Crystalline forms of neurotrophin mimetic compounds and their salts

Abstract

The present invention includes crystalline forms of (2S,3S)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide and salts thereof. Furthermore, the present invention provides compositions comprising the crystalline forms and therapeutic uses of the crystalline forms.

1 - 5 . (canceled) 
     
     
         6 . A composition comprising a crystalline form of a pharmaceutically acceptable salt of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide, wherein said pharmaceutically acceptable salt is selected from a sulfonic acid addition salt, a carboxylic acid addition salt, and a polyhydroxy acid addition salt. 
     
     
         7 . The composition according to  claim 6 , wherein said pharmaceutically acceptable salt is a sulfonic acid addition salt, and wherein said crystalline form is a crystalline form of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide dimesylate, exhibiting one or more of the following properties:
 (a) an X-ray powder diffraction pattern comprising peaks at 8.499±0.3, 21.162±0.3, and 22.292±0.3 degrees two-theta;   (b) a Raman spectrum comprising peaks at 2935±10 cm −1 , 1040±10 cm −1 , and 778±10 cm −1 ; and   (c) a Differential Scanning calorimetry (DSC) thermogram having a single maximum value at 180.77±2.0.   
     
     
         8 . The composition according to  claim 7 , wherein said X-ray powder diffraction pattern further comprises peaks at 9.421±0.3, 16.543±0.3, and 18.912±0.3 degrees two-theta. 
     
     
         9 . The composition according to  claim 7 , wherein said Raman spectrum further comprises peaks at 1444±10 cm −1  and 557±10 cm −1 . 
     
     
         10 . The composition according to  claim 6 , wherein said pharmaceutically acceptable salt is a sulfonic acid addition salt, and wherein said crystalline form is a crystalline form of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide ditosylate, exhibiting one or more of the following properties:
 (a) an X-ray powder diffraction pattern comprising peaks at 6.021±0.3 and 18.078±0.3 degrees two-theta;   (b) a Raman spectrum comprising peaks at 2980±10 cm −1 , 1123±10 cm −1 , and 800±10 cm −1 ; and   (c) a Differential Scanning calorimetry (DSC) thermogram having a single maximum value at 191.85±2.0.   
     
     
         11 . The composition according to  claim 10 , wherein said X-ray powder diffraction pattern further comprises peaks at 17.557±0.3, 20.475±0.3, and 11.029±0.3 degrees two-theta. 
     
     
         12 . The composition according to  claim 10 , wherein said Raman spectrum further comprises peaks at 2922±10 cm −1 , 1599±10 cm −1 , and 637±10 cm −1 . 
     
     
         13 . The composition according to  claim 6 , wherein said pharmaceutically acceptable salt is a sulfonic acid addition salt, and wherein said crystalline form is a crystalline form of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide dinapsylate, exhibiting one or more of the following properties:
 (a) an X-ray powder diffraction pattern comprising peaks at 5.943±0.3, 15.872±0.3, and 18.515±0.3 degrees two-theta;   (b) a Raman spectrum comprising peaks at 3053±10 cm −1 , 1380±10 cm −1 , and 766±10 cm −1 ; and   (c) a Differential Scanning calorimetry (DSC) thermogram having a single maximum value at 185.56±2.0.   
     
     
         14 . The composition according to  claim 13 , wherein said X-ray powder diffraction pattern further comprises peaks at 22.046±0.3 degree two-theta. 
     
     
         15 . The composition according to  claim 13 , wherein said Raman spectrum further comprises peaks at 2974±10 cm −1  and 514±10 cm −1 . 
     
     
         16 . The composition according to  claim 6 , wherein said pharmaceutically acceptable salt is a sulfonic acid addition salt, and wherein said crystalline form is a crystalline form of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide monoedisylate, exhibiting one or more of the following properties:
 (a) an X-ray powder diffraction pattern comprising peaks at 7.447±0.3 and 20.406±0.3 degrees two-theta;   (b) a Raman spectrum comprising peaks at 2954±10 cm −1 , 1058±10 cm −1 , and 825±10 cm −1 ; and   (c) a Differential Scanning calorimetry (DSC) thermogram having a single maximum value at 317.25±2.0.   
     
     
         17 . The composition according to  claim 16 , wherein said X-ray powder diffraction pattern further comprises peaks at 23.443±0.3 and 22.244±0.3 degrees two-theta. 
     
     
         18 . The composition according to  claim 16 , wherein said Raman spectrum further comprises peaks at 3003±10 cm −1  and 521±10 cm −1 . 
     
     
         19 . The composition according to  claim 6 , wherein said pharmaceutically acceptable salt is a carboxylic acid addition salt, and wherein said crystalline form is a crystalline form of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide monooxalate, exhibiting one or more of the following properties:
 (a) an X-ray powder diffraction pattern comprising peaks at 7.260±0.3 and 19.671±0.3 degrees two-theta;   (b) a Raman spectrum comprising peaks at 2897±10 cm −1 , 1692±10 cm −1 , and 491±10 cm −1 ; and   (c) a Differential Scanning calorimetry (DSC) thermogram having a single maximum value at 233.07±2.0.   
     
     
         20 . The composition according to  claim 19 , wherein said X-ray powder diffraction pattern further comprises peaks at 18.917±0.3 and 16.024±0.3 degrees two-theta. 
     
     
         21 . The composition according to  claim 19 , wherein said Raman spectrum further comprises peaks at 2955±10 cm −1 , 1443±10 cm −1 , and 1252 cm −1 . 
     
     
         22 . The composition according to  claim 6 , wherein said pharmaceutically acceptable salt is a polyhydroxy acid addition salt, and wherein said crystalline form is a crystalline form of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide digluconate, exhibiting one or more of the following properties:
 (a) an X-ray powder diffraction pattern comprising peaks at 19.447±0.3, 24.377±0.3, and 22.637±0.3 degrees two-theta;   (b) a Raman spectrum comprising peaks at 2957±10 cm −1 , 2928±10 cm −1 , and 910±10 cm −1 ; and   (c) a Differential Scanning calorimetry (DSC) thermogram having a single maximum value at 182.33±2.0.   
     
     
         23 . The composition according to  claim 22 , wherein said X-ray powder diffraction pattern further comprises peaks at 15.730±0.3 and 7.768±0.3 degrees two-theta. 
     
     
         24 . The composition according to  claim 22 , wherein said Raman spectrum further comprises peaks at 1450±10 cm −1 , 1139±10 cm −1 , and 883±10 cm −1 . 
     
     
         25 . A method for treating a disease or disorder involving degeneration or dysfunction of cells expressing p75 in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition according to  claim 6 , wherein said disease or disorder involving degeneration or dysfunction of cells expressing p75 is selected from the group consisting of Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, epilepsy, Parkinson's disease, spinal cord injury, stroke, hypoxia, ischemia, brain injury, diabetic neuropathy, peripheral neuropathy, nerve transplantation, multiple sclerosis, peripheral nerve injury, and hair loss.