WO2016019868A1

WO2016019868A1 - Salt of thiadiazole derivative dpp-iv inhibitor

Info

Publication number: WO2016019868A1
Application number: PCT/CN2015/086121
Authority: WO
Inventors: 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: 2014-08-05
Filing date: 2015-08-05
Publication date: 2016-02-11
Also published as: CN105315301B; CN105315301A

Abstract

Provided are a citric acid salt of a thiadiazole derivative DPP-IV inhibitor, and preparation method, pharmaceutical composition and use thereof for treating and/or preventing diseases benefiting from DPP-IV inhibition, particularly for treating and/or preventing type II diabetes.

Description

Salt of thiadiazole derivative DPP-IV inhibitor

Technical field

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.

Background technique

Chinese patent application CN102807568 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.

Summary of the invention

In one aspect, 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).

In another aspect, the application provides a monocaprate of a compound of formula I, the structural formula of which is as follows:

In another aspect, 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.

In another aspect, 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.

In a further aspect, the application provides 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 .

In a further aspect, 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.

In a further aspect, 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.

In a further aspect, 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.

Detailed description of the invention

In the following description, certain specific details are included to provide a comprehensive understanding of the various disclosed embodiments. However, one skilled in the relevant art will recognize that the embodiments may be practiced without the use of one or more of these specific details, and other methods, components, materials, and the like.

The word "comprise" and its English variants such as "comprises" and "comprising" should be interpreted as open-ended throughout the specification and the claims that follow. Inclusive meaning, including but not limited to.

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 specific reference elements, structures or features described. 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. Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

It will be understood that the singular articles "a", "the", "the", "the" Regulations. Thus, for example, a reaction including a "catalyst" includes a catalyst, Or two or more catalysts. It is also to be understood that the term "or" is generally used in its meaning including "and/or" unless it is specifically defined otherwise.

In one aspect, 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).

Wherein 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.

In certain embodiments, 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.

In yet another aspect, the present invention provides a monocaprate of the compound of Formula I, the structural formula of which is as follows:

In another aspect, 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.

In certain embodiments, in the above preparation process, 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.

In certain embodiments, 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 compounds of formula I of the present application can be prepared by reference to the method disclosed in Chinese Patent Application No. CN102807568.

In certain embodiments, in the preparation methods described herein, the reaction temperature is from 0 to 50 ° C, preferably from 0 to 35 ° C.

In certain embodiments, in the preparation methods described herein, the reaction can be carried out under an inert atmosphere such as nitrogen for a reaction time of 1-5 h.

In certain embodiments, 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.

In certain embodiments, 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.

In a further aspect, the application provides 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. In certain embodiments, the decanoate salt of the compound of Formula I is a monocaprate of the compound of Formula I.

In a further aspect, 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. In certain embodiments, the decanoate salt of the compound of Formula I is a monocaprate of the compound of Formula I. In certain embodiments, the disease that benefits from DPP-IV inhibition is type II diabetes.

In a further aspect, 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. In certain embodiments, the decanoate salt of the compound of Formula I is a monocaprate of the compound of Formula I. In certain embodiments, the disease that benefits from DPP-IV inhibition is type II diabetes.

In a further aspect, the application provides for the treatment and/or prevention of a disease that benefits from DPP-IV inhibition The citrate of the compound of formula I and its pharmaceutical composition. In certain embodiments, the decanoate salt of the compound of Formula I is a monocaprate of the compound of Formula I. In certain embodiments, the disease that benefits from DPP-IV inhibition is type II diabetes.

It has been found that 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.

Example

The following examples are intended to illustrate the invention in more detail, but are not intended to limit the invention in any way.

The compound of formula I is prepared according to the method disclosed in Chinese patent application CN102807568.

Preparation of Monocaprate of the Compound of Formula I of Example 1

The compound of the formula I (2 g, 4.3 mmol) and decanoic acid (0.9 g, 4.7 mmol) were added to acetone (20 ml) at room temperature, then the reaction mixture was stirred for 2 h. The reaction mixture was cooled to room temperature and filtered, and the filter cake was dried in vacuo to dryness <RTIgt;

Example 2 Preparation of a Monocaprate of a Compound of Formula I

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;

Preparation of the bismuth salt of the compound of formula I of Example 3

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.

Pharmacokinetic Evaluation of the Acid Addition Salt of the Compound of Formula I of Example 4

Test purposes:

In this test, different basic salt forms of the compound of formula I were administered by cynomolgus monkey respectively, and their basic pharmacokinetic parameters were obtained to compare the in vivo exposure and bioavailability of different salt forms at the same dose (21.48 nM/kg). Differences such as degrees.

Experimental animals:

Species and strains: Crab-eating monkeys (general level)

Gender and quantity: 9 out of 6 females and 3 males

Weight range: 2.7-4.8kg

Source and animal certificate number: Hainan Xinzhengyuan Biotechnology Co., Ltd. SCXK (Joan) 2011-0002

experimental method:

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).

1. Preparing a solution of the test compound

Weigh accurately the above three salts into the solution bottle, measure the appropriate amount of ultrapure water and add to the solution bottle, stir, dissolve and mix, and use within 4 hours after preparation.

2. Administration

Route of administration: nasal administration

Dosing capacity: 5ml/kg

Dosing frequency: single dose

Delivery rate: about 0.5ml / sec

3, blood collection

Blood collection site: small saphenous vein

Sampling amount: 1 ml of venous blood was collected into a vacuum blood collection tube treated with EDTA-K ₂ anticoagulation.

Whole blood pretreatment: After collecting blood into the vacuum blood collection tube treated with EDTA-K ₂ anticoagulation, the tube was placed in an ice box (2-8 ° C) and centrifuged (3500 rpm, 10 min) in 1 h. The plasma was then stored frozen in a -80 ° C freezer.

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).

4. Pretreatment of plasma samples

Take 30 μL of cynomolgus monkey plasma sample into a 1.5 mL centrifuge tube, add 100 μL of 20 ng/mL internal standard (diazepam) acetonitrile solution, vortex for 1 min, centrifuge at 12000 rpm for 5 min, and then transfer 90 μL of the supernatant to In a 96-well sample plate, 100 μL of a 50% acetonitrile-water solution was added to the respective wells, and shaken on a shaker for 5 min for LC-MS/MS analysis.

5, data processing

The plasma concentration-time data of cynomolgus monkey individuals were calculated using the non-compartmental model of the pharmacokinetic professional software Phoenix WinNonlin 6.3. The results are detailed in the table below:

Experimental results

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.

Claims

A bismuth salt of a compound of formula I wherein the compound of formula I has the structure:
A ceric acid salt of a compound of formula I according to claim 1 wherein the molar ratio of the compound of formula I to citric acid is from 1:0.5 to 2, preferably from 1:0.5 to 1.5, more preferably from 1:0.9 to 1.
A citrate salt of a compound of formula I according to claim 1 which is a monocaprate of a compound of formula I having the formula:
Process for the preparation of a decanoate salt of a compound of the formula I according to any one of claims 1 to 3, which comprises mixing and reacting a compound of the formula I with citric acid in a suitable single solvent or mixed solvent.
The process according to claim 4, wherein a compound of the formula I is mixed with citric acid in a molar ratio of from 1:1 to 1.2, preferably from 1:1 to 1.1, and reacted to obtain a single compound of the formula I. Citrate.
The production method according to claim 4 or 5, wherein the reaction temperature is from 0 ° C to 50 ° C, preferably from 0 ° C to 35 ° C.
The production method according to any one of claims 4 to 6, wherein the solvent is selected from the group consisting of ethers, alcohols, ketones, nitriles, esters, alkanes, halogenated alkanes, and any combination thereof.
The process according to claim 7, wherein the solvent is selected from the group consisting of tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, ethyl formate, Hexane, dichloromethane, chloroform, and any combination thereof.
The production process according to any one of claims 4 to 8, wherein the reaction is carried out under an inert atmosphere, preferably under a nitrogen atmosphere.
The production method according to any one of claims 4 to 9, wherein the reaction time is 1-5h.
The process according to any one of claims 4 to 10, which further comprises separating the ceric acid salt of the compound of the formula I from the reaction mixture.
The process of claim 11 further comprising recrystallizing the decanoate salt of the compound of formula I for further purification.
A pharmaceutical composition comprising a decanoate salt of a compound of formula I as claimed in any one of claims 1 to 3 and a pharmaceutically acceptable carrier, excipient or diluent.
The citrate of the compound of the formula I according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 13 in the preparation of a medicament for the treatment and/or prevention of a disease which benefits from DPP-IV inhibition the use of.
The use according to claim 14, wherein the disease benefiting from DPP-IV inhibition is type II diabetes.
A method for the treatment and/or prevention of a disease which is beneficial for the inhibition of DPP-IV, comprising the citrate of the compound of the formula I according to any one of claims 1 to 3 or the combination of the drug of claim 13. The substance is administered to an individual in need thereof.
The method of claim 16 wherein said disease benefiting from DPP-IV inhibition is type II diabetes.
A citrate of the compound of formula I according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 13 for use in the treatment and/or prevention of a disease which is beneficial for the inhibition of DPP-IV.
A citrate or pharmaceutical composition of a compound of formula I according to claim 18, wherein the disease which benefits from DPP-IV inhibition is type II diabetes.