Novel anti-inflammatory androstane derivative compositions

Abstract

There is provided a crystalline chemical composition comprising a compound of formula (I) in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1 having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å when determined at either 120K or 150K.

What is claimed is:  
     
         1 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
       when determined at either 120K or 150K, wherein at about 295K, said composition exhibits one or more of the following XRPD profiles: 
 (i) a peak in the range of around 7.8-8.2;  
 (ii) a peak in the range of around 8.8-96.2;  
 (iii) a peak in the range of around 10.5-11.1;  
 (iv) a peak in the range of around 15.0-15.8; and  
 (v) a peak often associated with a pair of peaks in the range of around 21.2-21.8.  
 
     
     
         2 . The composition of  claim 1 , which exhibits XRPD profiles (i)-(v).  
     
     
         3 . A crystalline chemical composition comprising a compound of formula  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K, wherein at about 295K, said composition exhibits one or more of the following XRPD profiles:  
         (i) absence of a peak at around 7; and  
         (ii) absence of a peak at around 11.5.  
       
     
     
         4 . The composition of  claim 3 , which exhibits both of XRPD profiles (i) and (ii).  
     
     
         5 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K, wherein the guest molecule is selected from the group consisting of an amide moiety containing compound, a carbonyl moiety containing compound, a sulphoxide, an alcohol, an ether, an ester, a carboxylic acid and water.  
       
     
     
         6 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K, wherein the compound of formula (I) is an unsolvated Form 1 polymorph.  
       
     
     
         7 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K, which is non-pressurized and adapted to be administered as a dry powder topically to the lung via the buccal cavity.  
       
     
     
         8 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K, which is non-pressurized and adapted to be administered topically to the nasal cavity.  
       
     
     
         9 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K, which further comprises a PDE4 inhibitor.  
       
     
     
         10 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K, wherein the composition is selected from the group consisting of an ointment, lotion, cream, gel, foam, preparation for delivery by transdermal patch, powder, spray, aerosol, capsule or cartridge for use in an inhaler or insufflator or drop, solution or suspension for nebulisation, suppositories, pessaries, retention enemas, chewable or suckable tablets or pellets, liposome preparation and microencapsulation preparation.  
       
     
     
         11 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K, wherein the composition is a dry powder or spray.  
       
     
     
         12 . The composition according to  claim 11 , wherein the composition is a dry powder.  
     
     
         13 . The composition according to  claim 11 , wherein the composition is a spray.  
     
     
         14 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K,  
         in combination with a long acting β 2 -adrenoreceptor agonist, said long acting β 2 -adrenoreceptor agonist is at least one selected from the group consisting of salmeterol, salbutamol, formoterol, salmefamol, fenoterol and terbutaline and salts thereof.  
       
     
     
         15 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K,  
         , wherein said compound of formula (I) is present in the amount of 0.001 to 10% by weight of said composition.  
       
     
     
         16 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K,  
         in combination with one or more therapeutically active agents selected from the group consisting an anti-histamine, anti-inflammatory agent or antiinfective agent.  
       
     
     
         17 . The composition according to  claim 16 , wherein said anti-histamine is methapyrilene or loratadine, said anti-inflammatory agent is an NSAID and said antiinfective agent is an antibiotic or antiviral.  
     
     
         18 . A crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K,  
         , wherein said compound of formula (I) is in unsolvated form in the form of equant or substantially equant particles.  
       
     
     
         19 . The composition according to  claim 14 , which contains lactose or starch as the diluent or carrier.  
     
     
         20 . A pharmaceutical composition comprising a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K,  
         together with water as the diluent or carrier.  
       
     
     
         21 . A pharmaceutical aerosol formulation comprising a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K,  
         , and a fluorocarbon or hydrogen-containing chlorofluorocarbon as propellant, optionally in combination with a surfactant and/or a cosolvent.  
       
     
     
         22 . A pharmaceutical aerosol formulation comprising a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K,  
         a fluorocarbon or hydrogen-containing chlorofluorocarbon as propellant and a suspending agent which is soluble in the propellant.  
       
     
     
         23 . A pharmaceutical aerosol formulation according to  claim 22 , wherein the suspending agent is an oligolactic acid.  
     
     
         24 . A pharmaceutical aerosol formulation according  claim 21 , wherein the propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.  
     
     
         25 . A pharmaceutical aerosol formulation according to  claim 21 , which consists essentially of a compound of formula (I) optionally in combination with another therapeutically active agent and a propellant selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.  
     
     
         26 . The method for the treatment of a human or animal subject with an anti-inflammatory and/or allergic condition according to, which method comprises administering to said human or animal subject an effective amount of a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K,  
         , wherein said effective amount of the composition is administered topically to said human or animal subject.  
       
     
     
         27 . The method for the treatment of a human or animal subject with an anti-inflammatory and/or allergic condition which method comprises administering to said human or animal subject an effective amount of a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K,  
         , wherein said effective amount of the composition is administered topically as a dry powder to the lung via the buccal cavity.  
       
     
     
         28 . The method for the treatment of a human or animal subject with an anti-inflammatory and/or allergic condition which method comprises administering to said human or animal subject an effective amount of a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K,  
         , wherein said effective amount of the composition is administered once per day.  
       
     
     
         29 . The method of treatment of a human or animal subject with an anti-inflammatory and/or allergic condition which method comprises administering to said human or animal subject an effective amount of a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K,  
         , wherein said composition is administered by inhalation or by nebulisation.  
       
     
     
         30 . The method of treatment of a human or animal subject with an anti-inflammatory and/or allergic condition which method comprises administering to said human or animal subject an effective amount of a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K,  
         , wherein said composition is administered orally, buccally, sublingually, parenterally, locally or rectally.  
       
     
     
         31 . A method for the treatment of at least one condition selected from the group consisting of skin disease, inflammatory condition of the nose, throat or lungs, inflammatory bowel condition, auto-immune disease, conjunctiva and conjunctivitis in a human or animal subject, which comprises administering an effective amount of a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K,  
         to said human or animal subject in need thereof for the treatment of said at least one condition.  
       
     
     
         32 . The method of treatment as recited in  claim 31 , wherein the skin disease is at least one selected from the group consisting of eczema, psoriasis, allergic dermatitis neurodermatitis, pruritis and hypersensitivity reactions.  
     
     
         33 . The method of treatment as recited in  claim 31 , wherein the inflammatory condition of the nose, throat or lungs is at least one selected from the group consisting of asthma, rhinitis, nasal polyps, chronic obstructive pulmonary disease, interstitial lung disease and fibrosis.  
     
     
         34 . The method of treatment as recited in  claim 33 , wherein the inflammatory condition of the nose, throat or lungs is asthma.  
     
     
         35 . The method of treatment as recited in  claim 33 , wherein the inflammatory condition of the nose, throat or lungs is rhinitis.  
     
     
         36 . The method of treatment as recited in  claim 33 , wherein the inflammatory condition of the nose, throat or lungs is chronic obstructive pulmonary disease.  
     
     
         37 . The method of treatment as recited in  claim 33 , wherein the inflammatory bowel condition is at least one selected from the group consisting of ulcerative colitis and Crohn's disease.  
     
     
         38 . The method of treatment as recited in  claim 31 , wherein said composition is administered by inhalation or by nebulisation.  
     
     
         39 . The method of treatment as recited in  claim 31 , wherein said composition is administered orally, buccally, sublingually, parenterally, locally or rectally.  
     
     
         40 . The method for the treatment as recited in  claim 31 , wherein said effective amount of the composition is administered topically to said human or animal subject.  
     
     
         41 . The method for the treatment as recited in  claim 31 , wherein said effective amount of the compound of formula (I) is administered topically as a dry powder to the lung via the buccal cavity.  
     
     
         42 . The method for the treatment as recited in  claim 31 , wherein said effective amount of the compound of formula (I) is administered once per day.  
     
     
         43 . An inhaler comprising a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K.  
       
     
     
         44 . The inhaler of  claim 43 , further comprising propellant.  
     
     
         45 . The inhaler of  claim 43 , further comprising at least one excipient selected from the group consisting of surfactant and cosolvent.  
     
     
         46 . The inhaler of  claim 43 , wherein the composition is free of excipient.  
     
     
         47 . The inhaler of  claim 43 , wherein the composition is retained in a pressurized canister closed with a valve.  
     
     
         48 . The inhaler of  claim 43 , wherein said composition has a particle size in the range of 1-10 μm.  
     
     
         49 . A process for preparing a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K,  
         which comprises:  
         (a) crystallising the composition from a solution containing a compound of formula (I) and the guest molecule; or  
         (b) contacting the compound of formula (I) or another crystalline chemical composition comprising a compound of formula (I)  
         
           
             
             
                 
                 
             
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K, in solid form, with a liquid containing the guest molecule and obtaining the composition therefrom; or  
         (c) contacting a compound of formula (I) or another crystalline chemical composition comprising a compound of formula (I)  
         
           
             
             
                 
                 
             
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K, in solid form, with a vapour containing the guest molecule,  
         , wherein the compound of formula (I), which is crystallized in (a), or contacted with a liquid containing the guest molecule in (b), or contacted with a vapor containing the guest molecule in (c), is in the form of a substantially amorphous solid.  
       
     
     
         50 . The process of  claim 49 , wherein the compound of formula (I) is in the form of substantially amorphous particles.  
     
     
         51 . A process for preparing a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å 
         when determined at either 120K or 150K,  
         which comprises:  
         (a) crystallising the composition from a solution containing a compound of formula (I) and the guest molecule; or  
         (b) contacting the compound of formula (I) or another crystalline chemical composition comprising a compound of formula (I) in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å when determined at either 120K or 150K, in solid form, with a liquid containing the guest molecule and obtaining the composition therefrom; or  
         (c) contacting a compound of formula (I) or another crystalline chemical composition comprising a compound of formula (I) in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å when determined at either 120K or 150K, in solid form, with a vapour containing the guest molecule,  
          wherein the compound of formula (I) as crystalline unsolvated Form 1 polymorph is prepared by dissolving the compound of formula (I) in methylisobutylketone or ethyl acetate and producing the compound of formula (I) as unsolvated Form 1 by addition of an anti-solvent.  
       
     
     
         52 . The process of  claim 51 , wherein the compound of formula (I) as crystalline unsolvated Form 1 polymorph is prepared by dissolving the compound of formula (I) in ethyl acetate and producing the compound of formula (I) as unsolvated Form 1 by addition of toluene as the anti-solvent.  
     
     
         53 . A process for preparing a crystalline chemical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
         in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å when determined at either 120K or 150K,  
         which comprises:  
         (a) crystallising the composition from a solution containing a compound of formula (I) and the guest molecule; or  
         (b) contacting the compound of formula (I) or another crystalline chemical composition comprising a compound of formula (I) in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å when determined at either 120K or 150K, in solid form, with a liquid containing the guest molecule and obtaining the composition therefrom; or  
         (c) contacting a compound of formula (I) or another crystalline chemical composition comprising a compound of formula (I) in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2 1 2 1 2 1  having unit cell dimensions of about 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å when determined at either 120K or 150K, in solid form, with a vapour containing the guest molecule,  
         wherein the compound of formula (I) as crystalline unsolvated Form 1 polymorph is prepared by dissolving the compound of formula (I) in methylisobutylketone and producing the compound of formula (I) as unsolvated Form 1 by addition of isooctane as the anti-solvent.