Claims for Patent: RE39128

Summary for Patent: RE39128

Title:	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.
Inventor(s):	Valerie Joan Berry, Steven Dabbs, Colin Henry Frydrych, Eric Hunt, Francis Dominic Sanderson, Gary Woodnutt
Assignee:	Almirall SA, SmithKline Beecham Ltd, GlaxoSmithKline LLC
Application Number:	US10/631,707
Patent Claims:	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)—, —SO2—, —CO.O—, —NH—, —CONH—, —NHCONH— and a bond; or n is 1 or 2 and m is 2 and X is —S—; and R1 is vinyl or ethyl; R2 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 R2 is attached through a ring carbon atom; R3 is H or OH; or the moiety R2(CH2)mX(CH2)nCH2COO at position 14 of (IA) or (IB) is replaced by RaRbC=CHCOO in which one of Ra and Rb is hydrogen and the other is R2 or Ra and Rb together form R2; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 in which R2 is substituted by alkyl, alkyloxy, alkenyl or alkenyloxy, which are optionally further substituted by one or more groups selected from aryl, heterocyclyl, (C1-6)alkoxy, (C1-6)alkylthio, aryl(C1-6)alkoxy, aryl(C1-6)alkylthio, amino, mono- or di-(C1-6)alkylamino, cycloalkyl, cycloalkenyl, carboxy and esters thereof, amides of carboxy, ureido, carbamimidoyl (amidino), guanidino, alkyl-sulfonyl, aminosulfonyl (C1-6)acyloxy, (C1-6)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 R2 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 R2A—(CH2)m—X—(CH2)n—CH2CO2H, where R2A is R2 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 (CH2)nCH2CO as an O-acyl group at position 14, where the acyl group is substituted with RL, which is a leaving group, OH or NH, coupling the 14-O-acyl-(epi) mutilin derivative with a compound R2A(CH2)mXH 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, RL is a leaving group and is reacted with (i) the alcohol R2—(CH2)m—OH; (ii) the thiol R2—(CH2)m—SH; (iii) the amine R2—(CH2)m—NH2; (b) when X is CONH, RL is amino and is reacted with the acid R2A—(CH2)m—CO2H, or an acylating agent derived therefrom; (c) when X is CO.O, RL is hydroxy and is reacted with an acylating agent derived from the acid R2A—(CH2)m—CO2H. 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 -[( 3R,4R)-acabicyclo[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; 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 -[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.