CN112107581A - Use of compounds of formula I for the preparation of medicaments for the treatment of obesity and related disorders - Google Patents
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Abstract
The invention provides an application of a compound shown in a formula I in preparing a medicament for treating obesity and obesity-related symptoms:
wherein R is1、R2And R3The same or different and are respectively selected from halogen elements; r4Is a substituted or unsubstituted C1-C10 straight or branched chain alkyl group; and R5Is a basic group. The research of the invention shows that: the compound of the formula I can effectively reduce the body weight of obese mice, OB mice and db/db mice induced by high fat diet, reduce the activity of alanine aminotransferase ALT and aspartate aminotransferase AST, and improve fatty liver symptoms. It can be seen that the compounds of formula I have an ameliorating effect on obesity caused by poor dietary habits as well as obesity due to genetic factors, and ameliorate symptoms associated with obesity, such as fatty liver.
Description
Technical Field
The invention relates to application of a compound shown in a formula I in preparing a medicament for treating obesity and obesity-related diseases.
Background
In recent decades, with the improvement of living standard and the change of life style, people with obesity have more and more people and have a trend of being younger. The world health organization has identified obesity as a disease, the third largest enemy to present health threats to humans following cardiovascular and cerebrovascular diseases and cancer.
Obesity is susceptible to the following conditions: 1. fatty liver: normal human liver tissue contains a small amount of fat, such as triglycerides, phospholipids, glycolipids, and cholesterol, and its weight is about 3% to 5% of the weight of the liver, and if too much fat accumulates in the liver, it exceeds 5% of the weight of the liver or when there is steatosis in more than 50% of the liver cells histologically, it is called fatty liver. 2. Diabetes mellitus: the obesity can cause excessive secretion of insulin in blood, and the more serious the obesity is, the higher the insulin concentration in the fasting state is, and the secretion of insulin after eating can not be relatively improved, so that the phenomenon of blood sugar rise is formed; in addition, the obesity patients have an increased risk of diabetes because they have fewer insulin receptors in their cells or are prone to problems when receiving insulin. 3. Hypertension: excessive insulin secretion and reduced insulin action are responsible for hypertension, and high concentrations of insulin promote the formation of hyperglycemia by enhancing sodium ion recovery and sympathetic frequency; in addition, fat tissue is increased in obese people, oxygen consumption is increased, cardiac burden is increased, cardiac muscle is thickened, and hypertension is more easily caused. In the case of weight loss, blood pressure usually decreases because systemic blood flow, stroke volume and sympathetic nerve action decrease. 4. Dyslipidemia: hyperlipidemia affects the rate at which the body carries cholesterol to the liver and is a risk factor for increasing heart disease. 5. Cardiovascular diseases: most of the obese people have high blood fat concentration, so the patients are easy to generate blood vessel embolism, accelerate the porridge-like change of blood vessels and easily cause diseases such as coronary heart disease, myocardial infarction, ischemic heart disease and the like. Studies have also shown that if a desired body weight is maintained, the incidence of cardiovascular disease, congestive heart failure and cerebral embolism may be reduced. 6. Gallbladder and pancreas diseases: fat in the body of the obese person is excessive, so that the synthesis of cholesterol is increased, the cholesterol in the bile is in a supersaturated state, and the formation of cholesterol calculus is facilitated. 7. Respiratory hypofunction (asthma): fat of the chest wall and the abdominal cavity is thickened due to obesity, so that the lung capacity is reduced, and the normal ventilation function of the lung is influenced; and because of hypoventilation, erythrocytosis may be caused, resulting in vascular embolism. Severe patients may develop pulmonary hypertension, cardiac enlargement and infarct heart failure. Fat accumulation may also affect the movement of cilia in the trachea, rendering it unable to perform normal function 8, joint disease: because the obese people need to bear more weight on bone joints, the joints are easy to age and damage to obtain osteoarthritis. 9. Endocrine disorders: obese women are susceptible to endocrine disorders, particularly hyperinsulinemia, impaired glucose tolerance, sex hormone level disorders, elevated adrenocortical hormones, and elevated leptin levels. 10. Skin diseases: obese people often suffer from eczema which causes red itching due to rash, frequent occurrence on skin folds of the head, armpits, interties and the like; and striae of pregnancy pattern, called striae of obesity, often appear at the waist, thighs, etc., due to the rupture of dermal tissue when it grows rapidly; in addition, the venous blood reflux is retarded and blocked due to cardiac hypertrophy, which is also likely to cause varicose veins.
At present, methods for losing weight generally comprise diet, increase of exercise amount, regulation of dietary structure, medicine intervention, reduction of absorption (such as laxative) and the like, and the methods either need to be adhered to for a long time, such as diet, increase of exercise amount and regulation of dietary structure, which are very conscious and only few people can adhere to, so that real effective weight loss is difficult to achieve; for weight loss through laxatives, rebound is very easy if the drug is stopped. Thus, there remains a need in the art for agents that are capable of rapidly losing weight.
Disclosure of Invention
The invention aims to provide application of a compound shown in a formula I in preparing a medicament for treating obesity and obesity-related symptoms:
wherein R is1、R2And R3The same or different and are respectively selected from halogen elements; r4Is a substituted or unsubstituted C1-C10 straight or branched chain alkyl group; and R5 is a basic group.
The research of the invention shows that: the compound of the formula I can effectively reduce the body weight of obese mice, OB mice and db/db mice induced by high fat diet, reduce the activity of alanine aminotransferase ALT and aspartate aminotransferase AST, and improve fatty liver symptoms. It can be seen that the compounds of formula I have an ameliorating effect on obesity caused by poor dietary habits as well as obesity due to genetic factors, and ameliorate symptoms associated with obesity, such as fatty liver.
Drawings
Figure 1 shows that oral administration of GCN2iB significantly reduced the body weight of high fat diet-induced obese mice;
figures 2A-2B show that oral administration of GCN2iB significantly reduced the activity of alanine Aminotransferase (ALT) (a) and aspartate Aminotransferase (AST) (B), respectively, in the serum of high fat diet-induced obese mice;
figures 3A-3B show that oral administration of GCN2iB significantly reduced triglycerides (a) and total cholesterol (B) in the liver of high-fat diet-induced obese mice; figure 3C shows that oral administration of GCN2iB significantly reduced lipid deposition in the liver of high fat diet-induced obese mice;
figure 4 shows that oral administration of GCN2iB significantly reduced body weight in ob/ob mice;
figures 5A-5B show that oral administration of GCN2iB significantly reduced the activity of alanine Aminotransferase (ALT) (a) and aspartate Aminotransferase (AST) (B), respectively, in the serum of ob/ob mice;
figures 6A-6B show that oral administration of GCN2iB significantly reduced triglycerides (a) and total cholesterol (B) in the liver of ob/ob mice; figure 6C shows that oral administration of GCN2iB significantly reduced lipid deposition in the liver of ob/ob mice;
FIG. 7 shows that oral GCN2iB maintained the body weight of db/db mice substantially unchanged, while the body weight of control db/db mice significantly increased;
figures 8A-8B show that oral administration of GCN2iB significantly reduced the activity of alanine Aminotransferase (ALT) (a) and aspartate Aminotransferase (AST) (B), respectively, in the serum of db/db mice;
figures 9A-9B show that oral GCN2iB significantly reduced triglycerides (a) and total cholesterol (B) in the liver of db/db mice; figure 9C shows that oral GCN2iB significantly reduced lipid deposition in the liver of db/db mice.
Detailed description of the preferred embodiments
The invention provides the use of a compound of formula I in the preparation of a medicament for the treatment of obesity and obesity-related disorders:
wherein R is1、R2And R3The same or different and are respectively selected from halogen elements; r4Is a substituted or unsubstituted C1-C10 straight or branched chain alkyl group; and R5Is a basic group.
In a preferred embodiment, R1、R2And R3Are respectively selected from F and Cl.
In a preferred embodiment, R1Is Cl.
In a preferred embodiment, R2And R3Are respectively F.
In a preferred embodiment, R1Is Cl; r2And R3Are respectively F.
In a preferred embodiment，R4Is a substituted or unsubstituted C1-C5 linear or branched alkyl group, e.g., C1 linear alkyl group, C2 linear alkyl group, C3 linear or branched alkyl group, C4 linear or branched alkyl group, C5 linear or branched alkyl group.
In a preferred embodiment, R5Is an amino group, a secondary amino group or a tertiary amino group.
In a preferred embodiment, R5Is an amino group, a secondary or tertiary amino group having a C2-C5 alkyl group, for example, a secondary or tertiary amino group of a C3 alkyl group, a secondary or tertiary amino group of a C4 alkyl group, a secondary or tertiary amino group of a C5 alkyl group.
In a preferred embodiment, R1、R2And R3Are respectively selected from F and Cl; r4Is a substituted or unsubstituted C1-C5 linear or branched alkyl group (e.g., C1 linear alkyl group, C2 linear alkyl group, C3 linear or branched alkyl group, C4 linear or branched alkyl group, C5 linear or branched alkyl group); r5Is an amino group, a secondary or tertiary amino group having a C2-C5 alkyl group (e.g., a secondary or tertiary amino group of a C3 alkyl group, a secondary or tertiary amino group of a C4 alkyl group, a secondary or tertiary amino group of a C5 alkyl group).
In a preferred embodiment, R1、R2And R3Are respectively selected from F and Cl; r4C1-C3 alkyl (e.g., C1 straight chain alkyl, C2 straight chain alkyl, C3 straight chain or branched chain alkyl); r5Is an amino group, a secondary amine group having a C2-C3 alkyl group, or a tertiary amine group having a C2-C3 alkyl group.
In a preferred embodiment, R1Is Cl, R2And R3Are respectively F, R4C1-C3 alkyl (e.g., C1 straight chain alkyl, C2 straight chain alkyl, C3 straight chain or branched chain alkyl); r5Is an amino group, a secondary amine group having a C2-C3 alkyl group, or a tertiary amine group having a C2-C3 alkyl group.
In a preferred embodiment, R1Is Cl, R2And R3Are respectively F, R4C1-C3 alkyl (e.g., C1 straight chain alkyl, C2 straight chain alkyl, C3 straight chain or branched chain alkyl); r5Is an amino group.
In a preferred embodiment, the compound has the structure of formula II:
the compounds of formula II are general regulated repressor protein kinase 2(GCN2) inhibitors, abbreviated GCN2 iB. GCN2 is a kinase that is activated in the absence of intracellular amino acids and phosphorylates the downstream protein eukaryotic initiation factor 2(eIF2 α), thereby lowering overall protein synthesis while up-regulating the levels of genes involved in amino acid synthesis and maintaining intracellular amino acid homeostasis.
In the present application, the symptoms associated with obesity are one or more of hypertension, coronary heart disease, fatty liver, diabetes, hyperlipidemia, endocrine disorders, skin diseases, joint diseases, gallbladder and pancreas diseases, and respiratory hypofunction.
In preparing the medicaments of the present invention, the above compounds are combined with a pharmaceutically acceptable carrier.
The pharmaceutically acceptable carrier may be, for example, a filler, a fragrance, a flavoring agent, a coloring agent, a wetting agent, an excipient, a disintegrant, a surfactant.
The medicine can be prepared into tablets, capsules, pills, powder, granules, suspending agents, emulsions or injections.
The medicine of the invention can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting agents, various particle drug delivery systems and the like.
The dosage of the drug of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, etc. The administration route of the medicine can be intestinal tract or parenteral tract, such as oral administration, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract administration, skin administration, rectal administration and the like.
The medicament can be independently administered, and can also be used together with other therapeutic medicaments or symptomatic medicaments. When the medicament of the invention and other therapeutic medicaments have synergistic effect, the dosage of the medicament is adjusted according to actual conditions.
Example 1
Wild type C57BL6 mice 8-10 weeks old were used as study subjects, and after 3 months of feeding with high fat diet containing 62 wt% fat, they were randomly divided into blank control group and GCN2 iB-treated group, and 5 mice per group had no significant difference in initial body weight between the two groups, as shown in FIG. 1. For the first day of molding, the drug GCN2iB was dissolved in olive oil and GCN2 iB-treated mice were administered by gavage at a dose of 5 mg/(kg body weight) once every 2 days for 4 weeks. The blank control group was given the same volume of olive oil, also every 2 days for 4 weeks. During the dosing period, both groups of mice continued to be fed high fat diet while weighing weekly. After the experiment is finished, blood sampling and standby examination are carried out on the eyeballs of the mice, and biochemical analysis and histological analysis are carried out on the liver, and the experimental results are respectively shown in fig. 1, fig. 2A-2B and fig. 3A-3C. It can be seen from figure 1 that oral administration of GCN2iB significantly reduced the body weight of high fat diet-induced obese mice (×) p < 0.01. As can be seen from fig. 2A and 2B, the activity of glutamic-pyruvic transaminase (ALT) (a) (glutamic-pyruvic transaminase/ALT/GPT test kit from tokyo institute of bioengineering using nanjing, cat # C009-2) and glutamic-oxaloacetic transaminase (AST) (B) (glutamic-oxaloacetic transaminase/AST/GOT test kit from tokyo institute of tokyo, cat # C010-2) in serum of high-fat diet-induced obese mice was significantly reduced by oral administration of GCN2iB ([ p ] represents p <0.05 and [ p ] represents p <0.01), indicating that oral administration of GCN2iB can improve liver function of obese mice. It can be seen from fig. 3A-3B that the oral administration of GCN2iB significantly reduced the content of triglycerides (a) (using the tissue triglyceride enzyme assay kit of beijing prilley gene technology ltd, cat # E1013-105) and total cholesterol (B) (using the tissue total cholesterol content assay kit of beijing prilley gene technology ltd, cat # E1015-105) in the liver of the high fat diet-induced obese mice (representing p < 0.05). FIG. 3C shows the results of oil red staining of cryo-sections of liver tissue (Solebao saturated oil red staining solution, cat # G1260), that oral administration of GCN2iB significantly reduced lipid deposition in the liver of obese mice induced by high fat diet, indicating that oral administration of GCN2iB reduced lipid content in the liver of obese mice.
Example 2
A homozygous mouse with a mutant leptin gene (Lepob, commonly written as ob or ob/ob) is a classical non-alcoholic fatty liver animal model. Ob/ob mice, 10-12 weeks old, were randomized into placebo and GCN2iB treatment groups of 5 mice each. The body weights of the groups were not significantly different. The administration and dose were the same as in example 1, with a duration of 6 weeks. During the period, the body weight is recorded, and when the experiment is finished, the eyeball blood sampling preparation examination is carried out on the mouse, and meanwhile, the biochemical analysis and the histological analysis are carried out on the liver. The experimental results are shown in fig. 4, fig. 5A to 5B and fig. 6A to 6C, respectively. It can be seen from figure 4 that oral administration of GCN2iB significantly reduced body weight in ob/ob mice (. beta. represents p < 0.05). As can be seen from fig. 5A and 5B, oral administration of GCN2iB significantly reduced the viability of glutamic-pyruvic transaminase (ALT) (a) (test of glutamic-pyruvic transaminase/ALT/GPT test cassette from tokyo institute of bioengineering, cat # C009-2) and glutamic-oxaloacetic transaminase (AST) (B) (glutamic-oxaloacetic transaminase/AST/GOT test cassette from tokyo institute of bioengineering, cat # C010-2) (p <0.05 and p <0.01), indicating that oral administration of GCN2iB improved liver function in ob/ob mice. As can be seen from FIGS. 6A-6B, the contents of triglyceride (A) (the test uses a tissue triglyceride enzyme method determination kit of Beijing prilley Gene technology, Inc., the product is No. E1013-105) and total cholesterol (B) (the test uses a tissue total cholesterol content determination kit of Beijing prilley gene technology, Inc., the product is No. E1015-105) in the liver of ob/ob mice are significantly reduced by oral administration of GCN2iB (representing that p is < 0.05). FIG. 6C shows the results of oil red staining of cryosections of liver tissue (Solebao saturated oil red staining solution, cat # G1260), with oral administration of GCN2iB significantly reduced lipid deposition in the liver of ob/ob mice, indicating that oral administration of GCN2iB reduced lipid content in the liver of ob/ob mice.
Example 3
The db/db mouse with leptin receptor mutation has typical clinical symptoms of diabetes such as extreme obesity, polyphagia, diabetes, polyuria and the like, and is also a typical fatty liver animal model. Db/db mice 6-8 weeks old were selected and randomized into near-weight placebo and GCN2 iB-treated groups. The administration and dose were the same as in example 1, with a duration of 4 weeks. After the experiment is finished, eyeball blood sampling and standby examination are carried out on the mouse, and meanwhile biochemical analysis is carried out on the liver. The experimental results are shown in fig. 7, fig. 8A to 8B and fig. 9A to 9C, respectively. It can be seen from figure 7 that GCN2iB administered orally maintained the body weight of db/db mice essentially unchanged, whereas the body weight gain of db/db mice in the control group was significant (. beta. represents p < 0.01). It can be seen from fig. 8A and 8B that oral administration of GCN2iB significantly reduced the viability of glutamic pyruvic transaminase (ALT) (a) (test of glutamic pyruvic transaminase/ALT/GPT test cassette from Nanjing institute of bioengineering, cat # C009-2) and glutamic oxaloacetic transaminase (AST) (B) (glutamic oxaloacetic transaminase/AST/GOT test cassette from Nanjing institute of bioengineering, cat # C010-2) (. beta. <0.05,. beta. <0.01), indicating that oral administration of GCN2iB improved liver function in db/db mice. It can be seen from FIGS. 9A-9B that the oral administration of GCN2iB significantly reduced the levels of triglyceride (A) (the assay kit for enzymatic determination of tissue triglyceride by Beijing prilley Gene technology, Inc., cat # E1013-105) and total cholesterol (B) (the assay kit for determination of total cholesterol in tissue by Gene technology, cat # E1015-105) in the liver of db/db mice (representing p < 0.05). FIG. 9C shows the results of oil red staining of cryo-sections of liver tissue (Solebao saturated oil red staining solution, cat # G1260), with oral administration of GCN2iB significantly reduced lipid deposition in the liver of db/db mice, indicating that oral administration of GCN2iB reduced lipid content in the liver of db/db mice.
Claims (9)
1. Use of a compound of formula I for the preparation of a medicament for the treatment of obesity and obesity-related disorders:
wherein R is1、R2And R3The same or different and are respectively selected from halogen elements; r4Is a substituted or unsubstituted C1-C10 straight or branched chain alkyl group; and R5Is a basic group.
2. Use according to claim 1, wherein R1、R2And R3Are respectively selected from F and Cl.
3. Use according to claim 1, wherein R4Is a substituted or unsubstituted C1-C5 straight or branched chain alkyl.
4. Use according to claim 1, wherein R5Is an amino group, a secondary amino group or a tertiary amino group.
5. Use according to claim 1, wherein R1、R2And R3Are respectively selected from F and Cl; r4Is a substituted or unsubstituted C1-C5 straight or branched chain alkyl group; r5Is an amino group, a secondary amino group having a C2-C5 alkyl group or a tertiary amino group.
6. Use according to claim 1, wherein R1、R2And R3Are respectively selected from F and Cl; r4Is C1-C3 alkyl; r5Is an amino group, a secondary amino group having a C2-C3 alkyl group or a tertiary amino group.
7. The use according to claim 1, wherein the compound has the structure of formula II:
8. the use according to any one of claims 1 to 7, wherein the obesity-related disorder is one or more of hypertension, coronary heart disease, fatty liver, diabetes, hyperlipidemia, endocrine disorders, skin disorders, joint disorders, gallbladder and pancreas disorders, and respiratory hypofunction.
9. The use of claim 8, wherein the medicament is a tablet, capsule, pill, powder, granule, suspension, emulsion or injection.
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| AKITO NAKAMURA等: "Inhibition of GCN2 sensitizes ASNS-low cancer cells to asparaginase by disrupting the amino acid response", 《PNAS》 * |
| CATIA M. PEREIRA等: "The GCN2 inhibitor IMPACT contributes to diet-induced obesity and body temperature control", 《PLOS ONE》 * |
| JUN FUJIMOTO等: "Identification of Novel, Potent, and Orally Available GCN2 Inhibitors with Type I Half Binding Mode", 《ACS MEDICINAL CHEMISTRY LETTERS》 * |
| MARK F. MCCARTY: "GCN2 and FGF21 are likely mediators of the protection from cancer, autoimmunity, obesity, and diabetes afforded by vegan diets", 《MEDICAL HYPOTHESES》 * |
| SHASHA LIU等: "GCN2 deficiency protects against high fat diet induced hepatic steatosis and insulin resistance in mice", 《BBA - MOLECULAR BASIS OF DISEASE》 * |
| WEI FENG等: "GCN2 deficiency ameliorates cardiac dysfunction in diabetic mice by reducing lipotoxicity and oxidative stress", 《FREE RADICAL BIOLOGY AND MEDICINE》 * |
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