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WO2016041514A1 - Dérivés de tétrahydroberbérine et leur application - Google Patents

Dérivés de tétrahydroberbérine et leur application Download PDF

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WO2016041514A1
WO2016041514A1 PCT/CN2015/089880 CN2015089880W WO2016041514A1 WO 2016041514 A1 WO2016041514 A1 WO 2016041514A1 CN 2015089880 W CN2015089880 W CN 2015089880W WO 2016041514 A1 WO2016041514 A1 WO 2016041514A1
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李德群
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Chengdu Bestchiralbio Limited-Liability Co
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Chengdu Bestchiralbio Limited-Liability Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine

Definitions

  • the present technology relates to the treatment of hyperlipidemia (including hypertriglyceridemia and hypercholesterolemia), hepatic steatosis, type II diabetes, hyperglycemia, insulin resistance, obesity and metabolic syndrome. Uses, compounds and compositions.
  • Metabolic Syndrome is a pathological state in which a variety of metabolic components are abnormally aggregated. It is a complex metabolic disorder syndrome and is a risk factor for diabetes and cardiovascular and cerebrovascular diseases.
  • Cardio-cerebral vascular disease is the number one killer of human health. Its cause is very complicated. Hyperlipidemia is regarded as a very important risk factor by most people. With the improvement of living standards and the acceleration of aging, hyperlipidemia The incidence and mortality of the disease increased significantly, and there are reports in the literature that dyslipidemia is the main cause of atherosclerosis, coronary heart disease, and myocardial infarction.
  • Hyperlipidemia is often explained by the fact that fat metabolism or abnormal function causes one or more lipids in plasma to be above normal. Hyperlipidemia is a systemic disease, usually referred to as serum total cholesterol (TC), triglyceride (TG) or high density lipoprotein cholesterol (HDL-C) is too low, modern medicine called dyslipidemia . Lipids are insoluble or sparingly soluble in water, so they must bind to proteins to form lipoproteins. Therefore, hyperlipidemia is also commonly referred to as hyperlipoproteinemia.
  • TC serum total cholesterol
  • TG triglyceride
  • HDL-C high density lipoprotein cholesterol
  • Hyperlipidemia and cerebral infarction The increase of cholesterol in the blood is easy to form atherosclerotic plaque. When these plaques accumulate in the arterial wall, the arterial cavity will be narrowed, and the blood will flow into the corresponding part, which will cause kinetic energy defect. When it occurs in the cerebral blood vessels, it can cause cerebral infarction. Medical evidence: long-term lipid-lowering treatment can not only treat cerebral infarction, but also prevent cerebral infarction.
  • Coronary heart disease is also known as coronary atherosclerotic heart disease. Coronary artery is the main artery that supplies blood to the heart. If too much fat is deposited, it will cause arteriosclerosis, which will hinder blood flow, cause heart ischemia, and a series of symptoms, namely coronary heart disease. There are many risk factors for coronary heart disease, such as: high blood lipids, smoking, obesity, high blood pressure, lack of physical activity, diabetes, family history of coronary heart disease, etc. Among them, high blood lipids are one of the important risk factors for coronary heart disease. Therefore, the most basic treatment for coronary heart disease is to regulate blood lipids.
  • Fatty liver refers to the accumulation of fat in the liver, often accompanied by increased blood lipids.
  • the incidence of fatty liver is as high as 5-10%, and about 35% of adult patients with transaminase are fatty liver. Some severe patients can develop cirrhosis. Therefore, fatty liver treatment should also be treated with lipid-lowering.
  • Hyperlipidemia and diabetes Hypertension, hyperlipidemia and hyperglycemia are often referred to as “three highs” and are a major factor threatening the health of people with diabetes. The three are closely related, high blood lipids can aggravate the symptoms of diabetes, most diabetic patients with high blood lipids, more likely to cause stroke, coronary heart disease, limb necrosis, fundus lesions, kidney disease, neuropathy, etc., therefore, in addition to treatment of hyperglycemia in diabetic patients In addition, attention should be paid to regulating blood lipids, which is very important to reduce mortality and disability in diabetic patients.
  • Hyperlipidemia is defined as a dyslipidemia or dyslipidemia. Usually refers to the body's blood lipid concentration is beyond the normal range. Includes triglyceride (TG), serum total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C) or low-density lipoprotein cholesterol (LDL-C) levels and high-density lipoprotein cholesterol (HDL-C) Level reduction With the in-depth study of hyperlipidemia and cardiovascular disease, people began to realize that hypolipidemicemia is very important for reducing the risk of cardiovascular disease.
  • TG triglyceride
  • TC serum total cholesterol
  • VLDL-C very low-density lipoprotein cholesterol
  • LDL-C low-density lipoprotein cholesterol
  • HDL-C high-density lipoprotein cholesterol
  • the blood lipid-lowering drugs commonly used in the market mainly include statins, fibrates, niacins, and bile acid sequestrants.
  • Statins represent drugs: atorvastatin, simvastatin, lovastatin, pravastatin, fluvastatin, and the like. These drugs are the fastest-developing lipid-lowering drugs in recent years, mainly to inhibit the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the serum total cholesterol (TC) synthesis pathway. The activity reduces TC synthesis; increases the number of low-density lipoprotein receptors, accelerates LDL degradation, and increases HDL content, which is beneficial to the clearance and transport of TC.
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A
  • statins the side effects are inevitable, such as: rhabdomyolysis, myositis and various enzyme activities in the liver, and some patients are not well adapted to the treatment of statins, more important The single statin treatment often does not achieve the desired results.
  • the fibrates represent drugs: clofibrate, gemfibrozil, fenofibrate, etc. After long-term clinical application, these drugs have been proven to be a class of drugs that are well tolerated and have good lipid-lowering effects.
  • its lipid-lowering pathway increases the activity of lipoprotein lipase, which increases the clearance of triglyceride (TG); lowers blood sugar, which makes the synthesis of glucose and free fatty acids tend to glucose. Lipid synthesis is reduced.
  • Niacin represents a drug: niacin, inositol niacin, acyclovir and the like. These drugs mainly inhibit the synthesis of triglyceride (TG) and very low density lipoprotein (VLD-L) by inhibiting the decomposition of fat and the formation of free fatty acids to reduce blood lipids.
  • TG triglyceride
  • VLD-L very low density lipoprotein
  • Inadequacies The effect of lowering blood lipids in diabetic patients is not obvious. Side effects such as: liver poisoning, high blood sugar is more obvious, and skin reactions such as skin plague and itching often occur.
  • the bile acid sequestrants represent drugs: Ezetimibe, polyunsaturated fatty acids, and the like. Such lipid-lowering drugs can be classified into two types: cholesterol absorption inhibitors and polyunsaturated fatty acids.
  • Cholesterol absorption inhibitor (Yibei Maibu): combined with bile acid, hinders the reabsorption of bile acid, thereby promoting the conversion of cholesterol into bile acid, which is excreted in the intestine and the drug.
  • Coptis is a valuable traditional Chinese medicine containing berberine, palmatine, coptisine and other important alkaloids. Its pharmacological effects are very broad, mainly involving tumors, inflammation, diabetes and cardiovascular diseases. In recent years, it regulates blood lipids. The attention has been significantly improved.
  • LDL low-density lipoprotein
  • LDLR low-density lipoprotein receptor
  • PCSK9 proprotein convertase subtilisin/kexin type 9
  • PCSK9 is a serine protease that is mainly synthesized in the liver, which can reduce the amount of LDLR in hepatocytes. After binding to LDLR located on the cell surface, PCSK9 internalizes into cells and promotes LDLR degradation in lysosomes. Inhibition of PCSK9 activity increases the number of LDLRs and decreases plasma LDL levels.
  • PCSK9 inhibitors are an important direction for large multinational pharmaceutical companies to develop new cardiovascular disease drugs. It is expected that these drugs will surpass statin mature lipid-lowering drugs. Large pharmaceutical companies are working hard to promote the development of PCSK9 inhibitor drugs, and the current research work is focused on the development of biologic drugs.
  • berberine is the main alkaloid of Coptis chinensis and has a good lipid-lowering effect.
  • the lipid-lowering mechanism of berberines has been revealed continuously. Studies have shown that berberine can inhibit the expression of PCSK9, increase the expression of LDLR, and complete the clearance of LDL by LDLR-mediated endocytosis, which can achieve a clear lipid-lowering effect. efficacy. This is completely different from the lipid-lowering mechanism commonly used in the market for statins.
  • the lipid-lowering effect of berberine has been clinically confirmed, but its water solubility is low due to its molecular structure. The oral berberine absorption is not good in patients. Occasionally, there are some side effects such as mild constipation. Therefore, the low utilization rate in the organism is The main factors directly affecting the lipid lowering effect of berberine.
  • a series of patent applications for small molecule compounds of PCSK9 inhibitors are disclosed, including WO2010075469, WO2011006000, WO2011051961, WO2011152508, WO2012090220, JP2013136572, WO2013132509, WO2013137371, WO2014017569, WO2014002105, WO2014002106, and the like.
  • the object of the present invention is to provide a compound of the formula (V), and their tautomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolism Precursor or prodrug.
  • a compound of formula V a compound of formula (V)
  • R 1 , R 2 , R 4 , R 9 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently hydrogen, halo, substituted or unsubstituted silicon, amino, nitro, Oxy, thio, sulfone, cyano, carbonyl, sulfonyloxy, phosphoryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, Heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl; alternatively, R 1 and R 2 together form an oxygen-containing, nitrogen-containing, sulfur- or silicon-containing 3 to 8 membered heterocyclic ring or 3 to 8 yuan carbon ring;
  • R 3 , R 3 ', R 8 and R 8 ' are each independently -H, or R 3 and R 3 ' are independently oxo, substituted or unsubstituted alkyl, aryl; or R 8 And R 8 ' are each independently an oxo group, a substituted or unsubstituted alkyl group, an aryl group;
  • R 10 and R 11 are each independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, hetero Arylalkyl, heterocyclic or heterocyclylalkyl,
  • NR 10 R 11 may be a 4-20 membered nitrogen-containing heterocyclic group;
  • the present invention relates to a compound of the formula (V) wherein R 5 , R 6 and R 7 are each independently hydrogen, halo, -OH, -NR 10 R 11 , -NO 2 , -CN, -(CH 2 ).
  • the present invention relates to a compound of the formula (V) wherein R 5 is independently selected from -SO 3 R 10 , -SO 2 R 10 , -OSO 2 R 10 , -OSO 2 NR 10 R 11 , -NHSO 2 R 10 , and R 10 and R 11 are as defined above.
  • the present invention relates to a compound of the formula (V) wherein R 6 is independently selected from -SO 3 R 10 , -SO 2 R 10 , -OSO 2 R 10 , -OSO 2 NR 10 R 11 , -NHSO 2 R 10 , R 10 and R 11 are as defined in claim 1.
  • the present invention relates to a compound of the formula (V) wherein R 7 is independently selected from -SO 3 R 10 , -SO 2 R 10 , -OSO 2 R 10 , -OSO 2 NR 10 R 11 , -NHSO 2 R 10 , and R 10 and R 11 are as defined above.
  • the present invention relates to a compound of the formula (V) wherein R 5 , R 6 and R 7 are each independently -H, -F, -OH, -N(CH 3 ) 2 , -CH 3 , -C 2 H 5 , -OCH 3 , -OC 2 H 5 , -NO 2 , -CN, -OC(O)CH 3 , -OC(O)C 2 H 5 , -NHC(O)OCH 2 CH 3 , -OC( O) OCH 3 , -OC(O)N(CH 3 ) 2 , -OC(O)-morpholinyl, -OC(O)N(CH 3 )(C 2 H 5 ),
  • C 1-6 alkyl is optionally substituted by 0 to 13 substituents
  • the thienyl and furyl groups are optionally substituted with from 0 to 3 substituents,
  • the pyridyl group is optionally substituted with from 0 to 4 substituents.
  • pyrimidinyl and pyridazinyl are optionally substituted by 0 to 3 substituents,
  • the phenyl group is optionally substituted with from 0 to 5 substituents.
  • the naphthyl group is optionally substituted with from 0 to 7 substituents.
  • substituents are selected from the group consisting of: hydroxy, halogen, cyano, nitro, -COOH, -N(CH 3 ) 2 , C 1-6 alkyl, C 1-6 alkoxy,
  • R 5 , R 6 and R 7 is not selected from -H, -F, -OH, -N(CH 3 ) 2 , -CH 3 , -C 2 H 5 , -OCH 3 , -OC 2 H 5 , -NO 2 , -CN.
  • R 13 , R 14 , R 15 and R 16 are each independently -H, halo, substituted or unsubstituted alkyl, aryl, heteroaryl, alkynyl.
  • the present invention relates to a compound of the formula (V) which is selected from the following compounds, but is not limited to the following compounds:
  • the present invention relates to a compound of the formula (V), which comprises a pharmaceutical composition comprising a compound of any one and a pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition consisting of a compound of the formula (V), which comprises a compound which is administered to any one of a therapeutically effective amount of a patient in need of treatment.
  • the present invention relates to the use of any one of the compounds of the formula (V) for the preparation of a medicament for lowering the lipid level of a patient's plasma and/or liver.
  • the present invention relates to a compound or a condition comprising a compound of the formula (V) for use in the treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis and metabolic syndrome. Use of the drug.
  • the present invention relates to the use of any one of the compounds of the general formula (V) for the preparation of a medicament for increasing LDLR expression and/or reducing PCSK9 expression.
  • the present invention relates to the use of any one of the compounds of the formula (V) for the preparation of a medicament for reducing LDL-cholesterol and/or plasma triglycerides.
  • the present invention relates to the use of a compound according to any one of the compounds of the formula (V) for the preparation of a medicament for the treatment of type 2 diabetes, hyperglycemia, obesity or insulin resistance.
  • the present invention discloses a process for preparing a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, which comprises the steps of:
  • V1 and V2 are dehydrated at a certain reaction temperature to obtain imine compound V3, and compound V3 is reduced to compound V4.
  • V4 is reacted with glyoxal to obtain a four-membered ring compound V5;
  • the compound V7 can obtain V under certain reducing conditions
  • compound V5 first obtains V6 under certain reducing conditions, and then compound V6 is further chemically modified to obtain compound V; wherein:
  • R 1 to R 9 and R 12 to R 16 are as defined above.
  • the present invention relates to a compound of the formula (V), wherein the tetracyclic structural fragment is 5,6,7,8,13,13a-hexahydroisoquino[2,1-b]isoquinoline (VIII),
  • VIII 5,6,7,8,13,13a-hexahydroisoquino[2,1-b]isoquinoline
  • the berberine and tetrahydroberberine which are currently reported in the literature, have the effect of down-regulating the expression of PCSK9 gene and enhancing the uptake of LDL by hepatocytes.
  • Further research and patent literature disclose a 4-linker fragment (eg, sulfonyloxy)
  • the VIII compound of the ligated fragment, carbonyloxy linking fragment has a similar effect.
  • the structural and active efficacy research strategies are concentrated in the 4 position.
  • there are few studies on the relationship between the structure and the activity efficiency of the 5,6,7-link fragment change and there are obvious limitations.
  • the structural changes based on the 5,6,7-link fragment have not been obtained and are not dependent on 4 The substitution results in a compound which is more excellent in activity than tetrahydroberberine.
  • Aromatic ring systems are abundant in drugs and are important drug structural fragments. Changes in the type and location of the aromatic ring linker in a drug often cause large changes in the physical, chemical, and biological properties of the drug molecule. The activity of a drug is the result of a combination of physical, chemical, and biological properties of the drug. Therefore, changes in the type of the linker and the position of the ligation in the drug molecule often cause unexpected pharmaceutically active effects (for example, even causing the drug to have the opposite effect on the same target of action such as activation and inhibition).
  • This patent has fully studied the 5,6,7-position ligation fragment on the aromatic D ring in the structural fragment VIII, and surprisingly found that at least one site at the 5, 6, and 7 positions is independently an acyloxy group.
  • a linking moiety such as a sulfonyloxy group, a carbonyloxy group and a phosphoryloxy group, especially selected from the group consisting of -SO 2 R 10 .
  • the compound of (VIII) obtained by the ligation fragment of -OSO 2 R 10 , -OSO 2 NR 10 R 11 has strongly inhibited the expression of the PCSK9 gene, strongly increasing the hepatocyte to LDL. Ingestion ability.
  • the synthesized 5,6,7-linked (VIII) compound disclosed in the present invention has the advantages of easy availability of raw materials, simple preparation process and low cost compared with the prior art synthesis of the 4-position-linked (VIII) compound. Advantage.
  • the raw materials are easy to obtain, the operation is simple, and the cost is low.
  • the raw materials used are all commercially available or raw materials obtained by a simple chemical reaction according to literature methods.
  • the starting materials of the prior art 4-position-linked (VIII) compounds require complex organic chemical reactions and can be prepared using harsh reaction conditions.
  • the starting material for the preparation method of the 4-position-linked (VIII) compound disclosed in the patent WO2010075469 requires a one-step high temperature (110 ° C) sealing reaction for 48 hours to obtain one of the starting materials, resulting in a large amount of energy consumption, cost. Increase, the number of unsafe hidden dangers increases.
  • the starting materials used in the synthesis of the 5,6,7-linked (VIII) compounds disclosed in the present invention are all common chemical reagents, and the synthesis of the 4-position-linked (VIII) compound disclosed in the patent WO2010075469, wherein the structural fragment (VIII)
  • the highly toxic reagent of phosphorus oxychloride is used as a dehydrating agent and an acylating reagent.
  • the toxicity of phosphorus oxychloride is equivalent to that of phosgene, which is liable to cause great harm to people and the environment.
  • the aromatic ring substitution site is an important site in the process of oxidative metabolism. Therefore, different substitution positions of the aromatic ring can produce unexpected new characteristics of drug metabolism, such as increasing half-life, etc., providing more enrichment for drug and composition development. More conducive to the choice of clinical treatment.
  • V1 and V2 are starting materials for the scheme, which can be obtained by commercially available products or prepared according to methods reported in the literature.
  • V1 and V2 are dehydrated to obtain imine compound V3 under certain reaction temperature conditions, and compound V3 is reduced to "amine" compound V4.
  • V4 reacts with glyoxal to obtain four-membered ring compound V5.
  • V7 is obtained by further modifying the compound V5, and the compound V7 is V under certain reducing conditions; on the other hand, the compound V5 first obtains V6 under certain reducing conditions, and then the compound V6 is further chemically modified to obtain the compound V. .
  • the preparation scheme of the general compound (V) is introduced by taking a representative synthetic preparation procedure and specific compound synthesis examples in the patent of the present invention as an example.
  • the preparation scheme of the compound of the present invention is not limited to the following representative processes and specific examples:
  • Representative Process I Mainly for the preparation of D ring has two important oxoyl functional groups (D ring contains two oxo functional groups, such as acetoxy, benzoyloxy, benzyloxy, sulfonyloxy , phosphoryloxy, etc.) compounds.
  • Representative Process 2 Mainly for the preparation of D ring, only one important oxo group functional group (D ring contains an oxo group, such as acetoxy, benzoyloxy, benzyloxy, sulfonyloxy, phosphorus A compound such as an acyloxy group.
  • Step 1 Preparation of sulfonyloxy and monohydroxy substituted benzaldehyde (S2A):
  • the substituted benzaldehyde S3 which is commercially available (or prepared according to literature methods), was sequentially introduced into the methanol, and the methylamine solution was added. The reaction was stirred at 50 ° C, and a large amount of yellow solid appeared. After the reaction was completed by TLC, it was allowed to cool and suction filtered. The yellow solid S4 was obtained by washing with a small amount of methanol.
  • the S4 obtained in the previous step was added to methanol and stirred vigorously to make it a turbid liquid. Further, ethanol and 1,4-dioxane were sequentially added to the eggplant-shaped flask, NaBH 4 was added in portions, and the suspension prepared previously was added dropwise with stirring. After the dropwise addition, the mixture was stirred at room temperature overnight. The solution gradually turned orange. The ice water was added to the next day, and the pH of the system was adjusted to 2 to 4 with glacial acetic acid. The mixture was transferred to a sep. funnel and extracted with ethyl acetate. The organic layer was washed with water and brine, and then evaporated. A brownish red oil S5. .
  • the phenylethylamine S6 and S2A substituted with a benzene ring are dissolved in dichloromethane, and reacted at 50 to 60 ° C to form an imine compound S13.
  • a methanol solution is added thereto at a low temperature of 10 to 5
  • the reduction reaction was carried out under the conditions of °C, sodium borohydride was added in portions, the methanol solvent was removed in vacuo, and the solvent was evaporated to ethyl acetate, washed with saturated brine, and the ethyl acetate layer was combined, and concentrated under reduced pressure to give S14.
  • Step 4 Further modification of the 5,6,7,8,13,13a-hexahydroisoquino[6,1-b]isoquinoline structure (S16A):
  • the S16 prepared in the above step is dissolved in dichloromethane, triethylamine is added, and then the appropriate halogenated compound (halogenated acyl compound, halogenated hydrocarbon, etc., such as sulfonyl chloride, is slowly added at a low temperature of -10 to 5 °C. Acetyl chloride, etc., slowly warming to room temperature and stirring the reaction. After the reaction is completed, it is added with water and dispersed, and extracted with an organic solvent such as ethyl acetate. The organic layer is combined and dried over anhydrous sodium sulfate to give a crude compound. Purification method to prepare the target compound S16A.
  • halogenated acyl compound, halogenated hydrocarbon, etc. such as sulfonyl chloride
  • the D ring is only one oxo group (for example: acetoxy, benzoyloxy, benzyloxy, sulfonyloxy, phosphoryloxy) Etc.)
  • the preparation method of the substituted compound is taken as an example, and an example is briefly described:
  • Figure 1 shows the effect of the fluorescence intensity observed under the microscope on the ability of the sample to take up LDL by hepatocytes after compound treatment.
  • Fig. 2 is a graph showing the comparison of serum low-density lipoprotein cholesterol (LDL-C) in high-fat SD rats after oral administration of some of the compounds of the present invention for four weeks.
  • LDL-C serum low-density lipoprotein cholesterol
  • Fig. 3 shows a comparison of the results of determination of total cholesterol (TC) in serum of a high-fat SD rat after oral administration of a part of the compound of the present invention for four weeks.
  • Figure 4 is a graph showing the comparison of serum alanine aminotransferase (ALT) levels in high-fat SD rats after oral administration of some of the compounds of the present invention for four weeks.
  • Fig. 5 is a graph showing the comparison of the results of serum aspartate aminotransferase (AST) in high-fat SD rats after oral administration of some of the compounds of the present invention for four weeks.
  • AST serum aspartate aminotransferase
  • the present technology provides novel compounds, and the use of the compounds in reducing plasma and/or liver lipid levels, as well as in the treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, Uses in hepatic steatosis, type 2 diabetes, hyperglycemia, insulin resistance, obesity, and metabolic syndrome.
  • the compounds provided herein can be formulated into pharmaceutical compositions and medicaments for use in the methods disclosed herein.
  • the invention also provides the use of the compound for the preparation of a pharmaceutical formulation and a medicament, the use of the compound for lowering lipid levels in plasma and/or liver, and the compound in the treatment of hyperlipidemia, hypercholesterolemia Use in disease, hypertriglyceridemia, hepatic steatosis, type 2 diabetes, hyperglycemia, insulin resistance, obesity, and metabolic syndrome.
  • an element such as hydrogen or H
  • R group is defined to include hydrogen or H, it also includes ruthenium and osmium.
  • Compound comprises a radioisotope (e.g., tritium, C 14, P 32 and S 35) is therefore also within the scope of the present invention. Means for inserting such markers into the compounds of the invention will be apparent to those skilled in the art based on the disclosure herein.
  • substituted means an organic group (e.g., an alkyl group) as defined below wherein one or more hydrogen-bonded bonds are replaced by a bond to a non-hydrogen atom or a non-carbon atom.
  • Substituted groups also include groups in which one or more bonds to a carbon or hydrogen atom are replaced by one or more bonds (including double or triple bonds) linking the heteroatoms.
  • a substituted group is substituted with one or more substituents. In some embodiments, the substituent is substituted with 1, 2, 3, 4, 5 or 6 substituents.
  • substituents examples include halogen (i.e., F, Cl, Br, and I), a hydroxyl group, an alkoxy group, an alkenyloxy group, an aryloxy group, an aralkyloxy group, a heterocyclic oxygen group, and a heterocyclic alkoxy group.
  • halogen i.e., F, Cl, Br, and I
  • a hydroxyl group an alkoxy group, an alkenyloxy group, an aryloxy group, an aralkyloxy group, a heterocyclic oxygen group, and a heterocyclic alkoxy group.
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclic, and heteroaryl, also include ring and ring systems in which a bond to a hydrogen atom is replaced by a bond to a carbon atom.
  • the substituted cycloalkyl, aryl, heterocyclic and heteroaryl groups may also be substituted by substituted or unsubstituted alkyl, alkenyl and alkynyl groups as defined below.
  • the alkyl group includes a linear or branched group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 12 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ring Alkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -C(O)R 10 , -C(O)OR 10 , -S(O) m R 10 ,- NR 10 R 11 , -C(O)NR 10 R 11 , -NR 10 C(O)R 11 , -NR 10 S(O) m R 11 or -S(O) m NR 10 R 11
  • a cycloalkylalkyl group means an alkyl group substituted with a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 Up to 10 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • Alkenyl refers to an unsaturated alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- Butyl group and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, -C(O)R 10 , -C(O)OR 10 , -S(O) m R 10 , -NR 10 R 11 , -C(O)NR 10 R 11 , -NR 10 C (O) R 11 , -NR 10 S(O) m R 11 or -S(O) m NR 10 R 11 .
  • Cycloalkenyl refers to an unsaturated cycloalkyl group as defined above having at least one double bond between two carbon atoms.
  • a cycloalkenyl group can have one, two or three double bonds but does not include an aromatic compound.
  • the cycloalkenyl group contains 4 to 14 carbon atoms or, in some embodiments, 5 to 14 carbon atoms, preferably 5 to 10 carbon atoms, more preferably 5, 6, 7 or 8 carbon atoms.
  • Examples of the cycloalkenyl group include a cyclohexenyl group, a cyclopentenyl group, a cyclohexadienyl group, a butadienyl group, a pentadienyl group, and a hexadienyl group.
  • alkynyl group means an unsaturated alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, -C(O)R 10 , -C(O)OR 10 , -S(O) m R 10 , -NR 10 R 11 , -C(O)NR 10 R 11 , -NR 10 C (O) R 11 , -NR 10 S(O) m R 11 or -S(O) m NR 10 R 11 .
  • the aryl group is a cyclic aromatic hydrocarbon containing no hetero atoms.
  • Aryl groups include monocyclic, bicyclic, and tricyclic systems herein.
  • aryl groups include, but are not limited to, phenyl, methoxyheptyl, diphenyl, indenyl, phenanthryl, anthracenyl, fluorenyl, indanyl, cyclopentadienyl, and naphthyl.
  • the aryl group contains 6-14 carbons, preferably 6 to 12, more preferably 6-10 carbon atoms in the ring portion of the group.
  • the aryl group is phenyl or naphthyl.
  • aryl includes groups containing a fused ring (eg, a fused aromatic-aliphatic ring system) (eg, indanyl, tetrahydronaphthyl, and the like), it does not include having members with rings
  • An aryl group of one of the other groups bonded for example, an alkyl group or a halogenated group.
  • a group such as a tolyl group is referred to as a substituted aryl group.
  • Representative substituted aryl groups can be monosubstituted or substituted more than once.
  • monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5- or 6-substituted phenyl or naphthyl groups, which may be substituted, for example, with the substituents listed above.
  • Aralkyl is an alkyl group as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined above.
  • the aralkyl group contains from 7 to 16 carbon atoms, preferably from 7 to 14 carbon atoms, more preferably from 7 to 10 carbon atoms.
  • the substituted aralkyl group may be substituted at the alkyl group, the aryl group, or both the alkyl group and the aryl moiety.
  • Representative aralkyl groups include, but are not limited to, benzyl and phenethyl and fused (cycloalkylaryl)alkyl (eg, 4-indolylethyl).
  • Representative substituted aralkyl groups can be substituted one or several times with, for example, the substituents listed above.
  • Heterocyclyl includes aromatic (also referred to as heteroaryl) and non-aromatic cyclic compounds containing three or more ring members, wherein one or more of the ring members are heteroatoms such as, but not limited to, N. , O and S.
  • a heterocyclic group contains 1, 2, 3 or 4 heteroatoms.
  • heterocyclyl includes mono, di, and tricyclic rings having from 3 to 16 ring members.
  • Heterocyclyl groups include aromatic, partially unsaturated and saturated ring systems such as imidazolyl, imidazolinyl and imidazolidinyl.
  • heterocyclyl includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as benzotriazolyl, 2,3-dihydrobenzo[1,4]. Dioxoalkyl and benzo[1,3]dioxolyl.
  • the phrase also includes bridged polycyclic systems containing heteroatoms such as, but not limited to, quinuclidinyl. However, the phrase does not include heterocyclic groups having other groups (eg, alkyl, oxo or halo groups) bonded to one of the ring members.
  • Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, Furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl , thiazolinyl, isothiazolyl, thiadiazo, oxadiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetra
  • substituted heterocyclic groups may be monosubstituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5- or 6-substituted or substituted by various substituents such as those listed above A disubstituted pyridyl or morpholinyl group.
  • a heteroaryl group is an aromatic ring compound containing five or more ring member atoms, wherein one or more ring members are heteroatoms such as, but not limited to, N, O and S.
  • Heteroaryl groups include, but are not limited to, the following groups, for example, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl , pyrazinyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, fluorenyl, azaindolyl (pyrrolopyridinyl), oxazolyl, benzimidazolyl, Imidazopyridyl (azabenzimidazolyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzox
  • Heteroaryl groups include fused ring compounds in which all of the rings are aromatic, such as fluorenyl groups, which also include fused ring compounds in which only one ring is aromatic, such as 2,3-dihydroindenyl.
  • heteroaryl includes fused ring compounds, the phrase does not include heteroaryl groups having other groups (eg, alkyl groups) bonded to one of the ring members.
  • a heteroaryl group having such a substitution is referred to as a "substituted heteroaryl group.”
  • Representative substituted heteroaryl groups can be substituted one or several times with, for example, the various substituents listed above.
  • Heterocyclylalkyl is an alkyl group as defined above, but wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to a heterocyclic group as defined above.
  • the substituted heterocyclic alkyl group may be substituted at the alkyl group or the heterocyclic group or at both the alkyl group and the heterocyclic group.
  • Representative heterocyclylalkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl, pyridin-3-yl-methyl, tetrahydrofuran 2-yl-ethyl and ind-2-yl-propyl.
  • Representative substituted heterocyclylalkyl groups can be substituted one or several times with, for example, the substituents listed above.
  • Heteroarylalkyl is an alkyl group as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined above. Substituted The heteroarylalkyl group may be substituted at the alkyl or heteroaryl portion or at both the alkyl and heteroaryl portions. Representative substituted heteroarylalkyl groups can be substituted one or several times with, for example, the substituents listed above.
  • the groups described herein having two or more points of attachment are designated by the prefix "sub".
  • the divalent alkyl group is an alkylene group
  • the divalent aryl group is an arylene group
  • the divalent heteroaryl group is a heteroarylene group, and the like.
  • Substituted groups having a single point of attachment to a compound of the invention do not use a "sub" designation.
  • chloroethyl is not referred to herein as chloroethylene.
  • An oxo group means a substituent group formed by linking with an oxygen atom, wherein the group bonded to the oxygen atom is a substituted or unsubstituted alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, an alkyl group. , aryl acyl, heteroaryl acyl.
  • the above group may be bonded to an oxygen atom to form an alkoxy group, an aryloxy group, a heteroaryloxy group, a cycloalkyloxy group, an alkyl acyloxy group, an aryl acyloxy group, a heteroaryl acyloxy group, and a ring.
  • Alkyl acyloxy Alkyl acyloxy.
  • the alkoxy group is a substituent in which a bond to a hydrogen atom in a hydroxyl group (-OH) is replaced by a bond to a carbon atom of the substituted or unsubstituted alkyl group defined above.
  • linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like.
  • branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy and the like.
  • cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Representative substituted alkoxy groups can be substituted one or several times with, for example, the substituents listed above.
  • alkanoyl and “alkanoyloxy” as used herein mean -C(O)-alkyl and -O-C(O)-alkyl, respectively, each of which contains from 2 to 5 carbon atoms.
  • aryloxy and arylalkoxy mean, respectively, a substituent formed by bonding a substituted or unsubstituted aryl group to an oxygen atom, a substituted or unsubstituted aralkyl group and an oxygen atom.
  • a substituent formed by bonding examples include, but are not limited to, phenoxy, naphthyloxy, and benzyloxy.
  • Representative substituted aryloxy and arylalkoxy groups can be substituted one or several times with, for example, the substituents listed above.
  • carboxylic acid refers to a -COOH group.
  • Carboxylate refers to a -COOR 10 group.
  • R 10 is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group, as defined herein.
  • amide includes C-amide groups and N-amide groups, i.e., -C(O)NR 10 R 11 and -NR 10 C(O)R 11 groups, respectively.
  • R 10 and R 11 are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocycle as defined herein. base.
  • the amide group thus includes, but is not limited to, a carbamoyl group (-C(O)NH 2 ) and a formamide group (-NHC(O)H).
  • the amide is -NR 10 C(O)-(C 1-5 alkyl), the group is referred to as “carbonylamino”, and in other embodiments, the amide is -NHC(O) -Alkyl, this group is referred to as "alkanoylamino".
  • nitrile or "cyano” as used herein refers to a -CN group.
  • Carbamates include N-carbamate groups and O-carbamate groups, i.e., -NR 10 C(O)OR 11 and -OC(O)NR 10 R 11 groups, respectively.
  • R 10 and R 11 are independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group, as defined herein.
  • R 10 can also be H.
  • amine refers to a radical -NR 10 R 11 wherein R 10 and R 11 are, independently, hydrogen or substituted or unsubstituted alkyl as defined herein, Alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclic.
  • the amine is an alkylamino, dialkylamino, arylamino or alkylarylamino group.
  • the amine is NH 2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino or benzylamino.
  • sulfonamide includes both S-sulfonamide groups and N-sulfonamide groups, i.e., -SO 2 NR 10 R 11 and -NR 10 SO 2 R 11 groups, respectively.
  • R 10 and R 11 are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocycle as defined herein. base.
  • Sulfonamide groups thus include, but are not limited to, sulfonyl groups (-SO 2 NH 2 ).
  • a sulfonamide -NHSO 2 - alkyl which is referred to as "alkylsulfonylamino.”
  • thiol refers to a -SH group
  • the sulfide includes a -SR 10 group
  • the sulfoxide includes a -S(O)R 10 group
  • the sulfone includes a -SO 2 R 10 group
  • the sulfonyloxy group includes -OSO 2 R 10
  • sulfonic acid oxy group includes -OSO 2 OR 10 .
  • R 10 is independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl group, as defined herein.
  • the sulfide is an alkyl thiol group, -S-alkyl.
  • urea refers to a -NR 10 -C(O)-NR 10 R 11 group.
  • the R 10 and R 11 groups are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclic or heterocyclic ring, as defined herein. Alkyl group.
  • ⁇ refers to -C(NR 10 )NR 10 R 11 and -NR 10 C(NR 10 )R 11 , wherein R 10 and R 11 are each independently hydrogen as defined herein or substituted or not Substituted alkyl, cycloalkyl, alkenyl, alkynyl, arylarylalkyl, heterocyclyl or heterocyclylalkyl.
  • ⁇ refers to -NR 10 C(NR 10 )NR 10 R 11 , wherein R 10 and R 11 are each independently hydrogen or substituted or unsubstituted alkyl, cycloalkyl, as defined herein, Alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl.
  • halo refers to bromo, chloro, fluoro or iodo. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.
  • hydroxy refers to -OH, or may be an ionized form as used herein -O -.
  • imide refers to -C(O)NR 10 C(O)R 11 , wherein R 10 and R 11 are each independently hydrogen or substituted or unsubstituted alkyl, ring, as defined herein. Alkyl, alkenyl, alkynyl, arylarylalkyl, heterocyclyl or heterocyclylalkyl.
  • nitrogen-containing heterocyclic group refers to a ring system containing a nitrogen atom which may "couple” aromatic and non-aromatic ring systems, or link other ring systems through “spirocarbon atoms", such as the following structure:
  • the term "imine” refers to a -CR 10 (NR 11 ) and -N(CR 10 R 11 ) group, wherein R 10 and R 11 are each independently hydrogen or substituted or unsubstituted as defined herein.
  • nitro means -NO 2 when used herein.
  • trifluoromethyl refers to a -CF 3.
  • salts of the compounds described herein are within the scope of the invention and include such acid addition or base addition salts which retain the desired pharmacological activity and are not biologically potential Poor effects (eg, salts are not excessively toxic, sensitizing or irritating, and are bioavailable).
  • the compound of the present invention has a basic group (for example, an amino group), it can be combined with a mineral acid (for example, hydrochloric acid, borohydride, nitric acid, sulfuric acid, and phosphoric acid), an organic acid (for example, alginate, formic acid, acetic acid, benzoic acid, Gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and p-toluenesulfonic acid) or acidic amino acids (eg aspartame)
  • a mineral acid for example, hydrochloric acid, borohydride, nitric acid, sulfuric acid, and phosphoric acid
  • an organic acid for example, alginate, formic acid, acetic acid, benzoic acid, Gluconic acid, fumaric
  • the compound of the present invention When the compound of the present invention has an acidic group such as a carboxylic acid group, it can be combined with a metal such as an alkali metal and an alkaline earth metal (for example, Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ) ), ammonia or organic amines (such as dicyclohexylamine, trimethylamine, triethylamine, pyridine, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (such as arginine, lysine and ornithine) ) form a salt.
  • a metal such as an alkali metal and an alkaline earth metal (for example, Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ )
  • ammonia or organic amines such as dicyclohexylamine, trimethylamine, triethylamine, pyridine, ethanolamine,
  • the compounds of the invention may exhibit tautomerism, conformational isomerism, geometric isomerism and/or stereoisomerism.
  • formulae in the specification and claims represent only one of the possible tautomeric, conformational, stereoisomeric or geometric isomeric forms, it is to be understood that the invention includes a compound having one of the ones described herein or Any tautomeric, conformational, stereoisomeric, and/or geometric isomeric form for a variety of uses, as well as mixtures of these various forms.
  • Stereoisomers of the compounds including all chiral, diastereomeric and racemic forms of the structure, unless explicitly indicated for stereochemistry.
  • compounds useful in the present invention include optical isomers that are enriched or resolved at any or all of the asymmetric atoms. Racemic and diastereomeric mixtures, as well as optical isomers, may be isolated or synthesized to be substantially free of their corresponding isomers or diastereomers, and these stereoisomers are also Within the scope of the invention.
  • the compounds of the invention may exist as solvates, especially as hydrates.
  • the hydrate can be formed during the manufacture of the compound or composition comprising the compound, or the hydrate can be formed over time due to the hygroscopic nature of the compound.
  • the compounds of the invention may also exist as organic solvates, including ethers and alcohol solvates, and the like. Identification and preparation of any particular solvate is known to those of ordinary skill in the art of synthetic organic or pharmaceutical chemistry.
  • Lipids include both synthetic and naturally occurring fat-soluble compounds, including both neutral and amphiphilic molecules.
  • Amphoteric lipids typically comprise a hydrophilic component and a hydrophobic component.
  • Exemplary lipids include fatty acids, triglycerides, neutral fats, phospholipids, glycolipids, fatty alcohols, waxes, hydrazines, steroids such as cholesterol, and surfactants.
  • Lipid-lowering agent refers to a compound that has one or more of the following effects when administered to a patient: increased liver expression of LDLR; increased half-life of LDLR mRNA in hepatocytes; increased liver to plasma LDL, cholesterol Or uptake of triglycerides; enhance fatty acid oxidation in the liver, reduce triglyceride synthesis and secretion in the liver, and lower total cholesterol, LDL-cholesterol, VLDL-cholesterol or triglyceride levels in plasma and/or liver.
  • the lipid reducing agents disclosed herein include the compounds of the invention.
  • the invention provides the use of a compound of the invention for the manufacture of a medicament for lowering lipid levels in a patient's plasma and/or liver, comprising administering to said patient a reduced effective amount of a compound as described herein or combination.
  • the reduced lipid level may be one or more of total cholesterol, LDL-cholesterol (LDL-C), triglyceride (TG), and unesterified long-chain fatty acids.
  • the compounds and compositions described herein are useful for the prevention or treatment of diseases including, for example, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver (hepatic steatosis), type 2 diabetes, hyperglycemia Disease, obesity or insulin resistance and metabolic syndrome.
  • a method of treatment comprises administering to a subject in need of treatment a therapeutically effective amount of a compound or composition described herein.
  • the compounds of the invention are also useful in the treatment or prevention of disease states or conditions characterized by elevated plasma or hepatic cholesterol or triglycerides or associated with elevated plasma or hepatic cholesterol or triglycerides.
  • the present technology also provides for the treatment or prevention of diseases using the compounds of the invention (eg, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver, type II diabetes, hyperglycemia, obesity or insulin)
  • diseases eg, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver, type II diabetes, hyperglycemia, obesity or insulin
  • the use of an effective amount of a drug for resistance or metabolic syndrome eg, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver, type II diabetes, hyperglycemia, obesity or insulin.
  • the compounds and compositions disclosed herein increase the stability of LDLR mRNA by increasing the LDLR mRNA stability by increasing the transcription of the LDLR gene by inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9). ) mediated degradation of LDLR proteins or all of the above possible cellular mechanisms to reduce lipid levels.
  • Increased levels of LDLR in the liver increase uptake and processing of plasma LDL-C, resulting in decreased plasma levels of cholesterol, LDL-C, and triglycerides.
  • compounds can increase phosphorylation of acetyl CoA carboxylase (ACC) by activating AMP-activated protein kinase (AMPK), a key molecule of bioenergy metabolism regulation.
  • ACC acetyl CoA carboxylase
  • AMPK AMP-activated protein kinase
  • Increased phosphorylation of ACC enhances fatty acid oxidation in the liver, resulting in reduced TG accumulation in the liver and TG secretion in VLDL, which also helps reduce TG, LDL-C, total cholesterol, and unesterified long chains. Plasma levels of fatty acids, thereby preventing or treating diseases associated with hyperlipidemia.
  • AMPK is essential for the body to maintain glucose balance, and that compounds can ultimately treat type 2 diabetes, hyperglycemia, obesity or insulin resistance or metabolism by activating AMPK. Syndrome.
  • the compounds provided herein have the use of increasing LDLR expression comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition described herein, thereby increasing LDLR in said subject expression.
  • the invention provides a use of a compound of the invention to reduce plasma LDL-cholesterol and/or plasma triglycerides, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein or The composition thereby reducing plasma LDL-cholesterol in the patient.
  • the invention provides a lipid lowering agent comprising a compound and a composition thereof.
  • the compounds and compositions are useful in the methods and treatments of reducing lipids described herein.
  • the invention provides a compound of formula V, a stereoisomer thereof, a tautomer thereof, a solvate thereof, and/or a pharmaceutically acceptable salt thereof.
  • the present technology provides pharmaceutical compositions and medicaments comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier or one or more excipients or fillers.
  • a pharmaceutical composition for treating a condition selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome is provided.
  • Such compositions include a lipid reducing effective amount of any of the compounds described herein.
  • the pharmaceutical composition is packaged in unit dosage form.
  • the unit dosage form is effective in reducing blood lipids and/or lipid levels in the liver (eg, total cholesterol, LDL-cholesterol, triglycerides, and unesterified long-chain fatty acids) when administered to a subject in need thereof. At least one).
  • blood lipids and/or lipid levels in the liver eg, total cholesterol, LDL-cholesterol, triglycerides, and unesterified long-chain fatty acids
  • compositions By diluting one or more compounds of the present invention, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, dilutions Agents and the like are mixed to prepare a pharmaceutical composition to prevent or treat a condition associated with increased plasma and/or liver lipid levels.
  • pharmaceutically acceptable carriers eg, hyperlipidemia, hypercholesterolemia, hepatic steatosis, and metabolic syndrome
  • compositions may be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • the compositions of the present invention may be formulated in a variety of forms for a variety of routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal or by implantation. The incoming reservoir is applied.
  • Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular, injection.
  • the dosage forms described below are given as examples and should not be construed as limiting the techniques of the present invention.
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
  • excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic and a lubricant such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
  • water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • Gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
  • Gelatin capsules provide oral preparations.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
  • excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol , or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitan monooleate, or a partial ester of ethylene oxide with a fatty acid and a hexitol anhydride Condensation products such as polyethylene oxide sorbitan
  • the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • preservatives such as ethylparaben or n-propylparaben
  • coloring agents such as ethylparaben or n-propylparaben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • the oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation.
  • These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.
  • the dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweeteners, flavoring agents, and coloring agents can also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate.
  • the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the bloodstream of the patient by a local injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension, such as a solution prepared in 1,3-butanediol, in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used.
  • fatty acids such as oleic acid can also be prepared as an injection.
  • Dosage forms for topical (including buccal and sublingual) or transdermal administration of a compound of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches.
  • the active component can be mixed under sterile conditions with apharmaceutically acceptable carrier or excipient and with any preservative or buffers which may be required.
  • Powders and sprays can be prepared, for example, with excipients such as sugars, mica, silicic acid, sodium hydroxide, calcium silicates and polyamine powders or mixtures of these materials.
  • Ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, waxes, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones. , bentonite, silicic acid, mica and zinc oxide or a mixture thereof.
  • Absorption enhancers can also be used to increase the flow of the compounds of the invention through the skin. The rate of such flow can be controlled by providing a rate controlling membrane (e.g., as part of a transdermal patch) or by dispersing the compound in a polymer matrix or gel.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
  • the compounds of the invention may also be administered with other conventional therapeutic agents useful in the treatment or prevention of hyperlipemia.
  • exemplary therapeutic agents for combination therapy with one or more compounds of the invention include, but are not limited to, anti-inflammatory drugs, therapeutic antibodies, and cholesterol lowering drugs, for example, statins.
  • Useful additional therapeutic agents useful in combination formulations and co-therapy include, for example, anti-hyperlipidemic agents; anti-dyslipidemic agents; anti-diabetic agents including, but not limited to, cholesterol biosynthesis inhibitors, such as HMG-CoA reductase Inhibitors (also known as statins, lovastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin, pitavastatin and atorvastatin); HMG-CoA reduction synthase inhibitors; Squalene epoxidase inhibitor or squalene synthetase inhibitor (also known as squalene synthase inhibitor); microsomal triglyceride transfer protein (MTP) inhibitor; bile acid sequestrant anion exchange resin, These include, but are not limited to, cholestyramine, cholestyramine, colesevelam or dialkylaminoalkyl derivatives of cross-linked dextran; LDL
  • Additional therapies may also include increased exercise, surgery, and changing diets (eg, becoming a low-cholesterol diet).
  • Some botanicals are also effective for combination formulations and collaborative therapies to treat hyperlipidemia, such as curcumin, gum ketone , garlic, soy, soluble fiber, fish oil, green tea, carnitine, chromium, coenzyme Q10, grape seed extract, dimeric pantothenic acid, red yeast rice and royal jelly.
  • Berberine and related compounds can also be used as a second therapeutic agent in combination with the lipid lowering agent of the present invention.
  • berberine sulfate, berberine hydrochloride, berberine chloride, berberine, dihydroberberine, 8-cyanodihydroberberine, tetrahydroberberine N-oxide can be used.
  • Compounds of the invention may also be modified, for example by covalently linking organic structural fragments or conjugates, to improve pharmacokinetic properties, toxicity or bioavailability (e.g., increased in vivo half-life).
  • the conjugate can be a linear or branched hydrophilic polymeric group, a fatty acid group or a fatty acid ester group.
  • the polymeric group can comprise a molecular weight that can be adjusted by one skilled in the art to improve, for example, pharmacokinetic properties, toxicity, or bioavailability.
  • Exemplary conjugates can include polyalkanols (eg, polyethylene glycol (PEG), polypropylene glycol (PPG)), carbohydrate polymers, amino acid polymers or polyvinylpyrrolidone, and fatty acid or fatty acid ester groups, which Each may independently comprise from about 8 to about 70 carbon atoms.
  • Conjugates for use with the compounds of the invention may also be used as linkers, for example, for any suitable substituent or group, radiolabel (marker or tag), halogen, protein, enzyme, polypeptide, other therapeutic agent (eg drugs or drugs), nucleosides, dyes, oligonucleotides, lipids, phospholipids and/or liposomes.
  • the conjugate can include polyvinylamine (PEI), polyglycine, a hybrid of PEI and polyglycine, polyethylene glycol (PEG), or methoxypolyethylene glycol (mPEG).
  • PI polyvinylamine
  • PEG polyethylene glycol
  • mPEG methoxypolyethylene glycol
  • Conjugates The compounds of the invention may also be linked to, for example, labeled (fluorescing or luminescent) or a label (radioactive, radioisotope and/or isotope) to comprise a probe of the invention. Conjugates for use with the compounds of the invention may improve in vivo half-life in one aspect.
  • linking and/or “binding” may refer to a chemical or physical interaction, such as between a compound of the invention and a target of interest. Examples of linkages or interactions include covalent bonds, ionic bonds, hydrophilic-hydrophobic interactions, hydrophobic-hydrophobic interactions, and complexes. "Links” may also generally be referred to as “binding” or “affinity,” each of which may be used to describe a variety of chemical or physical interactions. Measuring binding or affinity is also a routine technique for those skilled in the art.
  • V1 and V2 are starting materials for the scheme, which can be obtained by commercially available products or prepared according to methods reported in the literature.
  • V1 and V2 are dehydrated to obtain imine compound V3 under certain reaction temperature conditions, and compound V3 is reduced to "amine" compound V4.
  • V4 reacts with glyoxal to obtain four-membered ring compound V5.
  • V7 is obtained by further modifying the compound V5, and the compound V7 is V under certain reducing conditions; on the other hand, the compound V5 first obtains V6 under certain reducing conditions, and then the compound V6 is further chemically modified to obtain the compound V. .
  • the preparation scheme of the general compound (V) is introduced by taking a representative synthetic preparation procedure and specific compound synthesis examples in the patent of the present invention as an example.
  • the preparation scheme of the compound of the present invention is not limited to the following representative processes and specific examples:
  • Representative Process I Mainly for the preparation of D ring has two important oxoyl functional groups (D ring contains two oxo functional groups, such as acetoxy, benzoyloxy, benzyloxy, sulfonyloxy , phosphoryloxy, etc.) compounds.
  • Representative Process 2 Mainly for the preparation of D ring, only one important oxo group functional group (D ring contains an oxo group, such as acetoxy, benzoyloxy, benzyloxy, sulfonyloxy, phosphorus A compound such as an acyloxy group.
  • Step 1 Preparation of sulfonyloxy and monohydroxy substituted benzaldehyde (S2A):
  • the substituted benzaldehyde S3 which is commercially available (or prepared according to literature methods), was sequentially introduced into the methanol, and the methylamine solution was added. The reaction was stirred at 50 ° C, and a large amount of yellow solid appeared. After the reaction was completed by TLC, it was allowed to cool and suction filtered. The yellow solid S4 was obtained by washing with a small amount of methanol.
  • the S4 obtained in the previous step was added to methanol and stirred vigorously to make it a turbid liquid. Further, ethanol and 1,4-dioxane were sequentially added to the eggplant-shaped flask, NaBH 4 was added in portions, and the suspension prepared previously was added dropwise with stirring. After the dropwise addition, the mixture was stirred at room temperature overnight. The solution gradually turned orange. The ice water was added to the next day, and the pH of the system was adjusted to 2 to 4 with glacial acetic acid. The mixture was transferred to a sep. funnel and extracted with ethyl acetate. The organic layer was washed with water and brine, and then evaporated. A brownish red oil S5. .
  • the phenylethylamine S6 and S2A substituted with a benzene ring are dissolved in dichloromethane, and reacted at 50 to 60 ° C to form an imine compound S13.
  • a methanol solution is added thereto at a low temperature of 10 to 5
  • the reduction reaction was carried out under the conditions of °C, sodium borohydride was added in portions, the methanol solvent was removed in vacuo, and the solvent was evaporated to ethyl acetate, washed with saturated brine, and the ethyl acetate layer was combined, and concentrated under reduced pressure to give S14.
  • Step 4 Further modification of the 5,6,7,8,13,13a-hexahydroisoquino[6,1-b]isoquinoline structure (S16A):
  • the S16 prepared in the above step is dissolved in dichloromethane, triethylamine is added, and then the appropriate halogenated compound (halogenated acyl compound, halogenated hydrocarbon, etc., such as sulfonyl chloride, is slowly added at a low temperature of -10 to 5 °C. Acetyl chloride, etc., slowly warming to room temperature and stirring the reaction. After the reaction is completed, it is added with water and dispersed, and extracted with an organic solvent such as ethyl acetate. The organic layer is combined and dried over anhydrous sodium sulfate to give a crude compound. Purification method to prepare the target compound S16A.
  • halogenated acyl compound, halogenated hydrocarbon, etc. such as sulfonyl chloride
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethyl.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS silane
  • chemical shift is given in units of 10 -6 (ppm).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm ⁇ 0.5mm silica gel plate.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from companies such as GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, TCI Chemicals, Angie Chemicals, and the like.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon balloon or a nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the hydrogenation reaction was usually evacuated, charged with hydrogen, and operated three times.
  • reaction temperature is room temperature, and the temperature range is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane And the acetone system, D: n-hexane, E: ethyl acetate, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent.
  • the system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane and acetone
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent.
  • the 3-benzyloxy-2-hydroxybenzaldehyde B obtained in the above step was dissolved in a 500 ml round bottom flask with 200 ml of CH 2 Cl 2 , and 12.1 g (120 mmol) of triethylamine was slowly added thereto at 0 ° C, and stirred for 30 minutes. 21.3 g (110 mmol) of m-fluorobenzenesulfonyl chloride was slowly added dropwise at 0 ° C. After the completion of the dropwise addition, the temperature was slowly raised to room temperature for 8 hours, then 200 ml of ice water was added to collect the CH 2 Cl 2 layer, and washed with saturated brine.
  • the compound 2 of the present invention is carried out in accordance with the following production method:
  • 3-methoxy-4-hydroxybenzaldehyde B 1.52 g (10 mmol) was dissolved in 30 ml of CH 2 Cl 2 , then 3-methoxyphenethylamine A 1.51 g (10 mmol) was added and refluxed at 60 ° C for 3 h During the addition, 10 ml of dichloromethane was added. After the reaction was completed, the mixture was concentrated under reduced pressure to give the imine C, which was directly transferred to the next reaction without separation.
  • the above product D was dissolved in 30 ml of formic acid, then 1.56 g (1.60) (10 mmol) of anhydrous copper sulfate was added, and 40% aqueous glyoxal solution was reacted at 80 ° C for 8 h, and then kept at 0 ° C for 2 hours, that is, a large amount
  • the solid precipitated the solid was filtered, methanol was added, and calcium oxide was added to adjust the pH. After 10 to 11, filtration, collecting the filtrate, concentrating under reduced pressure, and recrystallizing from a methanol solution of hydrogen chloride to obtain a core E for use.
  • the compound 5 of the present invention was first prepared by referring to the scheme of Example 2, and then carried out according to the following scheme:
  • the above product D was dissolved in 30 ml of formic acid, then 1.60 g (10 mmol) of anhydrous copper sulfate was added, and 40% aqueous glyoxal solution was reacted at 80 ° C for 8 h, and then kept at 0 ° C for 2 hours, that is, a large amount of solid precipitated.
  • the solid was filtered, dispersed with methanol, adjusted to pH 10 to 11 by adding calcium oxide, filtered, and the filtrate was collected, concentrated under reduced pressure, and then recrystallized from a methanol solution of hydrogen chloride to obtain a core E.
  • the compound 7 of the present invention was first prepared by referring to the scheme of Example 2, and then carried out according to the following scheme:
  • the compound 9 of the present invention was first prepared by referring to the scheme of Example 2, and then carried out according to the following scheme:
  • the compound 10 of the present invention was first prepared by referring to the scheme of Example 2, and then synthesized according to the following embodiment:
  • the crude product of G was added to a 100 mL round bottom flask, dissolved in methanol (10 mL), stirred under ice-cooling, and sodium borohydride (121 mg, 3.21 mmol) was added in portions, and the mixture was reacted at room temperature for 30 min, the reaction solution was dried, and the residue was added with water. The organic phase was dried over anhydrous sodium sulfate and dried, and the obtained residue was purified by chromatography (dichloromethane: methanol 50:1; petroleum ether: ethyl acetate 1:1) 10 (200 mg, yield 45.1%).
  • the compound 11 of the present invention was first prepared by the method of Example 2, and then subjected to the following chemical reaction:
  • the crude product of G was added to a 100 mL round bottom flask, dissolved in methanol (10 mL), stirred under ice-cooling, and sodium borohydride (121 mg, 3.21 mmol) was added in portions, and the mixture was reacted at room temperature for 30 min, the reaction solution was dried, and the residue was added with water. The organic phase was dried over anhydrous sodium sulfate and dried, and the obtained residue was purified by chromatography (dichloromethane: methanol 50:1; petroleum ether: ethyl acetate 1:1) 11 (76 mg, yield 20.8%).
  • the compound 12 of the present invention was first prepared by the method of Example 2, and then subjected to the following chemical reaction:
  • the compound 13 of the present invention was first prepared by the method of Example 2, and then subjected to the following chemical reaction:
  • the compound 14 of the present invention was prepared according to the following procedure:
  • the product F of the previous step was dissolved in methanol, palladium carbon was added thereto, hydrogenation was carried out under normal pressure for 24 hours, and palladium carbon was filtered, and methanol was concentrated to obtain a 2.8 g of a core structural compound G (yield about 50%).
  • the compound 15 of the present invention was first prepared by the method of Example 2, and then subjected to the following chemical reaction:
  • 2-methyl-3-methoxyphenethylamine was prepared according to the literature protocol (WO201212234), and then the solution of Example 2 was used instead of 2-methyl-3-methoxyphenethylamine hydrochloride.
  • -Methoxyphenethylamine a mother ring compound is prepared, and then compound 16 is obtained by using m-fluorobenzenesulfonyl chloride in place of acetic anhydride.
  • 1-(3,4-dimethoxyphenyl)-2-methylpropyl-2-amine was prepared according to the literature protocol (Tetrahedron Letters, Volume 26, Issue 9, 1985, Pages 1245-1248), and then Referring to the protocol of Example 2, 1-(3,4-dimethoxyphenyl)-2-methylpropyl-2-amine was used instead of 3-methoxyphenethylamine hydrochloride to prepare a parent ring. Compounds were then prepared using iso-fluorobenzenesulfonyl chloride in place of acetic anhydride to give compound 17. MS (ESI), m / z : 528.3 [M + H] +.
  • 3,4,5-trimethoxyphenethylamine was prepared according to the literature protocol (Bioorganic & Medicinal Chemistry, Volume 20, Issue 15, Pages 4862-4871), and then referring to the scheme of Example 2, using 3,4,5-trimethyl
  • the oxophenethylamine is substituted for 3-methoxyphenethylamine hydrochloride to prepare a parent ring compound, and then compound 19 is prepared by using m-fluorobenzenesulfonyl chloride in place of acetic anhydride.
  • MS (ESI) m / z : 530.2 [M + H] +.
  • the compound 20 of the present invention was first prepared by referring to the scheme of Example 2, and then carried out according to the following scheme:
  • the compound 22 of the present invention was first prepared by the method of Example 2, and then subjected to the following chemical reaction:
  • the compound 24 of the present invention was prepared according to the following reaction:
  • the compound 25 of the present invention is carried out in accordance with the following scheme:
  • the above product D was dissolved in 30 ml of formic acid, then 1.60 g (10 mmol) of anhydrous copper sulfate was added, and 40% aqueous glyoxal solution was reacted at 80 ° C for 8 h, and then kept at 0 ° C for 2 hours, that is, a large amount of solid precipitated.
  • the solid was filtered, dispersed with methanol, adjusted to pH 10 to 11 by adding calcium oxide, filtered, and the filtrate was collected, concentrated under reduced pressure, and then recrystallized from a methanol solution of hydrogen chloride to obtain a core E.
  • the compound 26 of the present invention is carried out in accordance with the following scheme:
  • 3-methoxy-4-hydroxybenzaldehyde B 1.52 g (10 mmol) was dissolved in 30 ml of CH 2 Cl 2 , then 3,4-dimethoxyphenethylamine A 1.81 g (10 mmol) was added at 60 ° C After refluxing for 3 hours, 10 ml of a solvent dichloromethane was added. After the reaction was completed, methylene chloride was concentrated under reduced pressure to give the imine C, which was directly transferred to the next reaction without isolation.
  • the above product D was dissolved in 30 ml of formic acid, then 1.60 g (10 mmol) of anhydrous copper sulfate was added, and 40% aqueous glyoxal solution was reacted at 80 ° C for 8 h, and then kept at 0 ° C for 2 hours, that is, a large amount of solid precipitated. , filter the solid, disperse with methanol, add calcium oxide to adjust the pH After 10 to 11, filtration, collecting the filtrate, concentrating under reduced pressure, and recrystallizing from a methanol solution of hydrogen chloride to obtain a core E for use.
  • 3-Hydroxy-4-methoxybenzaldehyde B 1.52 g (10 mmol) was dissolved in 30 ml of CH 2 Cl 2 , then 3-methoxyphenethylamine A 1.51 g (10 mmol) was added and refluxed at 60 ° C for 3 h During the addition, 10 ml of a solvent dichloromethane was added. After the reaction was completed, the dichloromethane was concentrated under reduced pressure to give the imine C, which was directly transferred to the next reaction without separation.
  • the above product D was dissolved in 30 ml of formic acid, then 1.60 g (10 mmol) of anhydrous copper sulfate was added, and 40% aqueous glyoxal solution was reacted at 80 ° C for 8 h, and then kept at 0 ° C for 2 hours, that is, a large amount of solid precipitated.
  • the solid was filtered, dispersed with methanol, adjusted to pH 10 to 11 by adding calcium oxide, filtered, and the filtrate was collected, concentrated under reduced pressure, and then recrystallized from a methanol solution of hydrogen chloride to obtain a core E.
  • the compound 30 of the present invention is carried out in accordance with the following scheme:
  • the compound 31 of the present invention was prepared according to the following scheme:
  • the above product D was dissolved in 30 ml of formic acid, then 1.60 g (10 mmol) of anhydrous copper sulfate was added, and 40% aqueous glyoxal solution was reacted at 80 ° C for 8 h, and then kept at 0 ° C for 2 hours, that is, a large amount of solid precipitated.
  • the solid was filtered, dispersed with methanol, adjusted to pH 10 to 11 by adding calcium oxide, filtered, and the filtrate was collected, concentrated under reduced pressure, and then recrystallized from a methanol solution of hydrogen chloride to obtain a core E.
  • the compound 33 of the present invention was first prepared by referring to the scheme of Example 2, and then subjected to the following chemical reaction:
  • the compound 34 of the present invention was first prepared by referring to the scheme of Example 2, and then subjected to the following chemical reaction:
  • the compound 35 of the present invention was first prepared by referring to the scheme of Example 2, and then subjected to the following chemical reaction:
  • Compound 36 of the present invention is referred to in Example 1, using 2-acetoxy-3-methoxybenzaldehyde instead of 2-(m-fluorobenzenesulfonate)-3-hydroxybenzaldehyde, using 3,4-dimethyl Compound 36 is prepared by substituting oxyphenethylamine for 3-methoxyphenethylamine followed by 3-fluorobenzenesulfinyl chloride in place of acetic anhydride.
  • Compound 37 of the present invention is referred to in Example 1, using 2-benzyloxy-3-methoxy-5-hydroxybenzaldehyde instead of 2-(m-fluorobenzenesulfonate)-3-hydroxybenzaldehyde, using 3,4 -Dimethoxyphenethylamine was used in place of 3-methoxyphenethylamine, followed by 3-fluorobenzenesulfinyl chloride in place of acetic anhydride to give a white solid.
  • the compound 38 of the present invention was first prepared by referring to the scheme of Example 2, and then synthesized according to the following scheme:
  • the crude product of G was added to a 100 mL round bottom flask, dissolved in methanol (10 mL), stirred under ice-cooling, and sodium borohydride (121 mg, 3.21 mmol) was added in portions, and the mixture was reacted at room temperature for 30 min, the reaction solution was dried, and the residue was added with water. The organic phase was dried over anhydrous sodium sulfate and dried, and the obtained residue was purified by chromatography (dichloromethane: methanol 50:1; petroleum ether: ethyl acetate 1:1) 38 (132 mg, yield 32.5%).
  • Compound 39 of the present invention was first prepared by the method of Example 2, and then subjected to the following chemical reaction:
  • Compound F was first prepared by the method of Example 2, and then subjected to the following chemical reaction:
  • the compound F (100 mg, 0.324 mmol) was dissolved in 10 ml of dichloromethane, then phenylethynyl carboxylic acid (98 mg, 0.67 mmol), DCC (166 mg, 0.80 mmol), DMAP (98 mg, 0.80 mmol).
  • Compound 41 of the present invention was first prepared by the method of Example 32, and was then prepared according to the following scheme:
  • the crude product of G was added to a 100 mL round bottom flask, dissolved in methanol (10 mL), stirred under ice-cooling, and sodium borohydride (121 mg, 3.21 mmol) was added in portions, and the mixture was reacted at room temperature for 30 min, the reaction solution was dried, and the residue was added with water. The organic phase was dried over anhydrous sodium sulfate and dried, and the obtained residue was purified by chromatography (dichloromethane: methanol 50:1; petroleum ether: ethyl acetate 1:1) 41 (100 mg, yield 24.3%).
  • Compound 42 of the present invention was first prepared by the method of Example 32 to give Compound E, which was then prepared according to the following scheme:
  • the crude product of G was added to a 100 mL round bottom flask, dissolved in methanol (10 mL), stirred under ice-cooling, and sodium borohydride (121 mg, 3.21 mmol) was added in portions, and the mixture was reacted at room temperature for 30 min, the reaction solution was dried, and the residue was added with water. The organic phase was dried over anhydrous sodium sulfate and dried, and the obtained residue was purified by chromatography (dichloromethane: methanol 50:1; petroleum ether: ethyl acetate 1:1) 42 (83 mg, yield 20.0%).
  • Compound 43 of the present invention was first prepared by the method of Example 2, and then prepared according to the following scheme:
  • the crude product of G was added to a 100 mL round bottom flask, dissolved in methanol (10 mL), stirred under ice-cooling, and sodium borohydride (121 mg, 3.21 mmol) was added in portions, and the mixture was reacted at room temperature for 30 min, the reaction solution was dried, and the residue was added with water. The organic phase was dried over anhydrous sodium sulfate and dried, and the obtained residue was purified by chromatography (dichloromethane: methanol 50:1; petroleum ether: ethyl acetate 1:1) 43 (106 mg, yield 26.1%).
  • Compound 44 of the present invention was first prepared by the method of Example 2 to give Compound E, which was then prepared according to the following scheme:
  • the crude product of G was added to a 100 mL round bottom flask, dissolved in methanol (10 mL), stirred under ice-cooling, and sodium borohydride (121 mg, 3.21 mmol) was added in portions, and the mixture was reacted at room temperature for 30 min, the reaction solution was dried, and the residue was added with water. The organic phase was dried over anhydrous sodium sulfate and dried, and the obtained residue was purified by chromatography (dichloromethane: methanol 50:1; petroleum ether: ethyl acetate 1:1) 44 (142 mg, yield 33.3%).
  • the compound 46 of the present invention was first prepared by referring to the scheme of Example 33, and then was prepared according to the following scheme:
  • Compound 46 of the present invention was first prepared by the method of Example 2, and then subjected to the following chemical reaction:
  • Compound 46 of the present invention was first prepared by the method of Example 2, and then subjected to the following chemical reaction:
  • Compound 48 of the present invention was first prepared by the method of Example 2, and then prepared according to the following scheme:
  • the crude product of G was added to a 100 mL round bottom flask, dissolved in methanol (10 mL), stirred under ice-cooling, and sodium borohydride (121 mg, 3.21 mmol) was added in portions, and the mixture was reacted at room temperature for 30 min, the reaction solution was dried, and the residue was added with water. The organic phase was dried over anhydrous sodium sulfate and dried, and the obtained residue was purified by chromatography (dichloromethane: methanol 50:1; petroleum ether: ethyl acetate 1:1) 48 (114 mg, yield 24.8%).
  • Compound 49 of the present invention was first prepared by the method of Example 2 to give Compound E, which was then prepared according to the following scheme:
  • the crude product of G was added to a 100 mL round bottom flask, dissolved in methanol (10 mL), stirred under ice-cooling, and sodium borohydride (121 mg, 3.21 mmol) was added in portions, and the mixture was reacted at room temperature for 30 min, the reaction solution was dried, and the residue was added with water. The organic phase was dried over anhydrous sodium sulfate and dried, and the obtained residue was purified by chromatography (dichloromethane: methanol 50:1; petroleum ether: ethyl acetate 1:1) 49 (95 mg, yield 22.6%).
  • Compound 50 of the present invention was first prepared by the method of Example 2 to give Compound E, which was then prepared according to the following scheme:
  • the crude product of G was added to a 100 mL round bottom flask, dissolved in methanol (10 mL), stirred under ice-cooling, and sodium borohydride (121 mg, 3.21 mmol) was added in portions, and the mixture was reacted at room temperature for 30 min, the reaction solution was dried, and the residue was added with water. The organic phase was dried over anhydrous sodium sulfate and dried, and the obtained residue was purified by chromatography (dichloromethane: methanol 50:1; petroleum ether: ethyl acetate 1:1) 50 (165 mg, yield 35.8%).
  • the compound 56 of the present invention is prepared by using 2-methoxy-5-p-toluenesulfonyloxybenzaldehyde instead of 2-(m-fluorobenzenesulfonate)-3-hydroxybenzaldehyde.
  • Compound 56 was obtained.
  • the compound 62 of the present invention is prepared by using 2,2-difluoro-2-phenylethylamine instead of 3-methoxyphenethylamine, and 4-(p-toluenesulfonyloxy)benzaldehyde is used.
  • Compound 62 was prepared instead of 2-(m-fluorobenzenesulfonate)-3-hydroxybenzaldehyde.
  • compound 2 was prepared by using 2,4-dihydroxy-3-methoxybenzaldehyde instead of 3-benzyloxy-2-hydroxybenzaldehyde, and the structure nucleus was prepared by the scheme 2, and then passed through the scheme. 3 gave compound 64.
  • Compound 68 of the present invention was prepared by referring to the preparation scheme of Example 14 using p-aminobenzaldehyde instead of m-aminobenzaldehyde.
  • Compound 70 of the present invention was prepared by referring to the scheme of Example 2, using 3-benzyloxy-4-methoxyphenethylamine in place of 3-methoxyphenethylamine.
  • Compound 71 of the present invention was prepared by referring to the scheme of Example 2, using 3-acetoxy-4-methoxyphenethylamine in place of 3-methoxyphenethylamine.
  • Compound 75 of the present invention was prepared by following the procedure of Example 39 using the appropriate starting materials and reagents (purchased or synthesized according to literature procedures). MS (ESI), m / z : 420.1 [M + H] +.
  • the compound 91 of the present invention uses 3-methoxy-4-phenylthiobenzaldehyde instead of 2-(m-fluorobenzenesulfonate)-3-hydroxybenzaldehyde, and uses 3,4-di.
  • Compound 91 was prepared by substituting methoxybenzaldehyde for 3-methoxybenzaldehyde.
  • the compound 92 of the present invention was prepared by referring to the scheme of Example 1, using 3-phenylsulfonylbenzaldehyde instead of 2-(m-fluorobenzenesulfonyl)-3-hydroxybenzaldehyde to prepare a compound.
  • the compound 93 of the present invention was prepared by referring to the scheme of Example 1, using 4-phenylsulfonylbenzaldehyde instead of 2-(m-fluorobenzenesulfonyl)-3-hydroxybenzaldehyde to prepare a compound.
  • the compound 94 of the present invention was prepared by referring to the scheme of Example 1, using 5-phenylsulfonylbenzaldehyde instead of 2-(m-fluorobenzenesulfonate)-3-hydroxybenzaldehyde to prepare a compound.
  • the compound 95 of the present invention was prepared by referring to the scheme of Example 1, using 3-phenylsulfonylbenzaldehyde instead of 2-(m-fluorobenzenesulfonate)-3-hydroxybenzaldehyde to prepare a compound.
  • Compound 100 of the present invention was prepared by reference to the protocol of Example 6 using the appropriate starting materials and reagents (purchased or synthesized according to literature procedures). MS (ESI), m / z : 498.5 [M + H] +.
  • Compound 106 of the present invention was prepared by reference to the protocol of Example 6 using the appropriate starting materials and reagents (purchased or synthesized according to literature procedures). MS (ESI), m / z : 514.3 [M + H] +.
  • Compound 110 of the present invention was prepared by reference to the protocol of Example 6 using the appropriate starting materials and reagents (purchased or synthesized according to literature procedures). MS (ESI), m / z : 470.2 [M + H] +.
  • the purpose of this experiment is to reflect the effect of the compound on the expression of PCSK9 gene.
  • a validated PCSK9 quantitative PCR primer, ⁇ -Actin quantitative PCR primer was used as a primer for PCSK9 and the internal reference gene ⁇ -Actin.
  • the quantitative PCR reaction system of each sample was prepared by using template, primer, Power SYBR Green PCR Master Mix (Invitrogen), and real-time PCR was performed on the quantitative PCR instrument CFX96 Real-Time PCR Detection System (Bio-Rad) according to the requirements of the PCR instrument. Reaction, obtaining expression amount data.
  • the expression level data were processed by ⁇ CT method, and ⁇ -Actin was used as the internal reference.
  • the expression level of PCSK9 in the blank control was set to 1, and the relative expression level of PCSK9 relative to the control in the remaining samples (multiples relative to the control) was obtained.
  • This experiment was to reflect the effect of compounds on lowering LDL at the cellular level. Excessive LDL levels can cause atherosclerosis. This experiment directly detects the ability of hepatocytes to take up LDL at the cellular level, which directly reflects the lipid-lowering effect of the compound.
  • the surface of hepatocytes expresses LDL receptors and has the ability to take up LDL.
  • the fluorescent substance Dil-labeled LDL (Dil-LDL) was added to the medium, and HepG2 liver cancer cells were observed to take Dil-LDL into the cells under a fluorescence microscope.
  • the drug can increase the amount of LDL receptors on the surface of hepatocytes to enhance the ability of hepatocytes to take up LDL. Therefore, the fluorescence intensity observed under a microscope can be used to evaluate the effect of the sample on the ability of hepatocytes to take up LDL.
  • HepG2 cells were routinely cultured, seeded into 96-well plates at a density of 2.5 x 104 cells per well, and cultured overnight at 37 ° C, 5% CO 2 . The next day, the supernatant was discarded, and samples and positive drugs were added for treatment for 20 hours. The supernatant was discarded, and fresh medium containing 2 ⁇ g/ml of fluorescent Dil-LDL (Invitrogen) was added to each well, and incubation was continued for 4 hours at 37 ° C under 5% CO 2 .
  • fluorescent Dil-LDL Invitrogen
  • the supernatant was discarded, and the cells were washed twice with PBS, replaced with fresh medium, and the fluorescence intensity of each well was observed under a fluorescence microscope (Leica DM IL LED Microsystems). Normal cells treated with no sample and Dil-LDL were used as negative controls. The effect of the sample on the ability of hepatocytes to take up LDL was evaluated by fluorescence intensity observed under a microscope and graded for comparison.
  • the classification method is as follows:
  • +++ indicates a strongly increased fluorescence intensity compared to normal cell controls
  • LDL uptake rate test indicates that the compound of the present invention and a reference compound (including palmatine hydrochloride, berberine hydrochloride, tetrahydroberberine, and 4-position-substituted tetrahydrogen prepared according to the literature CN200980151491.7 Compared with the muscarinic C1 ⁇ C6 compound, it can strongly down-regulate the expression of PCSK9 gene, significantly enhance the uptake ability of hepatocytes to LDL, and exhibit a more excellent lipid-lowering effect.
  • Model establishment SD rats were fed with high-fat diet, and the normal group was fed with normal large mouse growth feed. After 4 weeks, animal serum was collected and the index was changed. Compared with the normal group, the levels of LDL-C and TC in serum induced by high-fat diet were significantly increased and statistically significant, which proved that the hyperlipidemia model was successfully established.
  • Acute toxicity test continuous administration of a single dose for 7 days, the test compound showed no significant side effects at a dose of 500 mg/kg.
  • Test group and dose design normal control group, high fat model control group, simvastatin group (8 mg/kg), compound 6 group (40 mg/kg), compound 11 group (40 mg/kg), compound 33 group (40 mg) /kg), compound 54 group (40 mg/kg).
  • Dosing frequency once a day.
  • Figures 4 and 5 show that the levels of alanine aminotransferase and aspartate aminotransferase in the high-fat model group and the simvastatin group are significantly elevated, indicating abnormal liver function, but the compound of the present invention exhibits significant lipid-lowering activity in vivo. At the same time, the levels of alanine aminotransferase and aspartate aminotransferase were not increased.
  • the levels of alanine aminotransferase and aspartate aminotransferase in the compound 6, compound 11, compound 33, and compound 54 animals were consistent with those in the normal diet group. It is indicated that the compound of the present invention does not cause damage to the liver at the same time as lipid-lowering, but the level of alanine aminotransferase and aspartate aminotransferase in the experimental animal is increased while the lipid-lowering simvastatin indicates the liver function of the model animal taking simvastatin. The damage was also revealed by the apparent hepatotoxicity of statins.
  • Study animals The experimental animals used in this experiment used the animals in the above-mentioned "SD rat model lipid-lowering experiment". After the animal serum index study was completed, the animals were sacrificed and dissected, and the liver tissue of the animals was taken, and some formalin was fixed. Partially stored at -80 ° C for cryopreservation, after more than 48 hrs, pathological section staining (H&E staining, oil red-O staining) was performed. Focus on liver structural integrity, inflammatory cell infiltration and fatty liver severity, and score (score: 0; normal; level 1: ⁇ 20%; level 2: 20-40%; level 3: 40-60 %; Level 4: 60-80%; Level 5: >80%).
  • the compounds 6, compound 11, compound 33 and compound 54 all have a certain protective effect on the liver structure from the vacuolar degeneration score, and the liver damage caused by the fat cells is repaired.
  • Compound 6, Compound 11, Compound 33, Compound 54 can also significantly reduce inflammatory cell infiltration, reduce liver inflammation, reduce fat accumulation and increase fat cell volume, and reduce liver fat .
  • liver anatomy of the simvastatin group, liver structural integrity, inflammatory cell infiltration and fatty liver severity were consistent with the high-fat model group, and fatty liver symptoms were not alleviated.
  • the compound 6, the compound 11, the compound 33 and the compound 54 of the present invention all have a certain protective effect on liver tissues, and the compound of the present invention has a medicinal value for treating fatty liver.
  • the compound of the present invention exhibits a lipid-lowering activity and does not affect the normal function of the liver. Within the safe dose range, the compounds of the present invention exhibited lipid-lowering activity in vivo and did not cause an increase in the level of transaminase in the rat, suggesting that no damage was caused to the liver. However, simvastatin lipid-lowering drugs, while exhibiting lipid-lowering activity, further increased the level of animal transaminase, indicating that normal liver function was damaged and showed significant liver toxicity. The compound of the present invention has the characteristics of lowering lipid but not affecting liver function, and clinical application indicates that the compound of the present invention has a more significant safety advantage than the statin.
  • the compound of the present invention has a potential therapeutic effect on fatty liver symptoms in a high-fat model animal, and the lipid-lowering drugs such as statins do not have the above effects. It can be seen from the "SD rat model non-alcoholic steatohepatitis experiment" that the compound of the present invention reduces the degree of liver inflammation, can reduce fat accumulation and increase the volume of fat cells, reduce the degree of liver fat, and obtain liver damage caused by fat cells. It has been repaired to reduce the degree of vacuolar denaturation. However, in the liver anatomy of the simvastatin group, liver structural integrity, inflammatory cell infiltration, and fatty liver severity were consistent with the high-fat model group, and fatty liver symptoms were not alleviated.
  • the lipid-lowering mechanism of the compound of the present invention is different from the existing listed lipid-lowering drugs (for example, statins, fibrates, etc.), and its excellent lipid-lowering activity and its Good safety characteristics and potential therapeutic value in the treatment of fatty liver are expected to become a new generation of lipid-lowering drugs for patients with cardiovascular diseases to obtain good therapeutic benefits.
  • lipid-lowering drugs for example, statins, fibrates, etc.

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Abstract

L'invention concerne des composés de formule (V), un procédé de préparation et une application pharmaceutique de ces composés. L'invention concerne spécifiquement des dérivés de composés ayant la formule générale (V), un procédé de préparation et une utilisation de ces dérivés en tant qu'agent thérapeutique pour la prévention et le traitement de l'hyperlipidémie, de l'hypercholestérolémie, de l'hypertriglycéridémie, de la stéatose hépatique, du diabète de type 2, de l'hyperglycémie, de l'obésité ou du syndrome de résistance à l'insuline et du syndrome métabolique. Les composés selon la présente invention permettent également de réduire le cholestérol total, le cholestérol LDL et les triglycérides, d'augmenter l'expression du récepteur hépatique des LDL, et de réduire l'expression de PCSK9.
PCT/CN2015/089880 2014-09-17 2015-09-17 Dérivés de tétrahydroberbérine et leur application Ceased WO2016041514A1 (fr)

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CN112851662A (zh) * 2021-01-21 2021-05-28 中国药科大学 异喹啉生物碱及其衍生物，制备方法、药物组合物和应用
WO2025159505A1 (fr) * 2024-01-25 2025-07-31 주식회사 알트메디칼 Composition pharmaceutique pour la prévention ou le traitement d'une néphropathie diabétique, comprenant un composé dérivé d'isoquinoléine en tant que principe actif

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CN106866652B (zh) * 2016-12-21 2019-04-23 四川大学 具有胰岛素增敏活性的小檗碱12-位衍生物及其制备方法
CN116847840A (zh) * 2020-09-03 2023-10-03 扬子江药业集团有限公司 3,10-二甲氧基-5,8,13,13a-四氢-6H-异喹啉并[3,2-a]异喹啉-9-基3-氟苯磺酸酯及其盐的晶型的多晶型物
CN116370469A (zh) * 2023-04-27 2023-07-04 常州大学 四氢小檗碱类化合物对trpv3的抑制应用

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