Pleuromutilin derivatives, process for their preparation and uses thereof

• US 20070167495A1
• Filed: 04/06/2004
• Published: 07/19/2007
• Est. Priority Date: 04/08/2003
• Status: Abandoned Application

• Current Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxosmithkline Services Unlimited (GlaxoSmithKline PLC)
• Inventors: Hunt, Eric, Brown, Pamela
• Application Number:
  US10/552,238
• Publication Number:
  US 20070167495A1
• Time in Patent Office: Days
• US Class Current: 514/345
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: C07C 2603/99 containing eight-membered rings
• CPC Class Codes: C07C 323/62 having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07D 213/80 in position 3

Abstract

Pleuromutilin compounds of the formula: are of use in antibacterial therapy.

Claims

1. A compound of formula (IA) or (IB):

wherein;

R¹ is phenyl or a five- or six-membered heteroaryl ring, wherein R¹ is substituted by a carboxylic acid group that is attached at a position which is not adjacent to the point of attachment of the sulphur, and wherein R¹ 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, amino, mono- and di-N-(C_1-6)alkylamino, acylamino, arylcarbonylamino, acyloxy, carbamoyl, mono- and 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;

R² is vinyl or ethyl; and

R³ is hydrogen, hydroxy or fluorine and R⁴ is hydrogen,

or R³ is hydrogen and R⁴ is fluorine;

or a pharmaceutically acceptable derivative thereof

2. A compound according to claim 1 wherein R¹ is a five- or six-membered aryl ring or a five- or six-membered heteroaryl ring containing up to three heteroatoms independently selected from nitrogen, sulphur or oxygen, substituted by a carboxylic acid group.

3. A compound according to claim 1 or 2 wherein R¹ is a six-membered aryl ring or a six-membered heteroaryl ring containing one or two nitrogen atoms, substituted by a carboxylic acid group.

4. A compound according to claim 1 wherein R¹ is phenyl or pyridyl, substituted by a carboxylic acid group.

5. A compound according to claim 1 selected from:

(4-carboxylato-phenylsulfanyl)-acetic acid mutilin 14-ester;

(4-carboxylato-phenylsulfanyl)-acetic acid 19,20-dihydro-mutilin 14-ester;

(3-carboxylato-phenylsulfanyl)-acetic acid mutilin 14-ester; and

(5-carboxylato-pyridin-2-yl-sulfanyl)-acetic acid mutilin 14-ester;

or a pharmaceutically acceptable derivative thereof.

6. A pharmaceutical composition comprising a compound as claimed in claim 1, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable excipient, diluent or carrier.

7. A compound as claimed in claim 1, or a pharmaceutically acceptable derivative thereof, for use in therapy.

10. A method of treating microbial infections in animals, which comprises administering a compound according to claim 1, or a pharmaceutically acceptable derivative thereof, or a composition according to the invention, to a patient in need thereof.

11. A method of treatment of skin and soft tissue infections in humans, which comprises topically administering a compound according to claim 1, or a pharmaceutically acceptable derivative thereof, or a composition according to the invention, to a patient in need thereof.

12. A process for preparing a compound of formula (IA) or (IB) as claimed in claim 1 which process comprises:

(a) reacting a compound of formula (IIA) or (IIB);

in which Y is hydrogen or a hydroxy protecting group, and R^2A, R^3A and R^4A are R², R³ and R⁴ as defined in claim 1 or groups convertible R², R³ and R⁴, with an active derivative of a carboxylic acid of formula (III);

R^1ASCH₂CO₂H 

 

(III)

where R^1A is R¹ as defined in claim 1 or a group convertible to R¹, under ester forming conditions and, where required or desired,

converting Y to hydrogen,

converting an R^2A, R^3A and R^4A group to a R², R³ and R⁴ group, and/or

converting one R², R³ and R⁴ group to another R², R³ and R⁴ group;

(b) for a compound of formula (IA) in which R³ and R⁴ are both hydrogen, reacting an epi-mutilin compound of formula (IIC);

in which R^2A is R² as defined in claim 1, or a group convertible to R²;

with a compound of formula (III) as hereinbefore defined;

to give a compound of formula (IV);

then treating the product with an acid and, where required or desired, converting an R^1A group to an R¹ group and an R^2A group to an R² group;

(c) reacting a compound of formula VA or VB

wherein X is a leaving group, Y is hydrogen or a hydroxy protecting group, and R^2A, R^3A and R^4A are R², R³ and R⁴ as defined in claim 1 or groups convertible to R², R³ and R⁴,

with a compound of formula (VI);

R^1ASH 

 

(VI)

where R^1A is R¹ as defined in claim 1 or a group convertible to R¹ and, where required or desired,

converting Y to hydrogen,

converting an R^1A, R^2A, R^3A or R^4A group to an R¹, R², R³ or R⁴ group, and/or

converting one R¹, R², R³ or R⁴ group to another R¹, R², R³ or R⁴ group;

or

(d) reacting a compound of formula (VC);

where X and R^2A are as defined for formulae VA and VB,

with the compound (VI),

then treating the product with an acid and, where required or desired,

converting an R^1A or R^2A group to a R¹ or R² group, and/or

converting one R¹ or R² group to another R¹ or R² group.

8. (canceled)

9. (canceled)