CN104557700A - Glucokinase activating agent containing nitrile quinoline structure and application thereof - Google Patents
Glucokinase activating agent containing nitrile quinoline structure and application thereof Download PDFInfo
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- CN104557700A CN104557700A CN201510079030.0A CN201510079030A CN104557700A CN 104557700 A CN104557700 A CN 104557700A CN 201510079030 A CN201510079030 A CN 201510079030A CN 104557700 A CN104557700 A CN 104557700A
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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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention relates to the field of medicines related to type 2-diabetes mellitus, and particularly relates to a glucokinase activating agent containing a nitrile quinoline structure, as well as a preparation method and application thereof in preparation of medicines for treating type 2-diabetes mellitus. The structure is as shown in the specification.
Description
Technical field
The present invention relates to the pharmaceutical field of the treatment of diabetes B.More particularly, the present invention relates to glucokinase activators, its preparation method to the quinoline structure that the medicative a kind of nitrile group-containing of diabetes B replaces, and the purposes in pharmacy.
Background technology
Diabetes comprise a series of syndrome, it is characterized by health and can not produce enough Regular Insulin or normally use Regular Insulin.Most diabetic subject can be divided into insulin-dependent diabetes mellitus (IDDM) or non insulin dependent diabetes (NIDDM) clinically.The diabetes of nearly all type all result from insulin secretion and blood level reduces or tissue reduces (insulin resistant) the reaction of Regular Insulin, and this raises relevant with hormone (the female's mouth glucagon) level contrary with insulin action usually.These abnormal conditions make carbohydrate, lipid and Proteometabolism change.This is syndromic is masked as hyperglycemia, and other complication can comprise cardiovascular disorder, retinopathy, DPN, ephrosis, tetter and gastroparesis.
The major objective for the treatment of often kind of this illness reduces and controls glucose level.In insulin-dependent diabetes (IDDM), the reduction of hyperglycemia can reduce generation (the DiabetesControl and Complications Trial Research Group of the adjoint complication of many IDDM, New England J.Med., 1993,329,977-986).Such as, the generation of the machine nethike embrane disease of each IDDM patient, ephrosis and DPN can be made to reduce more than 50% by the insulinize strict control glucose level of high strength.This discovery shows that together with the pathology similarity seen in IDDM with NIDDM controlling glucose level can produce similar benefit (American Diabetes Association in NIDDM patient, Diabetes Care, 1998,21, S88-90).
Attempt the method for several treatment hyperglycemia.Type i diabetes patient accepts Regular Insulin.In type ii diabetes patient, pancreas can excreting insulin, but its quantity not sufficient is to overcome inherent insulin resistant disease.Give medicine such as diformazan couple orphan, glitazone and can relax political affairs insulin resistance at least partly, but this medicine can not promote insulin secretion.According to the show, insulin secretion is promoted by affecting ionic channel with some sulphonylurea therapy, but, by such drug-induced Regular Insulin be not glucose dependency or or even glucose-sensitive, in fact this treatment can increase the risk of obvious hypoglycemia.By incretin mechanism, DPP-IV inhibitor, as GLP or GLP analogue (as Exedin), promotes that cAMP secretes in β cell, gives this medicine and can promote that Regular Insulin discharges with glucose-dependent fashion.But even if adopt this effectively to treat, or the glucose level of very difficult strict control NIDMM patient makes the guilding principle that it meets America Diabetes association, club is recommended.Therefore, the novel method for the treatment of that fully can carry out glycemic control is starved of.
The possible method of glycemic control comprises raising glucose from the clearance rate blood and this rate accelerating glucose stock or utilization.Glucose enters most cells by specific translocator, and wherein glucose is phosphorylated formation G-6-P in by the reaction of hexokinase catalysis.In cell, G-6-P has one of several destiny: be degraded by glycolytic pathway, is converted into Tangyuan County, or oxidized by pentose-phosphate pathway.
Glucokinase (GK) is one of the Mammals hexokinase of Four types (hexokinase IV), plays an important role in glucostasis.Glucokinase is mainly arranged in liver and pancreatic beta cell, and wherein expressed have the glucokinase of several types: due to different montage modes, the type is different in the amino acid whose sequence of 15N end, but their enzymatic property is substantially identical.Glucokinase is also at hypothalamic neuron expression.
Different from the enzymic activity of other three kinds of hexokinase (1, II, III), they just reach capacity at below glucose concn 1mM, and glucokinase is 8mM to the Km of glucose, and it is close to physiological glucose level (5mM).Therefore, under comparatively low dextrose level, compared with in liver, glucose is utilized quickly and is transformed instead of glucokinase by hexose one by one in brain, muscle and other external application tissue.Under higher glucose level, as after the meal or supernutrition time (postprandial glucose levels can more than 10-15mM), glucose metabolism acceleration in liver and pancreas of glucokinase mediation.In addition, hexokinase I, II and III are suppressed by the G-6-P of high density, and glucose utilization rate reduces, even and if under high-caliber glucose phosphate, glucokinase can continue the utilization of catalysis glucose.
In the tissue of expressing glucokinase, it plays very important effect in glucose uptake and application: in β cell, the required signal of the generation insulin releasing of G-6-P, in hypothalamus, glucose-phosphoric acid also may promote the secretion of incretin as signal of being satiated with food, in liver, the G-6-P generated by glucokinase effect is as the mechanism by saving as glycosuria process excessive glucose.In liver cell and pancreatic beta-cell, the glucose phosphorylation of glucokinase enzyme catalysis act as the reaction of glucolytic rate limiting.In liver, glucokinase determines the speed of glucose uptake and Glycogen synthesis, and it is also considered to regulate the necessary material of various glucose-sensitive genes.In liver and pancreatic beta cell, glucokinase can limit the speed of glucose utilization, and therefore it regulates the main component from the glycogen storage β cells secrete insulin and liver.And control the element secretion of political affairs islands and control glycogen storage just diabetes lack.The theoretical significance of glucokinase in diabetes is supported to the genetic group of NIDDM animal model and the research of genetic manipulation.It is cause teenager's youth patients with type Ⅰ DM occurring compared with low activity form that glucokinase sports kinase whose.On the contrary, the people of glucokinase Activating mutations not easily suffers from hyperglycemia, and the secretion increasing Regular Insulin comes the examination of response glucose tolerance (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 low dextrose kinase activity.In addition, the overexpression of glucokinase in the diet type (dietary) or genotype (genetic) animal model of diabetes can stop, alleviates or reverse the process of the pathological state in this disease.Due to this reason, pharmaceutical industries at oneself seek can the compound of activating glucokinase.
The carbamovl replaced, the assorted benzyl ammonia first look down base of replacement, the phenylcarbamoyl of replacement and the heteroaryl carboxamides based compound of replacement are disclosed as glucokinase activators.See: WO03/000267, WO 03/015774, WO 04/045614, WO 04/046139, WO 05/04480, WO05/054200, 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, WO 03/095438, WO 04/031179 and WO 04/052869.This compound can reduce the Km of glucose and/or increase the V of glucokinase
max.Owing to not yet there being the glucokinase activators of list marketing at present, therefore still need a series of glucokinase activators that the Km of glucose suitably can be reduced to 2-5mM under lower activator concentration.
The invention discloses the glucokinase activators of the quinoline structure that a kind of nitrile group-containing replaces, this compound can be used for the medicine preparing treatment diabetes B.
Summary of the invention
An object of the present invention is to provide a kind of glucokinase activators with the excellent activity of formula I.
Another object of the present invention is to provide the method that preparation has the compound of formula I.
Another object of the present invention is to provide compound containing formula I as effective constituent and the application in treatment diabetes B 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, through n-BuLi process, obtains the lithium aryl III of its correspondence; III under the catalysis of boron trifluoride diethyl etherate with (R)-epichlorohydrin generation addition reaction, obtain compound IV; Compound V and acid anhydrides Ac
2o is obtained by reacting VIA, and VIA uses the process such as ammoniacal liquor or methylamine to obtain compound VI; Compound IV and VI react in alkaline environment, obtain VII; Compound VI I use is oxidizing obtains product I.
Formula I of the present invention has glucokinase activation, can be used as the medicine of effective constituent for the preparation of diabetes B.The activity of formula I of the present invention is verified by receptor binding assays.
Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-1000mg/ people, is divided into once or administration for several times.The actual dosage taking formula I 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 synthesis of embodiment 1 Compound I
A. the synthesis of compound IV
In the dry round-bottomed flask of 100mL, 2.33g (10mmol) Compound II per is dissolved in the THF of 20mL drying, be cooled to-78 DEG C, stir, the THF solution of the n-BuLi of 6.25mL (10mmol) 1.6M is slowly dripped by syringe, after dropwising, reaction mixture continues stirring 1 hour at such a temperature.1.42g (10mmol) boron trifluoride diethyl etherate is slowly dripped with syringe, then slowly drip 0.93g (10mmol) (R)-3-chloro-1 again, 2-propylene oxide is dissolved in the solution made in the THF of 2mL drying, after dropwising, reaction mixture at room temperature stirs 5 hours, and TLC shows reaction to be completed.After having reacted, pour in 100mL frozen water toward reaction mixture, stir, use the CH of 50mL × 3
2cl
2extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound IV, white solid, ESI-MS, m/z=247 ([M+H]
+).
B. the synthesis of compound VI
Be dissolved in 10mL acetic anhydride by 1.39g (10mmol) compound V, add 0.3g sodium acetate, anhydrous, reflux 3 hours under nitrogen protection, TLC checks that reaction completes.After having reacted, pour in 100mL frozen water toward reaction mixture, stir 3 hours, use the CH of 50mL × 3
2cl
2extraction, merges extraction phase, uses saturated NaHCO successively
3solution and salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained is dissolved in 20mL dehydrated alcohol, adds strong aqua 5mL, refluxes 5 minutes.After cooling, mixture pours in 100mL frozen water, stirs 3 hours, uses the CH of 50mL × 3
2cl
2extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound VI, white solid, ESI-MS, m/z=182 ([M+H]
+).
C. the synthesis of compound VI I
1.24g (5mmol) compound IV-1 and 0.91g (5mmol) VI-1 are dissolved in the DMF of 20mL drying, add 2.07g (15mmol) potash solid, then room temperature for overnight, TLC checks that reaction completes.After having reacted, pour in 100mL frozen water toward reaction mixture, stir, use the CH of 50mL × 3
2cl
2extraction, merges extraction phase, salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound VI I, white solid, ESI-MS, m/z=392 ([M+H]
+).
D. the synthesis of Compound I
1.56g (4mmol) compound VI I-1 is dissolved in 15mL CH
2cl
2in, stirred at ambient temperature, adds 3.45g (20mmol) metachloroperbenzoic acid (mCPBA), and after reaction mixture at room temperature stirs 1 hour, temperature rising reflux 3 hours, TLC checks that reaction completes.After having reacted, pour in 100mL frozen water toward reaction mixture, stir, use the CH of 50mL × 3
2cl
2extraction, merges extraction phase, uses saturated sodium bicarbonate solution and salt water washing successively, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains Compound I, white solid, ESI-MS, m/z=424 ([M+H]
+).
the synthesis of embodiment 2 reference compound D-1
A. the synthesis of compound IV-2
In the dry round-bottomed flask of 100mL, 2.06g (10mmol) Compound II per-2 is dissolved in the THF of 20mL drying, be cooled to-78 DEG C, stir, the THF solution of the n-BuLi of 6.25mL (10mmol) 1.6M is slowly dripped by syringe, after dropwising, reaction mixture continues stirring 1 hour at such a temperature.1.42g (10mmol) boron trifluoride diethyl etherate is slowly dripped with syringe, then slowly drip 0.93g (10mmol) (R)-3-chloro-1 again, 2-propylene oxide is dissolved in the solution made in the THF of 2mL drying, after dropwising, reaction mixture at room temperature stirs 5 hours, and TLC shows reaction to be completed.After having reacted, pour in 100mL frozen water toward reaction mixture, stir, use the CH of 50mL × 3
2cl
2extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound IV-2, white solid, ESI-MS, m/z=222 ([M+H]
+).
B. the synthesis of compound VI
Be dissolved in 10mL acetic anhydride by 1.25g (10mmol) compound V, add 0.3g sodium acetate, anhydrous, reflux 3 hours under nitrogen protection, TLC checks that reaction completes.After having reacted, pour in 100mL frozen water toward reaction mixture, stir 3 hours, use the CH of 50mL × 3
2cl
2extraction, merges extraction phase, uses saturated NaHCO successively
3solution and salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained is dissolved in 20mL dehydrated alcohol, adds strong aqua 5mL, refluxes 5 minutes.After cooling, mixture pours in 100mL frozen water, stirs 3 hours, uses the CH of 50mL × 3
2cl
2extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound VI, white solid, ESI-MS, m/z=168 ([M+H]
+).
C. the synthesis of compound VI I-2
1.11g (5mmol) compound IV-2 and 0.84g (5mmol) VI are dissolved in the DMF of 20mL drying, add 2.07g (15mmol) potash solid, then room temperature for overnight, TLC checks that reaction completes.After having reacted, pour in 100mL frozen water toward reaction mixture, stir, use the CH of 50mL × 3
2cl
2extraction, merges extraction phase, salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound VI I-2, white solid, ESI-MS, m/z=353 ([M+H]
+).
D. the synthesis of Compound D-1
1.41g (4mmol) compound VI I-2 is dissolved in 15mL CH
2cl
2in, stirred at ambient temperature, adds 3.45g (20mmol) metachloroperbenzoic acid (mCPBA), and after reaction mixture at room temperature stirs 1 hour, temperature rising reflux 3 hours, TLC checks that reaction completes.After having reacted, pour in 100mL frozen water toward reaction mixture, stir, use the CH of 50mL × 3
2cl
2extraction, merges extraction phase, uses saturated sodium bicarbonate solution and salt water washing successively, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains Compound D-1, white solid, ESI-MS, m/z=420 ([M+H]
+).
embodiment 3 Compound ira vitro is to the activation of glucokinase
Extracorporeal glucose kinases is tested
The external activity of glucokinase activators of the present invention is evaluated in two independently test: use EC
50test to evaluate the effect of each compound under glucose that is fixing, physiology related concentrations, and the glucose S under the compound of fixing, closely saturated (if may) concentration
0.5test to evaluate its Vm and S for glucose
0.5effect.For this test each, glucokinase, by the test macro of the coupling containing NAD+ and G 6 PD, is monitored the increase of optical density at 340nm and estimates.Test, at 30 DEG C, utilizes thermostatically controlled microplate reader (absorbance plate reader) and transparent, 96 holes, flat, polystyrene board (Costar 3695, Coming) carries out.Each 50 μ L test mixing things contain 10mMK+MOPS, pH 7.2,2mM MgCl
2, 50mM KCl, 0.01% Triton X-100,2%DMSO, 1mM DTT, 1mM ATP, 1mM NAD+, 5U/mL G 6 PD, about 5nM human glocose swashs glucose and the test compounds of dark and (depending on test) different concns.In the optical density of 340nm dynamic monitoring 5 minute period (10s/ circulation), and speed (rate) is estimated by the oblique soldier of the straight line of matching raw data.
Glucokinase EC50 tests:
For this test, glucose concn is fixed on 5mM, and contrast or test compounds with 10 points (l-point), 3 times of dilution series and usually scope be that high dosage 50 μMs is about 2.5nM to low dosage.By standard, 4 parameter logistic model matching raw 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, A and B is respectively lower asymptotic line and upper asymptotic line, and C is EC
50, D is Hill slope.EC
50be defined as the mid point between asymptotic line and lower asymptotic line or flex point.The EC of some compound in the present invention
50data are as shown in the table:
| Compound | EC 50(nM) |
| Reference compound D-1 | 24.1 |
| Compound I-1 | 6.8 |
Glucose S0.5 tests:
For this test, the concentration of contrast or test compounds is fixed on or close to saturation concentration, if possibility, be generally 50 μMs, and glucose concn is from 80 to about 0.16mM, through 10 points, 2 times of dilution series changes.Use with for EC
50test 4 identical parameter logistic model and measure relevant kinetic parameter.In this test, the definition for variable and parameter is similar, and except x represents the concentration of glucose, B is the speed (Vm) of saturated glucose, and C is the S of glucose
0.5(under the concentration of Vm/2 glucose) and D are Hill coefficient.The S of some compound in the present invention
0.5data are as shown in the table:
| Compound | S 0.5(mM) |
| Reference compound D-1 | 5.4 |
| Compound I-1 | 2.3 |
The determination of activity result of above-mentioned two tables shows, compound of the present invention is strong glucokinase activators, can be used for preparing the medicine for the treatment of diabetes B.10 -->
Claims (3)
1. there is the compound of formula I structure,
2. synthesize the method for the compound of formula I described in claim 1:
Compound II per, through n-BuLi process, obtains the lithium aryl III of its correspondence; III under the catalysis of boron trifluoride diethyl etherate with (R)-epichlorohydrin generation addition reaction, obtain compound IV; Compound V and acid anhydrides Ac
2o is obtained by reacting VIA, and VIA uses the process such as ammoniacal liquor or methylamine to obtain compound VI; Compound IV and VI react in alkaline environment, obtain VII; Compound VI I use is oxidizing obtains product I.
3. the application of formula I described in claim 1 in preparation treatment diabetes B medicine.
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| CN201710034115.6A CN106800532A (en) | 2015-02-12 | 2015-02-12 | A kind of glucokinase activators of nitrile group-containing quinoline structure and application thereof |
| CN201510079030.0A CN104557700A (en) | 2015-02-12 | 2015-02-12 | Glucokinase activating agent containing nitrile quinoline structure and application thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2015
- 2015-02-12 CN CN201510079030.0A patent/CN104557700A/en active Pending
- 2015-02-12 CN CN201710034115.6A patent/CN106800532A/en active Pending
Patent Citations (3)
| 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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Application publication date: 20150429 |