WO2017202003A1

WO2017202003A1 - Glycogen phosphorylase inhibitor and preparation method and use thereof

Info

Publication number: WO2017202003A1
Application number: PCT/CN2016/108865
Authority: WO
Inventors: 李晶; 张丽颖; 张雷
Original assignee: 华南理工大学
Priority date: 2016-05-25
Filing date: 2016-12-07
Publication date: 2017-11-30
Also published as: CN106046101A; CN106046101B

Abstract

Disclosed is a compound of formula (I) as a glycogen phosphorylase inhibitor or a pharmaceutically acceptable salt or ester thereof, wherein formula (I) is as defined in the description. The effect of the compound on inhibiting glycogenolysis on a cellular level is equivalent to that of PSN-357. The compound can be used in preparing drugs for preventing and treating diabetes and complications thereof, hyperlipidemia, hypertension and complications thereof, atherosclerosis, obesity and metabolic syndromes.

Description

Glycogen phosphorylase inhibitor and preparation method and application thereof

Technical field

The invention belongs to the technical field of drug synthesis, and particularly relates to a glycogen phosphorylase inhibitor and a preparation method and application thereof.

Background technique

Diabetes is the third most serious non-communicable disease that threatens human health after cancer and cardiovascular disease. At present, there are more than 92 million people with diabetes in China, making it the world's largest diabetes country, and about 97% of them are type 2 diabetes. For the treatment of type 2 diabetes, according to the different pharmacological mechanisms of action, it is divided into insulin and its similar drugs, insulin sensitizers, insulin secretagogues, and carbohydrate reducing agents. However, these drugs have limited hypoglycemic effects. As people's understanding of the pathogenesis of diabetes continues to deepen, many new targets for the treatment of diabetes have been discovered, and new drugs are constantly being introduced.

Glycogen phosphorylase (GP) is an important enzyme in the sugar metabolism pathway and a key enzyme that catalyzes the degradation of glycogen. Inhibition of the activity of the enzyme can reduce the degradation of glycogen, thereby reducing the production of hepatic glucose, thereby lowering blood sugar. In recent years, GP inhibitors have received widespread attention as potential hypoglycemic agents. It is characterized by a significant protective effect on ischemic myocardial injury while lowering blood glucose, which is especially important for diabetic patients with ischemic cardiovascular complications.

Substituted N-(indol-2-carbonyl) amides and derivatives as GP inhibitors are reported in US Pat. No. 6,297,269 and EP 0 832 066. Substituted N-(indol-2-carbonyl)glycinamides and derivatives as GP inhibitors are reported in US Pat. No. 6,107,329 and US Pat. No. 6,277,877. US 6,396,601 reports bicyclic pyrrolamide GP inhibitors. US5952322 discloses a method for reducing non-cardiac ischemic tissue damage by a GP inhibitor.

At present, Pfizer's CP-368296 and OSI's azaindole derivative PSN-357 have entered the clinical research stage. In addition, there are some natural pentacyclic triterpenoids that have been inhibited by the liver. Glucose production achieves the goal of lowering blood glucose, and molecular simulations have confirmed that these pentacyclic triterpenoids have potential interaction sites with GP.

In conclusion, GP is associated with modulation of excess hepatic glucose production, and the hypoglycemic effects of its inhibitors will be highly beneficial for the treatment of combination therapies and their associated cardiovascular diseases.

Summary of the invention

In order to further develop a safe and effective new drug for treating diabetes, the primary object of the present invention is to provide a glycogen phosphorylase inhibitor.

Another object of the present invention is to provide a process for producing the above glycogen phosphorylase inhibitor.

A further object of the present invention is to provide a medicament for preventing and treating diabetes and its complications, hyperlipemia, hypertension and its complications, atherosclerosis, obesity, metabolic syndrome, and the like by the above-mentioned glycogen phosphorylase inhibitor. Application in .

The object of the invention is achieved by the following technical solutions:

A glycogen phosphorylase inhibitor having the structural formula represented by formula (I) or a pharmaceutically acceptable salt or ester thereof:

Wherein: X ₁ , X ₂ , X ₃ and X ₄ are each a carbon atom linking group or one of X ₁ , X ₂ , X ₃ and X ₄ is a nitrogen atom linking group and the other is a carbon atom linking group. ; R ₁ is H, halogen, hydroxy, cyano, C _1-6 alkyl, C _1-6 alkoxy, trifluoromethyl, vinyl or ethynyl.

Preferably, said R ₁ is H, halogen or cyano.

More preferably, the glycogen phosphorylase inhibitor has the structural formula represented by the following formula (I ₁ ) or a pharmaceutically acceptable salt or ester thereof:

The preparation method of the above glycogen phosphorylase inhibitor comprises the following preparation steps:

(1) A compound of the formula 2 ((E)-3-(2-((4)) is obtained by a compound of the formula 1 (o-nitrophenyl acrylate) as a starting material, by hydrogenation reduction, oxidation, azidation. -(tert-Butoxycarbonyl)phenyl)azido)phenyl)propanoic acid);

(2) A compound of the formula 2 is esterified with a compound having the structure of formula 3 under the catalysis of DCC (dicyclohexylcarbodiimide) and DMAP (4-dimethylaminopyridine) to obtain a structure having the structure of formula 4. Esterifying the product, and then deprotecting the trifluoroacetic acid to obtain a free carboxyl group-containing compound of the formula 5;

(3) Compounds of the formula 5 are in HATU (2-(7-oxybenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate) and DIPEA (N,N- The target compound glycogen phosphorylase inhibitor having the structure of formula (I) is obtained by acylation with a cholic acid derivative of the structure of formula 6 catalyzed by diisopropylethylamine;

The synthetic route diagram of the above preparation method is shown in FIG.

Preferably, the hydrogenation reduction in the step (1) means hydrogenation reduction using a Pd/C catalyst under basic conditions; the oxidation means using potassium persulfate complex salt (Oxone) in water and dichloromethane Oxidation in a mixed solvent; said azidation means azidation with tert-butyl 4-aminobenzoate under AcOH solvent.

The above compound having the structure of Formula 3 can be prepared by referring to CN200480021117.2.

Preferably, the cholic acid derivative having the structure of Formula 6 is prepared by the following method:

The cholic acid was dissolved in anhydrous DMF, and then N-Boc-ethylenediamine, diethylpyrocarbonate (DEPC) and triethylamine (Et ₃ N) were added, and the reaction was stirred at room temperature, and the reaction product was isolated and purified to obtain white. Solid product N-(3α,7α,12α-trihydroxy-5β-cholanoamide)-N'-tert-butoxycarbonylethylenediamine; then dissolved in methanol, and freshly prepared hydrogen chloride was added dropwise in an ice bath. Deprotection of the methanol solution gave the cholic acid derivative N-(3?,7?,12?-trihydroxy-5?-cholanoamide)-ethylenediamine having the structure of Formula 6.

The above-mentioned glycogen phosphorylase inhibitor is used for the preparation of a medicament for preventing and treating diabetes and its complications, hyperlipemia, hypertension and its complications, atherosclerosis, obesity, metabolic syndrome.

In the above application, the medicament comprises, as an active agent, a compound of the formula (I) or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier.

The above pharmaceutically acceptable carrier means a conventional pharmaceutical carrier in the pharmaceutical field, and means one or several inert, non-toxic solid or liquid fillers, diluents, auxiliaries, etc., which are not reversed with the active compound or the patient. It works.

The dosage form of the above-mentioned drug may be a pharmaceutically acceptable dosage form such as a tablet, a capsule, a pill, a suppository, an oral solution, a suspension, or an injection.

The above tablets, pills and capsules contain conventional excipients such as fillers, diluents, lubricants, and sub-fractions. Powder and adhesive. The various dosage forms described above can be prepared according to methods well known in the art of pharmacy. The dosage of the above active agents will vary depending on the formulation.

The invention has the following advantages and beneficial effects:

The present invention synthesizes a novel structure of glycogen phosphorylase inhibitor. This inhibitor has an inhibitory effect on glycogen phosphorylase and its inhibition of glycogen decomposition at the cellular level is comparable to that of PSN-357. Therefore, it can be used for the preparation of a medicament for preventing and treating diabetes and its complications, hyperlipemia, hypertension and its complications, atherosclerosis, obesity, and metabolic syndrome.

DRAWINGS

Figure 1 is a synthetic route diagram of the glycogen phosphorylase inhibitor of the present invention.

detailed description

The present invention will be further described in detail below with reference to the embodiments, but the embodiments of the present invention are not limited thereto.

Example 1

In this embodiment, a preparation of a glycogen phosphorylase inhibitor is prepared as follows:

(1) Synthesis of (E)-3-{2-[(4-tert-butoxycarbonylphenyl) azide]phenyl}propionic acid:

(E)-3-(Nitrophenyl)acrylic acid (10.0 g, 52.0 mmol) dissolved in water (500 mL), NaOH (4.1 g, 39 mmol) and 10% Pd/C (0.5 g) overnight. The reactant was filtered to remove Pd/C, and the solvent was evaporated to dryness to give a white powdery solid (7.5 g, 87%). This crude product was dissolved in a mixed solvent of water (200 mL) and dichloromethane (300 mL), and a mixture of potassium hydrogen persulfate (Oxone, 55.3 g, 90.0 mmol) was stirred at room temperature for 2 h. The organic phase of the dichloromethane was collected, and the aqueous phase was extracted with methylene chloride. The organic phase was combined, dried over anhydrous sodium sulfate, and evaporated to give a crude solid (7.5 g, 92.5%). This crude product was dissolved in AcOH (75.0 mL), EtOAc (EtOAc) The solvent was evaporated under reduced pressure. EtOAcjjjjjjjj The product identification data is as follows:

ESI-MS m/z: 355.2 [M+H] ⁺ ;

¹ H NMR: (CDCl ₃ , 400 MHz) 8.15 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.40.7.47 ( m, 2H), 7.32 - 7.37 (m, 1H), 3.49 (t, J = 7.6 Hz, 2H), 2.79 (t, J = 8.0 Hz, 2H).

(2) (E)-3-{2-[(4-tert-Butoxycarbonylphenyl)azido]phenyl}propionic acid-{1-[2-(5-chloro-1H-pyrrolo[2 Synthesis of 3-(3-pyridyl-2-carboxamide)-3-(4-fluorophenyl)propanoyl]-piperidin-4-yl} ester:

(E)-3-{2-[(4-tert-Butoxycarbonylphenyl) azide]phenyl}propanoic acid (240.0 mg, 0.68 mmol), catalyzed in DMAP (8.3 mg, 0.068 mmol) In dichloromethane (8.0 mL), DCC (153.4 mg, 0.75 mmol) was added under ice-cooling, and the mixture was stirred for 30 min under ice-cooling, and then the compound of formula 7 (300 mg, 0.68 mmol, prepared with reference to CN200480021117.2) was added. Stir at room temperature overnight. The reaction mixture was filtered, and the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, An orange solid (440.0 mg, 82%). The product identification data is as follows:

ESI-MS m/z: 781.2 [M+H] ⁺ ;

^{1 H 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, 28.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.22-7.46 (m, 5H), 7.07 (d, J=5.6 Hz, 1H), 6.92-7.00 ( m, 2H), 5.23 (dd, J = 7.2, 11.6 Hz, 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 = 9.6 Hz, 9H).

(3) (E)-3-{2-[(4-benzoic acid) azido]phenyl}propionic acid-{1-[2-(5-chloro-1H-pyrrolo[2,3-c Synthesis of pyridine-2-carboxamide-3-(4-fluorophenyl)propanoyl]-piperidin-4-yl} ester:

(E)-3-{2-[(4-tert-Butoxycarbonylphenyl)azido]phenyl}propionic acid-{1-[2-(5-chloro-1H-pyrrolo[2,3- c]pyridine-2-carboxamide)-3-(4-fluorophenyl)propanoyl]-piperidin-4-yl} ester (650.0 mg, 0.83 mmol) dissolved in dichloromethane (10 mL) Trifluoroacetic acid (10 mL, 140 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction solution was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous Na ₂ SO _4. The desiccant was removed by filtration and concentrated to give a crude brown solid. This crude material was used in the next step without purification. The product identification data is as follows:

ESI-MS m/z: 725.1 [M+H] ⁺ ;

^{_{1 H NMR: (CDCl 3,}} 400MHz) 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 = 20.0 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 8.0, 30.0 Hz, 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).

(4) Synthesis of N-(3α,7α,12α-trihydroxy-5β-cholanoamide)-N'-tert-butoxycarbonylethylenediamine:

Cholic acid (2.0 g, 4.9 mmol) was dissolved in anhydrous DMF (20.0 mL), and N-Boc-ethylenediamine (784.3 mg, 4.9 mmol) was added slowly, diethyl carbonate (DEPC, 879.0 mg, 5.4 mmol) And triethylamine (Et ₃ N, 2.5 g, 5.0 mmol), added, and stirred at room temperature for 24 h. The reaction mixture was filtered, EtOAcjjjjjjjjj The product identification data is as follows:

ESI-MS m/z: 451.2 [M+H] ⁺ ;

¹ H NMR: (DMSO-d ₆ , 400 MHz) 7.73 (t, J = 5.2 Hz, 1H), 6.73 (t, J = 5.6 Hz, 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 = 6.4 Hz, 3H), 0.76 (s, 3H), 0.54 (s, 3H).

(5) Synthesis of N-(3α,7α,12α-trihydroxy-5β-cholanoamide)-ethylenediamine:

N-(3α,7α,12α-trihydroxy-5β-cholanoamide)-N'-tert-butoxycarbonylethylenediamine (200.0 mg, 0.36 mmol) was dissolved in MeOH (20 mL). A freshly prepared solution of hydrogen chloride in methanol (2N, 20 mL). Filtration, the filter cake was washed with EtOAc (EtOAc) The product identification data is as follows:

ESI-MS m/z: 473.3 [M+Na] ⁺ ;

^{1 H NMR: (DMSO-d} 6, 400MHz) 8.01-8.14 (m, 4H), 3.74 (br s, 4H), 3.56 (br s, 1H), 3.24 (dd, J = 6.0,11.6Hz, 2H) , 3.14 - 3.18 (m, 1H), 2.78 (dd, J = 5.6, 11.2 Hz, 2H), 0.88 (d, J = 6.0 Hz, 2H), 0.76 (s, 3H), 0.54 (s, 3H).

(6) (E)-3-[2-({4-[N-(3α,7α,12α-trihydroxy-5β-cholanoamide)-ethylenediamino]benzoyl}azido)benzene Propionate-{1-[2-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide)-3-(4-fluorophenyl)propanoyl]-piperidine Synthesis of -4-yl} ester:

(E)-3-{2-[(4-benzoyl)azido]phenyl}propionic acid-{1-[2-(5-chloro-1H-pyrrolo[2,3-c]pyridine 2-formamide)-3-(4-fluorophenyl)propanoyl]-piperidin-4-yl} ester (150 mg, 0.207 mmol) was dissolved in DMF (3 mL). 0.248 mmol) and DIPEA (0.1 mL, 0.621 mmol), stirred at room temperature for 10 min, then added N-(3α,7α,12α-trihydroxy-5β-cholaneamide)-ethylenediamine (120 mg, 0.266 mmol), stirred at room temperature overnight. Dried solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, the organic phase washed with saturated brine, dried over anhydrous Na ₂ SO _4, filtered, concentrated and the residue was isolated by reverse phase HPLC to give a white solid (25mg, 10.4%), i.e., The final glycogen phosphorylase inhibitor is obtained. The product identification data is as follows:

ESI-MS m/z: 1157.6 [M+H] ⁺ ;

^{1 H 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=6.0 Hz, 1H), 6.95-7.04 (m, 2H), 5.24-5.31 (m, 1H), 4.80-4.86 (m, 1H), 4.63 (br s, 1H), 3.86 (br s, 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 = 5.2 Hz, 3H) , 0.83 (d, J = 5.6 Hz, 3H), 0.54 (d, J = 12.4 Hz, 3H).

The identified product has the structural formula shown by formula (I ₁ ):

(1) The product of the structure of the formula (I ₁ ) obtained in this example was used for the in vitro GPase activity inhibition activity test:

1) Developer: 5 g of ammonium molybdate, 500 mL of 1 M HCl, add 190 mg of malachite green after stirring. Continue stirring until all is dissolved, and tin foil is stored in the dark;

2) Buffer: a) Accurately weigh 0.5958g of Hepes, dissolve it in 5mL of distilled water, adjust the pH to 7.2 with 10M NaOH, and set aside; b) accurately weigh 0.3728g of potassium chloride, dissolve it in 5mL of distilled water, and set aside; c) Weigh accurately 0.0255g of magnesium chloride, dissolved in 1mL of distilled water, spare; d) accurately weigh EGTA 0.0476g, dissolve in 5mL of distilled water, adjust the pH to 7.0 with 10M NaOH, spare; e) accurately weigh G- 1-P 0.0152g, dissolved in 10mL of distilled water, spare; f) accurately weighed 10mg of glycogen, dissolved in 1mL of distilled water, spare.

3) positive drug solution: accurately weigh a certain amount of caffeine, dissolved in 10mL of distilled water, formulated into 0.5, 5, 50, 500μM caffeine solution;

4) GPa solution: 1 μL of GPa was added to 100 μL of the reaction system to prepare a final concentration of 250 ng/100 μL of GPa solution;

5) The test compound solution: the compound to be tested is dissolved in DMSO to prepare a 10 mM stock solution, and an appropriate amount is added to the reaction system to different final concentrations;

6) Experimental procedure: (a) Design a PC (positive control) well, a Blank (blank control) well, a positive drug well (caffeine) and a test compound well in a 96-well plate; (b) a reaction buffer of 52 μL per well; (c) Add the test compound to the test compound to a final concentration of 1 μM, 5 μM, 10 μM, 25 μM, 50 μM, 100 μM. (d) Add 1 μL of enzyme to a final concentration of 250 ng/100 μL. PC (positive control) wells were only added with enzyme, Blank (blank control) wells were not added with enzyme; (e) 150 μL of coloring solution was added; (6) reaction was carried out for 20 min at 20-25 ° C; (f) at a wavelength of 655 nm Color; (g) preliminary calculation of the results. The results are shown in Table 1:

Inhibition rate = [(PC-B) - (X-B)] / (PC-B).

Table 1. In vitro GPase activity inhibitory activity of compounds

(2) The product of the structure of the formula (I ₁ ) obtained in the present example is used for hepatocyte glycogen degradation inhibition activity test:

Rat hepatocytes and human HepG2 cells were used separately, according to the literature report method (Proc.Natl.Acas. Sci, 1998, 95, 1776-1781; Brain Res., 2005, 1060, 89-99) Determination of the inhibition of glycogen degradation by compounds, the results are shown in Table 2:

Table 2. Inhibition of hepatic cell glycogenolysis by compounds

Data show that the activity of the above, the compound of formula Example (I ₁₎ of the present embodiment has glycogen phosphorylase inhibition, and the inhibition of the cellular level and glycogenolysis in quite PSN-357. Therefore, it can be used for preparing anti-diabetic drugs, anti-ischemic drugs, anti-cardiovascular drugs, hypolipidemic drugs, weight-loss drugs, anti-atherosclerotic drugs or anti-tumor drugs.

The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and modifications may be made without departing from the spirit and scope of the invention. Simplifications should all be equivalent replacements and are included in the scope of the present invention.

Claims

A glycogen phosphorylase inhibitor, characterized in that the glycogen phosphorylase inhibitor has the structural formula represented by formula (I) or a pharmaceutically acceptable salt or ester thereof:

Wherein: X 1 , X 2 , X 3 and X 4 are each a carbon atom linking group or one of X 1 , X 2 , X 3 and X 4 is a nitrogen atom linking group and the other is a carbon atom linking group. ; R 1 is H, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl, vinyl or ethynyl.
A glycogen phosphorylase inhibitor according to claim 1, wherein said R 1 is H, halogen or cyano.
According to a glycogen phosphorylase inhibitor according to claim 1, wherein: said glycogen phosphorylase inhibitor has the following formula acceptable (the I 1) of the formula or a pharmaceutically acceptable salt thereof or ester:
A method for preparing a glycogen phosphorylase inhibitor according to claim 1 or 2, which comprises the following steps:

(1) using a compound of the formula 1 as a starting material, obtaining a compound of the formula 2 by hydrogenation reduction, oxidation, azide;

(2) The compound of the formula 2 is esterified with a compound having the structure of formula 3 under the catalysis of DCC and DMAP to obtain an esterified product having the structure of the formula 4, and then obtained by the trifluoroacetic acid deprotecting agent. a structure containing a free carboxyl compound;

(3) a compound of the formula 5 is catalyzed by HATU and DIPEA, and is acylated with a cholic acid derivative of the structure of formula 6 to obtain a target compound glycogen phosphorylase inhibitor having the structure of formula (I);
The method for preparing a glycogen phosphorylase inhibitor according to claim 4, wherein the hydrogenation reduction in the step (1) refers to hydrogenation reduction using a Pd/C catalyst under alkaline conditions; The oxidation refers to the oxidation of a potassium persulfate composite salt in a mixed solvent of water and dichloromethane; the azidation means azidation with tert-butyl 4-aminobenzoate in an AcOH solvent. .
The method for producing a glycogen phosphorylase inhibitor according to claim 4, wherein the cholic acid derivative having the structure of formula 6 is prepared by the following method:

The bile acid was dissolved in anhydrous DMF, and then N-Boc-ethylenediamine, diethylpyrocarbonate and triethylamine were added, and the reaction was stirred at room temperature, and the reaction product was separated and purified to obtain a white solid product N-(3?,7? , 12α-trihydroxy-5β-cholanoamide)-N'-tert-butoxycarbonylethylenediamine; then it is dissolved in methanol, and deprotected by adding a freshly prepared solution of hydrogen chloride in methanol under ice bath to obtain a formula. 6 structure of the cholic acid derivative N-(3α,7α, 12α-trihydroxy-5β-cholinamide)-ethylenediamine.
The glycogen phosphorylase inhibitor according to any one of claims 1 to 3 for the preparation and prevention of diabetes and its complications, hyperlipemia, hypertension and its complications, atherosclerosis, obesity and metabolism Application in disease drugs.
The use according to claim 7, characterized in that the medicament comprises as an active agent a compound of the formula (I) or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier.
The use according to claim 8, characterized in that the pharmaceutically acceptable carrier means one or several inert, non-toxic solid or liquid fillers which do not adversely interact with the active agent or the patient. , thinner or auxiliaries.
The use according to any one of claims 7 to 9, characterized in that the pharmaceutical dosage form is a tablet, a capsule, a pill, a suppository, an oral solution, a suspension or an injection.