOPS, pH 7.2,2mM MgCl2, 50mM KCl, 0.01%Triton X-100,2%DMSO,
1mM DTT, 1mM ATP, 1mM NAD+, 5U/mL G 6 PDs, about 5nM human glocoses swash dark and (depend on surveying
Examination) various concentrations glucose and test compound.In the trap of 5 minute period of 340nm dynamic monitorings (10s/ circulations), and
Speed (rate) is estimated by the oblique soldier of the straight line of fitting initial data.
Glucokinase EC50 is tested:
For the test, concentration of glucose is fixed on 5mM, and control or test compound are with 10 points (l-point), 3
Times dilution series and usual scope are 50 μM of high dose to low dosage about 2.5nM.It is fitted with standard, 4 parameter logistic models original
Data (speed is compared to compound concentration)：
Y=A+ (B-A)/[1+C/x]D
Wherein x is the concentration of compound, and y is the speed of estimation, and A and B is respectively lower asymptote and upper asymptote, and C is
EC50, D is Hill slopes.EC50The midpoint being defined as between asymptote and lower asymptote or flex point.Some chemical combination in the present invention
The EC of thing50Data are as shown in the table：
| Compound | EC50(nM) |
| Reference compound D-1 | 24.1 |
| Compound I-1 | 7.2 |
Glucose S0.5 is tested:
For this test, the concentration of control or test compound is fixed on or close to saturated concentration, if may, usually 50 μ
M, and concentration of glucose changes from 80 to about 0.16mM through 10 points, 2 times of dilution series.Using with for EC50Test identical
4 parameter logistic models determine related kinetic parameter.It is similar with the definition of parameter for variable in the test, except x tables
Show the concentration of glucose, B is the speed (Vm) of saturation glucose, and C is the S of glucose0.5(under the concentration of Vm/2 glucose) and
D is Hill coefficients.The S of some compounds in the present invention0.5Data are as shown in the table：
| Compound | S0.5(mM) |
| Reference compound D-1 | 5.4 |
| Compound I-1 | 2.6 |
The determination of activity result of above-mentioned two table shows that compound of the invention is strong glucokinase activators, can
For preparing the medicine for the treatment of diabetes B.
Claims (3)
1. there is the compound of Formulas I structure,
2. the method for synthesizing the compound of Formulas I described in claim 1：
Compound II obtains its corresponding aryl lithium III by n-BuLi treatment；III under the catalysis of BFEE with
(R) there is addition reaction in chloro- 1, the 2- expoxy propane of -3-, obtain compound IV；Compound V and acid anhydrides Ac2O reactions obtain VIA,
VIA is processed using ammoniacal liquor or methylamine etc. and is obtained compound VI；Compound IV and VI react in alkaline environment, obtain
VII；Compound VII obtains product I using oxidizing.
3. application of the compound of formula I described in claim 1 in terms for the treatment of diabetes B medicine is prepared.
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| WO2001012591A1 (en) * | 1999-07-29 | 2001-02-22 | Telik, Inc. | Novel naphthylsulfonic acids and related compounds as glucose uptake agonists |
| CN1751038A (en) * | 2003-02-24 | 2006-03-22 | 艾尼纳制药公司 | Substituted aryl and heteroaryl derivatives as modulators of glucose metabolism and the prophylaxis and treatment of disorders thereof |
| CN101417964A (en) * | 1998-05-29 | 2009-04-29 | 阿斯特拉曾尼卡有限公司 | Use of compounds for the elevation of pyruvate dehydrogenase activity |
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| CN101437512A (en) * | 2006-01-27 | 2009-05-20 | 阿雷生物药品公司 | Glucokinase activators |
| EP2547679B1 (en) * | 2010-03-19 | 2015-11-04 | Pfizer Inc | 2,3 dihydro-1h-inden-1-yl-2,7-diazaspiro[3.6]nonane derivatives and their use as antagonists or inverse agonists of the ghrelin receptor |
| AU2011322117B2 (en) * | 2010-10-29 | 2015-01-22 | Pfizer Inc. | N1/N2-lactam acetyl-CoA carboxylase inhibitors |
| CN102558167A (en) * | 2010-12-29 | 2012-07-11 | 中国医学科学院药物研究所 | Thiazolidine derivant with GK and PPAR double excitation activity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101417964A (en) * | 1998-05-29 | 2009-04-29 | 阿斯特拉曾尼卡有限公司 | Use of compounds for the elevation of pyruvate dehydrogenase activity |
| WO2001012591A1 (en) * | 1999-07-29 | 2001-02-22 | Telik, Inc. | Novel naphthylsulfonic acids and related compounds as glucose uptake agonists |
| CN1751038A (en) * | 2003-02-24 | 2006-03-22 | 艾尼纳制药公司 | Substituted aryl and heteroaryl derivatives as modulators of glucose metabolism and the prophylaxis and treatment of disorders thereof |
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