Compositions and methods for promoting neural regeneration

Abstract

The present invention relates to compositions and methods for promoting tissue regeneration, preferably neural tissue regeneration. Compositions of the invention include (i) certain diphenyl sulfides, diphenyl sulfoxides, diphenyl sulfones, and sulfide, sulfoxide and sulfones of dibenzothiophene and thioxanthene, as well as various analogues and derivatives of these compounds; (ii) one or more cells harvested from an animal or organism subsequent to the administration of a composition comprising a compound of (i); or (iii) any combination of (i) and (ii). The invention can be useful in treating decreases in neuronal function, for example from injury or disease.

1 - 7 . (canceled)  
     
     
         8 . A method for increasing neural expression of one or more proteins on neural precursor cells in vitro, wherein said one or more proteins are selected from the group consisting of eNCAM, MAP II, β-tubulin, nestin, NF and NF—PO 4 , comprising exposing said cells in vitro to an effective amount of a composition containing a compound having one of the following structural formulas:  
       
         
           
           
               
               
           
         
       
       wherein m is 0,1 or 2; X and Y are independently hydrogen or halogen, nitro, alkoxy or —NHCOCH 2 NHCH 3 ; R and R 0  are independently H, halogen or a moiety of one of the following formulas:  
       
         
           
           
               
               
           
         
       
       or —N═CHOC 2 H 5  or —(CH 2 ) q CN where q is an integer from 1 to 5;  
       wherein R 1  is hydrogen or linear or branched alkyl; cycloalkyl or aryl rings, which cycloalkyl or aryl rings can comprise one or more heteroatoms selected from O, N and S and which cycloalkyl or aryl rings can be substituted with linear or branched alkyl, halo, nitro or amino; or R 1  is a moiety of the formula:  
       
         
           
           
               
               
           
         
         R 2  is hydrogen, alkyl or branched alkyl or benzyl;  
         R 1  and R 2  taken together may be —(CH 2 ) p — where p is an integer from 2 to 4 and wherein  
         R 3  is methyl;  
         R 3  is alkyl, branched alkyl, or cycloalkyl;  
         R 4  is linear or branched alkyl optionally substituted with 1 or more halogen, amino or alkylamino; or aryl optionally substituted with one or more alkyl, halo, nitro or amino moieties; —(CH 2 ) q CN where q is an integer from 1 to 5, —CH 2 COR 6  or —CH 2 —NR 7 R 8 ;  
         R 2  and R 3  taken together with the associated nitrogen can be pyrrolidino, piperidino, morpholino, thiomorpholino, 4-methylpiperazino, 3-azabicyclo[3.2.2]nonyl, azetidino or azaspirol[5,5]undecanoyl;  
         R 5  is hydrogen, alkyl or branched alkyl; and  
         R 6 , R 7  and R 8  are independently hydrogen, or linear or branched alkyl optionally substituted with 1 or more halo, nitro or amino groups;  
         and pharmacologically acceptable salts thereof.  
       
     
     
         9 . The method of  claim 8 , wherein the neural precursor cells are obtained from neural tissue or bone marrow.  
     
     
         10 . The method of  claim 9 , wherein the neural tissue is nervous system tissue.  
     
     
         11 . The method of  claim 10 , wherein the nervous system tissue is central nervous system (CNS) tissue.  
     
     
         12 - 18 . (canceled)  
     
     
         19 . A method for promoting growth or differentiation of neural precursor cells in vitro, wherein said neural precursor cells express one or more proteins selected from the group consisting of eNCAM, MAP II, β-tubulin, nestin, NF and NF—PO 4 , the method comprising exposing said cells in vitro to an effective amount of a composition containing a compound having one of the following structural formulas:  
       
         
           
           
               
               
           
         
       
       wherein m is 0, 1 or 2; X and Y are independently hydrogen or halogen, nitro, alkoxy or —NHCOCH 2 NHCH 3 ; R and R 0  are independently H, halogen or a moiety of one of the following formulas:  
       
         
           
           
               
               
           
         
       
       or I(d), or —N═CHOC2H5 or —(CH2)qCN where q is an integer from 1 to 5;  
       wherein R 1  is hydrogen, or linear or branched alkyl; cycloalkyl or aryl rings, which cycloalkyl or aryl rings can comprise one or more heteroatoms selected from O, N and S and which cycloalkyl or aryl rings can be substituted with linear or branched alkyl, halo, nitro or amino; or R 1  is a moiety of the formula:  
       
         
           
           
               
               
           
         
         R 2  is hydrogen, alkyl or branched alkyl or benzyl;  
         R 1  and R 2  taken together may be —(CH 2 ) p — where p is an integer from 2 to 4 and wherein  
         R 3  is methyl;  
         R 3  is alkyl, branched alkyl, or cycloalkyl;  
         R 4  is linear or branched alkyl optionally substituted with 1 or more halogen, amino or alkylamino; or aryl optionally substituted with one or more alkyl, halo, nitro or amino moieties; —(CH 2 ) q CN where q is an integer from 1 to 5, —CH 2 COR 6  or —CH 2 —NR 7 R 8 ;  
         R 2  and R 3  taken together with the associated nitrogen can be pyrrolidino, piperidino, morpholino, thiomorpholino, 4-methylpiperazino, 3-azabicyclo[3.2.2]nonyl, azetidino or azaspirol[5,5]undecanoyl;  
         R 5  is hydrogen, alkyl or branched alkyl; and  
         R 6 , R 7  and R 8  are independently hydrogen, or linear or branched alkyl optionally substituted with 1 or more halo, nitro or amino groups;  
         and pharmacologically acceptable salts thereof.  
       
     
     
         20 . The method of  claim 19 , wherein the composition additionally comprises a pharmaceutically acceptable carrier.  
     
     
         21 . The method of  claim 19 , wherein the neural precursor cells are obtained from a normal, non-injured mammal, or from a mammal suffering from an injury to neural tissue resulting from a contusion injury, or an acute or chronic spinal cord injury, or from surgery, or wherein the nerve cells of the mammal have been damaged by an excitotoxic agency.  
     
     
         22 - 23 . (canceled)  
     
     
         24 . The method of  claim 21 , wherein the excitotoxic agent is glutamate.  
     
     
         25 - 26 . (canceled)  
     
     
         27 . The method of  claim 21  wherein the damage to nerve cells is due to surgery.  
     
     
         28 - 54 . (canceled)  
     
     
         55 . A method for increasing the number of neural precursor cells expressing one or more proteins selected from the group consisting of β-tubulin, MAP II, eNCAM and nestin, either in vitro or in vivo at the site of injury, comprising one of the following: 
 I. a) obtaining a population of neural precursor cells; and 
 b) treating said cells in vitro with an effective amount of a composition containing a compound having one of the following structures:  
                     
 wherein m is 0, 1 or 2; X and Y are independently hydrogen or halogen, nitro, alkoxy or —NHCOCH 2 NHCH 3 ; R and R 0  are independently H, halogen or a moiety of one of the following formulas:  
                     
 or (Id), or —N═CHOC 2 H 5  or —(CH 2 ) q CN where q is an integer from 1 to 5;  
 wherein R 1  is hydrogen, or linear or branched alkyl; cycloalkyl or aryl rings, which cycloalkyl or aryl rings can comprise one or more heteroatoms selected from O, N and S and which cycloalkyl or aryl rings can be substituted with linear or branched alkyl, halo, nitro or amino; or R 1  is a moiety of the formula:  
                     
 
 R 2  is hydrogen, alkyl or branched alkyl or benzyl;  
 R 1  and R 2  taken together may be —(CH 2 ) p — where p is an integer from 2 to 4 and wherein  
 R 3  is methyl;  
 R 3  is alkyl, branched alkyl, or cycloalkyl;  
 R 4  is linear or branched alkyl optionally substituted with 1 or more halogen, amino or alkylamino; or aryl optionally substituted with one or more alkyl, halo, nitro or amino moieties; —(CH 2 ) q CN where q is an integer from 1 to 5, —CH 2 COR 6  or —CH 2 —NR 7 R 8 ;  
 R 2  and R 3  taken together with the associated nitrogen can be pyrrolidino, piperidino, morpholino, thiomorpholino, 4-methylpiperazino, 3-azabicyclo[3.2.2]nonyl, azetidino or azaspirol[5,5]undecanoyl;  
 R 5  is hydrogen, alkyl or branched alkyl; and  
 R 6 , R 7  and R 8  are independently hydrogen, or linear or branched alkyl optionally substituted with 1 or more halo, nitro or amino groups;  
 and pharmacologically acceptable salts thereof; or 
 II. a) administering an effective amount of a composition containing a compound having one of the following structures to a first mammal:  
                     
 wherein m is 0, 1 or 2; X and Y are independently hydrogen or halogen, nitro, alkoxy or —NHCOCH 2 NHCH 3 ; R and R 0  are independently H, halogen or a moiety of one of the following formulas:  
                     
 or (Id), or —N═CHOC 2 H 5  or —(CH 2 ) q CN where q is an integer from 1 to 5;  
 wherein R 1  is hydrogen, or linear or branched alkyl; cycloalkyl or aryl rings, which cycloalkyl or aryl rings can comprise one or more heteroatoms selected from O, N and S and which cycloalkyl or aryl rings can be substituted with linear or branched alkyl, halo, nitro or amino; or R 1  is a moiety of the formula:  
                     
 
 R 2  is hydrogen, alkyl or branched alkyl or benzyl;  
 R 1  and R 2  taken together may be —(CH 2 ) p — where p is an integer from 2 to 4 and wherein  
 R 3  is methyl;  
 R 3  is alkyl, branched alkyl, or cycloalkyl;  
 R 4  is linear or branched alkyl optionally substituted with 1 or more halogen, amino or alkylamino; or aryl optionally substituted with one or more alkyl, halo, nitro or amino moieties; —(CH 2 ) q CN where q is an integer from 1 to 5, —CH 2 COR 6  or —CH 2 —NR 7 R 8 ;  
 R 2  and R 3  taken together with the associated nitrogen can be pyrrolidino, piperidino, morpholino, thiomorpholino, 4-methylpiperazino, 3-azabicyclo[3.2.2]nonyl, azetidino or azaspirol[5,5]undecanoyl;  
 R 5  is hydrogen, alkyl or branched alkyl; and  
 R 6 , R 7  and R 8  are independently hydrogen, or linear or branched alkyl optionally substituted with 1 or more halo, nitro or amino groups;  
 and pharmacologically acceptable salts thereof; 
 b) collecting a population of neural precursor cells from said first mammal; and  
 c) delivering said neural precursor cells to the site of injury in the first mammal or to a site of injury in a second mammal; wherein said delivery results in an increase in the number of neural precursor cells at the site of injury in the first or second mammal.  
 
 
     
     
         56 . The method of  claim 55 , wherein the neural precursor cells are mammalian cells.  
     
     
         57 - 66 . (canceled)  
     
     
         67 . The method of  claim 8 , wherein the composition comprises a compound of the following formula:  
       
         
           
           
               
               
           
         
       
       wherein m is 0, 1 or 2; R 9  is hydrogen, fluoro, chloro, bromo, nitro, alkoxy having up to 3 carbon atoms or —NHCOCH 2 NHCH 3 ; R 10  is hydrogen or chloro; and R 11  is —(CH 2 ) q CN wherein q is an integer from 1 to 5, —COCH 2 NH 2 , —COCH 2 NHCH 3 , —COCH 2 Cl, —COCH 2  CH 2 Cl or —C(O)R 12  wherein R 12  is an alkyl group having up to 4 carbon atoms; and  
       pharmaceutically acceptable salts thereof.  
     
     
         68 . The method of  claim 67 , wherein R 9  is fluoro, m is 2, and R 11  is —C(O)R 12  and R 10  is hydrogen.  
     
     
         69 . The method of  claim 68 , wherein the compound is N-[4-[4-fluorophenyl)sulfonyl]phenyl]acetamide.  
     
     
         70 . The method of  claim 19 , wherein the composition comprises a compound of the following formula:  
       
         
           
           
               
               
           
         
       
       wherein m is 0, 1 or 2; R 9  is hydrogen, fluoro, chloro, bromo, nitro, alkoxy having up to 3 carbon atoms or —NHCOCH 2 NHCH 3 ; R 10  is hydrogen or chloro; and R 11  is —(CH 2 ) q CN wherein q is an integer from 1 to 5, —COCH 2 NH 2 , —COCH 2 NHCH 3 , —COCH 2 Cl, —COCH 2  CH 2 Cl or —C(O)R 12  wherein R 12  is an alkyl group having up to 4 carbon atoms; and  
       pharmaceutically acceptable salts thereof.  
     
     
         71 . The method of  claim 70 , wherein R 9  is fluoro, m is 2, and R 11  is —C(O)R 12  and R 10  is hydrogen.  
     
     
         72 . The method of  claim 71 , wherein the compound is N-[4-[4-fluorophenyl)sulfonyl]phenyl]acetamide.  
     
     
         73 . The method of  claim 55 , wherein the composition comprises a compound of the following formula:  
       
         
           
           
               
               
           
         
       
       wherein m is 0, 1 or 2; R 9  is hydrogen, fluoro, chloro, bromo, nitro, alkoxy having up to 3 carbon atoms or —NHCOCH 2 NHCH 3 ; R 10  is hydrogen or chloro; and R 1  is —(CH 2 ) q CN wherein q is an integer from 1 to 5, —COCH 2 NH 2 , —COCH 2 NHCH 3 , —COCH 2 Cl, —COCH 2  CH 2 Cl or —C(O)R 12  wherein R 12  is an alkyl group having up to 4 carbon atoms; and  
       pharmaceutically acceptable salts thereof.  
     
     
         74 . The method of  claim 73 , wherein R 9  is fluoro, m is 2, and R 11  is —C(O)R 12  and R 10  is hydrogen.  
     
     
         75 . The method of  claim 74 , wherein the compound is N-[4-[4-fluorophenyl)sulfonyl]phenyl]acetamide.