CN104356059B - Trans cvclohexvl alkyl amide compound containing halogenated pyridyl and purposes - Google Patents

Abstract

The invention relates to the field of medicine related to thrombotic diseases. Specifically, the present invention relates to a class of PAR-1 antagonists with a trans-cyclohexaneamide structure containing a halogenated pyridyl group, a preparation method thereof, and their application in the preparation of drugs for treating thrombotic diseases. Wherein, R is selected from C ₁ -C ₃ alkyl, F, Cl, Br, I substituents.

Description

Halogenated pyridyl-containing trans-cyclohexane amides and uses thereof

technical field

The invention relates to the field of drugs related to thrombosis diseases. Specifically, the present invention relates to a class of PAR-1 antagonists with a trans-cyclohexyl amide structure containing halogenated pyridyl and other structures that have a therapeutic effect on thrombotic diseases and their preparation methods, pharmaceutical compositions containing them and Use in medicine.

Background technique

Protease Activated Acceptor-1 (PAR-1) is a new target of anti-platelet antithrombotic drugs discovered recently. Protease-activated receptor 1 is also called thrombin receptor. After thrombin is activated by the coagulation chain, it acts on platelets through PAR-1 receptors to activate platelets, causing platelet aggregation and causing thrombus and coagulation. Thrombus induced by PAR-1 is rich in platelet components, which is the main cause of arterial thrombus. PAR-1 antagonists can block thrombin from activating platelets, thereby blocking arterial thrombosis, and can be used to treat acute coronary syndrome (Acute Coronary Syndrome). There are already several PAR-1 inhibitors in clinical research (Chackalamannil S., Thrombin Receptor (Protease Activated Receptor-1) Antagonists as Potent Antithrombotic Agents with Strong Antiplatelet Effects, J.Med.Chem., 2006, 49 (18), 5389- 5403).

The drugs traditionally used to prevent and treat thrombotic diseases are divided into three categories. The first category is anticoagulation, which is divided into direct thrombin inhibitors and indirect thrombin inhibitors. These drugs inhibit thrombus formation by acting on different links of the blood coagulation chain, and have the effect of inhibiting various thrombus formation, such as vitamin K antagonists and factor Xa inhibitors, etc.; the second category is anti-platelet drugs, such as COX-1 inhibitors and ADP receptor antagonists, etc., which are mainly used to prevent and treat arterial thrombosis; the third category is fibrinolytic agents , mainly used to dissolve fibrin formed in the blood.

Antiplatelet drugs are mostly traditional arterial thrombosis prevention and treatment drugs, such as clopidogrel and aspirin. The disadvantage of these drugs is that there is a greater risk of bleeding. However, PAR-1 antagonists, which are newly discovered antiplatelet antithrombotic drugs, have a small risk of bleeding, so these compounds can be used as promising drugs for the treatment of arterial thrombosis.

The invention discloses a class of PAR-1 antagonists with a trans-cyclohexane amide structure containing halogenated pyridyl and the like, which can be used to prepare drugs for resisting arterial thrombosis.

Contents of the invention

An object of the present invention is to provide a compound of general formula I and a pharmaceutically acceptable salt thereof with good antithrombotic activity.

Another object of the present invention is to provide methods for the preparation of compounds of general formula I and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a pharmaceutical composition containing a compound of general formula I and a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers, excipients or diluents , and its application in the treatment of arterial thrombosis.

The content of the present invention will now be specifically described in conjunction with the purpose of the present invention.

Compounds of the present invention having general formula I have the following structural formula:

Wherein, R is selected from C ₁ -C ₃ alkyl, F, Cl, Br, and I substituents.

Further, the following compounds having the general formula I are preferred,

Further, the following compounds of general formula I are preferred,

Formula I compound of the present invention is synthesized by the following method:

Compound II and compound III are reacted in the presence of a condensing agent to give product I. The condensing agent is selected from DCC (N,N'-dicyclohexylcarbodiimide), EDC (N-ethyl-N'-dimethylaminocarbodiimide), CDI (carbonyldiimidazole).

The pharmaceutically acceptable salts of the compound of formula I of the present invention include but are not limited to salts formed with various inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, etc., and also include salts formed with various organic acids such as acetic acid , succinic acid, maleic acid, malic acid and various amino acid salts.

The compound of general formula I in the present invention has PAR-1 antagonism, and can be used as an active ingredient in the preparation of antithrombotic therapeutic drugs. The activity of the compound of general formula I of the present invention is verified by in vitro models.

The compounds of general formula I according to the invention are effective over a fairly wide dosage range. For example, the daily dose is about in the range of 1mg-500mg/person, divided into one or several administrations. The actual dosage of the compound of general formula I of the present invention can be determined by a doctor according to relevant conditions. These conditions include: the physical state of the person being treated, the route of administration, age, weight, individual response to the drug, and the severity of symptoms.

detailed description

The present invention will be further described below in conjunction with embodiment. It should be noted that the following examples are only for illustration, but not for limiting the present invention. Various changes made by those skilled in the art according to the teaching of the present invention shall be within the scope of protection required by the claims of the present application.

Example 1 Preparation of Compound I-1

Raw materials: commercially available or homemade.

In a 100mL round bottom flask, add 1.84g (10mmol) compound II, 1.98g (10mmol) compound III-1 and 20mL dry THF, the resulting mixture was stirred under ice-water bath cooling, after adding 2.48g (12mmol) DCC, Stirring was continued overnight at room temperature. TLC showed the reaction was complete.

The reaction mixture was poured into ice water, stirred, extracted with 50mL×3 dichloromethane, combined and extracted organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated on a rotary evaporator, and the obtained residue column Purified by chromatography to obtain product I-1 as a white solid, ESI-MS, m/z=365 ([M+H] ⁺ ).

Example 2-8

Referring to the method of Example 1, the following compounds with general formula I were synthesized.

Example 9 In vitro platelet aggregation inhibition test

Pharmacological tests of substances were performed in TRAP (thrombin receptor activating peptide)-induced platelet aggregation in 96-well plates. 3.13% sodium citrate solution was added to the syringe in advance, and then 20 mL of blood from healthy volunteers was drawn in, centrifuged at 1500 g for 20 minutes, platelet-rich plasma (PRP) was separated and mixed with 1 μL of PGE1 solution (500 μg/mL ethanol solution)/mL PRP for treatment. After incubation at room temperature for 5 minutes, they were centrifuged at 1200 g for 20 minutes to remove leukocytes. Transfer the leukocyte-free PRP to 15 mL PP tubes in batches at 5 mL/portion, and centrifuge at 3600 g to pellet the platelets. Then, the upper plasma was decanted, and the platelet pellet obtained from 5 mL of PRP was resuspended in 1 mL of Tyrode (120 mM NaCl, 2.6 mM KCl, 12 mM NaHCO ₃ , 0.39 mM NaH ₂ PO ₄ , 10 mM HEPES, 0.35% BSA, 5.5 mM glucose , pH=7.4), and adjusted to a platelet count of 3×10 5 /μL with Tyrode. 13 mL of this cell suspension was treated with 866 μL of 10 mM CaCl ₂ solution, and pipetted at 120 μL per well into a 96-well plate to which 15 μL of the substance to be tested had been added in advance. Incubate in the dark at room temperature for 30 minutes, add 15 μL TRAP solution (70-100 μM) as agonist, shake in SpectraMax at 37°C for 20 minutes, record kinetics at 650 nm, calculate negative control (tyrode/DMSO) and positive control (15 [mu]L agonist/DMSO) and the difference was taken as 100%. The compounds to be tested were pipetted in the form of serial dilutions and assayed in duplicate, the AUC of each concentration of the substance was also determined, and the % inhibition of AUC compared to the control was calculated. From this % inhibition _IC50 values are calculated by means of nonlinear regression analysis according to a 4 parameter equation. The table below gives the results.

compound Platelet Aggregation Inhibition IC ₅₀ (μM) Compound I-1 0.9 Compound I-2 4.1

Compound I-3 3.5 Compound I-4 3.2 Compound I-5 2.0 Compound I-6 4.7 Compound I-7 4.2 Compound I-8 3.8

As can be seen from the above table, the compounds of the present invention all exhibit inhibitory effects in the platelet aggregation test.

Claims (3)

1. The following compounds, 2. The compound of claim 1, selected from the following compounds: 3. The use of the compound of general formula I defined in any one of claims 1-2 and pharmaceutically acceptable salts thereof in the preparation of medicaments for treating thrombosis.