Pleuromutilin derivatives as antimicrobials
View Patent ↗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.
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.