WO2016019868A1 - Sel d'inhibiteur de la dpp-iv dérivé de thiadiazole - Google Patents

Sel d'inhibiteur de la dpp-iv dérivé de thiadiazole Download PDF

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Publication number
WO2016019868A1
WO2016019868A1 PCT/CN2015/086121 CN2015086121W WO2016019868A1 WO 2016019868 A1 WO2016019868 A1 WO 2016019868A1 CN 2015086121 W CN2015086121 W CN 2015086121W WO 2016019868 A1 WO2016019868 A1 WO 2016019868A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
dpp
salt
inhibition
Prior art date
Application number
PCT/CN2015/086121
Other languages
English (en)
Chinese (zh)
Inventor
刘飞
彭岩
朱波
徐宏江
陈智林
田心
杨玲
张喜全
Original Assignee
连云港润众制药有限公司
北京赛林泰医药技术有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Application filed by 连云港润众制药有限公司, 北京赛林泰医药技术有限公司 filed Critical 连云港润众制药有限公司
Publication of WO2016019868A1 publication Critical patent/WO2016019868A1/fr

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Classifications

    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This application belongs to the field of medicinal chemistry, and in particular relates to an acid addition salt of a thiadiazole derivative DPP-IV inhibitor.
  • Cisokain derivative DPP-IV inhibitors discloses thiadiazole derivative DPP-IV inhibitors and their use in the treatment and/or prevention of diseases which benefit from DPP-IV inhibition, in particular in the treatment of type 2 diabetes. There is still a need for a thiadiazole derivative DPP-IV inhibitor having good drug-forming properties and bioavailability and a pharmaceutically acceptable salt thereof.
  • the application provides 8-((R)-3-amino-piperidin-1-yl)-1-([1,2,5]thiadiazolo[3,4-b]pyridine-5- A decanoate of methyl)-7-(2-butyn-1-yl)-3-methyl-xanthine (having the structure of formula I below, hereinafter referred to as a compound of formula I).
  • the application provides a monocaprate of a compound of formula I, the structural formula of which is as follows:
  • the present application provides a process for the preparation of a decanoate salt of the compound of formula I, which comprises mixing and reacting a compound of formula I with citric acid in a suitable single solvent or mixed solvent.
  • the present application provides a process for the preparation of a monocaprate of the compound of formula I, which comprises reacting a compound of formula I with citric acid in a molar ratio of from 1:1 to 1.2, preferably from 1:1 to 1.1. Moore It is mixed and reacted in a suitable single solvent or mixed solvent.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient or diluent and a citrate of a compound of formula I as an active ingredient, preferably a monocaprate of a compound of formula I .
  • the application provides a citrate of a compound of formula I, preferably a monocaprate of a compound of formula I, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment and/or prevention of benefit from DPP-IV inhibition Use of the drug.
  • the application provides a method for the treatment and/or prevention of a disease that benefits from DPP-IV inhibition, comprising citrate of a compound of formula I, preferably a monocaprate of a compound of formula I, or
  • the pharmaceutical composition is administered to an individual in need thereof.
  • the application provides a citrate salt of a compound of formula I for use in the treatment and/or prevention of a disease that would benefit from DPP-IV inhibition, preferably a monocaprate of a compound of formula I, or a pharmaceutical composition thereof.
  • references to “an embodiment” or “an embodiment” or “in another embodiment” or “in certain embodiments” throughout this specification are meant to be included in the at least one embodiment.
  • the appearances of the phrase “in one embodiment” or “in an embodiment” or “in another embodiment” or “in some embodiments” are not necessarily all referring to the same embodiment.
  • the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • the present application provides 8-((R)-3-amino-piperidin-1-yl)-1-([1,2,5]thiadiazolo[3,4-b]pyridine-5-A
  • An acid addition salt of 7-(2-butyn-1-yl)-3-methyl-xanthine (having the structure of formula I below, hereinafter referred to as a compound of formula I).
  • the acid is selected from the group consisting of citric acid, fumaric acid, maleic acid, benzoic acid, oxalic acid, acetic acid, p-toluenesulfonic acid, sulfuric acid or hydrochloric acid.
  • Another aspect of the present application provides a decanoate salt of a compound of formula I.
  • the molar ratio of the compound of formula I to citric acid in the cerate of the compound of formula I is from 1:0.5 to 2, preferably from 1:0.5 to 1.5, more preferably 1:0.9. 1.
  • the present invention provides a monocaprate of the compound of Formula I, the structural formula of which is as follows:
  • the present application provides a process for the preparation of an acid addition salt of a compound of formula I, which comprises reacting a compound of formula I with a corresponding acid (eg, citric acid, fumaric acid, maleic acid, benzoic acid, Oxalic acid, acetic acid, p-toluenesulfonic acid, sulfuric acid or hydrochloric acid are mixed and reacted in a suitable single solvent or mixed solvent.
  • a corresponding acid eg, citric acid, fumaric acid, maleic acid, benzoic acid, Oxalic acid, acetic acid, p-toluenesulfonic acid, sulfuric acid or hydrochloric acid are mixed and reacted in a suitable single solvent or mixed solvent.
  • the present application provides a process for the preparation of a decanoate salt of the compound of formula I, which comprises mixing and reacting a compound of formula I with citric acid in a suitable single solvent or mixed solvent.
  • the compound of formula I is mixed with citric acid in a molar ratio of from 1:0.5 to 2.5, preferably from 1:0.5 to 1.8, more preferably from 1:0.9 to 1.1.
  • the present application provides a process for the preparation of a monocaprate of a compound of formula I, which comprises reacting a compound of formula I with capric acid in a suitable single or mixed solvent. The mixture is reacted and reacted, wherein the compound of the formula I is mixed with citric acid in a molar ratio of 1:1 to 1.2, preferably in a molar ratio of 1:1 to 1.1.
  • the reaction temperature is from 0 to 50 ° C, preferably from 0 to 35 ° C.
  • the reaction in the preparation methods described herein, can be carried out under an inert atmosphere such as nitrogen for a reaction time of 1-5 h.
  • the solvent includes, but is not limited to, ethers, alcohols, ketones, nitriles, esters, alkanes, and halogenated alkanes, such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, Methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, ethyl formate, hexane, dichloromethane, chloroform, and the like.
  • ethers such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, Methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, ethyl formate, hexane, dichloromethane, chloroform, and the like.
  • an acid addition salt of a compound of Formula I of the present application, a decanoate salt of a compound of Formula I, and a monocaprate salt of a compound of Formula I can all be from the reaction mixture by using conventional techniques in the art. Isolation, such as filtration, concentration, spray drying, and the like.
  • the acid addition salts of the compounds of formula I of the present application, the decanoates of the compounds of formula I and the monophthalates of the compounds of formula I can also be further dried using conventional techniques, and can be further carried out by conventional techniques such as recrystallization. Purification and purification.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a decanoate salt of a compound of formula I and a pharmaceutically acceptable carrier, excipient or diluent.
  • the decanoate salt of the compound of Formula I is a monocaprate of the compound of Formula I.
  • the application provides the use of a decanoate salt of the compound of formula I and a pharmaceutical composition thereof for the manufacture of a medicament for the treatment and/or prevention of a disease which benefits from DPP-IV inhibition.
  • the decanoate salt of the compound of Formula I is a monocaprate of the compound of Formula I.
  • the disease that benefits from DPP-IV inhibition is type II diabetes.
  • the application provides a method for treating and/or preventing a disease that benefits from DPP-IV inhibition, comprising administering a citrate of the compound of Formula I and a pharmaceutical composition thereof to an individual in need thereof medicine.
  • the decanoate salt of the compound of Formula I is a monocaprate of the compound of Formula I.
  • the disease that benefits from DPP-IV inhibition is type II diabetes.
  • the application provides for the treatment and/or prevention of a disease that benefits from DPP-IV inhibition
  • the decanoate salt of the compound of Formula I is a monocaprate of the compound of Formula I.
  • the disease that benefits from DPP-IV inhibition is type II diabetes.
  • the decanoate salt of the compound of the formula I has an unexpectedly significant advantage over other salts of the compounds of the formula I, such as fumarates and benzoates: the bismuth salt of the compound of the formula I has Better pharmacokinetic parameters, for example, higher bioavailability. Furthermore, the phthalates of the compounds of formula I have better chemical and physical stability, for example, less impurities due to decomposition under high temperature or high humidity conditions or during preparation and storage. In addition, the decanoate of the compound of formula I is readily salted and can be more conveniently obtained at low cost and in high yield.
  • the compound of formula I is prepared according to the method disclosed in Chinese patent application CN102807568.
  • the compound of the formula I (2 g, 4.3 mmol) and citric acid (0.99 g, 5.16 mmol) were added to a mixed solvent of ethanol (4 ml) and ethyl acetate (16 ml) at 50 ° C, then the reaction mixture was stirred for 2 h At this time, the reaction is exothermic. The reaction mixture was cooled to room temperature and filtered, and the filter cake was dried in vacuo to dryness ⁇ RTIgt;
  • the compound of formula I (2 g, 4.3 mmol) and citric acid (0.75 g, 3.9 mmol) were added to acetone (20 ml) at room temperature and then the reaction mixture was stirred for 2 h, then the reaction was exotherm. The reaction mixture was cooled to room temperature and filtered, and the filter cake was dried in vacuo to dryness ⁇ RTIgt; In the citrate salt of the compound of formula I, the compound of formula I and hydrazine The molar ratio of acid is 1:0.9.
  • Cynomolgus monkeys were randomly divided into 3 groups according to the principle of weight balance, with 3 in each group.
  • Group A monofumarate salt of the compound of formula I (dose of 12.55 mg/kg)
  • group B monobenzoate salt of the compound of formula I (dose of 12.69 mg/kg)
  • group C administration Monocaprate of the compound I (dose of 14.21 mg/kg).
  • Sampling amount 1 ml of venous blood was collected into a vacuum blood collection tube treated with EDTA-K 2 anticoagulation.
  • Blood collection time before administration (0min) and 5min ( ⁇ 30s), 15min ( ⁇ 30s), 30min ( ⁇ 30s), 1h ( ⁇ 2min), 2h ( ⁇ 2min), 4h ( ⁇ 5min), 6h ( ⁇ 5min), 8h ( ⁇ 5min), 12h ( ⁇ 5min), 24h ( ⁇ 10min).
  • the monocaprate of the compound of formula I has greater exposure ( Cmax and AUC) and better organisms in cynomolgus monkeys compared to monofumarate and monobenzoate of the compound of formula I. Utilization.

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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)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un sel d'acide citrique d'un inhibiteur de la DPP-IV dérivé de thiadiazole. Elle concerne une méthode de préparation, une composition pharmaceutique et l'utilisation de celui-ci pour le traitement et/ou la prévention de maladies contre lesquelles l'inhibition de la DPP-IV est bénéfique, en particulier pour le traitement et/ou la prévention du diabète de type II.
PCT/CN2015/086121 2014-08-05 2015-08-05 Sel d'inhibiteur de la dpp-iv dérivé de thiadiazole WO2016019868A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410381575.2A CN105315301B (zh) 2014-08-05 2014-08-05 噻二唑类dpp‑ⅳ抑制剂的枸橼酸盐
CN201410381575.2 2014-08-05

Publications (1)

Publication Number Publication Date
WO2016019868A1 true WO2016019868A1 (fr) 2016-02-11

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102807568A (zh) * 2011-05-31 2012-12-05 江苏正大天晴药业股份有限公司 噻二唑衍生物类dpp-iv抑制剂

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19727707A1 (de) * 1997-06-30 1999-01-07 Bayer Ag 5-Chlormethyl-2,1,3-benzothiadiazol und Verfahren zur Herstellung von Halogenmethyl-2,1,3-benzothiadiazolen
DK2055302T3 (da) * 2000-03-31 2014-10-27 Royalty Pharma Collection Trust Fremgangsmåde til forbedring af signalering af øceller ved diabetes mellitus og til forebyggelse deraf
AR086675A1 (es) * 2011-06-14 2014-01-15 Merck Sharp & Dohme Composiciones farmaceuticas de combinaciones de inhibidores de la dipeptidil peptidasa-4 con simvastatina

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102807568A (zh) * 2011-05-31 2012-12-05 江苏正大天晴药业股份有限公司 噻二唑衍生物类dpp-iv抑制剂

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CN105315301B (zh) 2018-04-03

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