Methods and compositions for the prevention and treatment of hearing loss

Abstract

In one aspect, pharmaceutical compositions comprising a CDK2 inhibitor and one or more of at least one agent known to treat a hearing impairment and at least one agent known to prevent a hearing impairment, and methods of treating and/or preventing hearing impairments or disorders using the compositions are disclosed. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

What is claimed is: 
     
         1 . A method of treating hearing impairment, the method comprising administering to a subject diagnosed with a need for treatment of hearing impairment a therapeutically effective amount of a cyclin-dependent kinase 2 (CDK2) inhibitor, or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein the CDK2 inhibitor is selected from a paullone derivative, a purine derivative, and a 3-(2-phenylhydrazono)indolin-2-one derivative, or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method of  claim 2 , wherein the CDK2 inhibitor is selected from: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The method of  claim 2 , wherein the CDK2 inhibitor is selected from: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The method of  claim 1 , wherein the CDK2 inhibitor is administered in an amount of from about 0.001 μM to about 1.0×10 4  μM at least once every three weeks. 
     
     
         6 . The method of  claim 1 , wherein the hearing impairment is drug-induced. 
     
     
         7 . The method of  claim 6 , wherein the drug is a chemotherapeutic agent. 
     
     
         8 . The method of  claim 6 , wherein the drug is an antibiotic. 
     
     
         9 . The method of  claim 9 , wherein the antibiotic is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C, amikacin, apramycin, arbekacin, astromicin, bekanamycin, dibekacin, framycetin, gentamicin, hygromycin B, isepamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, and verdamicin, or a pharmaceutically acceptable salt thereof. 
     
     
         10 . A pharmaceutical composition comprising a CDK2 inhibitor, wherein the CDK2 inhibitor is not a paullone derivative, or a pharmaceutically acceptable salt thereof; and one or more of:
 a) at least one agent known to treat hearing impairment, or a pharmaceutically acceptable salt thereof; and   b) at least one agent known to prevent hearing impairment, or a pharmaceutically acceptable salt thereof; and   a pharmaceutically acceptable carrier.   
     
     
         11 . The composition of  claim 10 , wherein the CDK2 inhibitor has a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein each of R 5a  and R 5b  is independently selected from hydrogen, C1-C8 alkyl, (CH 2 ) q R 8 , and C═O(CH 2 ) q R 8  and wherein each of R 5a  and R 5b  is independently substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl;
 wherein q, when present, is an integer selected from 1, 2, 3, and 4; 
 wherein R 8 , when present, is selected from hydrogen, —OH, —SH, —NH 2 , C1-C4 alkoxy, C1-C4 thioalkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino; 
 
         wherein R 6  is selected from halogen, OR 9 , and NR 10a R 10b ;
 wherein R 9 , when present, is selected from C1-C8 alkyl, (CH 2 ) p Cy 1 , and (CH 2 ) p Ar 1  and wherein R 9 , when present, is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl;
 wherein p, when present, is an integer selected from 0, 1, 2, and 3; 
 wherein Cy 1 , when present, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl; 
 wherein Ar 1 , when present, is selected from aryl and heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl; 
 
 wherein each of R 10a  and R 10b , when present, is independently selected from C1-C8 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2  and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl;
 wherein r, when present, is an integer selected from 0, 1, 2, and 3; 
 wherein Cy 2 , when present, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl; 
 wherein Ar 2 , when present, is selected from aryl and heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl; and 
 
 
         wherein R 7 , when present, is selected from hydrogen and C1-C8 alkyl, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The composition of  claim 10 , wherein the CDK2 inhibitor has a structure represented by a formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 . The composition of  claim 10 , wherein the 3 CDK2 inhibitor has a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein each of R 11a , R 11b , R 11c , and R 11d  is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 ;
 wherein each occurrence of R 15 , when present, is independently selected from hydrogen, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 ; 
 
         wherein each of R 12  and R 13  is independently selected from hydrogen and C1-C4 alkyl; 
         wherein each of R 14a , R 14b , R 14c , R 14d , and R 14e  is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 16 , and —CO 2 R 16 ; and
 wherein each occurrence of R 16 , when present, is independently selected from hydrogen, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 , 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         14 . The composition of  claim 10 , wherein the CDK2 inhibitor has a structure represented by a formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         15 . The composition of  claim 10 , wherein the CDK2 inhibitor has a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 20  is selected from —SO 2 R 20a , —OH, NH 2 , substituted amide, C1-C4 alkyl carbonyl, C1-C4 monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8 alkyl and is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl; 
         wherein each of R 21 , R 23 , and R 25  is independently selected from hydrogen, halogen, —OH, NH 2 , C1-C4 monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8 alkyl and is independently substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl; and 
         wherein each of R 22  and R 24  is independently selected from hydrogen and C1-C8 alkyl and is independently substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl, or a pharmaceutically acceptable salt thereof. 
       
     
     
         16 . The composition of  claim 10 , wherein the CDK2 inhibitor has a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein each occurrence of X is independently a halogen; 
         wherein each of R 30 , R 31 , R 32 , and R 33  is independently selected from hydrogen and C1-C8 alkyl and is independently substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl; and 
         wherein R 34  is selected from —OH, NH 2 , C1-C4 monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8 alkyl and is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . The composition of  claim 10 , wherein the CDK2 inhibitor is selected from: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         18 . The composition of  claim 10 , wherein the CDK2 inhibitor is selected from: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         19 . The composition of  claim 10 , wherein the pharmaceutical composition is used to treat hearing impairment. 
     
     
         20 . The composition of  claim 10 , wherein the pharmaceutical composition is used to prevent hearing impairment.