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CN103626826B - Containing the glycogen phosphorylase inhibitors cholic acid derivative of azo bond, its preparation method and medicinal use - Google Patents

Containing the glycogen phosphorylase inhibitors cholic acid derivative of azo bond, its preparation method and medicinal use Download PDF

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CN103626826B
CN103626826B CN201310454072.9A CN201310454072A CN103626826B CN 103626826 B CN103626826 B CN 103626826B CN 201310454072 A CN201310454072 A CN 201310454072A CN 103626826 B CN103626826 B CN 103626826B
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glycogen phosphorylase
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methylene dichloride
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CN103626826A (en
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张丽颖
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Chengde Medical University
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Abstract

The present invention relates to a class containing the glycogen phosphorylase inhibitors cholic acid derivative of azo bond, also relate to they preparation method and containing their drug regimen.Glycogen phosphorylase inhibitors cholic acid derivative containing azo bond is the Liver targeting prodrug of glycogen phosphorylase, the concentration of glycogen phosphorylase inhibitors in liver can be improved after oral compared with glycogen phosphorylase inhibitors, can be used as the preferred agents of hypoglycemic particularly hyperglycemia treatment.This compounds can be used for prevention and therapy diabetes and complication, hyperlipidemia, obesity, high hyperglycemic-glycogenolytic factor disease, insulin resistant, fasting hyperglycaemia, hypertension and complication, atherosclerosis, metabolism syndrome or tumour.

Description

Containing the glycogen phosphorylase inhibitors cholic acid derivative of azo bond, its preparation method and medicinal use
Technical field
The present invention relates to a class containing the glycogen phosphorylase inhibitors cholic acid derivative of azo bond, also relate to they preparation method and containing their drug regimen.Glycogen phosphorylase inhibitors cholic acid derivative containing azo bond is the Liver targeting prodrug of glycogen phosphorylase, the concentration of glycogen phosphorylase inhibitors in liver can be improved after oral compared with glycogen phosphorylase inhibitors, can be used as the preferred agents of hypoglycemic particularly hyperglycemia treatment.This compounds can be used for prevention and therapy diabetes and complication, hyperlipidemia, obesity, high hyperglycemic-glycogenolytic factor disease, insulin resistant, fasting hyperglycaemia, hypertension and complication, atherosclerosis, metabolism syndrome or tumour.
Background technology
Diabetes especially diabetes B are the Chronic Non-Communicable Diseasess of the third-largest serious threat human health after tumour, cardiovascular disorder.On January 9th, 2012, China's Healthy Education Center discloses and combined by mechanisms such as Chinese Disease Control and Prevention Centers " Chinese chronic disease monitoring and diabetes special topic adjust difference report " result display carried out in 2010, China 18 years old and above diabetic morbidity are 9.7%, within more than 60 years old, the elderly's morbidity is up to 19.6%, and about there is maturity-onset diabetes patient 9,700 ten thousand people in the whole world.World Health Organization's statistics of 2011 shows, the diabetic subject in the whole world has reached 3.66 hundred million people, and the overwhelming majority belongs to diabetes B, and annual 4600000 people die from diabetes.
The diabetes B cause of disease is complicated, is a kind of disease of multifactorial inheritance.The metabolic disturbance of most diabetes B can be divided into: 1. insulin resistant; 2. insulin secretion obstacle; 3. glycogen exports increases.In most of diabetes B, at least observe 3 kinds of pathophysiological changes: 1. basic glycogen output rate increases, and shows as the hyperglycemia of all diabetes B patients.2. insulin resistant is even more serious, wherein may exist inherited genetic factors in various degree and the day after tomorrow acquired factor such as: fat, do not get enough athletic exercise, old and feeble etc. impact.3. islet beta cell function goes down further, hypoinsulinism, finally causes islet function exhaustion.The antidiabetic medicine of current Clinical practice mainly comprises Regular Insulin and analogue, biguanides, sulfonylurea, thiazolidinediones and alpha-glucosidase inhibitor etc. [6].Above medicine mostly also exists offer limited effectiveness, causes hypoglycemia in treatment diabetes B disease, cannot the shortcoming such as Prevention and Curation complication, therefore little in the urgent need to exploitation good effect, side effect and the novel treatment diabetes medicament of complication can be prevented and treated.
Glycogen phosphorylase (Glycogen phosphorylase, GP) be the first step key enzyme of catalysis glycogenolysis metabolism, inorganic phosphate is utilized to make glycogenolysis for Cori ester (G-1-P), the latter directly can carry out glycolysis-in muscle, or the effect of the phosphoglucomutase through liver, is decomposed into glucose after changing G6P into again.Due to the key factor that glycogen phosphorylase is in Glycogen Metabolism, therefore, suppress likely to be used for the treatment of the disease relevant to glycogen excessive degradation to its pharmacological, as (Curr.Protein.Pept.Sci. such as diabetes, ischemia myocardial damage and tumours, 2002,3,561; Am.J.Physiol.Heart.Girc.Physiol., 2004,286, H1177).In addition, hypertension and relevant pathological change thereof such as atherosclerosis, hyperlipidaemia and hypercholesterolemia etc. are all relevant with the insulin level raised.Glycogen phosphorylase inhibitors effectively can reduce insulin level, therefore can be used for treating hypercholesterolemia, hyperinsulinemia, hyperlipidemia, atherosclerosis and myocardial ischemia.
In recent years, research and develop this field of novel glycogen phosphorylase inhibitors and be subject to extensive concern.Such as, U.S. Patent application No.6,297,269 and european patent application No.EP0832066 describe N-(indole-2-carbonyl) acid amides and the derivative thereof of the replacement as glycogen phosphorylase inhibitors, U.S. Patent application No.6,107,329 N-(indole-2-carbonyl) G-NH2 and the derivatives thereof describing the replacement as glycogen phosphorylase inhibitors, european patent application No.WO2006059163 describes the pyrrolopyridine-2-benzoic acid amides derivative as glycogen phosphorylase inhibitors.But there are three kinds of glycogen phosphorylase isozyme in tissue, be named as flesh type glycogen phosphorylase, BPG, liver type glycogen phosphorylase respectively according to organizing of its predominant expression, three has the homology of height.Flesh type glycogen phosphorylase is mainly present in muscle tissue, its function is Muscle contraction supplying energy, BPG is mainly expressed at the brain of grownup and heart, can provide the emergency service of glucose when anoxic or severe hypoglycemia, liver type glycogen phosphorylase is then by regulating the glucose of liver glycogen storage to affect whole body blood sugar.Because this enzyme three kinds of isozyme homologys are high, cause this target spot inhibitor of at present report generally to lack selectivity to liver glycogen phosphorylase enzyme, thus cause producing flesh toxic reaction to muscle tissue, clinical application is restricted.In order to reduce the flesh toxic reaction of glycogen phosphorylase inhibitors, improve its hypoglycemic activity, increase bioavailability, modification research is carried out to the glycogen phosphorylase inhibitors reported, find the alternative novel derivative acting on liver glycogen phosphorylase enzyme.
Cholic acids compound is endogenic liver cell specificity natural carrier as cholic acid and ursodesoxycholic acid, has that specificity is high, turn-over capacity is strong, a good and oral advantage such as effectively of bio-compatibility.In recent years, the research of people to the hepatic targeting drug taking cholic acid as carrier deepens continuously, the hepatic targeting drug having polypeptide, lipid lowerers, antiviral drug, antitumour drug, antidiabetic drug and nitrate esters medicine etc. to be combined with cholic acid of bibliographical information.Shown by cell and animal experiment study, after medicine and cholic acid coupling, the liver adding medicine in various degree absorbs, and reduces the toxic side effect of medicine.Some medicine such as cholic acid and nitric ether conjugates NCX-1000 have entered II phase clinical investigation phase (Cardiovasc.DrugRev., 2004,22,135).Kramer etc. utilize Chlorambucil as model drug and cholic acid coupling, have investigated liver target and the anti-tumor activity of conjugates.Chlorambucil is connected to 3 hydroxyls of cholic acid, obtains cholic acid-Chlorambucil conjugates.Result shows, former medicine only has faint effect to liver bile acid transporter, and the liver of corresponding cholic acid conjugates strongly inhibited taurocholate absorbs; illustrate there is stronger interaction (Eur.J.Chin.Invest. between conjugates and bile acid transporter; 1996,26,715).Visible, cholic acid conjugates has the transport features of cholic acid, and the liver that can increase medicine absorbs, and reaches target object.
Spacer groups in the middle of targeting vector and small-molecule drug is one of key component in targeted prodrug structure.Because most of targeting vector is not directly connected by chemical bond with small-molecule drug, or both direct chemical bonds formed that are connected are difficult to dissociate further, discharge small-molecule drug.So, need to introduce new group, spacer groups that Here it is between targeting vector and small-molecule drug.It needs to keep the stability of medicine in blood circulation to produce injury to avoid drug release normal tissue, and it is active that medicine must be made in target cell effectively to discharge generation.Suitable spacer groups should possess: chemistry can occur and dissociate, or discharges medicine under specific enzyme effect, can Drug controlled release speed and drug release position.Due to enriched azo reductase in human hepatocyte's microsome, be therefore the liver target prodrug of spacer with azo bond, can by the action specificity release medicine of azo reductase after prodrug arrives liver.Up to the present the target azo prodrug of bibliographical information is only based on the prodrug that 5-aminosalicylic acid is connected with azobenzene polymer.The polymeric prodrugs that azo bond on 5, the salicylate sodium such as Brown is connected with polymkeric substance, finds that this prodrug can alleviate the inflammation (J.Med.Chem., 1983,26,300) of mouse and pig ulcer colonitis preferably.
Summary of the invention
The present invention makes public for the first time the glycogen phosphorylase inhibitors cholic acid derivative containing azo bond with pharmaceutical use, its preparation method and the medicinal use shown in formula (I), is included in the purposes preparing anti-diabetic and complication medicine, blood lipid-lowering medicine, slimming medicine, Antiatherosclerosis medicine, treatment Metabolic syndrome disease drug and antitumor drug aspect.Especially the compound shown in formula (I) is the Liver targeting prodrug of glycogen phosphorylase inhibitors, therefore may be used for treating relevant disease abnormal to Glycogen Metabolism in liver, these diseases comprise: diabetes and complication, hyperlipidemia, obesity, high hyperglycemic-glycogenolytic factor disease, insulin resistant, fasting hyperglycaemia, hypertension and complication, atherosclerosis, metabolism syndrome or tumour.In addition, the present invention also provides a kind of pharmaceutical preparation containing compound shown in formula (I).
The present invention relates to the compound shown in formula (I) and pharmacy acceptable salt thereof or ester:
Wherein:
X 1, X 2, X 3and X 4complete is C or X 1, X 2, X 3and X 4one of for N and other be necessary for C;
R 1and R 1' independently represent H, halogen, hydroxyl, cyano group, C separately 0-4alkyl, C 1-4alkoxyl group, fluoromethyl, difluoromethyl, trifluoromethyl, vinyl, ethynyl;
R 2, R 3, R 4and R 5independently represent H, hydroxyl, R separately 6cOO;
R 6represent the straight or branched alkyl of the non-substituted of 1 ~ 20 carbon or X replacement, alkylene, alkynes base, aryl and heteroaryl;
X represents H, F, Cl, Br, I, CN, NO 2, NH 2, CF 3, SH, OH, OCH 3, OC 2h 5, COOH, the straight or branched alkyl of 1 ~ 10 carbon, alkylene, alkynes base, aryl, heteroaryl;
In above-claimed cpd, preferred compound is:
X 1, X 2, X 3and X 4complete is C or X 1, X 2, X 3and X 4one of for N and other be necessary for C;
R 1and R 1' be independently H, halogen, cyano group separately;
R 4, R 5, R 6and R 7respective is independently H, hydroxyl;
X represents H, F, Cl, Br, I, CN, NO 2, NH 2, CF 3, SH, OH, OCH 3, OC 2h 5, COOH, the straight or branched alkyl of 1 ~ 10 carbon, alkylene, alkynes base, aryl, heteroaryl
More preferred compound is:
Compound of the present invention can adopt the processing method preparation reported, following method also can be adopted to prepare:
A) glycogen phosphorylase inhibitors containing exposed hydroxyl will prepared, dissolve in organic solvent with (the E)-3-prepared (2-((4-(tertbutyloxycarbonyl) phenyl) azido-) phenyl) propionic acid, add coupling reagent and carry out into ester reaction, reaction 1-72 hour, temperature is 0 DEG C to 45 DEG C.Coupling reagent can adopt conventional condensation reagent, as 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI), N, N '-dicyclohexylcarbodiimide (DCC), O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid (TBTU), 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU), 1-propyl group tricresyl phosphate cyclic acid anhydride (T 3p).The suitable selecting catalyst of situation can be carried out, as DMAP by visual response;
B) dissolved in organic solvent by a product, add trifluoroacetic acid deprotecting regent and slough tertbutyloxycarbonyl protecting group, temperature is 0 DEG C of extremely backflow.The solvent adopted can be the mixed solvent of acetonitrile, methyl alcohol, tetrahydrofuran (THF), methylene dichloride, 1,2-ethylene dichloride, chloroform, toluene, normal hexane, hexanaphthene, t-butyl methyl ether or above-mentioned solvent, and preferential acetonitrile or the methylene dichloride of adopting is as solvent;
C) by cholic acid free for carboxyl terminal and derivative thereof, quadrol protect with tertbutyloxycarbonyl dissolves in organic solvent, and add coupling reagent and organic amine or mineral alkali, react 1-72 hour, temperature is 0 DEG C to 45 DEG C.Solvent generally selects inert solvent, particularly non-protonic solvent, comprise acetonitrile, chloroform, methylene dichloride, 1,2-ethylene dichloride, N, the mixed solvent of dinethylformamide, toluene, normal hexane, hexanaphthene, tetrahydrofuran (THF), t-butyl methyl ether or above-mentioned solvent, preferential employing methylene dichloride, 1,2-ethylene dichloride or DMF.Coupling reagent can adopt conventional condensation reagent, as 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI), N, N '-dicyclohexylcarbodiimide (DCC), O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid (TBTU), 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester and 1-hydroxy benzo triazole (HATU), 1-propyl group tricresyl phosphate cyclic acid anhydride (T 3p), diethylpyrocarbonate (DEPC).The mineral alkali adopted is sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus, and the organic bases adopted is N, N-2 wopropyl ethyl amine or triethylamine;
D) dissolved in organic solvent by c product, add trifluoroacetic acid deprotecting regent and slough tertbutyloxycarbonyl protecting group, temperature is 0 DEG C of extremely backflow.The solvent adopted can be the mixed solvent of acetonitrile, methyl alcohol, tetrahydrofuran (THF), methylene dichloride, 1,2-ethylene dichloride, chloroform, toluene, normal hexane, hexanaphthene, t-butyl methyl ether or above-mentioned solvent, and preferential acetonitrile or the methylene dichloride of adopting is as solvent;
E) by b product, dissolve in organic solvent with d product, add coupling reagent and organic amine or mineral alkali, reaction 1-72 hour, temperature is 0 DEG C to 45 DEG C.Solvent generally selects inert solvent, particularly non-protonic solvent, comprise acetonitrile, chloroform, methylene dichloride, 1,2-ethylene dichloride, N, the mixed solvent of dinethylformamide, toluene, normal hexane, hexanaphthene, tetrahydrofuran (THF), t-butyl methyl ether or above-mentioned solvent, preferential employing methylene dichloride, 1,2-ethylene dichloride or DMF.Coupling reagent can adopt conventional condensation reagent, as 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI), N, N ' dicyclohexylcarbodiimide (DCC), O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid (TBTU), 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester and 1-hydroxy benzo triazole (HATU), 1-propyl group tricresyl phosphate cyclic acid anhydride (T 3p), diethylpyrocarbonate (DEPC).The mineral alkali adopted is sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus, and the organic bases adopted is DIPEA or triethylamine.
The present invention also comprises pharmaceutical preparation, and said preparation comprises as general formula (I) compound or pharmaceutically acceptable salt thereof of promoting agent, ester or pharmaceutically acceptable carrier.
Above-mentioned pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, refer to one or more inertia, atoxic solid or liquid filler material, thinner, auxiliary agents etc., they are not reverse has an effect with active compound or patient.
The formulation of the present composition can be formulation conventional in the pharmaceuticies such as tablet, capsule, pill, suppository, soft capsule, oral liquid, suspensoid, injection liquid.
Tablet for oral use and capsule contain traditional vehicle as weighting material, thinner, lubricant, dispersion agent and tackiness agent.
The various formulations of pharmaceutical composition of the present invention can be prepared according to the method known in pharmaceutical field.
The dosage of above promoting agent will be different because of formula.
Usually, proved favourable amount, for reaching results needed, the total amount of formula (1) compound of every kilogram of administration in every 24 hours is about 0.01-800mg, and preferred total amount is 0.1-100mg/kg.If necessary, with the form administration of single dose several times.But if necessary, also can depart from above-mentioned consumption, namely this depends on the type of experimenter to be treated and body weight, the individual type to the behavior of medicine, the character of disease and seriousness, preparation and administration and administration time and interval.
Accompanying drawing explanation
Fig. 1 is the preparation process representing partial derivatives of the present invention.
In FIG, X 1, X 2, X 3, X 4, R 1, R 1', R 2, R 3, R 4, R 5, R 6, R 7, R 8with the definition of X as in above-mentioned formula (I) define, R 9represent various amino acid whose N and hold protecting group, as tertbutyloxycarbonyl (Boc) or fluorenylmethyloxycarbonyl (Fmoc).
Embodiment:
Content of the present invention is illustrated below by embodiment.In the present invention, the example of the following stated is to better set forth the present invention, is not for limiting the scope of the invention.
Further illustrate enforcement of the present invention by the following examples
Embodiment 1
(S)-2-t-butoxycarbonyl amino-3-(4-fluorophenyl)-1-(4-hydroxy piperidine-1-base) acetone
By fluoro-for BOC-4-L-Phe (15.6g, 55.1mmol) be dissolved in anhydrous methylene chloride (160mL), HATU (25g is added under ice bath, 66.1mmol) with DIPEA (8.54g, 66.1mmol), stirring at room temperature 10 minutes, then add 4-hydroxy piperidine (6.7g, 66.1mmol), stirred overnight at room temperature.Reaction solution is washed with saturated common salt, anhydrous Na 2sO 4drying, filters, and concentrated, residue is separated through reversed-phase HPLC, obtains white solid (50mg, 29.8%).Rapid column chromatography (petrol ether/ethyl acetate 1/1, V/V), obtains white solid (19.7g, 98%).
ESI-MS m／z：367.2[M+H] +.
1H NMR(CDCl 3，400MHz)：7.14-7.18(m，2H)，6.95-7.00(m，2H)，5.47(dd，J=8.8，14.8Hz，1H)，4.83(dd，J=6.0，13.6Hz，1H)，3.81-4.01(m，2H)，3.46-3.62(m，1H)，3.15-3.33(m，1H)，2.89-3.00(m，2H)，1.73-1.83(m，2H)，1.42-1.52(m，2H)，1.40(s，9H).
(S)-2-amino-3-(4-fluorophenyl)-1-(4-hydroxy piperidine-1-base) acetone
By (S)-2-t-butoxycarbonyl amino-3-(4-fluorophenyl)-1-(4-hydroxy piperidine-1-base) acetone (19g, 52mmol) be dissolved in methylene dichloride (50mL), under ice bath, dichloromethane solution (the 2N of the hydrogenchloride of the fresh preparation of slow dropping, 50mL), stirred overnight at room temperature.Next day, reaction solution concentrating under reduced pressure obtains white solid (14g, 89%).
ESI-MS m／z：267.2[M+H] +.
1H NMR(MeOD，400MHz)：8.52(br s，1H)，7.29(dd，J=7.2，13.6Hz，2H)，7.09-7.14(m，2H)，4.63(br s，1H)，3.86-4.06(m，1H)，3.73-3.83(m，1H)，3.35-3.62(m，1H)，2.78-3.21(m，4H)，0.92-1.85(m，4H).
(S)-1-[2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-4-hydroxy piperidine
By the similar approach of preparation (S)-2-t-butoxycarbonyl amino-3-(4-fluorophenyl)-1-(4-hydroxy piperidine-1-base) acetone, by (S)-2-amino-3-(4-fluorophenyl)-1-(4-hydroxy piperidine-1-base) acetone (14g, 46.4mmol) with the chloro-1-hydrogen-pyrroles [2 of 5-, 3-c] and pyridine-2-carboxylic acids (9.08g, 46.4mmol) reaction, obtain white solid (14.2g, 99%).
ESI-MS m／z：444.9[M+H] +.
1H NMR(DMSO-d 6，400MHz)：12.27(s，1H)，9.22(t，J=8.8Hz，1H)，8.57(s，1H)，7.77(s，1H)，7.36(d，J=9.6，3H)，7.06(d，J=3.6，1H)，5.16(d，J=6.4，1H)，4.75(s，1H)，3.67-4.04(m，3H)，2.91-3.30(m，4H)，1.57-1.67(m，2H)，1.13-1.24(m，2H).
(E)-3-{2-[(4-tertbutyloxycarbonyl phenyl) azido-] phenyl } propionic acid
By (E)-3-(nitrophenyl) vinylformic acid (10.0g, 52.0mmol) water-soluble (500mL), add NaOH (4.1g, 39mmol) and 10%Pd/C (0.5g), room temperature normal pressure hydrogenation spends the night.Reactant is crossed and is filtered Pd/C, obtains white powdered solid crude product (7.5g, 87%) after pressure reducing and steaming solvent.In the mixed solvent of this crude product water-soluble (200mL) and methylene dichloride (300mL), add ammonium persulfate-sodium bisulfate (Oxone, 55.3g, 90.0mmol), stirring at room temperature 2 hours.Methylene dichloride organic phase is collected in extraction, and aqueous phase extracts repeatedly with methylene dichloride, merges organic phase, boils off solvent, obtain tangerine look solid crude product (7.5g, 92.5%) after anhydrous sodium sulfate drying.This crude product is dissolved in AcOH (75.0mL), adds the PABA tert-butyl ester (8.1g, 42.0mmol), and 80 DEG C are stirred 16 hours.Remove solvent under reduced pressure, residue obtains tangerine look solid (3.5g, 25%) through rapid column chromatography (petrol ether/ethyl acetate: 10/1, V/V).
ESI-MS m／z：355.2[M+H] +.
1H NMR:(CDCl 3, 400MHz) and 8.15 (d, J=8.4Hz; 2H); 7.93 (d, J=8.4Hz, 2H); 7.72 (d; J=7.6Hz, 1H), 7.40.7.47 (m; 2H); 7.32-7.37 (m, 1H), 3.49 (t; J=7.6Hz; 2H), 2.79 (t, J=8.0Hz; 2H). (E)-3-{2-[(4-tertbutyloxycarbonyl phenyl) azido-] phenyl } propionic acid-{ 1-[2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-piperidin-4-yl } ester
By (E)-3-{2-[(4-tertbutyloxycarbonyl phenyl) azido-] phenyl } propionic acid (240.0mg; 0.68mmol); DMAP (the 8.3mg of catalytic amount; 0.068mmol) be dissolved in methylene dichloride (8.0mL); DCC (153.4mg is added under ice bath; 0.75mmol); half an hour is stirred under ice bath; add (S)-1-[2-(chloro-1H-pyrrolo-[2 of 5-again; 3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-4-hydroxy piperidine (300mg; 0.68mmol), stirred overnight at room temperature.Reaction mixture filters, and filtrate boils off solvent, and residue with ethyl acetate dissolves, put refrigerator overnight, filter, filtrate boils off solvent, residue rapid column chromatography (petrol ether/ethyl acetate: 10/1, V/V) obtains tangerine look solid (440.0mg, 82%).
ESI-MS m／z：781.2[M+H] +.
1H NMR：(MeOD，400MHz)8.49(d，J=9.6Hz，1H)，8.07(dd，J=8.8，20.4Hz，2H)，7.88(dd，J=8.8，20.8Hz，2H)，7.63(dd，J=7.6，28.0Hz，1H)，7.58(d，J=8.0Hz，1H)，7.22-7.46(m，5H)，7.07(d，J=5.6Hz，1H)，6.92-7.00(m，2H)，5.23(dd，J=7.2，11.6Hz，1H)，4.76-4.85(m，1H)，3.37-3.50(m，5H)，2.98-3.22(m，3H)，2.64-2.71(m，2H)，1.82-1.86(m，2H)，1.63-1.72(m，2H)，1.58(d，J=9.6Hz，9H).
(E)-3-{2-[(4-benzoyl) azido-] phenyl } propionic acid-1-[2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-piperidin-4-yl] ester
By (E)-3-{2-[(4-tertbutyloxycarbonyl phenyl) azido-] phenyl } propionic acid-{ 1-[2-(chloro-1H-pyrrolo-of 5-[2; 3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-piperidin-4-yl } ester (650.0mg; 0.83mmol) be dissolved in methylene dichloride (10mL); trifluoracetic acid (10mL is dripped under ice bath; 140mmol), drip complete this temperature that maintains and stir 2 hours.Remove reaction solution under reduced pressure, residue is dissolved in ethyl acetate, successively with saturated sodium bicarbonate solution and saturated common salt water washing, and anhydrous Na 2sO 4dry.Cross and filter siccative, concentrated, obtain tangerine look solid crude product, this crude product can be directly used in next step reaction without the need to purifying.
ESI-MS m／z：725.1[M+H] +.
1h NMR:(CDCl 3, 400MHz) and 8.62 (s, 1H), 8.22 (d, J=13.6Hz, 1H), 8.20 (d, J=14.0Hz, 1H), 7.99 (d, J=20.0Hz, 1H), 7.96 (d, J=20.0Hz, 1H), 7.75 (d, J=2.4Hz, 1H), 7.70 (dd, J=8.0, 30.0Hz, 1H), 7.27-7.53 (m, 5H), 7.10 (s, 1H), 6.97-7.04 (m, 2H), 5.27 (t, J=7.2Hz, 1H), 4.79-4.85 (m, 1H), .41-3.70 (m, 5H), 3.04-3.27 (m, 3H), 2.69-2.79 (m, 2H), 1.85-1.89 (m, 2H), 1.69-1.79 (m, 2H) .N-(3 α, 7 α, 12 α-trihydroxy--5 β-cholane acid amides)-N '-tertbutyloxycarbonyl quadrol
Cholic acid (2.0g, 4.9mmol) is dissolved in dry DMF (20.0mL), slowly adds N-Boc-quadrol (784.3mg, 4.9mmol), diethylpyrocarbonate (DEPC, 879.0mg, 5.4mmol) and triethylamine (Et 3n, 2.5g, 5.0mmol), finish, stirring at room temperature 24 hours.Reaction mixture filters, and filtrate boils off solvent, and residue rapid column chromatography (ethyl acetate/tetrahydrofuran (THF): 10/1, V/V) obtains white solid (2.0g, 73%).
ESI-MS m／z：451.2[M+H] +.
1H NMR：(DMSO-d 6，400MHz)7.73(t，J=5.2Hz，1H)，6.73(t，J=5.6Hz，1H)，4.28(br s，1H)，4.06(s，1H)，3.96-3.99(m，1H)，3.74(s，1H)，3.56(s，1H)，3.11-3.17(m，1H)，2.97-3.00(m，2H)，2.89-2.92(m，2H)，1.33(s，9H)，0.87(d，J=6.4Hz，3H)，0.76(s，3H)，0.54(s，3H).
N-(3 α, 7 α, 12 α-trihydroxy--5 β-cholane acid amides)-quadrol
By N-(3 α, 7 α, 12 α-trihydroxy--5 β-cholane acid amides)-N '-tertbutyloxycarbonyl quadrol (200.0mg, 0.36mmol) be dissolved in methyl alcohol (20mL), under ice bath, the methanol solution (2N, 20mL) of the hydrogenchloride of the fresh preparation of slow dropping, stirring at room temperature 2 hours.Next day, by reacting liquid filtering, filter cake is with washed with dichloromethane, and vacuum-drying obtains faint yellow solid (170mg, 97%).
ESI-MS m／z：473.3[M+Na] +.
1H NMR：(DMSO-d 6，400MHz)8.01-8.14(m，4H)，3.74(brs，4H)，3.56(brs，1H)，3.24(dd，J=6.0，11.6Hz，2H)，3.14-3.18(m，1H)，2.78(dd，J=5.6，11.2Hz，2H)，0.88(d，J=6.0Hz，2H)，0.76(s，3H)，0.54(s，3H).
(E)-3-[2-({ 4-[N-(3 α; 7 α; 12 α-trihydroxy--5 β-cholane acid amides)-quadrol base] benzoyl } azido-) phenyl] propionic acid-{ 1-[2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-piperidin-4-yl } ester
By (E)-3-{2-[(4-benzoyl) azido-] phenyl } propionic acid-{ 1-[2-(chloro-1H-pyrrolo-of 5-[2, 3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-piperidin-4-yl } ester (150mg, 0.207mmol) be dissolved in DMF (3mL), HATU (94mg is added under ice bath, 0.248mmol) with DIPEA (0.1mL, 0.621mmol), stirring at room temperature 10 minutes, add N-(3 α again, 7 α, 12 α-trihydroxy--5 β-cholane acid amides)-quadrol (120mg, 0.266mmol), stirred overnight at room temperature.Remove solvent under reduced pressure, residue is dissolved in ethyl acetate, and organic phase is washed with saturated common salt, anhydrous Na 2sO 4drying, filters, and concentrated, residue is separated through reversed-phase HPLC, obtains white solid (25mg, 10.4%).
ESI-MS m／z：1157.6[M+H] +.
1H NMR：(MeOD，400MHz)8.56(d，J=8.0Hz，1H)，7.92-8.05(m，4H)，7.65-7.74(m，2H)，7.26-7.49(m，5H)，7.15(d，J=6.0Hz，1H)，6.95-7.04(m，2H)，5.24-5.31(m，1H)，4.80-4.86(m，1H)，4.63(brs，1H)，3.86(brs，1H)，3.63-3.71(m，2H)，3.35-3.56(m，9H)，2.98-3.20(m，2H)，268-2.75(m，2H)，0.97(t，J=5.2Hz，3H)，0.83(d，J=5.6Hz，3H)，0.54(d，J=12.4Hz，3H).
External glycogen phosphorylase inhibitory activity test:
The preparation of reagent: the 1) preparation of nitrite ion: weigh ammonium molybdate 5g, be dissolved in 500ml1M HCl, stirs with agitator, is adding Victoria Green WPB 190mg, continue to be stirred to whole dissolving, and use masking foil lucifuge after all dissolving; 2) preparation of damping fluid: 1. precision weighing Hepes0.5958g, is dissolved in 5ml H 2in O, adjust PH to 7.2 with 10M NaOH, be mixed with the Hepes that final concentration is 0.5M; 2. precision weighing KCl0.3728g, is dissolved in 5ml H 2in O, be mixed with the KCl that final concentration is 1M; 3. precision weighing MgCl 20.0255g, is dissolved in 1ml H 2in O, be mixed with the MgCl that final concentration is 125mM 2; 4. precision weighing EGTA0.0476g, is dissolved in 5ml H 2in O, adjust PH to 7.0 with 10M NaOH, be mixed with the EGTA that final concentration is 25mM; 5. precision weighing G-1-P0.0152g, is dissolved in 10ml H 2in O, be mixed with the G-1-P that final concentration is 5mM; 6. precision weighing glycogen10mg, is dissolved in 1ml H 2in O, be mixed with the glycogen that final concentration is 10mg/ml; 3) preparation of positive drug caffeine solution: caffeine is dissolved in 10ml H 2the solution of O preparation 0.5,5,50 and 500 μM; 4) GPa solution is prepared: the GPa getting 1 μ l joins in 100 μ l reaction systems, and final concentration is 250ng/100 μ l; 5) preparation of compound solution to be tested: compound to be tested being dissolved in DMSO, to be mixed with concentration be 10mM solution, gets appropriate compound solution and joins in reaction system to different final concentration.
Measure the amount effect curve of rabbit muscle glycogen phosphorylase activities: add the OD value under 655nm after nitrite ion by the GPa reading different concns, measure its amount effect curve.The amount of GPa can be selected to be 250ng by amount effect curve.
Experimental procedure: 1) design PC (positive control), Blank (blank), positive drug (caffeine); 2) reaction buffer52 μ l is added; 3) test compounds is added to final concentration; 4) enzyme-added 1 μ l, final concentration is 250ng/100 μ l; 5) nitrite ion 150 μ l is added; 6) react 20 minutes under 30 degrees celsius; 7) colorimetric under wavelength 655nm condition; 8) reading of data and the calculating of inhibiting rate: inhibiting rate=[positive control-testing sample]/[positive control-blank].
Test result: list the inhibit activities data of glycogen phosphorylase Liver targeting prodrugs to rabbit muscle glycogen Starch phosphorylase in table, result shows, and such glycogen phosphorylase Liver targeting prodrugs has inhibit activities in various degree to glycogen phosphorylase.
Glycogen phosphorylase Liver targeting prodrugs is to the inhibit activities of rabbit muscle glycogen Starch phosphorylase
aiC 50value is the mean value of three experiments;
bnI represents do not have activity under 100 μMs of concentration.
Above pharmacology data display, general formula of the present invention (I) compound has the restraining effect of potential glycogen phosphorylase, therefore can be used for prevention and therapy diabetes and complication, hyperlipidemia, obesity, high hyperglycemic-glycogenolytic factor disease, insulin resistant, fasting hyperglycaemia, hypertension and complication, atherosclerosis, metabolism syndrome or tumour.

Claims (12)

1. the compound be shown below or its pharmacy acceptable salt or ester:
Wherein:
X 1, X 2, X 3and X 4complete is C or X 1, X 2, X 3and X 4one of for N and other be necessary for C;
R 1and R 1' independently represent H, halogen, hydroxyl, cyano group, C separately 4alkyl, C 1-4alkoxyl group, fluoromethyl, difluoromethyl, trifluoromethyl, vinyl, ethynyl;
R 2, R 3, R 4and R 5independently represent H, hydroxyl, R separately 6cOO;
R 6represent the straight or branched alkyl of the non-substituted of 1 ~ 20 carbon or X replacement, alkylene, alkynes base, aryl and heteroaryl;
X represents H, F, Cl, Br, I, CN, NO 2, NH 2, CF 3, SH, OH, OCH 3, OC 2h 5, COOH, the straight or branched alkyl of 1 ~ 10 carbon, alkylene, alkynes base, aryl, heteroaryl.
2. compound as claimed in claim 1 or its pharmacy acceptable salt or ester, is characterized in that:
X 1, X 2, X 3and X 4complete is C or X 1, X 2, X 3and X 4one of for N and other be necessary for C;
R 1and R 1' be independently H, halogen, hydroxyl, cyano group separately;
R 2, R 3, R 4and R 5respective is independently H, hydroxyl.
3. compound as claimed in claim 1 or its pharmacy acceptable salt or ester, wherein, compound is following arbitrary compound or its pharmacy acceptable salt or ester:
4. the preparation method of the compound according to any one of claim 1-3, comprises the steps:
A) glycogen phosphorylase inhibitors containing exposed hydroxyl will prepared, dissolve in organic solvent with (the E)-3-prepared (2-((4-(tertbutyloxycarbonyl) phenyl) azido-) phenyl) propionic acid, add coupling reagent and carry out into ester reaction, reaction 1-72 hour, temperature is 0 DEG C to 45 DEG C; Coupling reagent adopts 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride, N, N '-dicyclohexylcarbodiimide, O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid, 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester or 1-propyl group tricresyl phosphate cyclic acid anhydride;
B) dissolved in organic solvent by step product a), add trifluoroacetic acid deprotecting regent and slough tertbutyloxycarbonyl protecting group, temperature is 0 DEG C of extremely backflow; The solvent adopted is the mixed solvent of acetonitrile, methyl alcohol, tetrahydrofuran (THF), methylene dichloride, 1,2-ethylene dichloride, chloroform, toluene, normal hexane, hexanaphthene, t-butyl methyl ether or above-mentioned solvent;
C) by cholic acid or derivatives thereof free for carboxyl terminal, quadrol protect with tertbutyloxycarbonyl dissolves in organic solvent, and add coupling reagent and organic amine or mineral alkali, react 1-72 hour, temperature is 0 DEG C to 45 DEG C; Solvent is the mixed solvent of acetonitrile, chloroform, methylene dichloride, 1,2-ethylene dichloride, DMF, toluene, normal hexane, hexanaphthene, tetrahydrofuran (THF), t-butyl methyl ether or above-mentioned solvent; Coupling reagent adopts 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride, N, N '-dicyclohexylcarbodiimide, O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid, 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester, 1-propyl group tricresyl phosphate cyclic acid anhydride or diethylpyrocarbonate; The mineral alkali adopted is sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus, and the organic amine adopted is DIPEA or triethylamine;
D) by step c) product dissolve in organic solvent, add trifluoroacetic acid deprotecting regent and slough tertbutyloxycarbonyl protecting group, temperature be 0 DEG C to backflow; The solvent adopted is the mixed solvent of acetonitrile, methyl alcohol, tetrahydrofuran (THF), methylene dichloride, 1,2-ethylene dichloride, chloroform, toluene, normal hexane, hexanaphthene, t-butyl methyl ether or above-mentioned solvent;
E) by step b) product, with steps d) product dissolve in organic solvent, add coupling reagent and organic amine or mineral alkali, reaction 1-72 hour, temperature is 0 DEG C to 45 DEG C; Solvent is the mixed solvent of acetonitrile, chloroform, methylene dichloride, 1,2-ethylene dichloride, DMF, toluene, normal hexane, hexanaphthene, tetrahydrofuran (THF), t-butyl methyl ether or above-mentioned solvent; Coupling reagent adopts 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride, N, N '-dicyclohexylcarbodiimide, O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid, 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester, 1-propyl group tricresyl phosphate cyclic acid anhydride or diethylpyrocarbonate; The mineral alkali adopted is sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus, and the organic amine adopted is DIPEA or triethylamine.
5. method as claimed in claim 4, wherein, step a) in add catalyzer DMAP.
6. method as claimed in claim 4, wherein, step b) in the solvent that adopts be acetonitrile or methylene dichloride.
7. method as claimed in claim 4, wherein, step c) in solvent be methylene dichloride, 1,2-ethylene dichloride or DMF.
8. method as claimed in claim 4, wherein, steps d) in the solvent that adopts be acetonitrile or methylene dichloride.
9. method as claimed in claim 4, wherein, step e) in solvent be methylene dichloride, 1,2-ethylene dichloride or DMF.
10. a pharmaceutical composition, wherein containing the treatment compound according to any one of claim 1-3 of significant quantity or its pharmacy acceptable salt or ester, and pharmaceutically acceptable carrier.
The purposes of 11. compounds according to any one of claim 1-3 in the medicine for the preparation of prevention or treatment diabetes or its complication, hyperlipidemia, obesity, high hyperglycemic-glycogenolytic factor disease, insulin resistant, fasting hyperglycaemia, hypertension or its complication, atherosclerosis, metabolism syndrome or tumour.
12. purposes as claimed in claim 11, it is characterized in that: described diabetes are diabetes Bs, its complication comprises: diabetic nephropathy, diabetic foot, diabetic neuropathy or diabetes complicated cardiovascular and cerebrovascular diseases.
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