WO2015027911A1 - Composé pour le traitement du diabète - Google Patents

Composé pour le traitement du diabète Download PDF

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Publication number
WO2015027911A1
WO2015027911A1 PCT/CN2014/085270 CN2014085270W WO2015027911A1 WO 2015027911 A1 WO2015027911 A1 WO 2015027911A1 CN 2014085270 W CN2014085270 W CN 2014085270W WO 2015027911 A1 WO2015027911 A1 WO 2015027911A1
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WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
solvate
hydrate
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PCT/CN2014/085270
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English (en)
Chinese (zh)
Inventor
谢永美
魏于全
耿福能
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四川好医生药业集团有限公司
四川大学
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Publication of WO2015027911A1 publication Critical patent/WO2015027911A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the present invention relates to a method of treating diabetes.
  • T2D type 2 diabetes
  • T2D therapeutic drugs commonly used in clinical practice include insulin, biguanide, sulfonylurea, glycosidase inhibitor, thiazolyldione, glitazone and glinide, but they often have different degrees of side effects, such as Hypoglycemia, weight gain, cardiovascular side effects, etc.
  • the present invention provides a novel compound for the treatment of diabetes. Another object of the invention is to provide the use of this novel compound. Specifically, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
  • Rl R2 R3 are each independently selected from H, hydrazine, C1 C3 fluorenyl, partially deuterated or fully deuterated C1 C3 fluorenyl;
  • R4 is selected from -CH - H H C ⁇ C or not;
  • R5 R6 are independently selected from H
  • R7 ⁇ R9 are independently selected from the group consisting of H, hydrazine, halogen, C 1 ⁇ C4 Or, R5, CH, R6, and its associated N-N NR 12 - NON
  • R11 is selected from a non-deuterated, partially or fully deuterated C1 ⁇ C4 sulfhydryl group
  • R12 is selected from H, C1-C4 sulfhydryl groups, a thiol group selected from H or C1 to C4;
  • R15 is selected from H, C1 C4 fluorenyl or decyloxy, _C-R 16;
  • R16 is selected from the group consisting of C1 to C4.
  • R1, R2, and R3 are each independently selected from the group consisting of H, ⁇ , C1 C3 ⁇ , partial or full C C1 C3 ⁇
  • R4 is selected from
  • R 5 and R 6 together with the N to which they are bonded form an OR, and R 10 and R 11 are selected from C 1 to C 4 alkyl groups which are undeuterated, partially or fully deuterated;
  • R1, R2, R3, R10, R11 is ⁇ or ⁇ .
  • R4 is selected from H H .
  • the thiol group of C1 to C3 and C1 C4 is a methyl group or an ethyl group.
  • the compound is selected from one of the following:
  • the compound is selected from the group consisting of
  • the pharmaceutically acceptable salt is an acid salt, a hydrobromide salt, a phosphate, a sulfate, a methanesulfonate, a p-toluenesulfonate, a citrate, a benzoate, or a rich salt of the compound.
  • the research of the invention shows that the salt of the above compound can also lower the blood sugar of the type 2 diabetes, improve the oral glucose tolerance, and has obvious therapeutic effect on the type 2 diabetic fatty liver, thereby effectively reducing the deposition of glycogen and collagen in the kidney, thereby May delay the progression of glomerular sclerosis and tubular fibrosis in diabetic nephropathy.
  • the present inventors have also found that the salt formation of the above compounds increases the water solubility of the compound more or less, and is also advantageous for improving bioavailability. Among them, different compounds with different acids will have different effects on the bioavailability of the drug.
  • the mesylate or p-toluenesulfonate of the compound has a higher bioavailability than other salts. To be significant, for example, the mesylate salt of the D1 compound or the p-toluenesulfonate of the D2 compound.
  • the present invention also provides the use of the above compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the manufacture of a medicament for improving insulin sensitivity, protecting liver and reducing enzymes, or improving blood sugar, blood fat or body weight.
  • the hepatoprotective enzyme of the invention can be used for preventing or treating fatty liver or diabetes with fatty liver.
  • the medicament is a medicament for treating diabetes, hyperlipemia, obesity or fatty liver.
  • the fatty liver is diabetic fatty liver or primary fatty liver.
  • the drug is a drug for alleviating or treating diabetic nephropathy.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt, hydrate or solvate thereof for the preparation of a medicament for treating pulmonary fibrosis or liver fibrosis.
  • the present invention also provides a pharmaceutical composition prepared by using the above compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, together with pharmaceutically acceptable excipients or auxiliary ingredients. preparation.
  • preparation is an oral, sublingual, topical, implant, inhalation, injection or transdermal absorption preparation.
  • the pharmaceutically acceptable excipient of the present invention means a substance contained in a dosage form other than the active ingredient, including but not limited to a filler (diluent), a lubricant (glidant or anti-adhesive), a dispersing agent, Wetting agents, binders, conditioners, solubilizers, antioxidants, bacteriostats, emulsifiers, disintegrators, and the like.
  • the binder comprises syrup, gum arabic, gelatin, sorbitol, tragacanth, cellulose and derivatives thereof (such as microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose) , gelatin paste, syrup, starch slurry or polyvinylpyrrolidone; fillers include lactose, powdered sugar, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salts (such as calcium sulfate, calcium phosphate , calcium hydrogen phosphate, precipitated calcium carbonate, etc.), sorbitol or glycine; lubricants include micronized silica gel, magnesium stearate, talc, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, etc.; disintegrants included Starch and its derivatives (such as sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch,
  • auxiliary component which has a certain physiological activity, but the addition of the component does not change the dominant position of the above compound or derivative in the course of disease treatment, but only plays an auxiliary effect, and these auxiliary functions are only
  • the use of known activity of this component is an adjuvant treatment that is commonly used in the medical field. If the above auxiliary components are used in combination with the compound of the present invention, it should still fall within the scope of protection of the present invention.
  • the deuterated compound prepared by the invention can obviously improve the body weight, fasting blood glucose, transaminase and fasting serum insulin of obese patients, improve insulin sensitivity, improve blood lipid index and oral glucose tolerance; the compound has good absorption in vivo and high bioavailability, It is beneficial to the exertion of the drug, and the half-life is prolonged, which can reduce the number of administrations, reduce the side effects, and provide a safe and reliable new choice for clinical use.
  • Figure 1 Liver HE, where NS: saline group; Normal: normal group; SIS3: control compound
  • 29 30 (012) 28 mg (0.1 mmol) of compound 4, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 1 mL of DMF, then added 0.025 mL of triethylamine, stirred at room temperature for 0.5 h and then added 19 mg ( 0.12 mmol) 3,5-dimethoxyaniline (29), stirring was continued overnight. After adding 20 ml of EA, it was washed with a saturated NaCI solution, dried over anhydrous sodium sulfate, filtered, and concentrated, and then purified to give a yellow powder 30 mg, yield 71%.
  • the lg compound D1 was weighed, 20 ml of dichloromethane was added, stirred and dissolved, 0.29 g of benzoic acid was added to the solution under ice bath, 50 ml of anhydrous diethyl ether was added to the solution, and solids were precipitated during the stirring, suction filtration, and diethyl ether washing. After drying, 0.85 g of D1 mesylate was obtained in a yield of 67.1%. Elemental analysis: C, 71.92%; H, 6.19%; N, 7.34% (theoretical: C, 72.64%; H, 6.27%; N, 7.26%)
  • mice Five-week-old C57BL/6J mice, male, were fed with common vocabulary and high-fat vocabulary for 10 weeks. Male mice that were successfully modeled were randomly divided into groups of 5, and body weight was recorded. The administration group was given 5 mg/kg of different compounds, and the blank control group and the normal group were given the same volume of physiological saline. The rats were intraperitoneally administered once a day, and after 5 days of continuous administration, the fasting basal blood glucose and glucose tolerance of the mice were examined. Data were presented as mean ⁇ standard deviation, and significant differences were determined by t test. When P 0.05, it is considered to have a significant difference. The test results are shown in Tables 1 and 2.
  • NS saline group
  • Normal normal group
  • SIS3 control compound (CAS: 521985-36-4); *- indicates significant difference compared with untreated group (P ⁇ 0.05)
  • Dl, D2, D3, D4, D5, D6, D7 and SIS3 can significantly reduce blood glucose levels in diabetic animal models. From the therapeutic effect, Dl, D2 and D3 are better than SIS3, D5 and D7 are similar to SIS3, and D4 and D6 are not as effective as SIS3.
  • the present invention selected Dl, D2, D3, D4, D5, D6, D7 and SIS3 for pharmacokinetic studies.
  • Test compound SIS3 compounds D1, D2, D3, D4, D5, D6, D7.
  • SD rats were randomly divided into 8 groups according to the mode of administration, 5 rats in each group: SIS3, Dl, D2, D3, D4, D5, D6, D7 were administered by intragastric administration at a dose of 50 mg/kg. Rats in each group were fasted 12 hours before the experiment. After oral administration of the drug solution, blood was collected at 0.25, 0.5, 1, 1.5, 2, 3, 5, 6, 8, 10, 12, 24, 48 h, and placed in a heparinized plastic centrifuge tube.
  • the collected blood was centrifuged at 4 °C (6000 r/min, lOmin), 100 ⁇ l of plasma was taken, 500 ⁇ l of methanol was added, vortexed for 1 min, centrifuged C13000r/min, lOmin), and the supernatant was transferred to EP.
  • nitrogen was blown dry, dissolved in a mobile phase, centrifuged at C13000 r/min, 2 min), and the supernatant was taken for 70 ⁇ l for HPLC analysis.
  • the pharmacokinetic compartment model was automatically fitted and the pharmacokinetic parameters were calculated. The results are shown in Table 3.
  • SIS3 Control compound (CAS: 521985-36-4); *- indicates significant difference compared with SIS3 group ( ⁇ 0.05)
  • AUC(0- ⁇ ) was 1.3 times, 5.6 times and 3.2 times of the original drug, respectively.
  • the half-life was 2.3 times and 5.4 times respectively. 3.5 times.
  • the absorption of D5 and D7 in vivo is comparable to that of SIS3, while the absorption of D4 and D6 in vivo is not as good as that of SIS3.
  • Dl, D2 and D3 are more easily absorbed than the compound SIS3, and the bioavailability of the drug is significantly improved at the same dose, which is more conducive to the exertion of the drug, and the half-life is prolonged, which can reduce the number of administrations and reduce the side effects.
  • the present invention selected Dl, D2 and D3 for pharmacodynamic studies.
  • Test Example 3 Anti-diabetes, hypolipidemic, cholesterol-lowering, weight loss and treatment of fatty liver
  • mice Five-week-old C57BL/6J mice, male, were fed with common vocabulary and high-fat words for 10 weeks. Male mice with successful modeling were randomly divided into groups of 5, and body weight was recorded. The administration group was given 10 mg/kg of different compounds, and the blank control group and the normal group were given the same volume of physiological saline. The drug was administered once a day by intraperitoneal injection for 8 weeks. Changes in body weight, food intake, and body temperature were recorded for different groups of mice. After 8 weeks of drug treatment, the biochemical parameters of each group of animals were examined. The results are shown in Table 4, Table 5 and Table 6. After the animals were sacrificed, liver HE staining, see Figure 1.
  • NS saline group
  • Normal normal group
  • SIS3 control compound (CAS: 521985-36-4); *- indicates significant difference compared with untreated group (P ⁇ 0.05)
  • NS saline group
  • Normal normal group
  • SIS3 control compound (CAS: 521985-36-4); *- indicates significant difference compared with untreated group (P ⁇ 0.05)
  • NS saline group
  • Normal normal group
  • SIS3 control compound (CAS: 521985-36-4); * ⁇ indicates significant difference compared with untreated group (P ⁇ 0.05)
  • the present invention investigates the acute toxicity of the compounds D1, D2 and D3.
  • the compounds D1, D2 and D3 of Examples 1, 2, and 3 were dispersed in 1% sodium carboxymethylcellulose, and ground to a suspension to prepare 300 mg/ml.
  • Kunming mice were given lg/kg by oral gavage alone. During the 14-day observation period, mice did not die.
  • blood biochemical tests were performed, and no obvious abnormal changes were found in blood biochemical indicators.
  • no abnormal drug-related changes were observed in the main organs of the pathological anatomy of the mice, and the animals in the administration group did not exhibit abnormalities compared with the vehicle control group and the normal group.
  • the oral absolute bioavailability of the drug D1 hydrochloride, D1 mesylate, and D1 p-toluenesulfonate was 18.5% 60.7% and 23.6%, respectively.
  • the oral absolute bioavailability of the drug D2 hydrochloride, D2 mesylate, and D2 p-toluenesulfonate was 13.3%, 22.9%, and 37.4%, respectively.
  • D1 mesylate was evaluated using a spontaneous type 2 diabetes model db/db mouse.
  • SPF male db/db mice and db/m mice were provided by Changzhou Cavans Experimental Animal Co., Ltd.
  • Eight-week-old db/db mice were randomly divided into three groups for drug treatment trials, namely 10 in the model vehicle group, 10 in the metformin positive control group, and 10 in the drug treatment group.
  • Ten male healthy db/m mice of the same age as the model group were selected as the normal control group.
  • Model vehicle group 15% propylene glycol + 35% PEG400 + normal saline, 1 time per day, volume 5ml 'kg times - 1 ; metformin group: 1 time per day, the dose is 300mg ' kg ⁇ days - 1 ;
  • Drug treatment group D1 mesylate was administered once a day at a dose of 50 mg_kg days- 1 ; in the normal control group, the same volume of normal saline was administered by gavage. The drug was administered for 8 weeks, and the body weight and food intake of the different groups were recorded weekly. At the end of the experiment, fasting blood glucose and glucose tolerance were measured.
  • the liver and adipose tissue were stained with HE, and the kidneys were stained with PAS and Masson.
  • the experimental results are as follows: As can be seen from Fig. 2, the D1 mesylate group did not affect the food intake of the mice compared with the solvent group.
  • D1 mesylate has a good weight-reducing effect.
  • Figure 8 shows the results of PAS staining of kidney tissue sections. It can be seen from the figure that the renal pathology of the mice in the solvent group is thickened by the glomerular capillary basement membrane, and the mesangial area is broadened, including the increase of mesangial cells and mesangial matrix and membrane. The red glycogen deposition inside; after the drug treatment, the above pathological changes were alleviated to some extent compared with the solvent group.
  • Figure 9 shows the results of Masson staining of kidney tissue sections. It can be seen from the figure that there is a large amount of collagen fiber deposition (blue) in the solvent group, collagen deposition in the metformin group is similar to that in the solvent group, and a large amount of muscle fibers (red) in the drug-treated group, and normal. The similarity of the group indicates that D1 mesylate can reduce renal collagen deposition, which may delay the progression of glomerular sclerosis and tubular fibrosis in diabetic nephropathy.
  • D1 mesylate when administered orally at a dose of 50 mg/kg, D1 mesylate can significantly reduce blood glucose and improve oral glucose tolerance in db/db mice after 8 weeks of treatment, and /db mouse fatty liver has obvious therapeutic effect, effectively reducing the deposition of glycogen and collagen in the kidney, which may delay the progression of glomerular sclerosis and tubular fibrosis in diabetic nephropathy.
  • Test Example 8 Therapeutic effect of compounds on pulmonary fibrosis
  • a healthy female Wistar rat was instilled with bleomycin (BLM) by endotracheal intubation at a concentration of 5 mg/kg to prepare a pulmonary fibrosis model.
  • Rats were then randomly divided into control group (15% propylene glycol + 35% PEG400 + normal saline;), D2 p-toluenesulfonate treatment group, and rats not injected with BLM were normal control group, 6 rats in each group.
  • the rats were intragastrically administered daily, the control group was given a corresponding volume of the vehicle, and the normal control group was given a corresponding volume of physiological saline.
  • Animal number rat weight (g) lung coefficient mean lung coefficient
  • the lung tissue structure of the solvent group was destroyed, the alveolar space was significantly reduced, and the pulmonary interstitial was replaced by collagen fibers and fibroblasts to form diffuse pulmonary fibrosis.
  • the lung structure was normal, and the alveolar septum showed no edema, inflammation, and pulmonary fibrosis.
  • the structure of the lungs was normal, and the alveolar septum was edema, inflammation, and pulmonary fibrosis.
  • the deuterated compound prepared by the invention can significantly improve body weight, fasting blood glucose, transaminase and fasting serum insulin in obese patients, improve insulin sensitivity, improve blood lipid index and oral glucose tolerance, and can effectively treat fibrosis-related Diseases; These compounds have good absorption in the body, high bioavailability, which is beneficial to the exertion of the drug, and the half-life is prolonged, which can reduce the number of administrations, reduce the side effects, and provide a safe and reliable new choice for clinical use.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un composé tel que représenté dans la formule I, ou ses sels pharmaceutiquement acceptables, hydrates ou solvates. L'invention porte également sur de nouvelles utilisations du composé ou de ses sels pharmaceutiquement acceptables, hydrates ou solvates. Le composé deutéré préparé dans la présente invention permet d'améliorer considérablement le poids, la glycémie à jeun, la transaminase et l'insuline sérique à jeun de patients obèses, d'augmenter la sensibilité à l'insuline, d'améliorer les taux de lipides et la tolérance au glucose par voie orale et de traiter efficacement des maladies liées à une fibrose. Le composé peut être bien absorbé dans le corps et a une biodisponibilité élevée qui est propice à une efficacité médicale et une demi-vie prolongée, ce qui de cette manière réduit le nombre d'administrations, abaisse les effets secondaires toxiques et fournit une nouvelle option sans danger pour la médecine clinique.
PCT/CN2014/085270 2013-08-30 2014-08-27 Composé pour le traitement du diabète WO2015027911A1 (fr)

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CN201310389332 2013-08-30
CN201310389332.9 2013-08-30

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103435612B (zh) * 2013-08-30 2016-03-09 四川好医生药业集团有限公司 一种治疗糖尿病的化合物
CN111606904B (zh) * 2020-04-07 2021-10-15 广州医科大学 氮杂吲哚类化合物及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020022624A1 (en) * 2000-07-13 2002-02-21 Kevin Dinnell Azaindole derivatives and their use as therapeutic agents
US20050014942A1 (en) * 2001-10-30 2005-01-20 Yasufumi Maruyama Amide derivatives and drugs
CN103435612A (zh) * 2013-08-30 2013-12-11 四川好医生药业集团有限公司 一种治疗糖尿病的化合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020022624A1 (en) * 2000-07-13 2002-02-21 Kevin Dinnell Azaindole derivatives and their use as therapeutic agents
US20050014942A1 (en) * 2001-10-30 2005-01-20 Yasufumi Maruyama Amide derivatives and drugs
CN103435612A (zh) * 2013-08-30 2013-12-11 四川好医生药业集团有限公司 一种治疗糖尿病的化合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MASATOSHI, J. ET AL.: "Characterization of SIS3, a Novel Specific Inhibitor of Smad3, and Its Effect on Transforming Growth Factor- beta 1-Induced Extracellular Matrix Expression", MOLECULAR PHARMACOLOGY, vol. 69, no. 2, 15 December 2005 (2005-12-15), pages 597 - 607 *

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