WO2017181924A1 - Pyrimidinedione substituée et composition pharmaceutique correspondante - Google Patents

Pyrimidinedione substituée et composition pharmaceutique correspondante Download PDF

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Publication number
WO2017181924A1
WO2017181924A1 PCT/CN2017/080762 CN2017080762W WO2017181924A1 WO 2017181924 A1 WO2017181924 A1 WO 2017181924A1 CN 2017080762 W CN2017080762 W CN 2017080762W WO 2017181924 A1 WO2017181924 A1 WO 2017181924A1
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Prior art keywords
compound
dipeptidyl peptidase
peptidase inhibitor
inhibitor according
hydrogen
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Ceased
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PCT/CN2017/080762
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English (en)
Chinese (zh)
Inventor
王义汉
赵九洋
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Shenzhen Targetrx Inc
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Shenzhen Targetrx Inc
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Priority to CN201780004366.8A priority Critical patent/CN108368085B/zh
Publication of WO2017181924A1 publication Critical patent/WO2017181924A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a substituted pyrimidinedione compound and a pharmaceutical composition thereof, which are useful for treating a dipeptidyl peptidase-mediated related disease.
  • Dipeptidyl peptidase IV is a type II membrane protein that acts as a non-classical serine aminodipeptidase that removes the Xaa-Pro dipeptide from the amino terminus (N-terminus) of the polypeptide and protein. Some naturally occurring peptides have also been reported to have DPP-IV dependent slow release of X-Gly or X-Ser type dipeptides.
  • DPP-IV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (intestine, liver, kidney, and placenta) and is also found in body fluids. DPP-IV is also expressed on circulating T-lymphocytes and has been shown to be synonymous with the cell-surface antigen CD-26. DPP-IV is responsible for the metabolic cleavage of certain endogenous peptides (GLP-1 (7-36), glucagon) in vivo and has been shown to be resistant to a variety of other peptides in vitro (GHRH, NPY, GLP-2, VIP). ) proteolytic activity.
  • GLP-1 (7-36) is a 29 amino acid peptide derived from post-translational processing of proglucagon in the small intestine. GLP-1 (7-36) has a variety of in vivo effects, including stimulation of insulin secretion, inhibition of glucagon secretion, promotion of satiety, and delay in gastric emptying. Based on its physiological behavior, it is believed that the role of GLP-1 (7-36) is beneficial for the prevention and treatment of type 2 diabetes, and possibly also obesity. For example, exogenous administration (continuous infusion) of GLP-1 (7-36) in diabetic patients has been found to be effective for this patient population. Unfortunately, GLP-1 (7-36) rapidly degrades in vivo and has been shown to have a short in vivo half-life (t 1/2 ).
  • DPP-IV is the major degrading enzyme of GLP-1 (7-36) in vivo.
  • GLP-1 (7-36) is efficiently degraded by DPP-IV to GLP-1 (9-36), which is presumed to act as a physiological antagonist of GLP-1 (7-36). It is therefore believed that inhibition of DPP-IV in vivo can be used to potentiate endogenous GLP-1 (7-36) levels and attenuate the production of its antagonist GLP-1 (9-36).
  • DPP-IV inhibitors are drugs that can be used to prevent, delay their progression and/or treat DPP-IV mediated disorders, in particular diabetes, more specifically type II diabetes, diabetic lipemia Abnormalities, impaired glucose tolerance (IGT), fasting plasma glucose reduction (IFG), metabolic acidosis, ketosis, appetite regulation, and obesity.
  • diabetes more specifically type II diabetes, diabetic lipemia Abnormalities, impaired glucose tolerance (IGT), fasting plasma glucose reduction (IFG), metabolic acidosis, ketosis, appetite regulation, and obesity.
  • the present invention discloses a dipeptidyl peptidase inhibitor, a pharmaceutical composition and use thereof, which have better dipeptidyl peptidase inhibitory activity and/or have better pharmacodynamics/pharmacokinetics Kinetic performance.
  • a dipeptidyl peptidase inhibitor such as a substituted pyrimidinedione compound represented by formula (I), or a crystalline form thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, Isotope variant, hydrate or solvent compound,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each independently hydrogen, deuterium, halogen or trifluoromethyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 At least one of R 17 and R 18 is deuterated or deuterated.
  • the shape and volume of the ruthenium in the drug molecule are substantially the same as those of the hydrogen. If the hydrogen in the drug molecule is selectively replaced with hydrazine, the deuterated drug generally retains the original biological activity and selectivity. At the same time, the inventors have confirmed through experiments that the binding of carbon-germanium bonds is more stable than the combination of carbon-hydrogen bonds, which can directly affect the absorption, distribution, metabolism and excretion of some drugs, thereby improving the efficacy, safety and tolerability of the drugs.
  • the strontium isotope content of the cerium in the deuterated position is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, and even more preferably greater than 95. %, more preferably greater than 99%.
  • the strontium isotope content of each of the R 9 , R 16 , R 17 and R 18 deuterated sites is at least 5%, preferably greater than 10%, more preferably greater than 15%, more preferably greater than 20%, and even more preferably greater than 25.
  • R 1 , R 2 , and R 3 are each independently hydrazine or hydrogen.
  • R 4 and R 5 are each independently hydrazine or hydrogen.
  • R 6 , R 7 and R 8 are each independently hydrazine or hydrogen.
  • R 9 is hydrazine
  • R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each independently hydrazine or hydrogen.
  • the compound may be selected from the following compounds or a pharmaceutically acceptable salt thereof, but is not limited to the following compounds:
  • the compound does not include a non-deuterated compound.
  • the invention also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the dipeptidyl peptidase inhibitor as described above, or a crystalline form thereof, a pharmaceutically acceptable salt, a hydrate or A pharmaceutical composition of a solvate, stereoisomer, prodrug or isotopic variation.
  • the pharmaceutically acceptable carrier includes a glidant, a sweetener, a diluent, a preservative, a dye/colorant, a flavor enhancer, a surfactant, a wetting agent, a dispersant At least one of a disintegrant, a suspending agent, a stabilizer, an isotonic agent, a solvent or an emulsifier.
  • the pharmaceutical composition is a tablet, a pill, a capsule, a powder, a granule, an ointment, an emulsion, a suspension, a solution, a suppository, an injection, an inhalant, a gel, a microsphere or Aerosol.
  • Typical routes of administration of the pharmaceutical compositions of the invention include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal , intramuscular, subcutaneous, intravenous administration. Oral administration or injection administration is preferred.
  • the pharmaceutical composition of the present invention can be produced by a method known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a pulverization method, an emulsification method, a freeze-drying method, and the like.
  • the present invention also provides a method of preparing a pharmaceutical composition comprising the steps of: pharmaceutically acceptable carrier with a dipeptidyl peptidase inhibitor as described above, or a crystalline form thereof, a pharmaceutically acceptable salt, hydrated The solvates or solvates are mixed to form a pharmaceutical composition.
  • the compound of the present invention has dipeptidyl peptidase enzyme inhibitory activity, and thus it is expected to be useful as a therapeutic agent for treating a patient suffering from a disease or condition which is treated by inhibiting dipeptidyl peptidase or by increasing its peptide substrate content. Accordingly, one aspect of the invention relates to a method of treating a patient suffering from a disease or condition treated by inhibition of a dipeptidyl peptidase comprising administering to the patient a therapeutically effective amount of a compound of the invention. Another aspect of the invention relates to a method of treating a cardiovascular disease comprising administering to a patient a therapeutically effective amount of a compound of the invention.
  • the invention in one aspect, relates to a method of treating hyperglycemia involving inhibition of a dipeptidyl peptidase in a mammal comprising administering to the mammal a dipeptidyl peptidase inhibitory amount of a compound of the invention.
  • the present invention also discloses the use of a substituted pyrimidinedione compound as described above as a dipeptidyl peptidase inhibitor, i.e., the compound of the present invention can be advantageously used as a therapeutic agent for treating a condition such as type II diabetes.
  • halogen means F, Cl, Br, and I unless otherwise specified. More preferably, the halogen atom is selected from the group consisting of F, Cl and Br.
  • deuterated means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuterated is used interchangeably with “one or more deuterated”.
  • non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid; Amino acids such as amino acid, phenylalanine, aspartic acid, and glutamic acid.
  • salts of the compounds of the invention are the salts of the compounds of the invention with bases, such as alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example Magnesium or calcium salt), ammonium salts (such as lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine Salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trishydroxyethylamine salt, and morpholine, piperazine, respectively An amine salt formed by lysine.
  • bases such as alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example Magnesium or calcium salt), ammonium salts (such as lower alkanolammonium salts and other pharmaceutically acceptable
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • the beneficial effects of the present invention are: the compound of the present invention has excellent inhibition to dipeptidyl peptidase; the technology of deuteration is used to change the metabolism of the compound in the organism, so that the compound has better Pharmacokinetic parameter characteristics.
  • the dosage can be changed and a long-acting preparation can be formed to improve the applicability; the substitution of a hydrogen atom in the compound with hydrazine increases the drug concentration of the compound in the animal due to its strontium isotope effect, and improves the therapeutic effect of the drug; Substituting a hydrogen atom in a compound inhibits certain metabolites and increases the safety of the compound.
  • Step 1 Synthesis of 4-fluoro-2-methylbenzonitrile (Compound 2).
  • Step 3 Synthesis of 2- ⁇ (2,4-dioxo-3,4-dipyrimidin-1(2H)-yl)methyl ⁇ -4-fluorobenzonitrile (Compound 5).
  • Step 4 2- ⁇ (3-d3-methyl-2,4-dioxo-3,4-dipyrimidin-1(2H)-yl)methyl ⁇ -4-fluorobenzonitrile (Compound 6) Synthesis.
  • Step 5 2- ⁇ (6-[(3R)-3-tert-Butoxycarbonylaminopiperidin-1-yl]-3-d3-methyl-2,4-dioxo-3,4-dipyrimidine Synthesis of -1(2H)-yl)methyl ⁇ -4-fluorobenzonitrile (Compound 8).
  • Step 6 2- ⁇ (6-[(3R)-3-Aminopiperidin-1-yl]-3-d3-methyl-2,4-dioxo-3,4-dipyrimidine-1 (2H Synthesis of -yl ⁇ methyl)-4-fluorobenzonitrile (Compound T-1).
  • the protease inhibitory activity of the DPP-IV inhibitor can be readily determined by methods known to those of ordinary skill in the art, as in vitro assays suitable for measuring protease activity and inhibition of test compounds are known. Examples of assays that can be used to measure protease inhibitory activity and selectivity are described below.
  • test compound solutions of different concentrations (final concentration ⁇ 10 mM) in dimethyl sulfoxide, followed by dilution
  • the assay buffer it contained: 20 mM Tris, pH 7.4, 20 mM KCl and 0.1 mg/mL BSA.
  • Human DPP-IV (final concentration 0.1 nM) was added to the dilution, pre-incubated for 10 minutes at ambient temperature, and then AP-7-carboxamido-4-trifluoromethylcoumarin (AP-AFC; final The reaction was initiated at a concentration of 10 ⁇ M.
  • the total volume of the reaction mixture is 10-100 ⁇ L depending on the assay format used (384 or 96-well plates).
  • the inhibition constant was calculated from the enzymatic process curve using a standard mathematical model.
  • test compound solutions of different concentrations (final concentration ⁇ 10 mM) in dimethyl sulfoxide and then dilute in assay buffer containing: 20 mM sodium phosphate, pH 7.4, 0.5 mM EDTA, 0.5 mM DTT and 0.1 Mg/mL BSA.
  • PREP EC 3.4.21.26 from G. septicum, final concentration 0.2 nM
  • the PRE and compound were pre-incubated for 10 minutes at ambient temperature and then primed with Z-G-P-AMC (final concentration 10 [mu]M).
  • the total volume of the reaction mixture is 10-100 ⁇ L depending on the assay format used (384 or 96-well plates).
  • the inhibition constant was calculated from the enzymatic process curve using a standard mathematical model.
  • the protease inhibition of the compounds of the present invention was tested according to the above assay, and it was observed to exhibit selective DPP-IV inhibitory activity.
  • the apparent inhibition constant (Ki) of the compounds of the invention for DPP-IV is in the range of from about 10 -9 M to about 10 -5 M.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • phosphate buffer 100 mM, pH 7.4.
  • the pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C. Take 100 ⁇ L of the supernatant to pre-add 100 ⁇ L of steam
  • the 96-well plates of the distilled water were mixed and analyzed by LC-MS/MS.
  • Example 2 The compound of Example 1 was analyzed according to the above procedure, and the results are shown in Table 2.
  • the compounds of the present invention exhibited excellent metabolic stability in both human liver microsomes and rat liver microsome experiments.
  • EXPERIMENTAL OBJECTIVE To investigate the pharmacokinetic behavior of the compounds of the present invention after administration of Trelagliptin, an example compound, in rats.
  • SD rat grade SPF grade
  • Weight range 180 ⁇ 220g (actual weight range is 187 ⁇ 197g)
  • the male SD rats were subjected to ig-administered Trelagliptin (3 mg/kg) and the compound of the example (3 mg/kg) according to the non-compartmental statistical moment theory using Winnonin software. Post-pharmacokinetic related parameters.
  • the compound of the present invention has better activity than Trelagliptin and has excellent pharmacokinetic properties, so it is more suitable as a compound for inhibiting dipeptidyl peptidase, and is suitable for preparing type II diabetes. drug.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une pyrimidinedione substituée et une composition pharmaceutique correspondante. La pyrimidinedione substituée est un composé représenté par la formule (I), ou sa forme cristalline, son sel pharmaceutiquement acceptable, son promédicament, son tautomère, son stéréoisomère, son isomère isotopique, son hydrate ou son solvate. Le composé de l'invention présente une inhibition améliorée vis-à-vis d'une dipeptidyl peptidase, une pharmacodynamique/pharmacocinétique améliorée, une bonne facilité d'utilisation du composé et des niveaux élevés de sécurité. Le composé peut être utilisé pour préparer un médicament destiné à traiter une maladie liée à la dipeptidyl peptidase.
PCT/CN2017/080762 2016-04-20 2017-04-17 Pyrimidinedione substituée et composition pharmaceutique correspondante Ceased WO2017181924A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201780004366.8A CN108368085B (zh) 2016-04-20 2017-04-17 一种取代的嘧啶二酮化合物及其药物组合物

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CN201610248713 2016-04-20
CN201610248713.9 2016-04-20

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1926128A (zh) * 2004-03-15 2007-03-07 武田药品工业株式会社 二肽基肽酶抑制剂
CN102127057A (zh) * 2004-03-15 2011-07-20 武田药品工业株式会社 二肽基肽酶抑制剂
CN105272963A (zh) * 2014-07-22 2016-01-27 成都贝斯凯瑞生物科技有限公司 作为二肽基肽酶iv(dpp-iv)抑制剂的2-氧代-4-硫代-3,4-二氢嘧啶衍生物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009045476A1 (fr) * 2007-10-02 2009-04-09 Concert Pharmaceuticals, Inc. Dérivés de pyrimidinedione

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1926128A (zh) * 2004-03-15 2007-03-07 武田药品工业株式会社 二肽基肽酶抑制剂
CN102127057A (zh) * 2004-03-15 2011-07-20 武田药品工业株式会社 二肽基肽酶抑制剂
CN105272963A (zh) * 2014-07-22 2016-01-27 成都贝斯凯瑞生物科技有限公司 作为二肽基肽酶iv(dpp-iv)抑制剂的2-氧代-4-硫代-3,4-二氢嘧啶衍生物

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