Granted Patent B2

US 7,816,389 · App. 11/814,673 · Granted Oct 19, 2010

Assignee: Nabriva Therapeutics Forschungs GmbH

Abstract

Claims (64)

1. A compound selected from the group consisting of

14-O—[(((C 1-6 )Alkoxy-(C 1-6 )alkyl)-phenylsulfanyl)-acetyl]-mutilins,

14-O—[(((C 1-6 )Mono- or dialkylamino-(C 1-6 )alkyl)-phenylsulfanyl)-acetyl]-mutilins,

14-O—[(((C 1-6 )Acylamino-(C 1-6 )alkyl)-phenylsulfanyl)-acetyl]-mutilins,

14-O-[((Hydroxy-(C 1-6 )-alkyl)-phenylsulfanyl)-acetyl]-mutilins,

14-O-[(Formyl-(C 0-5 )-alkyl)-phenylsulfanyl)-acetyl]-mutilins,

14-O-[((Guanidino-imino-(C 1-6 )alkyl)-phenylsulfanyl)-acetyl]-mutilins,

14-O-[((Ureido-imino-(C 1-6 )alkyl)-phenylsulfanyl)-acetyl]-mutilins,

14-O-[((Thioureido-imino-(C 1-6 )alkyl)-phenylsulfanyl)-acetyl]-mutilins,

14-O-[((Isothioureido-imino-(C 1-6 )alkyl)-phenylsulfanyl)-acetyl]-mutilins,

14-O-[(Cyano-(C 0-5 )-alkyl)-phenylsulfanyl)-acetyl]-mutilins,

14-O-[(Azido-(C 0-5 )-alkyl)-phenylsulfanyl)-acetyl]-mutilins,

14-O—[(((C 1-6 )Acyloxy-(C 1-6 )alkyl)-phenylsulfanyl)-acetyl]-mutilins, and

14-O-[((Benzoyloxy-(C 1-6 )alkyl)-phenylsulfanyl)-acetyl]-mutilins,

wherein the phenyl-ring is optionally further substituted by up to four groups independently selected from halogen, (C 1-6 )alkyl, aryl, aryl(C 1-6 )-alkyl, (C 1-6 )alkoxy, (C 1-6 )alkoxy(C 1-6 )alkyl, halo(C 1-6 )alkyl, aryl(C 1-6 )alkoxy, hydroxy, nitro, cyano, azido, acyloxy, carbamoyl, mono- or di-N—(C 1-6 )alkylcarbamoyl, (C 1-6 )-alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, (C 1-6 )alkylguanidino, amidino, (C 1-6 ) alkylamidino, sulphonylamino, aminosulphonyl, (C 1-6 )alkylthio, (C 1-6 )-alkylsulphinyl, (C 1-6 ) alkylsulphonyl, heterocyclyl, heteroaryl, heterocyclyl(C 1-6 )alkyl and heteroaryl(C 1-6 )alkyl, or two adjacent ring carbon atoms may be linked by a (C 3-5 ) alkylene chain, to form a carbocyclic ring.

2. A compound according to claim 1 which is selected from the group consisting of

14-O—[(((C 1-6 )Alkoxy-(C 1-6 )alkyl)-phenylsulfanyl)-acetyl]-mutilins,

14-O—[(((C 1-6 )Mono- or dialkylamino-(C 1-6 )alkyl)-phenylsulfanyl)-acetyl]-mutilins,

14-O-[((Hydroxy-(C 1-6 )-alkyl)-phenylsulfanyl)-acetyl]-mutilins,

14-O-[((Formyl-(C 0-5 )-alkyl)-phenylsulfanyl)-acetyl]-mutilins, and

14-O-[((Guanidino-imino-(C 1-6 )alkyl)-phenylsulfanyl)-acetyl]-mutilins.

3. A compound of formula (I)

wherein

n is 1 to 6;

X is oxygen or NR 2 wherein R 2 is hydrogen or linear or branched (C 1-6 )-alkyl, or hydroxy-(C 1-6 )alkyl or (C 1-6 )alkoxy-(C 1-6 )alkyl,

R 1 is hydrogen, linear or branched (C 1-6 )-alkyl, mono- or dihalogenated (C 1-6 ) -alkyl, amino(C 1-6 )-alkyl, hydroxy(C 1-6 )-alkyl, phenyl(C 1-6 )-alkyl, (C 1-6 )-alkylen, furanyl(C 1-6 )-alkyl, (C 3-4 )-cycloalkyl, and the corresponding ammonium salts, e.g. chlorides, or

R 1 and R 2 together with the nitrogen atom to which they are attached form a 5 to 7 membered heterocycle containing at least one nitrogen atom, or

XR 1 is piperazinyl or morpholinyl.

4. A compound of formula (II)

wherein

n is 0 to 5,

Y is oxygen or NR 3 ,

R 3 is

X is oxygen, sulfur, NH or NR 7 ,

or

together with a corresponding anion, e.g. chloride, R 4 , R 5 , R 6 , R 7 are hydrogen, linear or branched C 1-6 alkyl or C 3-8 cycloalkyl,

R 8 is C 1-4 alkyl.

5. A compound according to claim 4 , wherein

Y is NR 3 , X is NR 7 , R 3 is

and at least one of:

R 4 and R 7 together with the nitrogen atoms to which they are attached form a 5 to 7 membered heterocyclic ring containing at least 2 nitrogen atoms, whereas R 5 and R 6 are defined as in claim 4 ,

R 5 and R 6 together with the nitrogen atoms to which they are attached form a 5 to 7 membered heterocyclic ring containing at least 2 nitrogen atoms, whereas R 4 and R 7 are defined as in claim 4 , and

R 4 and R 5 together with the nitrogen atoms to which they are attached form a 5 to 7 membered heterocyclic ring containing one or more nitrogen atoms, whereas R 6 and R 7 are defined as in claim 4 .

6. A compound according to claim 5 , wherein

Y is NR 3 , X is NR 7 , R 3 is

R 9 is hydrogen, linear or branched C 1-6 alkyl or acyl, e.g. C 1-6 acyl.

7. A compound according to claim 3 , wherein said (CH 2 ) n -group is in meta position in relation to the sulphur bound to the phenyl-ring.

8. A compound according to claim 3 , wherein said (CH 2 ) n -group is in ortho position in relation to the sulphur bound to the phenyl-ring, with the proviso that the phenyl-ring is further substituted by up to four groups independently selected from halogen, (C 1-6 )alkyl, aryl, aryl(C 1-6 )-alkyl, (C 1-6 )alkoxy, (C 1-6 )alkoxy(C 1-6 )alkyl, halo(C 1-6 )alkyl, aryl (C 1-6 )alkoxy, hydroxy, nitro, cyano, azido, acyloxy, carbamoyl, mono- or di-N—(C 1-6 )alkylcarbamoyl, (C 1-6 )-alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, (C 1-6 )alkylguanidino, amidino, (C 1-6 ) alkylamidino, sulphonylamino, aminosulphonyl, (C 1-6 ) alkylthio, (C 1-6 )-alkylsulphinyl, (C 1-6 ) alkylsulphonyl, heterocyclyl, heteroaryl, heterocyclyl(C 1-6 )alkyl and heteroaryl(C 1-6 )alkyl, or two adjacent ring carbon atoms may be linked by a (C 3-5 ) alkylene chain, to form a carbocyclic ring.

9. A compound selected from the group consisting of

14-O-[(3-Hydroxymethyl-phenylsulfanyl)-acetyl]-mutilin,

14-O-{[3-(Aminoimino-methyl)-hydrazonomethyl-phenylsulfanyl]-acetyl}-mutilin,

14-O-[{3-[((1-Piperazinoiminomethyl)-methylhydrazono)-methyl]-phenylsulfanyl}-acetyl]-mutilin,

14-O-[{3-[(3-Ethyl-(2-ethylimino)-imidazolidin-1-ylimino)-methyl]-phenylsulfanyl}-acetyl]-mutilin,

14-O-[{3-[(1-Piperazinoiminomethyl)-hydrazonomethyl]-phenylsulfanyl}-acetyl]-mutilin,

14-O-[{3-[(2-Morpholin-4-yl-ethoxyimino)-methyl]-phenylsulfanyl}-acetyl]-mutilin,

14-O-[3-{[(2-Pyrrolidin-1-yl-ethoxyimino)-methyl]-phenylsulfanyl}-acetyl]-mutilin,

14-O-[(3-Aminomethyl-phenylsulfanyl)-acetyl]-mutilin,

14-O-[(3-Allylaminomethyl-phenylsulfanyl)-acetyl]-mutilin,

14-O-[3-{[(Furan-2-ylmethyl)-amino]-methyl}-phanylsulfanyl-acetyl]-mutilin and

14-O-[(3-Cyclopropylaminomethyl-phenylsulfanyl)-acetyl]-mutilin.

10. A compound of claim 1 , wherein the compound is in the form of a salt.

11. A compound of claim 1 , wherein the compound is configured for pharmaceutical administration.

12. A method of treatment of acne mediated by microbes which comprises administering to a subject in need of such treatment an effective amount of a compound of claim 1 .

13. A pharmaceutical composition comprising a compound of claim 1 , in association with at least one pharmaceutical excipient.

Assignments (9)

Priority Claims (1)

Continuity (1)