Opioid receptor (mor) agonist salt, fumarate salt crystal form i thereof and preparation method thereof

Abstract

Relating to an opioid receptor agonist (1S,4S)-4-ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]deca-9-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine fumarate salt, a fumarate salt crystal form I thereof, and a preparation method and an application therefor.

1 - 20 . (canceled) 
     
     
         21 . Crystal form I of the compound represented by formula (I), 
       
         
           
           
               
               
           
         
       
       wherein the crystal form I has an X-ray powder diffraction spectrum comprising characteristic peaks at diffraction angle 2θ±0.2 of 5.76, 10.82, 11.47, 12.69, 13.86, 14.77, 15.27, 15.74, 17.26, 17.61, 18.34, 22.39, 23.06, 23.75 and 24.23. 
     
     
         22 . The crystal form I of  claim 21 , wherein the X-ray powder diffraction spectrum comprises characteristic peaks at diffraction angles 2θ±0.2 of 5.76, 10.82, 11.47, 12.69, 13.86, 14.77, 15.27, 15.74, 17.26, 17.61, 18.34, 19.27, 19.94, 20.37, 21.42, 21.73, 22.02, 22.39, 23.06, 23.75, 24.23 and 24.73. 
     
     
         23 . The crystal form I of  claim 22 , wherein the X-ray powder diffraction spectrum comprises characteristic peaks at diffraction angles 2θ±0.2 of 5.76, 7.86, 10.82, 11.47, 12.28, 12.69, 13.86, 14.77, 15.27, 15.74, 16.26, 17.26, 17.61, 18.34, 19.27, 19.94, 20.37, 21.42, 21.42, 21.73, 22.02, 22.39, 23.06, 23.75, 24.23, 24.73, 25.54, 26.68, 28.59, 29.48, 31.04, 32.90 and 35.73. 
     
     
         24 . A method for preparing the crystal form I of  claim 21 , wherein said method is selected from:
 (i) dissolving the compound represented by formula (I) in a solvent to form a solution, crystallizing from the solution to precipitate a solid, filtering and drying the solid to obtain the crystal form I; and   (ii) adding the compound represented by formula (I) into a solvent to form a solution, triturating in a second solvent to precipitate a solid, filtering and drying the solid to obtain the crystal form I, wherein the solvent is ethers, ketones, esters or nitriles, and wherein the ether solvent is tetrahydrofuran, dioxane, diethyl ether or methyl tert-butyl ether, the ketone solvent is acetone, acetophenone, methyl isobutyl ketone or methyl pyrrolidone, the ester solvent is ethyl acetate, isopropyl acetate or butyl acetate, and the nitrile solvent is acetonitrile or propionitrile.   
     
     
         25 . The method of  claim 24 , wherein the solvent in method (i) is an ether solvent. 
     
     
         26 . The method of  claim 25 , wherein the solvent in method (i) is tetrahydrofuran. 
     
     
         27 . A pharmaceutical composition comprising the crystal form I of  claim 21  and one or more pharmaceutically acceptable carriers, diluents or excipients. 
     
     
         28 . A method for treating a disease mediated by an opioid receptor (MOR) agonist in a subject in need thereof, comprising administering an effective amount of the crystal form I of  claim 21  to the subject. 
     
     
         29 . The method of  claim 28 , wherein said disease mediated by an MOR receptor agonist is selected from the group consisting of pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric diseases, urinary and reproductive diseases, cardiovascular diseases, and respiratory diseases.