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Details for Patent: 6,281,226

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Details for Patent: 6,281,226

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): Berry; Valerie (Chester Springs, PA), Dabbs; Steven (Harlow, GB), Frydrych; Colin Henry (Sawbridgeworth, GB), Hunt; Eric (Great Dunmow, GB), Sanderson; Francis Dominic (Harlow, GB), Woodnutt; Gary (Chester Springs, PA)
Assignee: SmithKline Beecham p.l.c. (Brentford, GB)
Filing Date:Apr 27, 2000
Application Number:09/530,446
Claims:1. A compound of general formula (IA) or (IB): ##STR10##

in which:

each of n and m is independently 0, 1 or 2; and

X is selected from --O--, --S(O)--, --SO.sub.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.sup.1 is vinyl or ethyl;

R.sup.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;

R.sup.3 is H or OH; or

the moiety R.sup.2 (CH.sub.2).sub.m X(CH.sub.2).sub.n CH.sub.2 COO at position 14 of (IA) or (IB) is replaced by R.sup.a R.sup.b C=CHCOO in which one of R.sup.a and R.sup.b is hydrogen and the other is R.sup.2 or R.sup.a and R.sup.b together form R.sup.2 ; or

a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 in which R.sup.2 is substituted by alkyl, alkyloxy, alkenyl or alkenyloxy, which are optionally further substituted by one or more groups selected from aryl, heterocyclyl, (C.sub.1-6)alkoxy, (C.sub.1-6)alkylthio, aryl(C.sub.1-6)alkoxy, aryl(C.sub.1-6)alkylthio, amino, mono- or di-(C.sub.1-6)alkylamino, cycloalkyl, cycloalkenyl, carboxy and esters thereof, amides of carboxy, ureido, carbamimidoyl (amidino), guanidino, alkyl-sulfonyl, amino-sulfonyl (C.sub.1-6)acyloxy, (C.sub.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.sup.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-ylsulfanyl)-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-(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;

2.alpha.-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.sup.2A --(CH.sub.2).sub.m --X--(CH.sub.2).sub.n --CH.sub.2 CO.sub.2 H , where R.sup.2A is R.sup.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 drivative having (CH.sub.2).sub.n CH.sub.2 CO as an O-acyl group at position 14, where the acyl group is substituted with R.sup.L, which is a leaving group, OH or NH, coupling the 14-O-acyl-(epi)mutilin derivative with a compound R.sup.2A (CH.sub.2).sub.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.sup.L is a leaving group and is reacted with

(i) the alcohol R.sup.2 --(CH2).sub.m --OH;

(ii) the thiol R.sup.2 --(CH.sub.2).sub.m --SH;

(iii) the amine R.sup.2 --(CH.sub.2).sub.m --NH.sub.2 ;

(b) when X is CONH, R.sup.L is amino and is reacted with the acid R.sup.2A --(CH.sub.2).sub.m --CO.sub.2 H, or an acylating agent derived therefrom;

(c) when X is CO.O, R.sup.L is hydroxy and is reacted with an acylating agent derived from the acid R.sup.2A --(CH.sub.2).sub.m --CO.sub.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.
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