WO2006136063A1 - Composés d’aporphine et de sécoaporphine pour le traitement du diabète - Google Patents

Composés d’aporphine et de sécoaporphine pour le traitement du diabète Download PDF

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Publication number
WO2006136063A1
WO2006136063A1 PCT/CN2005/001311 CN2005001311W WO2006136063A1 WO 2006136063 A1 WO2006136063 A1 WO 2006136063A1 CN 2005001311 W CN2005001311 W CN 2005001311W WO 2006136063 A1 WO2006136063 A1 WO 2006136063A1
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WIPO (PCT)
Prior art keywords
compound
group
insulin
diabetes
rats
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PCT/CN2005/001311
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English (en)
Chinese (zh)
Inventor
Shoei-Sheng Lee
Ming-Jai Su
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Lotus Pharmaceutical Co., Ltd.
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Publication of WO2006136063A1 publication Critical patent/WO2006136063A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/18—Ring systems of four or more rings
    • 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

Definitions

  • the present invention relates to a compound which can treat diabetes, and in particular to an apofen or subapoff compound which is used for the prevention and treatment of diabetes by enhancing the action of insulin and type 2 diabetes.
  • Diabetes is a common metabolic disease in clinical diseases in the world today. It has been found that patients with high blood sugar levels have more than 100 million people, most of which are non-insulin dependent due to obesity and diet.
  • NIDDM National Diabetes Management
  • the description of the pathological changes of diabetes has a history of more than 2,000 years.
  • J and the "Golden Chambers are slightly loaded” there are related records and descriptions.
  • the ancient name of diabetes is “diabetes”, mainly because the amount of insulin secreted by the pancreas is insufficient, and the sugar in the blood is increased, and there is more sugar in the urine; the characteristic symptoms are thirst, polyuria, Burnout, people are getting thinner, etc.
  • the ratio of diabetic patients is increasing in China, and it has been one of the top ten causes of death in China for five consecutive years. It is also listed as a medical profession with cardiovascular disease.
  • IDM insulin-dependent
  • NIDDM non-insulin-dependent
  • sulfonylurea drugs are suitable for the control of non-insulin-dependent patients by stimulating insulin secretion in vivo, and are ineffective for insulin-dependent patients who cannot synthesize and secrete insulin; such drugs that promote insulin secretion include early Tolbutamide (tolbutamide) to the current commonly used gl ipizi de (Gl ibenese) and so on.
  • biguanide drugs are mainly used to improve glucose utilization without stimulating insulin secretion, so they are often used in patients with insulin resistance, including obese non-insulin dependent patients.
  • the drugs used clinically to improve insulin resistance are mainly Metformin and peroxisome proliferator-activated receptor gamma (PPAR y ) acting rosiglitazone ( Rosiglii: a ZO ne), pioglitazone and other drugs.
  • PPAR y peroxisome proliferator-activated receptor gamma
  • mefluramine The main role of mefluramine is to increase the sensitivity of the liver to insulin and reduce the regeneration of liver and kidney sugar, reduce the absorption of glucose in the intestine, increase the role of insulin in adipose tissue and skeletal muscle, and improve the tolerance of insulin to patients.
  • sexually, but mefluramine needs to be administered at a higher dose as shown by Sindelar et al., 1997, Diabetes, Vol. 46, pp. 187, 196, which promotes the delivery of glucose type 4 (Glut 4) in muscle and fat.
  • the performance of the tissue in addition, promotes the metabolism of fatty acids in peripheral tissues [7], so as reported by Bailey et al.
  • the main object of the present invention is to provide a novel apofen or sub-aprefen compound, and a pharmaceutical composition comprising the same for preventing and treating diabetes, the composition comprising at least an effective amount of the formula I - A compound of IV, and a pharmaceutically acceptable carrier or excipient.
  • Some of the compounds of formula I and formula III are constituents in natural plants, and although natural apofen or sub-abufen alkaloids are known to have many activities, the compounds of formulas I-IV of the present invention have been found to have reduced for the first time. Blood sugar effect.
  • Another object of the present invention is to provide a novel method for synthesizing apofen or sub-apufen compounds.
  • a first aspect of the present invention provides an apofen compound of the formula I for preventing and treating diabetes, and a pharmaceutical composition comprising the same.
  • the composition includes an effective amount of a compound of formula I and a pharmaceutically acceptable carrier or excipient.
  • R, R 2 selected from hydroxy (0H), methoxy (OMe);
  • R 3 , R 5 are selected from the group consisting of hydrogen (H), hydroxy (0H), methoxy (OMe);
  • 6 is selected from the group consisting of hydrogen (H) and methyl (Me).
  • the second aspect of the present invention provides a formula II Apofen combination for preventing and treating diabetes And a pharmaceutical composition
  • a pharmaceutical composition comprising the compound, the composition comprising an apren compound of formula II and a pharmaceutically acceptable carrier or excipient.
  • R 2 and R 4 are selected from the group consisting of 0-acyl, ethoxy (0Et), n-propoxy (0 n Pr), isopropoxy ((Pr);
  • R 3 , R 5 is selected from hydrogen, 0-acyl, methoxy, ethoxy, n-propoxy or isopropoxy;
  • R 6 is selected from allyl or C n H 2n +1 and 6 ⁇ ⁇ 2
  • a third aspect of the present invention provides a hydrazone apofene compound for preventing and treating diabetes, and a pharmaceutical composition containing the same.
  • the composition comprises a sub-apofen compound of the formula and a pharmaceutically acceptable carrier or excipient.
  • R 2 and R 4 are selected from a hydroxyl group and a methoxy group
  • R 3 and R 5 are selected from the group consisting of hydrogen, a hydroxyl group and a methoxy group
  • R 6 and R 7 are selected from the group consisting of hydrogen (H) and methyl group (Me).
  • a fourth aspect of the present invention provides a pharmaceutical composition according to the present invention for preventing and treating diabetes, and a pharmaceutical composition comprising the same, which comprises a sub-apufen compound of the formula A pharmaceutically acceptable carrier or excipient.
  • R 2 , R 4 are selected from the group consisting of 0-acyl, ethoxy, n-propoxy or isopropoxy
  • R 3 and R 5 are selected from hydrogen (H), 0-acyl, ethoxy. , n-propoxy or isopropoxy
  • R 6 is selected from the group consisting of hydrogen (H) and methyl (Me).
  • a fifth aspect of the present invention provides a formula IV apofene compound for preventing and treating diabetes; and a pharmaceutical composition containing the same.
  • the composition comprises a sub-apofen compound of formula IV and a pharmaceutically acceptable carrier or excipient.
  • R, R 2 selected from hydrogen, methyl, 0-acyl, ethoxy, n-propoxy or isopropoxy
  • R 3 , R 5 are selected from 0-acyl, ethoxy , n-propoxy or isopropoxy
  • R 7 is selected from allyl or C n H and 6
  • composition of the present invention may optionally be added with various excipients, carriers, or diluents as a liquid, or as a patch for direct application to the affected area.
  • a dosage form or a type of binder such as starch or sodium carboxycellulose sodium is added to a tablet, a tablet or a capsule according to a known preparation method.
  • These dosage forms can also be used as sustained release lozenges and capsules according to known preparation methods or addition of sustained release agents.
  • the preparation method for the preparation according to the present invention can be made into different granules according to requirements, pressed into double-layer ingots with different release degrees, or mixed granules with different release degrees, or coated techniques can be used differently.
  • a formulation composition of a film coating, a sustained release film coat, an acid resistant film coat, and the like which is rapidly and immediately released by granule coating.
  • the experimental results show that compounds 13, 13 and 15 have hypoglycemic effects in both injection and oral administration, and have hypoglycemic effects in type 1 diabetes (insulin-dependent) rats, when administered for 4 consecutive days. Will increase the myocardial expression of the fourth type of glucose transport protein (Glut 4), the effect is similar to the results of insulin injection, in addition to the hypoglycemic effect on type 1 diabetes, the experimental results also prove that compounds 13, 14 and Compounds such as 15 also have hypoglycemic effects in rats with type 2 diabetes (non-insulin dependent).
  • the pharmacodynamic evaluation of the combination of drugs with different mechanisms of hypoglycemia showed that 0.05 mg/kg of compound 15 can significantly enhance insulin at a dose with insignificant hypoglycemic effect.
  • Compound 15 can also significantly enhance the hypoglycemic effect of Metformin in type 2 diabetic rats at doses where blood glucose lowering is not significant.
  • inventive drugs can also be combined with other hypoglycemic drugs to enhance the hypoglycemic effect.
  • Compound 15 showed a significant increase in glucose utilization.
  • the present invention does demonstrate that apofen and sub-apofen compounds can effectively reduce the blood glucose level of hyperglycemic diabetic rats when administered alone, and that such compounds can be administered at doses that do not affect blood glucose levels. Combined with existing hypoglycemic drugs, it can effectively lower blood sugar levels, but it will not cause hypoglycemia. From the above experimental results, it is known that such compounds have a lowering effect on blood sugar levels of different types of diabetes, and the advantages thereof are (1) In the insulin-dependent (IDDM) rats, the expression of the fourth type of glucose transport protein (Glut 4) can still be exhibited in insulin alone; (2) the combination with insulin can enhance the hypoglycemic effect of insulin;
  • IDDM insulin-dependent
  • Figure 1 shows the results of a glucose challenge test in a normal rat administered with Compound 15.
  • Figure 2 is a graph showing the results of a glucose challenge test in a non-insulin dependent rat administered with Compound 15.
  • Figure 5A and Figure 5B are statistically continuous by Western blotting method. Injecting compound 15 restored the protein expression of the first and fourth types of protein (Glut 1, Glut 4) in ventricular myocytes in insulin-dependent diabetic rats.
  • Figure 5A shows the protein expression of the first and fourth types of transport proteins (Glut 1, Glut 4).
  • Fig. 5B is a quantogram of Fig. 5A, the results obtained in normal rats of Table A, the results obtained by injecting coal in B-insulin-dependent rats, the results obtained by administering insulin in C-insulin-dependent rats, and D indicating the administration of insulin-dependent rats.
  • the result obtained for compound 15. detailed description
  • the bolding base (compound 1) and the phenyltrimethylammonium chloride are dissolved in the dry dimethylformamide (DMF), and the reaction is completed by heating under nitrogen gas after adding potassium carbonate. After removing the solvent by concentration under reduced pressure, Suspension in chloroform (CHC1 3 ), washing with distilled water, drying the organic layer with anhydrous sodium sulfate, concentration, and separation by column chromatography to obtain the compound (Predi centrine, 2) and nitrogen-methyl hexabase (y A mixture of ⁇ methyl laurotetanine, 3) and sea papaverine (glaucine, 4).
  • DMF dry dimethylformamide
  • the mixed product is dissolved in ethanol and ammonium acetate, and heated under reflux in an oil bath overnight, and concentrated to remove a part of the solution under reduced pressure.
  • the white precipitate is obtained after standing, filtered and washed with water, and the product can be obtained after drying. Secopredi centrine (5).
  • the filtrate was concentrated, then partitioned with water and chloroform, and the chloroform layer was evaporated to yield compound (3).
  • the pharmacological effect test of the compound of the present invention in vivo in experimental animals is evaluated for the prevention and treatment of diabetes by the action of enhancing insulin and type 2 diabetes by administering the apofen or subalbufen compound riv).
  • mice Male rats purchased from the National Animal Center's Wi star line are aged over 8 weeks and weigh between 200 and 250 g. The animals were kept in the animal center of the National Taiwan University Medical School with air conditioning to maintain the room temperature at 25 ⁇ 1 °C. The light time and dark time were 12 hours each, allowing the rats to eat and drink freely.
  • NIDDM non-insulin-dependent
  • the compound 15 is 0.1, 0.3, 1 mg/tnl, the compound 14 is 1, 3, 5 mg/ral, and the compound 13 is 3, 5, 7 mg / ml concentration, then administered to different types of diabetic rats by feeding or intravenous injection; with the difference in body weight, different doses of liquid are injected to maintain the injection volume The required concentration (mg/kg).
  • Wistar rats, streptozotocin or non-insulin dependent diabetic rats were fasted the night before the experiment.
  • the rats were anesthetized with intraperitoneal injection of pentobarbital 30 mg/kg.
  • pentobarbital 30 mg/kg After the rats were fixed on the fixation plate with rubber bands, open the groin, and after finding the femoral vein, first take the fasting blood glucose 0. 2-0. 6 ml, then give the compound by feeding or intravenous injection. 14, 15 to the body of the rat. After 60 and 90 minutes, blood was drawn and centrifuged (13, OOO rpm, 3 minutes) to separate serum and plasma.
  • insulin-dependent diabetic rats were divided into experimental group and control group. Both groups of rats were injected with tail vein intravenously, and compound 15 was given an effective dose of hypoglycemic effect in insulin-dependent diabetic rats. 3 mg/kg or an equal volume of vehicle was administered twice daily for four consecutive days to insulin-dependent rats; after four days of treatment, the rats were sacrificed to remove the rat heart and subjected to Western blotting. Changes in the transport of proteins in the first and fourth types of glucose.
  • the results obtained from the experiment are expressed as the mean soil standard error (mean ⁇ SE), and the difference between the two is evaluated by Student's t-test.
  • the multivariate comparison uses the variance analysis method (AN0VA). )with Differences between Dunnett's Post-hoc test to assess. P ⁇ 0.05, which is considered to be a significant difference.
  • Insulin-dependent hypoglycemic agents 1.0, 3.0, 5.0 mg/kg of compound 14 were also administered by intravenous administration. After 90 minutes, the hypoglycemic effect of 1 mg/kg of Compound 14 was 9.5 ⁇ 1.4%. Injection 3. Omg/kg of compound 14 The hypoglycemic effect produced by insulin-dependent rats was 13.0 ⁇ 5.8%, and the hypoglycemic effect of oral administration of 5.0 mg/kg of compound 14 was 13.6 ⁇ 1.3%, as shown in Table 4. Hypoglycemic effect of compound 14 on insulin-dependent rats
  • Insulin-dependent rats were also injected with 3.0, 5.0, and 7.0 mg/kg of compound 13 into the body by intravenous administration.
  • the hypoglycemic effect produced by the rats 90 minutes after the injection was 3.0 mg/kg of the compound. 13 is 1.7 ⁇ 4.0 and, at a dose of 7.0 mg / kg, the effect of hypoglycemia produced by compound 13 can be maximized, about 16.6 ⁇ 3.9%, as shown in Table 5.
  • Non-insulin-dependent rats were divided into two groups, one group was given 0.3 mg/kg of compound 15, the other group was given the same amount of vehicle, and the rats were anesthetized for 10 minutes and then intravenously injected with 1000 mg/ml/kg of glucose. Water, blood samples were taken at 5, 10, 20, 30, 60, 90, and 120 minutes to detect changes in blood glucose. The results are shown in Figure 2.
  • Non-insulin-dependent rats were divided into three groups. The first group was given a dose of 0. 01 mg / kg of compound 15 which did not affect the blood glucose change of non-insulin-dependent rats. The second group was only given mefluramine orally, the third group. The dose of 0. 01 rag / kg compound 15 plus oral mefluramine 100 mg / kg was administered by injection. Each group was tested for blood glucose changes at 60 and 90 minutes respectively. The results were as follows. Figure 3 shows.
  • the insulin-dependent type was divided into three groups. The first group was given a dose of 0.05 mg / kg of compound 15 which did not affect the blood glucose change of insulin-dependent rats, the second group was only injected with insulin, and the third group was administered without affecting insulin-dependent type.
  • the dose of blood glucose change in rats was 0.05 mg / kg compound 15 plus short-acting insulin 0. 5 IU / kg, blood glucose changes were measured at 60 and 90 minutes, respectively, and the results are shown in Figure 4.
  • the insulin-dependent type was divided into three groups, the first group was given 0.3 mg/kg, iv compound 15 for 4 consecutive days, the second group was given short-acting insulin (0.5 IU/kg/ml), another group was injected. The same amount of vehicle was given.
  • the heart and the normal rats in the control group were subjected to Western blotting experiments.
  • the changes of glucose type 1 and type 4 transfer proteins were compared and analyzed, and ⁇ actin ( ⁇ The protein expression level of -actin) was used as a control, as shown in Fig. 5A; Fig. 5 ⁇ is the result of quantification in Fig. 5 ⁇ .
  • a shows the results obtained from normal rats
  • b results in insulin-dependent rats
  • coal is obtained from insulin-dependent rats
  • d indicates insulin-dependent rats.
  • predentrine (2) (Predicentrine), nitrogen-methylhexapeptide (3) and sea papaverine (4) (glaucine)
  • Nitro-methylhexapeptide (3) R t 0. 57 (10% MeOH/CHCl 3 ); - R (CDC1 3 , 400 MHz): 8. 03 (1H, s, H - 11), 6 79 (1H, s, H-8), 6. 56 (1H, s, H-3), 3. 91 (3H, s, 9-0Me), 3. 89 (3H, s, 10-OMe) , 3. 63 (3H, s, 2 - OMe), 2. 53 (s, N- C ).
  • Example 2 Example 2
  • Avandia [package insert] Research Triangle Park, NC GlaxoSmithKline; 2003; Lebovitz HE, Kreider M, Freed MI. Evaluation of liver function in type 2 diabetic patients during clinical trials Evidence that rosiglitazone does not cause hepatic dysfunction. Diabetes Care. 2002;25:815-821

Abstract

La présente invention concerne un nouveau type de composés d’aporphine ou de sécoaporphine, un procédé pour sa fabrication et une composition pharmaceutique comprenant lesdits composés qui est utilisée pour prévenir et traiter le diabète. Ladite composition comprend au moins une quantité efficace de composés de formule I à IV et des vecteurs et un excipient médicalement acceptables.
PCT/CN2005/001311 2005-06-20 2005-08-22 Composés d’aporphine et de sécoaporphine pour le traitement du diabète WO2006136063A1 (fr)

Applications Claiming Priority (2)

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CNA2005100786034A CN1884265A (zh) 2005-06-20 2005-06-20 治疗糖尿病的阿朴芬及次阿朴芬化合物
CN200510078603.4 2005-06-20

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CN115490637B (zh) * 2022-06-21 2024-03-29 海南医学院 一个阿朴菲类生物碱化合物制备方法及其应用

Citations (3)

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US4309542A (en) * 1977-12-22 1982-01-05 Warner-Lambert Company Process for the O-methylation of hydroxyaporphines
CN1103863A (zh) * 1993-12-14 1995-06-21 苏铭嘉 司可阿朴啡类化合物，其制备方法以及含有该化合物的药物组合

Patent Citations (3)

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US4188495A (en) * 1977-11-14 1980-02-12 Pfizer Inc. 1,9-Dihydroxyoctahydrophenanthrenes and intermediates therefor
US4309542A (en) * 1977-12-22 1982-01-05 Warner-Lambert Company Process for the O-methylation of hydroxyaporphines
CN1103863A (zh) * 1993-12-14 1995-06-21 苏铭嘉 司可阿朴啡类化合物，其制备方法以及含有该化合物的药物组合

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Title
LEE S.-S. ET AL.: "A facile semisynthesis of litebamine, a novel phenanthrene alkaloid, from boldine via a biogenetical approach", TETRAHEDRON LETTERS, vol. 33, no. 42, 1992, pages 6309 - 6310, XP003005369 *
LEE S.-S. ET AL.: "Preparation of phenanthrene alkaloids via solvolysis of 2-hydroxyaporphines", TETRAHEDRON LETTERS, vol. 36, no. 9, 1995, pages 1531 - 1532, XP004028620 *

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