CN103626837A - Glycogen phosphorylase inhibitor cholic acid derivative containing bio-cleavable dipeptide and preparation method and medical application thereof - Google Patents

Glycogen phosphorylase inhibitor cholic acid derivative containing bio-cleavable dipeptide and preparation method and medical application thereof Download PDF

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CN103626837A
CN103626837A CN201310454058.9A CN201310454058A CN103626837A CN 103626837 A CN103626837 A CN 103626837A CN 201310454058 A CN201310454058 A CN 201310454058A CN 103626837 A CN103626837 A CN 103626837A
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glycogen phosphorylase
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cholic acid
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CN103626837B (en
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张丽颖
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Chengde Medical University
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Abstract

The invention relates to a glycogen phosphorylase inhibitor cholic acid derivative containing bio-cleavable dipeptide, a preparation method thereof and a pharmaceutical composition containing the same. The glycogen phosphorylase inhibitor cholic acid derivative is a liver-targeted pro-drug for glycogen phosphorylase; compared with a glycogen phosphorylase inhibitor, the concentration of the glycogen phosphorylase inhibitor in a liver can be increased after the glycogen phosphorylase inhibitor cholic acid derivative is taken orally, so that the glycogen phosphorylase inhibitor cholic acid derivative can serve as a preferred drug for lowering blood sugar, particularly for treating impaired fasting glucose. The compound can be used for preventing and treating diabetes and complications thereof, hyperlipidemia, obesity, high-glucagon disease, insulin resistance, impaired fasting glucose, hypertension and complications thereof, atherosclerosis, metabolic syndrome or tumor.

Description

Glycogen phosphorylase inhibitors cholic acid analog derivative, its preparation method and medicinal use containing biological cleavable dipeptides
Technical field
The present invention relates to a class containing the glycogen phosphorylase inhibitors cholic acid analog derivative of biological cleavable dipeptides, the drug regimen that also relates to their preparation method and contain them.Glycogen phosphorylase inhibitors cholic acid analog derivative is the liver Target prodrug of glycogen phosphorylase, compare with glycogen phosphorylase inhibitors after oral and can improve the concentration of glycogen phosphorylase inhibitors in liver, can be used as the preferred agents of hypoglycemic particularly hyperglycemia treatment.This compounds can be used for prevention and treatment diabetes and complication, hyperlipidemia, obesity, high hyperglycemic-glycogenolytic factor disease, insulin resistant, fasting hyperglycemia, hypertension and complication, atherosclerosis, metabolism syndrome or tumour.
Background technology
Diabetes B is one group of take on an empty stomach and metabolic disturbance syndrome that postprandial hyperglycemia is principal character of jointly being caused by hereditary defect and acquired environment factor.Lasting hyperglycemia can cause the generation of the complication such as blood vessel, kidney, neural system and retina, therefore, keeps glucose level normally very important.Clinical study shows, the remarkable increase of diabetic subject's glucose that liver is exported is one of major reason causing hyperglycemia.With 3studies show that of H labelled glucose, healthy individual is under base state, and the speed of glucose that liver is exported is 1.8-2.0mgkg -1min -1; And with the diabetes B patient of moderate hyperglycemia, the speed of its liver output glucose approximately increases 0.5mgkg -1min -1, be significantly higher than normal people.
The generation of liver glucose is mainly derived from two aspects: 1) glyconeogenesis; 2) enzymatic degradation of glycogen.Research shows, glyconeogenesis and glycogen degraded generate and have equal contribution diabetic subject's liver sugar.It should be noted that N1,N1-Dimethylbiguanide is as one of first-selected clinically antidiabetic drug, it is mainly to reduce blood sugar by suppressing liver glyconeogenesis that its mechanism of action is considered to.And on the other hand, there is no clinically the medicine of effective inhibition liver glycogen excessive degradation at present.
On an empty stomach, in situation, liver starch generates Cori ester through the effect of glycogen phosphorylase, then changes G-6-P under phosphoglucomutase catalysis, last dephosphorylation under the effect of glucose-6-phosphatase and export glycogen.Or directly enter anaerobic metabolism and aerobic metabolism approach to participate in energy supply.Because glycogen phosphorylase is a key factor in Glycogen Metabolism, therefore, its pharmacological is suppressed to be likely used for the treatment of the disease relevant to glycogen excessive degradation, 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 such as atherosclerosis, hyperlipidaemia and hypercholesterolemia etc. thereof are all relevant with the insulin level raising.Glycogen phosphorylase inhibitors can effectively 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.For example, U.S. Patent application No.6,297,269 and european patent application No.EP0832066 recorded N-(indole-2-carbonyl) acid amides and the derivative thereof as the replacement of glycogen phosphorylase inhibitors, U.S. Patent application No.6,107,329 have recorded N-(indole-2-carbonyl) G-NH2 and the derivative thereof as the replacement of glycogen phosphorylase inhibitors, and european patent application No.WO2006059163 has recorded the pyrrolopyridine-2-benzoic acid amides derivative as glycogen phosphorylase inhibitors.But, in tissue, there are three kinds of glycogen phosphorylase isozyme, according to organizing of its predominant expression, be named as respectively flesh type glycogen phosphorylase, BPG, liver type glycogen phosphorylase, three has the homology of height.Flesh type glycogen phosphorylase is mainly present in muscle tissue, its function is to be Muscle contraction supplying energy, BPG is mainly expressed at grownup's brain and heart, the emergency service of glucose can be provided when anoxic or severe hypoglycemia, and liver type glycogen phosphorylase affects whole body blood sugar by the glucose that regulates liver glycogen to store.Because three kinds of isozyme homologys of this enzyme are high, cause this target spot inhibitor of report at present generally to lack the selectivity to liver glycogen phosphorylase enzyme, thereby cause muscle tissue to produce flesh toxic reaction, clinical application is restricted.In order to reduce the flesh toxic reaction of glycogen phosphorylase inhibitors, improve its hypoglycemic activity, increase bioavailability, the glycogen phosphorylase inhibitors of having reported is modified to research, find the alternative novel derivative that acts on liver glycogen phosphorylase enzyme.
Cholic acid is current unique oral hepatic targeting drug carrier, and it has special movement system in vivo.Cholic acid can be by the absorption of liver specificity, and this absorption is by the Na on liver plasma membrane +dependency movement system (NTCP) and Na +dependent/non-dependent movement system (OTAP) realizes.Cholic acid is the specific natural aglucon of endogenic liver cell, has the organ specificity of height.Cholic acid by Biosynthesis of cholesterol, is then combined with glycine or taurine in liver cell, enters small intestine, then be absorbed into liver with bile, constantly carries out liver sausage and circulates into liver sausage circulation in human body.Repeat 6-15 every day, and the cholic acid total amount that participates in circulation reaches 17-40 gram.Therefore there is higher turn-over capacity.As endogenic natural aglucon cholic acid, there is good bio-compatibility, be suitable for the carrier as targeted drug, take cholic acid as targeting vector, not only can realize the liver target of medicine, reduce toxic side effect, and can improve medicine bioavailability in vivo.
Spacer groups in the middle of targeting vector and small-molecule drug is being brought into play very important effect.Spacer groups makes low-molecule drug and targeting vector form stable or temporary transient combination, can in blood circulation, keep certain stability, under the effect of body fluid and enzyme, by hydrolysis, ion-exchange or enzymatic reaction, make under pharmaceutical group ruptures again, to there is certain stability and hydrolyzable and enzymolysis.Suitable spacer groups, can control speed and drug release position that medicine discharges from polymkeric substance.Peptide class spacer groups is Recent study a kind of spacer groups comparatively widely.The oligopeptides forming due to aminoacid sequence can, by the enzymatic hydrolysis in lysosome, therefore can be coupled together medicine and targeting vector as spacer groups by specially designed oligopeptides.The position of different peptide classes being had an effect due to different enzymes is difference to some extent, so the length of peptide class spacer groups and form the release rate that can affect medicine.De Marre etc. study the ametycin connecting with oligopeptides-poly-[N-(2-hydroxyethyl)-L-glutamine] prodrug, under pH5.5 condition, with after tritosomes hydrolysis 3h, the prodrug that the Ala-Leu-Ala-Leu of take is spacer groups, the release of ametycin can reach 81.0%, and take the prodrug that Gly-Phe-Leu is spacer groups, the release of ametycin only reaches 2.4%, the oligopeptides structure of spacer groups is described and forms the release of medicine is had a significant impact to (J. Control Release, 1994,31,89-97).
Summary of the invention
The present invention discloses glycogen phosphorylase inhibitors cholic acid analog derivative, its preparation method and the medicinal use containing biological cleavable dipeptides with pharmaceutical use shown in formula (I) first, is included in the purposes of preparing anti-diabetic and complication medicine, blood lipid-lowering medicine, slimming medicine, Antiatherosclerosis medicine, treatment metabolic syndrome medicine and antitumor drug aspect.Especially the compound shown in formula (I) is the liver Target prodrug of glycogen phosphorylase inhibitors, therefore can be used for the treatment of disease extremely relevant to Glycogen Metabolism in liver, these diseases comprise: diabetes and complication thereof, hyperlipidemia, obesity, high hyperglycemic-glycogenolytic factor disease, insulin resistant, fasting hyperglycemia, hypertension and complication, atherosclerosis, metabolism syndrome or tumour.In addition, the present invention also provides a kind of pharmaceutical preparation that contains compound shown in formula (I).
The present invention relates to the compound shown in formula (I) and pharmacy acceptable salt or ester:
Figure BSA0000095711900000031
Wherein:
X 1, X 2, X 3and X 4complete is C or X 1, X 2, X 3and X 4one of for N other be necessary for C;
R 1and R 1' independently represent separately H, halogen, hydroxyl, cyano group, C 0-4alkyl, C 1-4alkoxyl group, fluoro methyl, difluoromethyl, trifluoromethyl, vinyl, ethynyl;
R 2represent CH 3-, (CH 3) 2cHCH 2-, CH 3cH 2(CH 3) CH-, H 2nCH 2cH 2cH 2cH 2-;
R 3representative (CH 3) 2cH-, C 6h 5cH 2-, p-HO-C 6h 4cH 2-;
R 4, R 5, R 6and R 7independently represent separately H, hydroxyl, R 8cOO;
R 8represent straight or branched alkyl, alkylene, alkynes base, aryl and the heteroaryl non-substituted or that X replaces of 1～20 carbon;
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 other be necessary for C;
R 1and R 1' be independently H, halogen, cyano group separately;
R 2represent CH 3-, H 2nCH 2cH 2cH 2cH 2-;
R 3representative (CH 3) 2cH-, C 6h 5cH 2-;
R 4, R 5, R 6and R 7independent is separately 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 of having reported, also can adopt following method to prepare:
A) by the glycogen phosphorylase inhibitors containing exposed hydroxyl preparing; be dissolved in organic solvent with the dipeptides of tertbutyloxycarbonyl for aminoterminal (Boc) or fluorenylmethyloxycarbonyl (Fmoc) protection; add coupling reagent to become ester reaction; reaction 1-72 hour, temperature is 0 ℃ to 45 ℃.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).Can carry out the suitable selecting catalyst of situation by visual response, as DMAP;
B) a product is dissolved in organic solvent, adds the protection of deprotecting regent deaminize end, temperature is 0 ℃ and extremely refluxes.Wherein, a product of tertbutyloxycarbonyl for aminoterminal (Boc) protection is sloughed protection with trifluoroacetic acid, and a product of fluorenylmethyloxycarbonyl for aminoterminal (Fmoc) protection is sloughed protection with piperidines.The solvent adopting can be acetonitrile, methyl alcohol, tetrahydrofuran (THF), methylene dichloride, 1, and the mixed solvent of 2-ethylene dichloride, chloroform, toluene, normal hexane, hexanaphthene, t-butyl methyl ether or above-mentioned solvent preferentially adopts acetonitrile or methylene dichloride as solvent;
C) by free cholic acid and the derivative thereof of carboxyl terminal, be dissolved in organic solvent with b product, add coupling reagent and organic amine or mineral alkali, reaction 1-72 hour, temperature is 0 ℃ to 45 ℃.Solvent is generally selected inert solvent, non-protonic solvent particularly, 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 methylene dichloride, 1,2-ethylene dichloride or the DMF of adopting.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).The mineral alkali adopting is sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus, and the organic bases adopting is DIPEA or triethylamine.
The present invention also comprises pharmaceutical preparation, and said preparation comprises general formula (I) compound or pharmaceutically acceptable salt thereof, ester or the pharmaceutically acceptable carrier as promoting agent.
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 agent etc., they are not reverse has an effect with active compound or patient.
The formulation of the present composition can be conventional formulation 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 for knowing 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 desired, with the form administration of single dose several times.Yet, if desired, also can depart from above-mentioned consumption, this depends on experimenter's to be treated type and body weight, individual to the type of the character of the behavior of medicine, disease and seriousness, preparation and administration and administration time and interval.
Accompanying drawing explanation
Fig. 1 means the preparation process of part derivative of the present invention.
In Fig. 1, 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 8as above-mentioned formula (I) is middle, define R with the definition of X 9represent various amino acid whose N end protecting groups, as tertbutyloxycarbonyl (Boc) or fluorenylmethyloxycarbonyl (Fmoc).
Embodiment:
Below by embodiment, illustrate content of the present invention.In the present invention, the example of the following stated is in order better to set forth the present invention, is not for limiting the scope of the invention.
Further illustrate by the following examples enforcement of the present invention
Embodiment 1
(S)-2-t-butoxycarbonyl amino-3-(4-fluorophenyl)-1-(4-hydroxy piperidine-1-yl) acetone
By the fluoro-L-Phe (15.6g of BOC-4-, 55.1mmol) be dissolved in anhydrous methylene chloride (160mL), under ice bath, add HATU (25g, 66.1mmol) and DIPEA (8.54g, 66.1mmol), stirring at room 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 4dry, filter, concentrated, residue is separated through reversed-phase HPLC, obtains white solid (50mg, 29.8%).Rapid column chromatography (petrol ether/ethyl acetate l/l, 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-yl) acetone
By (S)-2-t-butoxycarbonyl amino-3-(4-fluorophenyl)-1-(4-hydroxy piperidine-1-yl) acetone (19g, 52mmol) be dissolved in methylene dichloride (50mL), under ice bath, slowly drip the dichloromethane solution (2N of the hydrogenchloride of fresh preparation, 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(brs，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-(the chloro-1H-pyrrolo-of 5-[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-yl) acetone, by (S)-2-amino-3-(4-fluorophenyl)-1-(4-hydroxy piperidine-1-yl) 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).
(S)-2-(the positive amide-based small of 2-t-butoxycarbonyl amino-3-methyl) methyl propionate
By N-tertbutyloxycarbonyl-Valine (4g; 18.4mmol) with alanine methyl ester hydrochloride (2.58g; 18.5mmol) be dissolved in dry DMF (80mL); under ice bath, add EDCI (5.3g; 27.7mmol), HOBt (3.73g, 27.65mmol) and DIPEA (5.93g; 46mmol), stirred overnight at room temperature under nitrogen protection.Reaction solution is successively with 1N hydrochloric acid soln, saturated sodium bicarbonate solution and saturated common salt water washing, anhydrous Na 2sO 4dry, evaporated under reduced pressure obtains white solid (4.5g, 80%).
ESI-MS?m/z：325.2[M+Na] +.
1H-NMR(CDCl 3，400MHz)：6.38(brs，1H)，5.07(brs，1H)，4.58-4.65(m，1H)，3.93-3.97(m，1H)，3.78(s，3H)，2.11-2.20(m，1H)，1.47(s，9H)，1.43(d，J＝7.2Hz，3H)，0.99(d，J＝6.8Hz，3H)，0.94(d，J＝6.8Hz，3H)；
(S)-2-(the positive amide-based small of 2-t-butoxycarbonyl amino-3-methyl) propionic acid
By (S)-2-(the positive amide-based small of 2-t-butoxycarbonyl amino-3-methyl) methyl propionate (2.5g, 8.3mmol) be dissolved in the mixing solutions of methanol/water (20mL, V/V=l/l), add sodium hydroxide (0.5g, 12.5mmol), stirring at room 3h.Remove methyl alcohol under reduced pressure, residual reaction liquid is used in 1N aqueous hydrochloric acid and pH to 2-3, filters, and filter cake is with washed with dichloromethane, and vacuum-drying obtains white solid (1.6g, 46%).
ESI-MS?m/z：287.0[M-H]-.
1H-NMR(CDCl 3，400MHz)：6.86(brs，1H)，5.26-5.34(m，1H)，4.59-4.63(m，1H)，3.99-4.02(m，1H)，2.04-2.25(m，1H)，1.47-1.49(m，12H)，0.98(d，J＝6.4，3H)，0.95(d，J＝6.8，3H).
(S)-N-(the positive butyryl radicals of 2-t-butoxycarbonyl amino-3-methyl) L-Ala-and 1-[2-(the chloro-1H-pyrrolo-of 5-[2,3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-piperidin-4-yl } ester
By (S)-2-(the positive amide-based small of 2-t-butoxycarbonyl amino-3-methyl) propionic acid (1g; 3.5mmol) with (S)-1-[2-(chloro-1H-pyrrolo-[2 of 5-; 3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-4-hydroxy piperidine (1.54g; 3.5mmol) be dissolved in DMF (30mL); under ice bath, add DCC (1.1g; 5.2mmol), stirred overnight at room temperature.Reaction mixture filters, and filtrate boils off solvent, and resistates acetic acid ethyl dissolution, puts refrigerator overnight, filters, and filtrate boils off solvent, and residue is separated through reversed-phase HPLC, obtains white solid (1.3g, 57%).
ESI-MS?m/z：715.0[M+H] +.
1H-NMR(MeOD，400MHz)：8.53(s，1H)，7.64(s，1H)，7.30-7.35(m，2H)，7.14(s，1H)，7.00-7.06(m，2H)，5.31-5.36(m，1H)，4.89-4.96(m，1H)，4.36-4.42(m，1H)，3.40-3.95(m，5H)，3.17-3.30(m，1H)，3.08-3.13(m，1H)，2.00-2.07(m，1H)，1.78-1.89(m，1H)，1.54-1.67(m，1H)，1.29-1.45(m，14H)，0.89-1.00(m，6H).
(S)-N-(the positive butyryl radicals of 2-amino-3-methyl) L-Ala 1-[2-(the chloro-1H-pyrrolo-of 5-[2,3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl] and-piperidin-4-yl } ester
By (S)-N-(the positive butyryl radicals of 2-t-butoxycarbonyl amino-3-methyl) L-Ala { 1-[2-(chloro-1H-pyrrolo-of 5-[2; 3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-piperidin-4-yl } ester (1g; 1.4mmol) be dissolved in methylene dichloride (10mL); under ice bath, drip trifluoracetic acid (1mL; 14mmol), dripping complete this temperature that maintains stirs 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, anhydrous Na 2sO 4dry.Remove by filter siccative, concentrated, obtain white solid crude product, this crude product can be directly used in next step reaction without purifying.
(S)-N-{2-[N-(3 α; 7 α; 12 α-trihydroxy--5 β-cholane amide group)]-positive butyryl radicals of 3-methyl } L-Ala 1-[2-(the chloro-1H-pyrrolo-of 5-[2,3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl] and-piperidin-4-yl } ester
By cholic acid (330mg; 0.80mmol) be dissolved in DMF (5mL); under ice bath, add HATU (456mg; 1.2mmol) and triethylamine (121mg, 1.2mmol), stirring at room 10 minutes; add again (S)-N-(the positive butyryl radicals of 2-amino-3-methyl) L-Ala { 1-[2-(chloro-1H-pyrrolo-[2 of 5-; 3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-piperidin-4-yl } ester (450mg, crude), 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 4dry, filter, concentrated, residue is separated through reversed-phase HPLC, obtains faint yellow solid (150mg, 24%).
ESI-MS?m/z：1005.0[M+H] +.
1H-NMR(MeOD，400MHz)：8.58(s，1H)，7.71(s，1H)，7.31-7.36(m，2H)，7.17-7.20(m，1H)，7.01-7.07(m，2H)，4.95-5.00(m，1H)，4.35(td，J＝7.2，14.4Hz，1H)，4.15-4.27(m，1H)，3.90-3.96(m，1H)，3.78-3.81(m，2H)，3.69(s，1H)，3.55-3.62(m，2H)，3.36-3.48(m，2H)，3.08-3.24(m，2H)，2.23-2.25(m，4H)，1.13-1.84(envelope，31H)，1.40(s，3H)，1.38(s，3H)，0.85-1.08(envelope，16H)，0.69-0.71(m，1H)，0.68(d，J＝26.0Hz，3H).
Embodiment 2
(S)-2-[(S)-2-t-butoxycarbonyl amino-3-hydrocinnamamide base]-6-(benzyloxy amide group) methyl caproate
By the similar approach of preparation (S)-2-(the positive amide-based small of 2-t-butoxycarbonyl amino-3-methyl) methyl propionate, by lysine methyl ester hydrochloride (2.49g, 7.6mmlo) with N-tertbutyloxycarbonyl-L-Phe (2g, 7.6mmol) reaction, obtain white solid (3g, 73%).
ESI-MS?m/z：542.3[M+H] +.
1H-NMR(CDCl 3，400MHz)：7.38(d，J＝4.4Hz，4H)，7.29-7.35(m，5H)，7.20-7.27(m，3H)，6.49(d，J＝7.2Hz，1H)，5.11(dd，J＝12.4，16.4Hz，2H)，4.54-4.59(m，1H)，4.35-4.40(m，1H)，3.72(s，3H)，3.16(dd，J＝6.0，12.0Hz，2H)，3.07(t，J＝6.0Hz，2H)，1.77-1.88(m，1H)，1.64-1.71(m，1H)，1.49-1.56(m，2H)，1.40(s，9H)，1.27-1.36(m，2H).
(S)-2-[(S)-2-t-butoxycarbonyl amino-3-hydrocinnamamide base]-6-(benzyloxy amide group) caproic acid
By the similar approach of preparation (S)-2-(the positive amide-based small of 2-t-butoxycarbonyl amino-3-methyl) propionic acid, by (S)-2-[(S)-2-t-butoxycarbonyl amino-3-hydrocinnamamide base] hydrolysis of-6-(benzyloxy amide group) methyl caproate, obtain white solid (2.5g, 91%).
ESI-MS?m/z：526.0[M-H] -.
1H-NMR(CDCl 3，400MHz)：7.35(brs，4H)，7.17-7.29(m，6H)，704(brs，1H)，5.32(d，J＝44.4Hz，1H)，5.09(dd，J＝12.4，18.8Hz，2H)，4.51(dd，J＝14.8，41.2Hz，1H)，2.98-3.18(m，4H)，1.88(brs，1H)，1.73(brs，1H)，1.43-1.51(m，2H)，1.38(s，9H)，1.24-1.29(m，2H).
(S)-2-[(S)-2-t-butoxycarbonyl amino-3-hydrocinnamamide base]-6-(fluorenes methoxy carbonyl amide group) caproic acid
By (S)-2-[(S)-2-t-butoxycarbonyl amino-3-hydrocinnamamide base]-6-(benzyloxy amide group) caproic acid (1g, 1.9mmol) be dissolved in methyl alcohol (10mL), the 10%Pd/C (20mg) that adds catalytic amount, room temperature normal pressure hydrogenation 24 hours.Normal pressure removes by filter Pd/C, filtrate evaporate to dryness.Residue is dissolved in dioxane (10mL), under ice bath, slowly adds NaHCO 3(404mg, 4.75mmol) and fluorenes methoxy dicarbonyl chloride (518mg, 2.0mmol), stir under ice bath 5 hours.Evaporated under reduced pressure solvent, residue dilutes with ethyl acetate, successively with 1N aqueous hydrochloric acid, saturated NaHCO 3the aqueous solution and saturated common salt water washing, boil off solvent and obtain white solid (1g, 86%) after anhydrous sodium sulfate drying.
ESI-MS?m/z：614.0[M-H] -.
1H?NMR(400MHz，DMSO-d 6)：7.89(d，J＝7.6Hz，2H)，7.68(d，J＝7.6Hz，2H)，7.53(d，J＝6.4Hz，1H)，7.41(t，J＝7.6Hz，2H)，7.33(t，J＝7.2Hz，2H)，7.24-7.29(m，4H)，7.15-7.19(m，2H)，4.26(d，J＝6.8Hz，2H)，4.19(t，J＝6.4Hz，1H)，4.05-4.11(m，1H)，3.83(dd，J＝5.6，11.6Hz，1H)，3.05-3.09(m，1H)，2.93(dd，J＝6.4，13.2Hz，2H)，2.70-2.76(m，1H)，1.68-1.76(m，1H)，1.52-1.61(m，1H)，1.34-1.14(m，2H)，1.29(s，9H)，1.20-1.23(m，2H).
(S)-N-[(S)-2-t-butoxycarbonyl amino-3-hydrocinnamoyl)]-N '-fluorenes methoxy carbonyl acyl-lysine-{ 1-[2-(the chloro-1H-pyrrolo-of 5-[2,3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-piperidin-4-yl } ester
By (S)-2-[(S)-2-t-butoxycarbonyl amino-3-hydrocinnamamide base]-6-(fluorenes methoxy carbonyl amide group) caproic acid (380mg; 0.6mmol) with (S)-1-[2-(chloro-1H-pyrrolo-[2 of 5-; 3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-4-hydroxy piperidine (550mg; 0.6mmol) be dissolved in dry methylene dichloride (30.0mL), slowly add the ethyl acetate solution (T of 1-propyl group tricresyl phosphate cyclic acid anhydride 3p, 50wt.%, 0.95mL, 3.1mmol).Finish stirred overnight at room temperature under nitrogen protection.Reaction finish after, in reaction solution successively with 1N aqueous hydrochloric acid, saturated NaHCO 3the aqueous solution and saturated common salt water washing, anhydrous sodium sulfate drying, filters, concentrated, and residue is through the separated (moving phase: ACN---H of reversed-phase HPLC 2o (0.05%TFA), gradient: 10%-30%), obtain white solid (380mg, 60%).
ESI-MS?m/z：1042.0[M+H] +.
1H-NMR(MeOD，400MHz)：8.55(d，J＝7.6Hz，1H)，7.71-7.79(m，2H)，7.60-7.66(m，3H)，7.36(dd，J＝7.2，14.4Hz，2H)，7.22-7.31(m，9H)，7.13(d，J＝10.0Hz，1H)，7.00(dd，J＝8.0，16.0Hz，2H)，5.26-5.33(m，1H)，4.31-4.38(m，4H)，4.14-4.20(m，1H)，3.39-3.77(m，4H)，3.08-3.16(m，5H)，2.67-2.87(m，2H)，1.05-1.85(envelope，20H)，1.32(s，9H).
(S)-N-[(S)-2-amino-3-hydrocinnamoyl)]-N '-fluorenes methoxy carbonyl acyl-lysine-{ 1-[2-(the chloro-1H-pyrrolo-of 5-[2,3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-piperidin-4-yl } ester
By preparation (S)-N-(the positive butyryl radicals of 2-amino-3-methyl) L-Ala { 1-[2-(chloro-1H-pyrrolo-[2 of 5-; 3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-piperidin-4-yl } similar approach of ester; by (S)-N-[(S)-2-t-butoxycarbonyl amino-3-hydrocinnamoyl)]-N '-fluorenes methoxy carbonyl acyl-lysine-{ 1-[2-(chloro-1H-pyrrolo-of 5-[2; 3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-piperidin-4-yl } ester deprotection; obtain white solid crude product, this crude product can be directly used in next step reaction without purifying.
(S)-N-{2-[N-(3 α; 7 α; 12 α-trihydroxy--5 β-cholane amide group)]-3-hydrocinnamamide base }-N '-fluorenes methoxy carbonyl acyl-lysine 1-[2-(the chloro-1H-pyrrolo-of 5-[2,3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl] and-piperidin-4-yl } ester
By preparation (S)-N-{2-[N-(3 α, 7 α, 12 α-trihydroxy--5 β-cholane amide group)]-positive butyryl radicals of 3-methyl } L-Ala { 1-[2-(the chloro-1H-pyrrolo-[2 of 5-, 3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-piperidin-4-yl } similar approach of ester, by cholic acid (155mg, 0.38mmol) with (S)-N-[(S)-2-amino-3-hydrocinnamoyl)]-N '-fluorenes methoxy carbonyl acyl-lysine-{ 1-[2-(chloro-1H-pyrrolo-[2 of 5-, 3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-piperidin-4-yl } reaction of ester 350mg crude product, obtain white solid (300mg, 61%).
ESI-MS?m/z：666.6[M/2+H] +.
1H-NMR(MeOD，400MHz)：8.70(d，J＝7.6Hz，1H)，7.73-7.81(m，3H)，7.61-7.68(m，2H)，7.39(t，J＝7.2Hz，2H)，7.25-7.33(m，6H)，7.14-7.20(m，1H)，7.23(d，J＝4.4Hz，2H)，7.00-7.05(m，2H)，5.26-5.37(m，1H)，4.94-4.98(m，1H)，4.61-4.72(m，1H)，4.29-4.39(m，2H)，4.17-4.24(m，1H)，3.86-3.93(m，1H)，3.71-3.76(m，2H)，3.47-3.56(m，2H)，3.04-3.22(m，4H)，2.70-2.95(m，3H)，2.14-2.33(m，3H)，1.91-2.11(m，3H)，1.30-1.82(envelope，23H)，1.30(s，3H)，1.12-1.21(m，3H)，0.89-1.03(envelope，8H)，0.91(d，J＝4.4Hz，3H)，0.63-0.68(m，1H)，0.62(d，J＝18.8Hz，3H).
(S)-N-{2-[N-(3 α; 7 α; 12 α-trihydroxy--5 β-cholane amide group)]-3-hydrocinnamamide base }-Methionin 1-[2-(the chloro-1H-pyrrolo-of 5-[2,3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl] and-piperidin-4-yl } ester
By (S)-N-{2-[N-(3 α; 7 α; 12 α-trihydroxy--5 β-cholane amide group)]-3-hydrocinnamamide base }-N '-fluorenes methoxy carbonyl acyl-lysine { 1-[2-(chloro-1H-pyrrolo-[2 of 5-; 3-c] pyridine-2-carboxamide)-3-(4-fluorophenyl) propionyl]-piperidin-4-yl } ester (260mg; 0.20mmol) be dissolved in acetonitrile (3mL); under ice bath, slowly drip piperidine solution (0.6mL), drip complete stirring at room 1h.Remove solvent under reduced pressure, residue is through the separated (moving phase: ACN---H of reversed-phase HPLC 2o (0.05%TFA), gradient: 10%-30%), obtain light brown solid (100mg, 45%).
ESI-MS?m/z：1110.0[M+H] +.
1H-NMR(MeOD，400MHz)：7.70(d，J＝3.6Hz，1H)，7.33(t，J＝5.2Hz，3H)，7.27(dd，J＝4.4，24.4Hz，4H)，7.18(d，J＝2.8Hz，1H)，7.02-7.06(m，2H)，5.32(dd，J＝7.2，14.0Hz，1H)，4.56-4.63(m，1H)，4.37(ddd，J＝5.2，12.2，23.0Hz，1H)，3.92(d，J＝23.6Hz，1H)，3.71-3.82(m，2H)，3.39-3.60(m，3H)，3.08-3.23(m，5H)，2.88-2.95(m，3H)，2.16-2.35(m，4H)，1.31-1.90(m，30H)，0.95-1.17(m，3H)，0.93(d，J＝5.2Hz，3H)，0.67(d，J＝21.2Hz，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, stir with agitator, adding Victoria Green WPB 190mg after all dissolving, continue to be stirred to whole dissolvings, and use masking foil lucifuge; 2) preparation of damping fluid: 1. precision weighing Hepes0.5958g, is dissolved in 5ml H 2in O, with 10M NaOH, adjust PH to 7.2, 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, with 10M NaOH, adjust PH to 7.0, 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 to 10ml H 2the solution of O preparation 0.5,5,50 and 500 μ M; 4) preparation GPa solution: the GPa that gets 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 is dissolved in to DMSO, and to be mixed with concentration be 10mM solution, gets appropriate compound solution and joins in reaction system to different final concentrations.
Measure the amount effect curve of rabbit muscle glycogen Starch phosphorylase activity: by reading the GPa of different concns, add the OD value under 655nm after nitrite ion, measure its amount effect curve.By amount effect curve, can select the amount of GPa is 250ng.
Experimental procedure: 1) design PC (positive control), Blank (blank), positive drug (caffeine); 2) add reaction buffer52 μ l; 3) add test compounds to final concentration; 4) enzyme-added 1 μ l, final concentration is 250ng/100 μ l; 5) add nitrite ion 150 μ l; 6) under 30 degrees celsius, react 20 minutes; 7) colorimetric under wavelength 655nm condition; 8) reading and the calculating of inhibiting rate of data: inhibiting rate=[positive control-testing sample]/[positive control-blank].
Test result: listed the inhibition activity data of glycogen phosphorylase liver targeted prodrug molecule to rabbit muscle glycogen Starch phosphorylase in table, result demonstration, the inhibition that such glycogen phosphorylase liver targeted prodrug molecule has in various degree glycogen phosphorylase is active.
Glycogen phosphorylase liver targeted prodrug molecule is active to the inhibition of rabbit muscle glycogen Starch phosphorylase
Figure BSA0000095711900000101
Figure 1
aiC 50value is the mean value of three experiments;
bnI is illustrated under 100M concentration does not have activity.
Above pharmacology data shows, general formula of the present invention (I) compound has the restraining effect of glycogen phosphorylase, therefore can be used for prevention and treatment diabetes and complication, hyperlipidemia, obesity, high hyperglycemic-glycogenolytic factor disease, insulin resistant, fasting hyperglycemia, hypertension and complication, atherosclerosis, metabolism syndrome or tumour.

Claims (10)

1. the present invention relates to the compound shown in formula (I) and 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 other be necessary for C;
R 1and R 1' independently represent separately H, halogen, hydroxyl, cyano group, C 0-4alkyl, C 1-4alkoxyl group, fluoro methyl, difluoromethyl, trifluoromethyl, vinyl, ethynyl;
R 2represent CH 3-, (CH 3) 2cHCH 2-, CH 3cH 2(CH 3) CH-, H 2nCH 2cH 2cH 2cH 2-;
R 3representative (CH 3) 2cH-, C 6h 5cH 2-, p-HO-C 6h 4cH 2-;
R 4, R 5, R 6and R 7independently represent separately H, hydroxyl, R 8cOO;
R 8represent straight or branched alkyl, alkylene, alkynes base, aryl and the heteroaryl non-substituted or that X replaces of 1～20 carbon;
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. the compound of claim 1 and pharmacy acceptable salt thereof 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 other be necessary for C;
R 1and R 1' be independently H, halogen, cyano group separately;
R 2represent CH 3-, H 2nCH 2cH 2cH 2cH 2-;
R 3representative (CH 3) 2cH-, C 6h 5cH 2-;
R 4, R 5, R 6and R 7independent is separately 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.
3. the compound of claim 1, wherein compound can be following arbitrary compound and medicinal salt or ester thereof:
Figure FSA0000095711890000021
4. the preparation method of claim 1,2,3 compound, comprising:
A) by the glycogen phosphorylase inhibitors containing exposed hydroxyl preparing; be dissolved in organic solvent with the dipeptides of tertbutyloxycarbonyl for aminoterminal (Boc) or fluorenylmethyloxycarbonyl (Fmoc) protection; add coupling reagent to become ester reaction; reaction 1-72 hour, temperature is 0 ℃ to 45 ℃.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).Can carry out the suitable selecting catalyst of situation by visual response, as DMAP;
B) a product is dissolved in organic solvent, adds the protection of deprotecting regent deaminize end, temperature is 0 ℃ and extremely refluxes.Wherein, a product of tertbutyloxycarbonyl for aminoterminal (Boc) protection is sloughed protection with trifluoroacetic acid, and a product of fluorenylmethyloxycarbonyl for aminoterminal (Fmoc) protection is sloughed protection with piperidines.The solvent adopting can be acetonitrile, methyl alcohol, tetrahydrofuran (THF), methylene dichloride, 1, and the mixed solvent of 2-ethylene dichloride, chloroform, toluene, normal hexane, hexanaphthene, t-butyl methyl ether or above-mentioned solvent preferentially adopts acetonitrile or methylene dichloride as solvent;
C) by free cholic acid and the derivative thereof of carboxyl terminal, be dissolved in organic solvent with b product, add coupling reagent and organic amine or mineral alkali, reaction 1-72 hour, temperature is 0 ℃ to 45 ℃.Solvent is generally selected inert solvent, non-protonic solvent particularly, 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 methylene dichloride, 1,2-ethylene dichloride or the DMF of adopting.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).The mineral alkali adopting is sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus, and the organic bases adopting is DIPEA or triethylamine.
5. a pharmaceutical composition, wherein contains general formula (I) compound, DL body, optical isomer or its pharmacy acceptable salt or ester and the pharmaceutically acceptable carrier for the treatment of significant quantity.
6. the compound of claims 1 to 3, is characterized in that: these compounds are the cholic acid analog derivatives containing the glycogen phosphorylase inhibitors of biological cleavable dipeptides.
7. the purposes of claim 6, is characterized in that: the cholic acid analog derivative that contains the glycogen phosphorylase inhibitors of biological cleavable dipeptides is the medicine of prevention and treatment diabetes and complication, hyperlipidemia, obesity, high hyperglycemic-glycogenolytic factor disease, insulin resistant, fasting hyperglycemia, hypertension and complication, atherosclerosis, metabolism syndrome or tumour.
8. the purposes of claim 7, is characterized in that: diabetes are diabetes Bs, and its complication comprises: diabetic nephropathy, diabetic foot, diabetic neuropathy or diabetes complicated cardiovascular and cerebrovascular diseases.
9. the purposes of claim 7, is characterized in that: the compound of claims 1 to 3 can be used for prevention and treatment hypertension and complication thereof.
10. the purposes of claim 7, is characterized in that: the compound of claims 1 to 3 can be used for prevention and treatment hyperlipidemia and atherosclerosis.
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