Salts and crystalline forms of an apoptosis-inducing agent

Abstract

Salts and crystalline forms of 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide are suitable active pharmaceutical ingredients for pharmaceutical compositions useful in treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl-2 family proteins, for example cancer.

1 . A compound having the systematic name 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (Compound 1) in a salt or crystalline form. 
     
     
         2 . The compound of  claim 1 , wherein the crystalline form is Compound 1 free base anhydrate, characterized by a powder X-ray diffraction pattern having at least one peak selected from those at 6.3, 7.1, 9.0, 9.5, 12.5, 14.5, 14.7, 15.9, 16.9, and 18.9 degrees 2θ (pattern A), each peak being ±0.2 degrees 2θ, when measured at about 25° C. with Cu Kα radiation at 1.54178 Å. 
     
     
         3 . The compound of  claim 1 , wherein the crystalline form is Compound 1 free base anhydrate, characterized by a powder X-ray diffraction pattern having at least one peak selected from those at 5.8, 7.7, 8.3, 9.9, 13.0, 13.3, 14.2, 15.3, 16.6, 17.9, 18.3, 19.8, 20.7, 21.2, 21.9, 22.5, 23.6, and 24.1 degrees 2θ (pattern B), each peak being ±0.2 degrees 2θ, when measured at about 25° C. with Cu Kα radiation at 1.54178 Å. 
     
     
         4 . The compound of  claim 1 , wherein the crystalline form is Compound 1 free base hydrate, characterized by a powder X-ray diffraction pattern having at least one peak selected from those at 5.8, 7.6, 7.9, 10.7, 11.7, 14.0, 15.3, 15.8, 17.4, 18.3, 19.9, 20.4, 20.7, 22.5, 24.9, 25.8, and 26.7 degrees 2θ (pattern C), each peak being ±0.2 degrees 2θ, when measured at about 25° C. with radiation at 1.54178 Å. Cu Kα radiation at 1.54178 Å. 
     
     
         5 . The compound of  claim 1 , wherein the crystalline form is Compound 1 free base hydrate, characterized by a powder X-ray diffraction pattern having at least one peak selected from those at 3.3, 6.4, 7.1, 7.3, 10.1, 11.4, 13.2, 14.4, 14.6, 15.1, 15.8, 16.2, 17.2, 17.6, 18.0, 18.6, 19.0, 19.5, 19.8, 20.2, 20.7, 21.0, 22.5, 23.0, 26.0, 28.9, and 29.2 degrees 2θ (pattern D), each peak being ±0.2 degrees 2θ, when measured at about 25° C. with Cu Kα radiation at 1.54178 Å. 
     
     
         6 . The compound of  claim 1 , wherein the crystalline form is Compound 1 free base dichloromethane solvate, characterized by a powder X-ray diffraction pattern having at least one peak selected from those at 5.9, 7.1, 9.6, 10.0, 10.7, 11.1, 13.2, 14.8, and 18.2 degrees 2θ, each peak being ±0.2 degrees 2θ (pattern E), when measured at about 25° C. with Cu Kα radiation at 1.54178 Å. 
     
     
         7 . The compound of  claim 1 , wherein the crystalline form is Compound 1 free base dichloromethane solvate, characterized by a monoclinic lattice type and P21/n space group having unit cell lengths for the three axes of about (a) 13.873 Å, (b) 12.349 Å, (c) 29.996 Å and the three unit cell angles of about (α) 90.00°, (β) 92.259°, and (γ) 90.00°. 
     
     
         8 . The compound of  claim 1 , wherein the crystalline form is Compound 1 free base ethyl acetate solvate, characterized by a powder X-ray diffraction pattern having at least one peak selected from those at 5.8, 7.1, 9.5, 9.9, 10.6, 11.6, 13.1, 13.8, 14.8, 16.0, 17.9, 20.2, 21.2, 23.2, 24.4, and 26.4 degrees 2θ (pattern F), each peak being ±0.2 degrees 2θ, when measured at about 25° C. with Cu Kα radiation at 1.54178 Å. 
     
     
         9 . The compound of  claim 1 , wherein the crystalline form is Compound 1 free base ethyl acetate solvate, characterized by a powder X-ray diffraction pattern having at least one peak selected from those at 3.3, 6.5, 7.0, 7.3, 9.2, 9.7, 11.2, 11.4, 11.9, 12.9, 14.4, 14.9, 15.8, 16.2, 17.2, 17.4, 17.8, 18.5, 18.9, 19.4, 20.1, 20.7, 20.9, 22.0, 22.7, 23.4, 23.8, 24.7, 25.9, 27.0, and 28.9 degrees 2θ (pattern G), each peak being ±0.2 degrees 2θ, when measured at about 25° C. with radiation at 1.54178 Å. 
     
     
         10 . The compound of  claim 1 , wherein the crystalline form is Compound 1 free base acetonitrile solvate, characterized by a powder X-ray diffraction pattern having at least one peak selected from those at 5.8, 7.4, 7.6, 10.2, 13.0, 13.6, 14.9, 16.4, 17.0, 17.5, 18.2, 19.4, 19.7, 20.4, 21.0, 21.2, 21.8, 22.4, 22.9, 24.2, 24.3, 26.1, and 29.2 degrees 2θ (pattern H), each peak being ±0.2 degrees 2θ, when measured at about 25° C. with radiation at 1.54178 Å. 
     
     
         11 . The compound of  claim 1 , wherein the crystalline form is Compound 1 free base acetonitrile solvate, characterized by a triclinic lattice type and P1 space group having unit cell lengths for the three axes of about (a) 12.836 Å, (b) 13.144 Å, (c) 15.411 Å and the three unit cell angles of about (α) 92.746°, (β) 95.941°, and (γ) 113.833°. 
     
     
         12 . The compound of  claim 1 , wherein the crystalline form is Compound 1 free base acetonitrile solvate, characterized by a powder X-ray diffraction pattern having at least one peak selected from those at 6.4, 6.9, 7.7, 8.8, 9.4, 11.1, 12.3, 12.8, 16.5, 17.0, 17.4, 18.3, 18.6, 19.0, 19.2, 20.3, 21.6, 22.3, 22.9, and 23.7 degrees 2θ (pattern I), each peak being ±0.2 degrees 2θ, when measured at about 25° C. with radiation at 1.54178 Å. 
     
     
         13 . The compound of  claim 1 , wherein the crystalline form is Compound 1 free base acetone solvate, characterized by a powder X-ray diffraction pattern having at least one peak selected from those at 6.0, 6.8, 8.0, 9.0, 9.7, 11.2, 11.9, 12.6, 14.7, 15.0, 15.2, 15.8, 16.4, 16.6, 17.6, 17.8, 17.9, 18.7, 20.2, 20.8, 21.6, 22.2, 22.6, 23.3, 23.8, 24.0, 24.4, 26.8, 27.1, 28.0, and 28.2 degrees 2θ (pattern J), each peak being ±0.2 degrees 2θ, when measured at about 25° C. with radiation at 1.54178 Å. 
     
     
         14 . The compound of  claim 1 , wherein the crystalline form is Compound 1 hydrochloride, characterized by a powder X-ray diffraction pattern having at least one peak selected from those at 5.1, 5.9, 7.7, 9.9, 10.2, 10.8, 13.6, 14.0, 15.4, 15.9, 16.2, 17.6, 18.3, 18.7, 19.7, 19.9, 20.1, 20.4, 20.7, 20.9, 22.9, and 26.2 degrees 2θ (Pattern K), each peak being ±0.2 degrees 2θ, when measured at about 25° C. with Cu Kα radiation at 1.54178 Å. 
     
     
         15 . The compound of  claim 1 , wherein the crystalline form is Compound 1 free base hydrochloride, characterized by a triclinic lattice type and P1 space group having unit cell lengths for the three axes of about (a) 10.804 Å, (b) 12.372 Å, (c) 19.333 Å and the three unit cell angles of about (α) 76.540°, (β) 87.159°, and (γ) 70.074°. 
     
     
         16 . The compound of  claim 1 , wherein the crystalline form is Compound 1 free base hydrochloride hydrate, characterized by a powder X-ray diffraction pattern having at least one peak selected from those at 4.6, 8.7, 9.6, 9.9, 12.3, 14.9, 15.7, 17.6, 18.1, 18.4, 19.3, 19.6, 21.0, 23.3, 23.9, 24.8, 26.5, 27.2, 27.4, 29.0, and 30.1 degrees 2θ (pattern L), each peak being ±0.2 degrees 2θ, when measured at about 25° C. with Cu Kα radiation at 1.54178 Å. 
     
     
         17 . The compound of  claim 1 , wherein the crystalline form is Compound 1 free base sulfate, characterized by a powder X-ray diffraction pattern having at least one peak selected from those at 4.8, 7.7, 8.3, 9.7, 10.2, 12.0, 12.6, 14.5, 15.4, 17.4, 17.9, 18.4, 19.1, 19.5, 21.0, 22.4, 23.3, 23.9, 25.1, and 26.8 degrees 2θ (pattern M), each peak being ±0.2 degrees 2θ, when measured at about 25° C. with Cu Kα radiation at 1.54178 Å. 
     
     
         18 . The compound of  claim 1 , wherein the crystalline form is Compound 1 free base tetrahydrofuran, characterized by a powder X-ray diffraction pattern having a least one peak selected from those at 4.0, 4.6, 8.0, 8.5, 9.4, 14.6, 17.1, 17.4, 17.8, 18.1, 19.2, 19.5, 20.1, 20.4, 20.5, and 21.7 degrees 2θ (pattern N), each peak being ±0.2 degrees 2θ, when measured at about 25° C. with Cu Kα radiation at 1.54178 Å. 
     
     
         19 - 106 . (canceled)