WO2011029359A1 - Médicaments contenant des régulateurs doubles de la 11-β hydroxystéroïde déshydrogénase 1 et leurs utilisations - Google Patents

Médicaments contenant des régulateurs doubles de la 11-β hydroxystéroïde déshydrogénase 1 et leurs utilisations Download PDF

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WO2011029359A1
WO2011029359A1 PCT/CN2010/075829 CN2010075829W WO2011029359A1 WO 2011029359 A1 WO2011029359 A1 WO 2011029359A1 CN 2010075829 W CN2010075829 W CN 2010075829W WO 2011029359 A1 WO2011029359 A1 WO 2011029359A1
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halogen
activity
dehydrogenase
formula
lower alkyl
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PCT/CN2010/075829
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Chinese (zh)
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李校堃
梁广
葛仁山
王怡
胡国新
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温州医学院
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Priority claimed from CN200910170884A external-priority patent/CN102018690B/zh
Priority claimed from CN2009102052902A external-priority patent/CN102038666B/zh
Priority claimed from CN2009102535895A external-priority patent/CN102091060A/zh
Application filed by 温州医学院 filed Critical 温州医学院
Publication of WO2011029359A1 publication Critical patent/WO2011029359A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/225—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention belongs to the technical field of medicine, in particular, the invention relates to the pharmaceutical application of a dual modulator of 11 ⁇ -hydroxyl dehydrogenase 1, in particular for preventing and/or treating diseases of glycolipid metabolism, tumor and hypogonadism. Obstacles and/or infertility, etc. Further, the present invention relates to a pharmaceutical composition comprising a dual modulator of ⁇ -hydroxydehydrogenase 1, a kit, and the like.
  • Glucocorticoid (herein referred to as GC) is one of the most important hormones that induce insulin resistance. GC mainly reduces insulin-mediated glucose uptake, promotes the breakdown of fat and protein, increases hepatic gluconeogenesis, and inhibits insulin secretion by pancreatic beta cells. GC can directly activate gene expression related to hepatic gluconeogenesis, and promote glucagon release and indirectly increase hepatic glucose output; GC can synergize with CRE binding protein to induce PPAR Y coactivator and reduce insulin secretion; GC can also interfere with insulin signaling, reducing GLUT4 translocation to the membrane, leading to insulin resistance. Therefore, GC is functionally antagonistic to insulin, and many diseases in clinic also show a relationship between GC and insulin.
  • GC metabolic abnormalities lead to a wide range of metabolic diseases, including pathological conditions caused by abnormalities in various metabolic components, such as abdominal obesity or overweight, atherosclerotic dyslipidemia (high triglycerides (abbreviated as TG) Hypertension and high-density lipoprotein cholesterol (herein referred to as HDL-C) are low), hypertension, insulin resistance, and impaired glucose tolerance.
  • Common metabolic diseases include diabetes, obesity, atherosclerosis and hypertension, among which diabetes is one of the most important, widespread and serious metabolic diseases.
  • WHO estimates by 2020, the global number of diabetic patients will be close to 300 million, which has become the third most serious disease that endangers human health after cardiovascular and cerebrovascular diseases.
  • Epidemiological and clinical studies have confirmed that type 2 diabetes is one of the metabolic diseases caused by insulin resistance.
  • glucocorticoids increase and plasma testosterone levels decrease.
  • luteinizing hormone is a major driver of testosterone production by testicular stromal cells, whereas glucocorticoids produced by adrenocortical cells are inhibitors.
  • Glucocorticoids also inhibit the secretion of luteinizing hormone. Glucocorticoids act by binding to the glucocorticoid receptor.
  • Leydig cells have a glucocorticoid receptor, suggesting that the glucocorticoid secreted by the adrenal gland can directly affect these cells. However, there is no direct evidence that reducing the amount of active glucocorticoids in the body can treat diseases such as sexual dysfunction and/or infertility.
  • ⁇ -HSD 11 ⁇ -hydroxysteroid dehydrogenase
  • 11PHSD 11 ⁇ -hydroxysteroid dehydrogenase
  • ⁇ -HSD includes two enzymes: ⁇ -HSD1 and llp-HSD2.
  • ⁇ -HSD1 the main role of ⁇ -HSD1 is to promote the conversion of inactive glucocorticoids (herein referred to as GC) to active GC
  • 11P-HSD2 only promotes the conversion of active GC to inactive GC.
  • ⁇ -HSD1 is an oxidoreductase, which has two enzyme forms, reductase and oxidase, wherein reductase promotes the conversion of inactive GC to active GC, while oxidase acts in the opposite direction, promoting active GC to inactive GC. Conversion. Since ⁇ -HSD1 reductase is dominant, and its oxidase is in a secondary position, it is apparent that ⁇ -HSD1 usually exhibits reductase activity. According to the type and function of ⁇ -HSD, many large pharmaceutical companies in the world have started research on ⁇ -HSD1 inhibitors, such as BVT7702, 138768 and NCB13793. Among them, Incyte's 1 ⁇ -HSD1 selective inhibitor NCB 13793 is undergoing Phase II clinical research.
  • ⁇ -HSD1 inhibitors simultaneously (mixed) inhibit ⁇ -HSD1 oxidase and reductase, some of which do not affect 11P-HSD2, but at the same time
  • the activity of ⁇ -HSD1 oxidase is inhibited.
  • ⁇ -HSD1 oxidase has the same effect as l ip-HSD2, which can reduce glucocorticoid concentration, increase insulin expression, reduce glycogen output and blood glucose levels, enhance insulin sensitivity, and resist the development of diabetes.
  • the effect of inhibiting oxidase is less than the effect of inhibiting reductase, apparently ⁇ -HSDl
  • the inhibition of reductase thus acts to reduce the activity of GC, but this will inevitably offset the partial efficacy of the ⁇ -HSD1 reductase inhibitor.
  • the activity of 11P-HSD2 is inhibited, the ⁇ -HSD1 reductase inhibitor will also be offset.
  • This compound with dual regulation of ⁇ -HSD1, especially a compound with specific regulation of ⁇ -HSD1, will form an ideal anti-diabetic drug through the “ ⁇ -HSD1-glucocorticoid ⁇ insulin ⁇ blood glucose” channel. .
  • ⁇ -HSD1-glucocorticoid ⁇ insulin ⁇ blood glucose a compound with specific regulation of ⁇ -HSD1
  • the particularly preferred compound LG13 (BP, B6) is administered at low doses for metabolic diseases such as diabetes.
  • the effect of prevention is best, and the poor effect at medium and high doses is not directly caused by drug toxicity, which not only reduces the cost of medication, but also reduces the risk of side effects that may be caused by larger doses.
  • these ⁇ -HSD1 dual modulators especially the preferred dual ⁇ -HSD1 modulators, will form an ideal pathway through the " ⁇ -HSD1-glucocorticoid ⁇ testosterone" channel.
  • the drug therefore, will have the effect of preventing and/or treating diseases such as hypogonadal dysfunction and/or infertility, and can be safely administered, meeting the increasing demands of current public and government regulatory authorities for drug safety.
  • tumors are one of the leading causes of human death.
  • Statistics show that malignant tumors have become the leading cause of death in urban and rural residents. It can be seen that the prevention and treatment of tumors is very urgent.
  • Drug therapy is one of the main treatments for cancer.
  • anti-tumor drugs have been developed, which effectively prolong the life of patients or improve the quality of life of patients, some anti-tumor drugs are very effective, such as drugs for the treatment of acute leukemia in children.
  • drugs that still require new tumors face enormous challenges in their research and development.
  • anti-tumor drugs are mostly cytotoxic drugs, and their side effects are obvious, which limits the efficacy of these drugs.
  • the object of the present invention is to supplement the vacancies of the prior art, and to provide a dual modulator of ⁇ -HSD1, especially a specific ⁇ -HSD1 dual modulator, which can be used for pharmaceuticals, safely, effectively and even low-cost for prevention and/or prevention. Therapeutic effects of various diseases. Further, the present invention provides a pharmaceutical composition and a kit comprising the ⁇ -HSD1 dual modulator, and a method of screening the ⁇ -HSD1 dual modulator, and the like.
  • the present invention provides a method of using a compound of Formula I in the manufacture of a medicament for preventing and/or treating a disease, wherein the disease is capable of reducing 11 ⁇ -hydroxydehydrogenase 1 Reductase activity and / or increase 11 ⁇ -hydroxyl dehydrogenase 1 / or prevent disease,
  • Ru and R 21 are each deuterium, halogen, optionally halogen-substituted lower alkyl, or lower alkoxy;
  • R 12 and R 22 are not alkenyloxy or halogen-substituted lower alkyl, preferably R 12 and R 22 are each H, halogen, or lower alkoxy;
  • R 13 and R 23 are not alkenyloxy, preferably R 13 and R 23 are each H, halogen, lower alkyl, hydroxy, or optionally hydrazine, fluorenyl-dimethylamino substituted lower alkoxy;
  • R 14 and R 24 are each deuterium or lower alkyl
  • R 15 and R 25 are each H or lower alkyl, or R 15 and R 25 are synthesized, wherein n is 1, 2, 3.
  • the first aspect of the invention also provides prevention and/or Or a method of treating a disease, wherein the disease is a disease which can be treated and/or prevented by reducing the activity of 11 ⁇ -hydroxyl dehydrogenase 1 reductase and/or increasing the activity of 11 ⁇ -hydroxyl dehydrogenase 1 oxidase.
  • the method comprises administering to a patient a drug comprising an effective amount of a compound of formula I
  • Ru and R 21 are each H, halogen, optionally halogen-substituted lower alkyl, or lower alkoxy;
  • R 12 and R 22 are not alkenyloxy or halogen-substituted lower alkyl, preferably R 12 and R 22 are each H, halogen, or lower alkoxy;
  • R 13 and R 23 are not alkenyloxy, preferably R 13 and R 23 are each H, halogen, lower alkyl, hydroxy, or optionally hydrazine, fluorenyl-dimethylamino substituted lower alkoxy;
  • R 14 and R 24 are each deuterium or lower alkyl
  • R 15 and R 25 are each H or lower alkyl, or R 15 and R 25 are synthesized, wherein n is 1, 2, 3, or 4.
  • the compound of formula I is a dual modulator of 11 ⁇ -hydroxydehydrogenase 1, preferably a specific 11 ⁇ -hydroxydehydrogenase 1 dual modulator.
  • the compound of formula I is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • Ri is oxime, halogen, or lower alkoxy
  • R 2 is an anthracene, a halogen, or a lower alkoxy group
  • R 3 is hydrazine, halogen, or hydrazine, ⁇ -dimethylamino substituted lower alkoxy;
  • R 4 is ⁇
  • R 2 is H or lower alkoxy
  • R 3 is H or a hydroxyl group
  • R 4 is H
  • Each is H, halogen, halogen-substituted lower alkyl, or lower alkoxy; 11 or lower alkoxy;
  • R 3 is H or a hydroxyl group
  • R 4 is H
  • the compound of formula I is selected from any of the following compounds
  • the compound of formula I is LG13
  • ⁇ 6 is preferably the first aspect of the invention, wherein the disease is due to an increase in activity of 11 ⁇ -hydroxydehydrogenase 1 reductase and/or activity of 11 ⁇ -hydroxydehydrogenase 1 oxidase A disease caused by a decrease; it is also preferred that the disease is a glycolipid metabolic disease, hypogonadal dysfunction, and/or infertility, preferably selected from the group consisting of diabetes, obesity, atherosclerosis, cirrhosis, fatty liver, high Blood glucose, hyperlipidemia, hypertension, hypogonadal dysfunction and/or infertility, most preferably diabetes, fatty liver, hypogonadal dysfunction caused by excessive glucocorticoids and its induced infertility, and / or stress testosterone reduction, such as sputum type diabetes, stress, disease or aging-induced gonadotropin dysfunction caused by excessive glucocorticoids and its resulting infertility, and so on.
  • the disease is due to an increase in activity of 11 ⁇ -hydroxydehydr
  • the compound of formula I is LG13 in an effective dose of from 1 to 10 mg/kg of the rat, such as 1-10 mg/kg of Wistar rat.
  • This low dose is surprisingly superior to higher doses of diabetes treatment (hypoglycemic), with advantages in both efficacy and safety applications.
  • the first aspect of the invention is particularly preferably provided The use of LG13 for the preparation of a medicament for treating diabetes or lowering blood glucose, wherein the medicament comprises LG13 at an effective dose of 1-10 mg/kg rat; accordingly, the first aspect of the invention also provides for treating diabetes or lowering blood glucose Methods, the method comprising administering to a patient an effective amount of a compound of formula I, wherein said effective amount is from 1 to 10 mg/kg of rat.
  • the present invention also provides an application method or method similar to the first aspect of the present invention, wherein the only difference is that the disease is capable of apoptotic cells by activating CHOP and/or by activating caspase -3 and caspase-9 and apoptotic cells to treat or prevent diseases.
  • the second aspect of the present invention is not treated and/or prevented by reducing the activity of the 11 ⁇ -hydroxyl dehydrogenase 1 reductase and/or increasing the activity of the 11 ⁇ -hydroxyl dehydrogenase 1 oxidase.
  • the disease is contradictory.
  • the compound of the present invention has no inhibitory ability, and therefore, in the second aspect of the invention, the disease is preferably gastric cancer, myeloid leukemia, oral cavity.
  • the disease is preferably gastric cancer, myeloid leukemia, oral cavity.
  • the compound of the formula I is B19 or ⁇ 63.
  • these compounds have been shown to be safe and effective in treating tumors. Therefore, the second aspect of the present invention particularly preferably provides the use of B19 or ⁇ 63 in the preparation of a medicament for treating a tumor, preferably the tumor is non-small cell lung cancer or glioblastoma; accordingly, the second aspect of the invention is also A method of treating a tumor is provided, the method comprising administering to a patient an agent comprising an effective amount of B19 or ⁇ 63, preferably the tumor is non-small cell lung cancer or glioblastoma.
  • the ruthenium 63 compound is preferred as a separate aspect.
  • the present invention provides a pharmaceutical composition comprising an effective amount of LG13 and a pharmaceutically acceptable carrier, wherein an effective dose is from 1 to 10 mg/kg of a rat, preferably from 1 to 10 mg/kg of a Wistar rat, such as 5 mg/kg Wistar rats.
  • the pharmaceutical composition is a pharmaceutical composition for treating diabetes or preventing stress-induced testosterone reduction.
  • the present invention provides a kit for treating diabetes comprising LG13, and indicating a rat at 1 - 1 Omg/kg (preferably 1 - 1 Omg/kg Wistar rat, such as 5 mg/kg Wistar rat)
  • the label for dosing is surprisingly superior to higher doses of diabetes treatment (hypoglycemic), has advantages in both efficacy and safe use, and can be conveniently used to guide medication.
  • the invention provides a method of screening a dual modulator of 11 ⁇ -hydroxydehydrogenase 1 in vitro, comprising
  • IC50 half-inhibitory concentration of the reductase activity of the test compound on the mesenchymal cells, the CHOP cells transfected with human 11PHSD1 and/or the 11 ⁇ -hydroxydehydrogenase 1 of the microsomal protein was determined in vitro;
  • the method further comprises measuring the half inhibitory concentration of the oxidase activity of the 11 ⁇ -hydroxydehydrogenase 2 of the microsomal protein in vitro by the dual modulator of iota ⁇ -hydroxyl dehydrogenase 1 (IC50), then the compound having an IC50 greater than ⁇ was selected as a dual modulator of specific 11 ⁇ -hydroxyl dehydrogenase 1.
  • IC50 dual modulator of iota ⁇ -hydroxyl dehydrogenase 1
  • the stromal cells are rat interstitial cells; and/or the microsomal proteins are rat testicular microsomes, human liver microsomes, rat kidney microsomes, and/or human kidneys Microsomes.
  • the compound to be tested is a compound represented by the formula
  • Rii, R2i, Ri2, R22 R 14 and R 24 are each H, halogen, hydroxy, amino, optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted alkenyloxy, wherein the substituent Including 3 ⁇ 4, hydroxy, amino, aryl and/or heterocyclic;
  • R 15 and R 25 are each H or lower alkyl, or R 15 and R 25 are synthesized, wherein n is 1, 2, 3, or 4.
  • the invention exemplifies the compounds listed in Example 1.
  • Figure 1 is a schematic representation of the chemical synthesis process of the compounds of the invention.
  • FIG. 2 Schematic diagram of the specific dual regulation of the ⁇ -HSD1 mechanism.
  • ⁇ -HSD1 As shown in the upper panel of Figure A, the currently reported specific inhibitors of ⁇ -HSD1 only refer to the primary selectivity between ⁇ -HSD1 and 11P-HSD2, and have not been involved in ⁇ -HSD1 reductase activity and oxidation. Enzyme activity is the selectivity between the two catalytic directions. These inhibitors simultaneously inhibit ⁇ -HSD1 reductase and oxidase, but because reductase is dominant, it can also be expressed as inhibition of reductase, reducing the body and local cortisol concentration. There have been no reports of screening tests for ⁇ -HSD1 reductase and oxidase, and ⁇ -HSD1 inhibitors with secondary selectivity.
  • the defects are: (1) will certainly offset some of the efficacy of the inhibitor; (2) two-way inhibition ⁇ ⁇ -HSDl can only Prevent the conversion of cortisone to cortisol, However, it is not possible to reduce the elevated cortisol concentration.
  • the elevated cortisol levels in the tissue will still maintain stimulating glycogen output and insulin resistance; the existing cortisol concentration needs to be stimulated by ⁇ -HSD1 oxidase. It is converted to inactive cortisone.
  • the lower panel of Figure A shows the ideal ⁇ -HSD1 dual modulator (the compound of the present invention is a ⁇ -HSD1 dual modulator), which inhibits ⁇ -HSD1 reductase and simultaneously activates ⁇ -HSD1 oxidase.
  • ⁇ -HSD1 dual modulator inhibits ⁇ -HSD1 reductase and simultaneously activates ⁇ -HSD1 oxidase.
  • the currently reported selective inhibitors of ⁇ -HSD1 only refer to the first-order selectivity between ⁇ -HSD1 and 11P-HSD2, and have not yet been related to ⁇ -HSD1 reductase.
  • This type of inhibitor inhibits both ⁇ -HSD1 reductase and oxidase, but since reductase is dominant, it is apparently inhibited by reductase and reduces local cortisol concentration, but may not affect stress or ke Syndrome causes systemic cortisol levels.
  • cortisol levels in the tissue will still maintain the inhibition of testosterone synthesis; the existing cortisol concentration needs to be stimulated ⁇ - ⁇ -HSD1 oxidase converts it to inactive cortisone, especially due to excessive circulating glucocorticoid levels, such as stress and Cushing's syndrome.
  • FIG. 3 LG13 dual regulation of ⁇ -HSD1 reductase and oxidase in murine microsomes.
  • Panel A shows the effect of LG13 on the inhibition of ⁇ -HSD1 oxidase
  • Figure 4 Effect of LG13 and curcumin on blood glucose levels and ester metabolism.
  • various indicators are: A picture is blood sugar, B picture is triacylglycerol, C picture is total cholesterol, D picture is low density lipoprotein, E picture is apolipoprotein-al, F picture is apolipoprotein- b. * and *** indicate statistical differences, * is P ⁇ 0.05, and *** is P ⁇ 0.001.
  • LG13 inhibits the formation of fatty liver in rats.
  • Group A was a normal diet rat;
  • Group B was a high-fat diet rat;
  • Group C was a high-fat diet rat with LG13 at a dose of 1 mg/kg;
  • Group D was administered with a dose of 5 mg/kg for LG13.
  • FIG. 7 Effect of in vitro administration of B19 and B63 on the survival rate of human non-small cell lung cancer H460 cells.
  • Figure 8 Flow cytometry of B19 and B63-induced apoptosis in human non-small cell lung cancer H460 cells
  • Figure 11 Effect of toxicity of B19 and B63 on animal body weight and visceral weight.
  • the ordinate indicates the weight difference; the horizontal coordinate indicates the number of days of continuous gavage administration.
  • Figure 12 Effect of toxicity of B19 and B63 on blood parameters.
  • Left middle White blood cell ratio detection, the ordinate represents the percentage, the abscissa represents the animal group, LYM is the lymphocyte, GRAN is the neutrophil, and MID is the intermediate cell group, including the fin acid, the fin granulocyte and the monocyte.
  • the object of the present invention is to provide a novel application method or method in which a compound capable of simultaneously reducing the activity of 11 ⁇ -hydroxysteroid dehydrogenase reductase and increasing the activity of 11 ⁇ -hydroxysteroid dehydrogenase oxidase is applied. That is, the ⁇ -HSD1 dual regulator, especially the specific ⁇ -HSD1 dual regulator, can be applied in the fields of pharmaceutical, therapeutic and preventive. Further, another object of the present invention is to provide a method for treating or preventing a disease in which a ⁇ -HSD1 dual modulator is apoptotic cells by activating CHAP and/or apoptotic cells by activating caspase-3 and caspase-9 or Pharmaceutical applications.
  • the present invention provides a pharmaceutical composition and kit comprising the ⁇ -HSD1 dual modulator, and a method for screening the ⁇ -HSD1 dual modulator. . Additionally, it is an object of the present invention to provide new low dose pharmaceutical compositions, kits and corresponding applications.
  • the present invention provides a method of using a compound of Formula I in the manufacture of a medicament for preventing and/or treating a disease, wherein the disease is capable of reducing 11 ⁇ -hydroxydehydrogenase 1 a disease which is treated and/or prevented by the activity of a reductase and/or an activity of increasing 11 ⁇ -hydroxyl dehydrogenase 1 oxidase, Formula I
  • Ru and R 21 are each H, halogen, optionally halogen-substituted lower alkyl, or lower alkoxy;
  • R 12 and R 22 are not alkenyloxy or halogen-substituted lower alkyl, preferably R 12 and R 22 are each H, halogen, or lower alkoxy;
  • R 13 and R 23 are not alkenyloxy, preferably R 13 and R 23 are each H, halogen, lower alkyl, hydroxy, or optionally hydrazine, fluorenyl-dimethylamino substituted lower alkoxy;
  • R 14 and R 24 are each deuterium or lower alkyl
  • R 15 and R 25 are each H or lower alkyl, or R 15 and R 25 are synthesized, wherein n is 1, 2, 3, or 4.
  • preferred compounds include A2, A6, A10, A12, A19, B6 (i.e., LG13), B12, B19, B63, C2, C6, C13, C19, and C66, and particularly preferably B6.
  • the first aspect of the invention also provides a method of preventing and/or treating a disease, wherein the disease is capable of reducing the activity of 11 ⁇ -hydroxyl dehydrogenase 1 reductase and/or increasing 11 ⁇ a disease which is treated and/or prevented by the activity of a hydroxydehydrogenase 1 oxidase, the method comprising administering to a patient a drug comprising an effective amount of a compound of formula I
  • Ru and R 21 are each H, halogen, optionally halogen-substituted lower alkyl, or lower alkoxy;
  • R 12 and R 22 are not alkenyloxy or halogen-substituted lower alkyl, preferably R 12 and R 22 are each H, halogen, or lower alkoxy;
  • R 13 and R 23 are not alkenyloxy, preferably R 13 and R 23 are each H, halogen, lower alkyl, hydroxy, or optionally ⁇ , ⁇ -dimethylamino substituted lower alkoxy;
  • R 14 and R 24 are each deuterium or lower alkyl
  • R 15 and R 25 are each H or lower alkyl, or R 15 and R 25 are bonded to e3 ⁇ 4 1T wherein n is 1, 2, 3, or 4.
  • preferred compounds include A2, A6, A10, A12, A19, B6 (i.e., LG13), B12, B19, B63, C2, C6, C13, C19, and C66, and particularly preferably B6.
  • drug has the meaning well known to those skilled in the art, which comprises an active active ingredient which is effective for the treatment and/or prevention of a disease, and optionally comprises a pharmaceutically acceptable carrier.
  • an entity which does not comprise a pharmaceutically acceptable carrier and which consists solely of the active active ingredient is also a drug.
  • the terms “treating” and “preventing” have the meanings well known to those skilled in the art, and administering to a patient after the onset of a symptom of the disease an action for eliminating or alleviating the symptoms of the disease or preventing, slowing or delaying the progression of the disease. It is called treatment, and the administration of an action for preventing or preventing the occurrence of a disease or slowing or delaying the deterioration after the occurrence of the disease before the onset of the disease symptoms is called prevention.
  • the compound of the present invention can treat diabetes, prevent fatty liver formation, prevent stress testosterone reduction, and treat non-small cell lung cancer and glioblastoma.
  • halogen means F, Cl, Br and I.
  • the compound of formula I is a dual modulator of 11 ⁇ -hydroxydehydrogenase 1, preferably a specific 11 ⁇ -hydroxydehydrogenase 1 dual modulator.
  • 11 ⁇ -hydroxydehydrogenase 1 preferably a specific 11 ⁇ -hydroxydehydrogenase 1 dual modulator.
  • 11 ⁇ -hydroxysteroid dehydrogenase 1 dual modulator or its abbreviation “dual regulator” refers to the ability to simultaneously reduce 11 ⁇ -hydroxydehydrogenase 1 reductase activity and increase 11 ⁇ -hydroxyl Dehydrogenase 1 oxidase activity compound.
  • the semi-inhibitory concentration (EC50) of the 11 ⁇ -hydroxydehydrogenase 1 reductase activity of the compound is less than 30 ⁇ and the semi-effective concentration (EC50) of the 11 ⁇ -hydroxydehydrogenase 1 oxidase activity is less than 30 ⁇ , preferably It has an IC50 of less than 20 ⁇ and an EC50 of less than 20 ⁇ , more preferably an IC50 of less than ⁇ and an EC50 of less than 10 ⁇ , more preferably an IC50 of less than 5 ⁇ and an EC50 of less than 5 ⁇ , particularly preferably an IC50 of less than ⁇ and an EC50 of less than 1 ⁇ .
  • the term "specific ⁇ -hydroxydehydrogenase 1 dual modulator” or its abbreviation “specific dual modulator” refers to a dual regulation that does not substantially affect the activity of 11 ⁇ -hydroxydehydrogenase 2 oxidase.
  • the half inhibitory concentration (IC50) of the oxidase activity of the dual modulator to 11 ⁇ -hydroxysteroid dehydrogenase 2 is greater than 100 ⁇ . This concentration is much greater than the inhibition of 11 ⁇ -hydroxydehydrogenase 1 reductase activity and activation of 11 ⁇ -hydroxyl dehydrogenase 1 oxygen as defined above.
  • the concentration of the enzyme activity therefore, the effective concentration of the dual modulator does not substantially affect the oxidase activity of 11 ⁇ -hydroxyl dehydrogenase 2.
  • the term "patient” refers to an animal having, or potentially suffering from, a disease, preferably a mammal, such as a mouse, a rat, a rabbit, a dog, a monkey, a human, etc., and most preferably a human.
  • the patient may have an increased or decreased 11 ⁇ -hydroxydehydrogenase 1 reductase activity and/or 11 ⁇ -hydroxyl depoting relative to a healthy or normal individual, organ, tissue or cell Symptoms of decreased activity of hydrogenase 1 oxidase, or symptoms that may or may occur by reducing the activity of 11 ⁇ -hydroxydehydrogenase 1 reductase and/or increasing the activity of ⁇ -hydroxydehydrogenase 1 oxidase And treatment and / or prevention.
  • the dual modulator of the present invention can simultaneously reduce the activity of ⁇ -hydroxydehydrogenase reductase and increase the activity of 11 ⁇ -hydroxysteroid dehydrogenase oxidase, thereby treating or preventing ⁇ - in vivo. Increased activity of hydroxydehydrogenase reductase and
  • the disease is a glycolipid metabolic disease, hypogonadal dysfunction, and/or infertility, preferably selected from the group consisting of diabetes, obesity, atherosclerosis, cirrhosis, fatty liver, Hyperglycemia, hyperlipidemia, hypertension, hypogonadal dysfunction and/or infertility, most preferably hypoglycemia dysfunction caused by diabetes, fatty liver, glucocorticoid excess and its induced infertility, And/or stress testosterone reduction, such as type 2 diabetes, stress, disease or aging-induced gonadotropin dysfunction caused by excessive glucocorticoids and its resulting infertility, etc.
  • the compound of formula I is LG13, and particularly preferably an effective dose of from 1 to 10 mg/kg of a rat, such as from 1 to 10 mg/kg of Wistar rat.
  • effective dose refers to the amount required for a single administration in the course of being effective to treat or prevent a disease, which may be in the form of a unit dosage (eg, a tablet, a needle, a pill or a The amount of the drug in the agent may also be the unit dose (e.g., unit weight dose) of the patient in need of treatment/prevention.
  • the drug manufacturer can easily convert the unit weight dose of the patient to be treated/prevented into the amount of the drug in a unit dosage form by the average body weight of the patient population to be treated/prevented, for example, the average of the adult patient.
  • the body weight can be 60 kg, so by multiplying the average body weight by the unit weight dose of the adult, the content in the drug for the unit dosage form for the adult can be obtained.
  • the patient is a human, but the patient used for the experiment is usually a non-human mammal such as a monkey, rabbit, dog or mouse. According to the equivalent dose conversion relationship between experimental animals and humans known to those skilled in the art (see generally the guidance of FDA, SFDA and other drug regulatory agencies, see also "Huang Jihan et al.
  • the human body weight dose can be derived from the dose of experimental animals.
  • the conversion relationship with adults is about 12: 1; for commonly used experimental animal rats, according to the above literature, its conversion relationship with adults is about 6: 1.
  • the dose is usually expressed herein in terms of rat unit body weight.
  • the effective dose refers to an effective dose of 0.167-1.67 mg/kg adult, that is, an effective dose of 10-100 mg in a human drug in a unit dosage form.
  • the inventors' research method now has the opposite effect of conventionally approved dose-dependent treatment/prevention, LG13 is best for low-dose treatment/prevention of diabetes, and at medium and high doses.
  • the poor effect is not due to drug toxicity. Therefore, without being limited to theory, it is preferred that in the first aspect, the medicament contains an effective dose of LG13, more preferably a dose of LG13 containing 1-10 mg/kg of Wistar rat, more preferably a dose of 3-8 mg/kg of Wistar rat.
  • LG13 such as LG13 at a dose of 5 mg/kg Wistar rats.
  • the present invention provides a method of using a compound of Formula I in the manufacture of a medicament for the prevention and/or treatment of a disease, wherein the disease is capable of apoptotic cells by activating CHOP and/or by activating caspase- 3 and caspase-9 and apoptotic cells to treat or prevent diseases,
  • Ru and R 21 are each H, halogen, optionally halogen-substituted lower alkyl, or lower alkoxy;
  • R 12 and R 22 are not alkenyloxy or halogen-substituted lower alkyl, preferably R 12 and R 22 are each H, halogen, or lower alkoxy;
  • R 13 and R 23 are not alkenyloxy, preferably R 13 and R 23 are each H, halogen, lower alkyl, hydroxy, or optionally hydrazine, fluorenyl-dimethylamino substituted lower alkoxy;
  • R 14 and R 24 are each deuterium or lower alkyl
  • R 15 and R 25 are each H or lower alkyl, or R 15 and R 25 are synthesized, wherein n is 1, 2, 3, or 4.
  • preferred compounds include A2, A6, A10, A12, A19, B6 (i.e., LG13), B12, B19, B63, C2, C6, C13, C19, and C66, and particularly preferably B19 and B63.
  • the first aspect of the invention also provides a method of preventing and/or treating a disease, wherein the disease is capable of apoptotic cells by activating CHOP and/or by activating caspase-3 and caspase- 9.
  • a disease in which apoptotic cells are treated or prevented the method comprising administering to the patient a drug comprising an effective amount of a compound of formula I
  • Ru and R 21 are each H, halogen, optionally halogen-substituted lower alkyl, or lower alkoxy;
  • R 12 and R 22 are not alkenyloxy or halogen-substituted lower alkyl, preferably R 12 and R 22 are each H, halogen, or lower alkoxy;
  • R 13 and R 23 are not alkenyloxy, preferably R 13 and R 23 are each H, halogen, lower alkyl, hydroxy, or optionally hydrazine, fluorenyl-dimethylamino substituted lower alkoxy;
  • R 14 and R 24 are each deuterium or lower alkyl
  • R 15 and R 25 are each H or lower alkyl, or R 15 and R 25 are bonded to e3 ⁇ 4 1T wherein n is 1, 2, 3, or 4.
  • preferred compounds include A2, A6, A10, A12, A19, B6 (i.e., LG13), B12, B19, B63, C2, C6, C13, C19, and C66, and particularly preferably B19 and B63.
  • the patient may have symptoms that are or will occur relative to healthy or normal individuals, organs, tissues or cells capable of activating cells by activating CHOP and/or by activating caspase-3 and caspase- 9 and apoptotic cells to treat or prevent.
  • the compounds of the present invention can also be treated or prevented by activating apoptotic cells by activating CHOP and/or apoptotic cells by activating caspase-3 and caspase-9, and thus can usually treat certain tumors and cancers.
  • the disease is gastric cancer, myeloid leukemia, oral epithelial cancer, lung cancer or sarcoma, and particularly preferably non-small cell lung cancer or glioblastoma.
  • the invention provides a compound of the formula
  • tumors such as gastric cancer, myeloid leukemia, oral epithelial cancer, lung cancer or sarcoma, particularly preferably non-small cell lung cancer or glioblastoma
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of LG13 and a pharmaceutically acceptable carrier, preferably a dose of from 1 to 10 mg/kg of a rat (e.g., l-10 mg/kg Wistar rat) LG13.
  • a pharmaceutically acceptable carrier preferably a dose of from 1 to 10 mg/kg of a rat (e.g., l-10 mg/kg Wistar rat) LG13.
  • Low dose pharmaceutical compositions are preferably used to prevent or treat diabetes or stress testosterone reduction.
  • the term "pharmaceutically acceptable carrier” refers to a non-toxic solid, semi-solid or liquid filler, diluent, adjuvant, encapsulating material or other formulation excipient.
  • the pharmaceutical compositions may be formulated into various dosage forms, such as tablets, films, pills, capsules (including sustained release), depending on the purpose of the treatment, the route of administration, in accordance with the teachings in the art. Or a delayed release form), a powder, a granule, an elixir, a syrup and an emulsion, a sterile solution or suspension, an aerosol or liquid spray, a drop, an injection, an automatic injection device or a suppository.
  • the dual modulator may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, isotonic glucose solution, glycerol, physiological saline or combination.
  • compositions of this invention may be administered by methods of administration well known to those skilled in the art, such as oral, rectal, sublingual, pulmonary, transdermal, iontophoretic, vaginal and intranasal administration.
  • the pharmaceutical composition of the present invention is preferably administered parenterally, such as subcutaneously, intramuscularly or intravenously.
  • the dose to be administered varies depending on the form of the preparation and the desired time of action and the condition of the subject to be treated, and the amount required for the actual treatment can be conveniently determined by the physician based on the actual conditions (e.g., the condition of the patient, the body weight, etc.).
  • the invention provides a kit for treating diabetes comprising LG13, and a label indicating administration at a dose of l-10 mg/kg rat.
  • the low dose refers to a dose of l-10 mg/kg Wistar rat, preferably a dose of 3-8 mg/kg Wistar rat, such as a dose of 5 mg/kg Wistar rat, if not stated to the contrary.
  • the kit is a common product for the general public and can be easily found in pharmacies.
  • the kit comprises a container containing LG13 or a pharmaceutical composition of the third aspect of the invention, in other words, LG13 or the pharmaceutical composition of the third aspect of the invention is contained in a container of the kit of the present invention.
  • the container may be a usual container such as a bottle, a box, a syringe or the like which can accommodate LG13 and the pharmaceutical composition of the second aspect of the invention.
  • the medicine may include only one container, and may also include a plurality of containers.
  • the label may be affixed to the container or printed directly onto the container, or may be present in a separate form, such as a cover for a cartridge that can hold the container or directly provided instructions.
  • the label indicates administration with a low dose of LG13, wherein the indication of the label may be expressed in units of body weight, or may be expressed in absolute doses of a specific population, such as "adult dosage” or "child dosage". It is necessary to perform a simple conversion based on the weight.
  • the container contains a composition such as a drug, a preparation, etc.
  • the low dose can be converted into a content according to the content of the LG13 in the unit dosage form (e.g., one tablet, one needle), which is indicated by a label, which is for people. Easy. It is also within the scope of the invention to package the kit further into larger packages as needed for convenient transportation and storage.
  • the present invention provides a method of screening a dual modulator of 11 ⁇ -hydroxydehydrogenase 1 in vitro, which comprises
  • IC50 half-inhibitory concentration of the reductase activity of the test compound on the mesenchymal cells, the 11OP-hydroxyl dehydrogenase 1 of CHOP cells and/or microsomal proteins transfected with human 11PHSD1 in vitro
  • EC50 half-effective concentration of the oxidase activity of the test compound on stromal cells, 11 ⁇ -hydroxyl dehydrogenase 1 of CHOP cells and/or microsomal proteins transfected with human 11PHSD1;
  • a compound having an IC50 of less than 30 ⁇ and an EC50 of less than 30 ⁇ is selected as a double regulator of 11 ⁇ -hydroxydehydrogenase 1.
  • a compound having an IC50 of less than 20 ⁇ and an EC50 of less than 20 ⁇ is preferably selected, and a compound having an IC50 of less than ⁇ and an EC50 of less than ⁇ is more preferably selected, and a compound having an IC50 of less than 5 ⁇ and an EC50 of less than 5 ⁇ is more preferably selected, and it is particularly preferable to select an IC50 of less than ⁇ and an EC50 of less than ⁇ .
  • the method further comprises measuring in vitro the half-inhibitory concentration of the 11 ⁇ -hydroxydehydrogenase 1 dual modulator on the oxidase activity of the 11 ⁇ -hydroxydehydrogenase 2 of the microsomal protein ( IC50), then the compound having an IC50 greater than ⁇ was selected as a dual modulator of specific 11 ⁇ -hydroxyl dehydrogenase 1.
  • the stromal cells are rat interstitial cells; and/or the microsomal proteins are rat testicular microsomes, human liver microsomes, rat kidney microsomes, and/or human kidneys Microsomes.
  • R u , R 21 , R 12 , R 22 , R 13 , R 23 , R 14 and BR 24 are each H, halogen, hydroxy, amino, optionally substituted alkyl, optionally substituted alkoxy, or any a substituted alkenyloxy group, wherein the substituent includes a 3 ⁇ 4 element, a hydroxyl group, an amino group, an aromatic group and/or a heterocyclic ring;
  • R 15 and R 25 are each H or lower alkyl, or R 15 and R 25 are synthesized, wherein n is 1, 2, 3, or 4.
  • the invention exemplarily screens the compounds listed in Example 1.
  • the present invention is hereby incorporated by reference in its entirety in its entirety in its entirety herein in its entirety herein in the invention in the invention.
  • the invention will be described in detail below by means of specific embodiments and the accompanying drawings. It is to be understood that the description is not intended to be limiting of the scope of the invention. Many variations and modifications of the invention will be apparent to those skilled in the ⁇ RTIgt; detailed description
  • Isolation method of hepatocytes and interstitial cells After the rats were sacrificed by C0 2 asphyxiation, the testis was removed to extract and purify the interstitial cells, and the method was referred to [ ⁇ , et al. J Androl. 2001, 22, 665-671]. The purity of mesenchymal cells was determined by 3 ⁇ -hydroxyindole dehydrogenase activity histochemical staining (with 0.4 mM of this cholesteryl ketone as a substrate), which can stain more than 95% of mature stromal cells; The separation was performed by the method described by Pertoft and Smedsrad [Cell Separation: Methods and Selected Applications.
  • Murine interstitial cells murine hepatocytes
  • human hepatocyte microsomes were prepared by the method reported by [fea, et ⁇ . Endocrinology, 1997, 138: 435-42].
  • 11PHSD oxidase and reductase activity detection method using detecting [3 H] - cortisone or [3 H] -11- concentration of hydrocortisone characterized ⁇ ⁇ -HSDl oxidase or reductase activity, respectively. 25 nM [ 3 H]-cortisone was added to each ⁇ -HSD1 activity assay tube (this concentration was within the physiological concentration range of cortisone).
  • the body in the incubation solution is extracted with an organic solvent, dried in a nitrogen gas stream, and then separated by chloroform/methanol (9:1) as a mobile phase, and the steroid is separated by thin layer chromatography, [ 3 H]-cortisone or
  • the radioactivity of [ 3 H]-11-hydrocortisone was detected by scanning radiography (System AR2000, Bioscan Inc., Washington, DC, USA), and the conversion between cortisone and hydrocortisone was determined by themselves.
  • the radioactive standard number is calculated and determined.
  • Oxidase activity can be measured by adding CORT (2 x 10-9 -10-5 M) and 0.2 mM NADP+ for 30 minutes in a 0.15 ⁇ ⁇ mouse liver microsome system.
  • ⁇ - ⁇ -HSD1 reductase can be measured by adding 11DHC (2 X 10-9 -10-5 M), 0.2 mM NADPH and 0.2 mM G6P in a 1.5 g rat liver microsome system for 30 minutes.
  • the detection method of lp-HSD2 is as follows: ⁇ -HSD1 oxidase detection method.
  • A rat interstitial cells
  • B rat testicular microsomes
  • C CHOP cells transfected with human 11PHSD1
  • D human liver microsomes
  • E rat kidney microsomes
  • F human kidney microsomes
  • - No detection
  • Cur Curcumin.
  • the compounds inhibited the inhibitory or activating activity of ⁇ -HSD1 reductase, ⁇ -HSD1 oxidase and 11P-HSD2 in six cell or microsomal systems.
  • curcumin analogs are not compounds that have dual regulation of ⁇ -HSD1, or have little or no inhibition of ⁇ -HSD1 reductase activity, or almost no
  • the ability to activate ⁇ -HSD1 oxidase activity, especially for alkenyloxy substituted compounds, is not only weakly activated by ⁇ -HSD1 oxidase activity, but also weakly inhibits ⁇ -HSD1 reductase activity;
  • Most of the tested curcumin analogues have a weak inhibitory effect on 11P-HSD2.
  • the particularly preferred compound B6 i.e., LG13
  • B6 has a dose-dependent activity for the inhibitory activity against ⁇ -HSD1 reductase and the activation activity for ⁇ -HSD1 oxidase.
  • Example 3 B6 (LG13) Decreases blood glucose and lipid levels in animals fed with high-fat foods in vivo
  • the livers of group A and group B6 were dark red, soft in texture and good in elasticity.
  • the left lobe was significantly larger than the right lobe.
  • the interlobular fissure was clear, the edges were sharp, and the cut surface was smooth.
  • the relevant organs and spleen were also dark. Red slender strips, full kidney, thinner perirenal fat sac.
  • group B and C65 the liver was evenly swollen, the liver was full, the right lobe was enlarged, the ratio of left and right lobe was decreased, the interlobular fissure was small, the liver margin became dull, and the color increased with darkness from dark red to pale white. Or milky white, occasionally the liver is obviously yellowed or fatty granuloma due to cholestatic.
  • Group B and C65 group formed vesicle-based steatosis, which occurred in different degrees of hepatic lobular inflammation, hepatocyte turbidity, balloon-like changes, point or focal necrosis, and neutrophil or lymphocyte infiltration, and more With varying degrees of fibrosis.
  • LG13 has been significantly inhibited. The formation of fatty liver.
  • LG13 has a significant effect on lowering blood glucose at high, medium and low doses, and it is particularly surprising that hypoglycemic effects last longer at low doses (5 mg/kg).
  • Example 6 Safety test of the compound of the present invention
  • LG13, B19, B63, A6 and B50 were suspended in 1% sodium carboxymethylcellulose solution, taking 14-18g Balb/C mice (male, normal diet), divided into 4 groups, respectively, negative group (normal word, no gavage), solvent group (administer the same amount of sodium hydroxymethylcellulose solution), 400mg /kg dose of LG13 group, 800mg/kg dose of LG 13 group, 400mg/kg dose of B 19 group, 800mg/kg dose of B 19 group, 400mg/kg dose of B63 group, 800mg/kg dose of B63 group, 400 mg/kg dose of A6 group, 800 mg/kg dose of A6 group, 400 mg/kg dose of B50 group, and 800 mg/kg dose of B59 group, 8 rats in each group, intragastric administration, once daily, continuous intragastric administration 14 day. No mice died of toxicity within 14 days, and no abnormal behavior and condition of the administered mice were observed.
  • mice in the B19 and B63 groups were killed, the body weight and visceral weight were weighed, and the change values were recorded.
  • the results are shown in Fig. 11; blood was taken from the eyelids, and half of them were directly subjected to whole blood analysis (blood cell analyzer). The amount of red blood cells, white blood cells, and hemoglobin was measured; the other half was centrifuged to separate the serum, and the contents of alanine aminotransferase and aspartate aminotransferase were measured. The results are shown in FIG.
  • LG13 was suspended in 1% sodium carboxymethylcellulose solution, and 14-18 g of Balb/C mice (male, normal diet) were taken at a higher dose of 3 g/kg. The dose of LG13 was intragastrically administered once a day for 3 days and then for another 3 days. No mice died of toxicity within 6 days, and no abnormal behavior and condition of the administered mice were observed.
  • the pharmacokinetics of LG13 mice were measured according to the method recommended by the drug regulatory department and the method described by Liang G, et al. Bioorg. Med. Chem., 2009, 17: 2623-2631. The main pharmacokinetics were determined. The data is shown in Table 3. As can be seen from Table 3, the peak dose of LG13 plasma reached 4.1 g/ml, also at a dose of 500 mg/kg orally. The corresponding LG13 has a lower in vivo clearance (CL) (125.4), indicating a significant decrease in the body's ability to remove compounds. The amount of LG13 entering the plasma was large, and the AUCO-t and AUCO-oo values reached 12.053 and 14.907 mg_h/L, respectively. It can be seen that LG13 has considerable advantages in terms of pharmacokinetic parameters.
  • AUC area under the curve
  • t m half-life
  • MRT mean residence time
  • CL clearance rate
  • C max highest blood concentration
  • T max peak time
  • the cell strains used were: human gastric cancer cell line BGC 823, human myeloid leukemia cell line HL-60, human oral epithelial cancer cell line KB, human colon adenocarcinoma cell line LS 174T, human prostate cancer cell line PC-3, Human cervical cancer cell line Hela cells were purchased from the Cell Center of Shanghai Institute of Life Sciences, Chinese Academy of Sciences.
  • the cells were inoculated into 96-well culture plates, and the cell suspension was adjusted to contain 5% heat-inactivated newborn bovine serum, penicillin 100 U/mL, streptomycin 10 (g/mL of 1640 medium, 100 ⁇ per well, so that the cells were The density was 5000/well. It was cultured in an incubator containing 5% C0 2 saturated humidity. After 24 h, various compounds dissolved in DMSO were added to the plates to give final concentrations of 100, 33.3, 11.1 and 3.7 g. /mL, after incubation for 72 h, 3 mg/ml MTT 20 ⁇ per well was added 3 h before the incubation.
  • the dose response curve was obtained by plotting the different concentrations of the same drug on the growth inhibition rate of the tumor cells.
  • the concentration of the drug against the cell growth inhibition rate of 50% according to the linear regression equation was the half-inhibitory concentration IC 5Q .
  • the results are shown in Table 4.
  • B19 and B63 can make a considerable difference in the ability to inhibit the proliferation of various human tumor cells.
  • the above two The compounds were significantly higher than the curcumin and the positive drug control cisplatin (DDP) in several cell lines such as HL-60 in this experiment, and the inhibitory ability against other cancer cell lines was varied by orders of magnitude.
  • the mechanism is anti-tumor, and the mechanism is not resistant to all tumors.
  • Human non-small cell lung cancer cell line (NCI-H460), available from US Cell, Strain Bank (ATCC). Human non-small cell lung cancer H460 cells were seeded in 96-well plates at a cell density of 5000 cells/well, The cells were cultured for 24 hours in a CO 2 incubator, and cells were treated with different concentrations of compounds for 24 hours. The number of cells was measured using a Cell Titer Cell Counting Kit (Promega Co., USA), and the method was performed according to the kit manual. Compared with the blank control group, the number of cells in the blank control group was calculated as 100%.
  • NCI-H460 and H358 Human non-small cell lung cancer cell line (NCI-H460 and H358), derived from American cell, strain cell (ATCC). H460 was inoculated into 6mm well culture plates, and B63 and B19 dissolved in DMSO were added to culture after 24 h. The plates were incubated for a final concentration of 5, 10 and 20 ⁇ for 24 h. Then rinsed three times with PBS buffer and added with 0.25% tryptan-EDTA. Centrifuge and then suspend the cells at 0.5 1 ⁇ 88.
  • Endoplasmic reticulum stress involves and mediates apoptosis induced by multiple drugs.
  • Haidara K et al Haidara K et al (Haidara K, et al. Toxicol Appl Pharmacol 2008, doi: 10.1016/i.taap.2008.01.010)
  • the test method described is a test for the development of ER stress toward apoptosis in H460 cells using B 19 and B63. Specifically, 1.2 ⁇ 10 6 cells were cultured at 37 ° C with culture medium, and after 24 hours, the culture solution was renewed and different concentrations of the compound were added (the control group was added with 3 uL of DMSO), and after the corresponding period of time was continued, the cells were collected. Total protein, Western blot was used to detect CHOP content, and Actin was used as a calibration protein. The result is shown in Figure 9.
  • the caspase channel is another important pro-apoptotic signaling protein in addition to CHOP downstream of ER stress.
  • B19 and B63 on caspase-3 and caspase-9. Specifically, 1.2 ⁇ 10 6 H460 cells were cultured at 16 ° C in 1640 culture medium, and the culture solution was updated 24 hours later. After treatment with different concentrations of B 19 , B63 and curcumin for 24 hours, the cells were harvested and total protein was collected. Western blot was used to detect caspase-3 p30 and pl7, caspase-9 p46, p35 and B p22, procaspase-3 and B procaspase. -9 content, Actin as a calibration protein.
  • Fig. 10 The active forms of caspase-3 and caspase-9 were significantly activated after 24 hours of B19 treatment at 20 ⁇ , indicating that caspase-3 and caspase-9 are also involved in the signal transduction pathway of B19-induced apoptosis.
  • the inactive forms of caspase-3 and caspase-9, procaspase-3 and procaspase-9 were significantly reduced after treatment with 20 ⁇ of ⁇ 63, indicating that the caspase gradually changed from inactive form to active form. Therefore, the compound of the present invention induces apoptosis by activation of caspase-3 and caspase-9.
  • Example 14 Inhibition rate of mouse S180 sarcoma
  • Kunming mice female, 18-22 grams, first grade, purchased from the Animal Center of the Academy of Military Medical Sciences; S 180 sarcoma cells, purchased from the Laboratory of Hematology, Institute of Radiation Medicine, Academy of Military Medical Sciences.
  • mice were intraperitoneally injected with 0.2 ml; negative control group per mouse peritoneal cavity 2 ml of physiological saline was administered continuously for 7 days; the positive control was administered with cyclophosphamide, administered once in group, and subcutaneous injection of 0.2 ml equivalent to a dose of 50 mg/kg.
  • the mice were sacrificed by cervical dislocation and weighed, and the tumor mass was removed. The tumor weight was called.
  • Example 15 Inhibition of Mouse LLC Non-small Cell Lung Cancer Kunming B6 mice, female, 18-22 grams, first grade, purchased from the Animal Center of the Academy of Military Medical Sciences; LLC non-small cell lung cancer cells, purchased from the Beijing Institute of Neurosurgery.
  • the tumors of the second-generation LLC non-small cell lung cancer cell tumor mice were inoculated subcutaneously under sterile peeling.
  • the well-growth tissues and normal saline were picked and homogenized at a ratio of about 3 ⁇ 10 6 /ml.
  • the grouping and administration were the same as above, and continuous administration was carried out for 13 days.

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Abstract

Cette invention concerne des composés capables de réduire l'activité de la 11β-hydroxystéroïde déshydrogénase 1 (11β-HSD1) réductase et/ou d'améliorer l'activité de la 11β-HSD1 oxydase, ainsi que les utilisations desdits composés dans la fabrication des médicaments utilisés dans la prévention ou le traitement du métabolisme du glucose, des tumeurs, des affections dégénératives des gonades et/ou de la stérilité. L'invention concerne également les compositions pharmaceutiques et les kits contenant lesdits composés, et la méthode de criblage desdits composés.
PCT/CN2010/075829 2009-09-12 2010-08-10 Médicaments contenant des régulateurs doubles de la 11-β hydroxystéroïde déshydrogénase 1 et leurs utilisations WO2011029359A1 (fr)

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CN2009102052902A CN102038666B (zh) 2009-10-18 2009-10-18 治疗或预防代谢疾病的药物及其应用
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CN2009102535895A CN102091060A (zh) 2009-12-10 2009-12-10 治疗或预防糖皮质激素介导的性腺功能减退性功能障碍和/或不育的药物及其应用

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CN103044224A (zh) * 2013-01-29 2013-04-17 牡丹江医学院 一种戊-1,4-二烯-3-酮类似物及其制备方法与应用
CN103113202A (zh) * 2013-01-29 2013-05-22 牡丹江医学院 一种（2e，5e）-2,5-双亚苄基环戊酮类似物及其制备方法与应用
WO2016109470A1 (fr) * 2014-12-30 2016-07-07 Baylor College Of Medicine Stimulateurs à petites molécules des protéines co-activatrices des récepteurs de stéroïdes et méthodes pour les utiliser
US10875841B2 (en) 2018-08-29 2020-12-29 Baylor College Of Medicine Small molecule stimulators of steroid receptor coactivator-3 and methods of their use as cardioprotective and/or vascular regenerative agents
WO2021088495A1 (fr) * 2019-11-07 2021-05-14 温州医科大学 Forme cristalline i de dérivé de curcumine, son procédé de préparation et son utilisation

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