Pleuromutilin derivatives as antimicrobials

Abstract

The present invention relates to pleuromutilin derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medical therapy, particularly antibacterial therapy.

What is claimed is: 
     
       1. A compound of general formula (IA) or (IB): 
       
         
           
           
               
               
           
         
       
       in which:
 each of n and m is independently 0, 1 or 2; and 
 X is selected from —O—, —S—, —S(O)—, —SO 2 —, —CO.O—, —NH—, —CONH—, —NHCONH— and a bond; or 
 n is 1 or 2 and m is 2 and X is —S—; and 
 R 1  is vinyl or ethyl; 
 R 2  is optionally substituted quinuclidinyl, azabicyclo[2.2.1]heptyl, azabicyclo[4,3,0]nonyl, azabicyclo[3.2.1]octyl, azabicyclo[3,3,0]octyl, azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octenyl, azabicyclo[3.3.1]nonyl or azabicyclo[4.4.0]decyl; wherein R 2  is attached through a ring carbon atom; 
 R 3  is H or OH; or 
 the moiety R 2 (CH 2 ) m X(CH 2 ) n CH 2 COO at position 14 of (IA) or (IB) is replaced by R a R b C=CHCOO in which one of R a  and R b  is hydrogen and the other is R 2  or R a  and R b  together form R 2 ; or 
 
       a pharmaceutically acceptable salt thereof. 
     
     
       2. A compound according to  claim 1  in which R 2  is substituted by alkyl, alkyloxy, alkenyl or alkenyloxy, which are optionally further substituted by one or more groups selected from aryl, heterocyclyl, (C 1-6 )alkoxy, (C 1-6 )alkylthio, aryl(C 1-6 )alkoxy, aryl(C 1-6 )alkylthio, amino, mono- or di-(C 1-6 )alkylamino, cycloalkyl, cycloalkenyl, carboxy and esters thereof, amides of carboxy, ureido, carbamimidoyl (amidino), guanidino, alkyl-sulfonyl, aminosulfonyl (C 1-6 )acyloxy, (C 1-6 )acylamino, azido, hydroxy, and halogen. 
     
     
       3. A compound according to  claim 1  in which n is 0. 
     
     
       4. A compound according to  claim 1  in which m is 0 or 1. 
     
     
       5. A compound according to  claim 1  in which R 2  is quinuclidinyl. 
     
     
       6. A compound according to  claim 1  which has the formula (IA). 
     
     
       7. A compound according to  claim 1  selected from:
 mutilin 14-(quinuclidin-4-yl-sulfanyl)-acetate; 
 19,20-dihydromutilin 14-(quinuclidin-4-yl-sulfanyl)-acetate; 
 mutilin 14-(quinuclidin-3-yloxy)-acetate; 
 mutilin 14-(quinuclidin-3-ylsulfonyl)-acetate; 
 mutilin 14-(quinuclidin-4-yl-sulfanyl)-acetate; 
 mutilin 14-[N-(2,2-dimethylazabicyclo[4.3.0]non-4-ylmethyl)]-aminoacetate; 
 mutilin 14-(quinuclidin-4-ylcarbonylamino)-acetate; 
 mutilin 14-[(3R,4R)-azabicyclo[2.2.1]hept-3-ylcarbonylamino]-acetate; 
 mutilin 14-(quinuclidin-4-ylmethylsulfanyl)-acetate; 
 19,20-dihydromutilin 14-(quinuclidin-4-ylsulfonyl) acetate; 
 19,10-dihydromutilin 14-(quinclidin-4-ylsulfoxy)-acetate; 
 mutilin 14-{(3RS,4SR)-1-aza-bicyclo[2.2.1]hept-3-yl-sulfanyl}-acetate; 
 mutilin 14-(quinuclidin-3-ylidene)-acetate; 
 mutilin 14-[quinuclidin-3-yl]-acetate; 
 mutilin 14-[quinuclidin-3-ylacetoxy]-acetate; 
 mutilin 14-(quinuclidin-3-ylmethylsulfanyl)-acetate; 
 1,2-didehydromutilin 14-(quinuclidin-4-ylsulfanyl)-acetate; 
 2α-hydroxymutilin 14-(quinuclidin-4-ylsulfanyl)-acetate; 
 mutilin 14-(quinuclidin-4-yl)-acetate; 
 mutilin 14-(quinuclidin-4-ylmethyl)-aminoacetate; 
 mutilin 14-[3-(quinuclidin-4-yl)-acrylate; 
 mutilin 14-[3-(quinuclidin-4-yl)]-propionate; 
 mutilin 14-(quinuclidin-4-ylmethyloxy)-acetate; 
 mutilin 14-[(3R)-quinuclidin-3-ylamino]-acetate; 
 mutilin 14-(quinuclidin-4-yl-amino)-acetate; 
 mutilin 14-[(3R)-quinuclidin-3-ylamino)]-acetate; 
 mutilin 14-(quinuclidin-4-yl-amino)-acetate; 
 mutilin 14-[4-(quinuclidin-4-yl)]-butyrate; 
 mutilin 14-(1-azabicyclo[3,3,0]oct-4-ylmethylsulfanyl)-acetate; 
 mutilin 14-(1-azabicyclo[3,3,0]oct-3-ylsulfanyl)-acetate; 
 mutilin 14-(endo 8-methyl-8-azabicyclo[3,2,1]oct-3-ylsulfanyl)-acetate; 
 mutilin 14-(1-azabicyclo[4,3,0]non-4-ylsulfanyl)-acetate; 
 19,20-dihydromutilin 14-(1-azabicyclo[4,3,0]non-4-ylsulfanyl)-acetate; 
 mutilin 14-{(3S,4R)-1-azabicyclo[2.2.1]hept-3-ylmethylsulfanyl}-acetate; 
 mutilin 14-(quinuclidin-2-ylmethylsulfanyl)-acetate; 
 mutilin 14-(1-azabicyclo[2.2.1]hept-4-ylmethylsulfanyl)-acetate; 
 mutilin 14-{(3R,4S)-1-azabicyclo[2.2.1]hept-3-ylmethylsulfanyl}-acetate; 
 mutilin 14-(1-azabicyclo[3.2.1]oct-5-ylmethylsulfanyl)-acetate; 
 mutilin 14-(quinuclidin-4-ylmethylsulfanyl)-acetate; 
 mutilin 14-(8-methyl-8-azabicyclo [3.2.1]oct-3-ylmethylsulfanyl)-acetate; 
 mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate; 
 mutilin 14-[(3-(quinuclidin-4-ylsulfanyl)]-propionate; 
 mutilin 14-[3 -(quinuclidin-4-ylmethylsulfanyl)]-propionate; 
 19,20-dihydromutilin 14-(8-methyl-8-azabicyclo[3.2.1]oct-3-ylmethylsulfanyl)-acetate; 
 mutilin 14-[4-(quinuclidin-4-ylsulfanyl)]-butyrate; and 
 mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate. 
 
     
     
       8. A process for preparing a compound according to  claim 1  which comprises:
 (a) coupling mutilin or epi-mutilin having a protected hydroxy group at position 11, with an active derivative, such as an acid chloride, of a carboxylic acid R 2A —(CH 2 ) m —X—(CH 2 ) n —CH 2 CO 2 H, where R 2A  is R 2  as defined in  claim 1  or a group convertible thereto, and n, m, and X are as defined in  claim 1 , and if necessary converting the epi-mutilin to mutilin, and where necessary or desired, before or after the coupling, modifying the mutilin nucleus to introduce 2—OH; 19,20-dihydro; or 1,2-dehydro substituents; or 
 (b) providing a mutilin or epi-mutilin derivative having (CH 2 ) n CH 2 CO as an O-acyl group at position 14, where the acyl group is substituted with R L , which is a leaving group, OH or NH, coupling the 14-O-acyl-(epi) mutilin derivative with a compound R 2A (CH 2 ) m XH or an active derivative therof, and if necessary converting the epi-mutilin configuration to mutilin, and where necessary or desired, before or after the coupling, modifying the mutilin nucleus to introduce 2-OH; 19,20-dihydro; or 1,2-dehydro substituents. 
 
     
     
       9. A process for preparing a compound according to  claim 8 (b) in which
 (a) when X is O, S or NH, R L  is a leaving group and is reacted with
 (i) the alcohol R 2 —(CH2) m —OH; 
 (ii) the thiol R 2 —(CH 2 ) m —SH; 
 (iii) the amine R 2 —(CH 2 ) m —NH 2 ; 
 
 (b) when X is CONH, R L  is amino and is reacted with the acid R 2A —(CH 2 ) m —CO 2 H, or an acylating agent derived therefrom; 
 (c) when X is CO.O, R L  is hydroxy and is reacted with an acylating agent derived from the acid R 2A —(CH 2 ) m —CO 2 H. 
 
     
     
       10. A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       11. A pharmaceutical composition according to  claim 10  in the form of a spray adapted for administration to the nasal cavity. 
     
     
       12. A pharmaceutical composition according to  claim 11  in which the spray is an aqueous spray. 
     
     
       13. A method of treating bacterial infection which method comprises administering an anti-bacterial effective amount of a compound of formula (IA) or (IB) according to  claim 1  to a patient in need thereof. 
     
     
       14. A method of reducing or eliminating the nasal carriage of pathogenic organisms which method comprises administering an effective amount of a compound of formula (IA) or (IB) according to  claim 1  to a patient in need thereof. 
     
     
       15. A method of prophylaxis of recurrent otitis media or recurrent acute bacterial sinusitis which comprises administering an effective amount of a compound of formula (IA) or (IB) according to  claim 1  to a patient in need thereof. 
     
     
       16. A compound according to claim 1 wherein X is —S—, n is 0 and m is 0 or 1. 
     
     
       17. A pharmaceutical composition according to claim 10 adapted for topical administration. 
     
     
       18. A pharmaceutical composition according to claim 17 in the form of an ointment. 
     
     
       19. A pharmaceutical composition according to claim 17 in the form of a cream. 
     
     
       20. A pharmaceutical composition according to claim 17 in the form of a lotion. 
     
     
       21. A method of treating bacterial infections of skin or soft tissue which method comprises topically administering an antibacterially effective amount of a compound of formula (IA) or (IB) according to claim 1 to a patient in need thereof. 
     
     
       22. A method according to claim 21 wherein the infection is caused by a Gram-positive bacteria. 
     
     
       23. A method according to claim 21 wherein the infection is caused by a Gram-negative bacteria. 
     
     
       24. A method according to claim 21 wherein the infection is caused by a mycoplasma. 
     
     
       25. The compound mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate. 
     
     
       26. A compound selected from
 mutilin 14-(quinuclidin-4-yl-sulfanyl)-acetate;   19,20-dihydromutilin 14-(quinuclidin-4-yl-sulfanyl)-acetate;   mutilin 14-(quinuclidin-3-yloxy)-acetate;   mutilin 14-(quinuclidin-3-ylsulfanyl)-acetate;   mutilin 14-[N-(2,2-dimethylazabicyclo[4.3.0]non-4-ylmethyl)]-aminoacetate;   mutilin 14-(quinuclidin-4-ylcarbonylamino)-acetate;   mutilin  14 -[( 3 R, 4 R)-acabicyclo[ 2 . 2 . 1 ]hept- 3 -ylcarbonylamino]-acetate;   mutilin 14-[(3R,4R)-azabicyclo[2.2.1]hept-3-ylcarbonylamino]-acetate;   mutilin 14-(quinuclid-4-ylmethylsulfanyl)-acetate;   19,20-dihydromutilin 14-(quinuclidin-4-ylsulfonyl) acetate;     19 , 20 -dihydromutilin  14 -(quinclidin- 4 -ylsulfoxy)-acetate;   19,20-dihydromutilin 14-(quinuclidin-4-ylsulfoxy)-acetate;   mutilin 14-{(3RS,4SR)-1-aza-bicyclo[2.2.1]hept-3-ylsulfanyl}-acetate;   mutilin 14-(quinuclidin-3-ylidene)-acetate;   mutilin 14-[quinuclidin-3-yl]-acetate;   mutilin 14-[quinuclidin-3-ylacetoxy]-acetate;   mutilin 14-(quinuclidin-3-ylmethylsulfanyl)-acetate;   1,2-didehydromutilin 14-(quinuclidin-4-ylsulfanyl)-acetate;   2α-hydroxymutilin 14-(quinuclidin-4-ylsulfanyl)-acetate;   mutilin 14-(quinuclidin-4-yl)-acetate;   mutilin 14-(quinuclidin-4-ylmethyl)-aminoacetate;   mutilin 14-[3-(quinuclidin-4-yl)-acrylate;]   mutilin 14-[3-(quinuclidin-4-yl)]-propionate;   mutilin 14-(quinuclidin-4-ylmethyloxy)-acetate;   mutilin 14-[(3R)-quinuclidin-3-ylamino]-acetate;   mutilin 14-(quinuclidin-4-yl-amino)-acetate;   mutilin 14-[4-(quinuclidin-4-yl)]-butyrate;   mutilin 14-(1-azabicyclo[3,3,0]oct-4-ylmethylsulfanyl)-acetate;   mutilin 14-(1-azabicyclo[3,3,0]oct-3-ylsulfanyl)-acetate;   mutilin 14-(endo 8-methyl-8-azabicyclo[3,2,1]oct-3-ylsulfanyl)-acetate;   mutilin 14-(1-azabicyclo[4,3,0]non-4-ylsulfanyl)-acetate;   19,20-dihydromutilin 14-(1-azabicyclo[4,3,0]non-4-ylsulfanyl)-acetate;   mutilin 14-{(3S,4R)-1-azabicyclo[2.2.1]hept-3-ylmethylsulfanyl}-acetate;   mutilin 14-(quinuclidin-2-ylmethylsulfanyl)-acetate;   mutilin 14-(1-azabicyclo[2.2.1]hept-4-ylmethylsulfanyl)-acetate;   mutilin 14-{(3R,4S)-1-azabicyclo[2.2.1]hept-3-ylmethylsulfanyl}-;   mutilin 14-(1-azabicyclo[3.2.1]oct-5-ylmethylsulfanyl)-acetate;   mutilin 14-(8-methyl-8-azabicyclo[3.2.1]oct-3-ylmethylsulfanyl)-acetate;   mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate;   mutilin 14-[(3-(quinuclidin-4-ylsulfanyl)]-propionate;   mutilin 14-[3-(quinuclidin-4-ylmethylsulfanyl)]-propionate;   19,20-dihydromutilin 14-(8-methyl-8-azabicyclo[3.2.1]oct-3-ylmethylsulfanyl)-acetate; and   mutilin 14-[4-(quinuclidin-4-ylsulfanyl)]-butyrate;   
       or a pharmaceutically acceptable salt thereof. 
     
     
       27. A compound according to claim 26 which is mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate, or a pharmaceutically acceptable salt thereof.