Carbamoyloxy derivatives of mutiline and their use as antibacterials

• US 6,020,368 A
• Filed: 12/04/1998
• Issued: 02/01/2000
• Est. Priority Date: 01/03/1996
• Status: Expired due to Fees

• Current Assignee: Andrew Kenneth Takle, Eric Hunt, Jeremy David Hinks
• Original Assignee: Andrew Kenneth Takle, Eric Hunt, Jeremy David Hinks
• Inventors: Takle, Andrew Kenneth, Hunt, Eric, Hinks, Jeremy David
• Primary Examiner(s): Geist, Gary
• Assistant Examiner(s): OH, TAYLOR V
• Application Number:
  US09/101,210
• Time in Patent Office: 424 Days
• Field of Search: 560/157, 560/162, 560/12, 560/13, 560/20, 560/29, 560/32, 560/115, 560/148, 560/160, 560/480, 558/14, 549/29, 548/146, 548/125, 546/341, 546/1, 544/242, 514/480
• US Class Current: 514/480
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2603/82 having three condensed rings with in total fourteen carbon atoms and having a having a [5.4.3.0(1,8)] ring structure, e.g. pleuromutiline
• CPC Class Codes: C07C 271/32 having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07C 271/36 with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 271/64 Y being a hydrogen or a carbon atom, e.g. benzoylcarbamates
• CPC Class Codes: C07C 271/66 Y being a hetero atom
• CPC Class Codes: C07C 281/02 Compounds containing any of the groups , e.g. carbazates
• CPC Class Codes: C07C 307/06 having nitrogen atoms of the sulfamide groups bound to acyclic carbon atoms
• CPC Class Codes: C07C 311/08 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/39 having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• CPC Class Codes: C07C 311/53 X and Y not being nitrogen atoms, e.g. N-sulfonylcarbamic acid
• CPC Class Codes: C07C 317/44 having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07C 323/60 with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• CPC Class Codes: C07C 331/14 having sulfur atoms of thiocyanate groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07D 203/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 203/20 by carbonic acid, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/08 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 211/62 : attached in position 4
• CPC Class Codes: C07D 213/40 : Acylated substituent nitrogen atom
• CPC Class Codes: C07D 213/70 : Sulfur atoms
• CPC Class Codes: C07D 213/75 : Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/80 : in position 3
• CPC Class Codes: C07D 213/81 : Amides; Imides
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 231/14 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/38 : One sulfur atom
• CPC Class Codes: C07D 241/24 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 249/04 : 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
• CPC Class Codes: C07D 249/10 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 261/18 : Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 271/113 : with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 277/36 : Sulfur atoms
• CPC Class Codes: C07D 277/80 : to a nitrogen atom
• CPC Class Codes: C07D 285/06 : 1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
• CPC Class Codes: C07D 285/125 : with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 295/088 : to an acyclic saturated chain
• CPC Class Codes: C07D 295/205 : Radicals derived from carbonic acid
• CPC Class Codes: C07D 295/215 : Radicals derived from nitrogen analogues of carbonic acid
• CPC Class Codes: C07D 307/10 : with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 307/66 : Nitrogen atoms
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 317/66 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/34 : Sulfur atoms
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 451/02 : containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• CPC Class Codes: C07D 453/02 : containing not further condensed quinuclidine ring systems
• CPC Class Codes: C07D 455/02 : containing not further condensed quinolizine ring systems
• CPC Class Codes: C07D 471/08 : Bridged systems
• CPC Class Codes: C07D 487/08 : Bridged systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems
• CPC Class Codes: C07H 15/24 : Condensed ring systems having three or more rings

Abstract

Derivatives of mutiline of formula (1A) and pharmaceutically acceptable salts and derivatives thereof, in which R¹ is ethyl or vinyl, Y is a carbamoyloxy group, in which the N-atom is unsubstituted, or mono- or di-substituted, are useful in the treatment of bacterial infections. ##STR1##

Claims

1. A compound of formula (1A) or a pharmaceutically acceptable salt or derivative thereof ##STR5## in which Y is a carbamoyloxy group, in which the N-atom is unsubstituted, or mono- or di-substituted.

4. A method for preparing a compound of claim 1 which comprises reacting a compound of formula (4) where X is hydrogen or a hydroxyl protecting group, or a compound of formula (5) with an appropriately substituted carbamate-forming reagent ##STR7##

7. A pharmaceutical composition comprising a compound according to claim 1, 2 or 3, together with a pharmaceutically acceptable carrier or excipient.

8. A method of treating microbial infections in humans comprising administering an antimicrobially effective amount of a compound according to claim 1, 2 or 3, or a pharmaceutical composition comprising a compound according to claim 1, 2 or 3, together with a pharmaceutically acceptable carrier or excipient, to a patient in need thereof.

9. A method comprising the step of using a compound according to claim 1, 2 or 3, in the preparation of a medicament composition for use in the treatment of microbial infections.

10. A method of treating microbial infections in domesticated mammals comprising administering an antimicrobially effective amount of a compound according to claim 1, 2 or 3, or a pharmaceutical composition comprising a compound according to claim 1, 2 or 3, together with a pharmaceutically acceptable carrier or excipient, to a patient in need thereof.

2. A compound of general formula (3), or a pharmaceutically acceptable salt or derivative thereof ##STR6## in which:

R¹ is vinyl or ethyl;

R² and R³ are the same or different groups selected from hydrogen;

a straight or branch chained, saturated or unsaturated, optionally substituted, C₁ to C₆ hydrocarbon group;

a saturated or unsaturated, optionally substituted, C₃ to C₈ cyclic hydrocarbon group;

an optionally substituted heterocyclic group;

an optionally substituted aryl group;

or together form an optionally substituted cyclic group of 3 to 8 ring atoms, optionally containing one additional heteroatom selected from N, O and S, and optionally fused to a hydrocarbon ring, a heterocyclic group or an aromatic group;

or

R² is one of the above monovalent groups and R³ is a group selected from SO₂ R⁴, COR⁵, OR⁵ and NR⁶ R⁷ where

R⁴ is selected from a straight or branch chained, saturated or unsaturated, optionally substituted, C₁ to C₆ hydrocarbon group;

a saturated or unsaturated, optionally substituted, C₃ to C₈ cyclic hydrocarbon group;

an optionally substituted heterocyclic group;

an optionally substituted aryl group;

an optionally substituted C₁ to C₆ alkylamino group; and

an optionally substituted arylamino group;

R⁵ is selected from hydrogen;

a straight or branch chained, saturated or unsaturated, optionally substituted, C₁ to C₆ hydrocarbon group;

a saturated or unsaturated, optionally substituted, C₃ to C₈ cyclic hydrocarbon group;

an optionally substituted heterocyclic group; and

an optionally substituted aryl group;

R⁶ and R⁷ are the same or different groups selected from hydrogen;

a straight or branch chained, saturated or unsaturated, optionally substituted, C₁ to C₆ hydrocarbon group;

a saturated or unsaturated, optionally substituted, C₃ to C₈ cyclic hydrocarbon group;

an optionally substituted heterocyclic group, and an optionally substituted aryl group;

or together form an optionally substituted cyclic group of 3 to 8 ring atoms, optionally containing one additional heteroatom selected from N, O and S, and optionally fused to a hydrocarbon ring, a heterocyclic group or an aromatic group.

3. A compound according to claim 2 being mutilin 14-(N-phenylcarbamate).

5. A process for the preparation of a compound according to claim 2, which comprises reacting a compound of formula (4) in which X is hydrogen or a hydroxyl protecting group, with (a) a compound R² NCO,

(b) a compound R² R³ NCOCl, or

(c) phosgene or a chloroformate or a carbonate followed by a compound R² R³ NH,

where R² and R³ are the same or different groups selected from hydrogen;

a straight or branch chained, saturated or unsaturated, optionally substituted, C₁ to C₆ hydrocarbon group;

a saturated or unsaturated, optionally substituted, C₃ to C₈ cyclic hydrocarbon group;

an optionally substituted heterocyclic group;

an optionally substituted aryl group;

or together form an optionally substituted cyclic group of 3 to 8 ring atoms, optionally containing one additional heteroatom selected from N, O and S, and optionally fused to a hydrocarbon ring. a heterocyclic group or an aromatic group;

or

R² is one of the above monovalent groups and R³ is a group selected from SO₂ R⁴, COR⁵, OR⁵ and NR⁶ R⁷ where

R⁴ is selected from a straight or branch chained, saturated or unsaturated, optionally substituted, C₁ to C₆ hydrocarbon group;

a saturated or unsaturated, optionally substituted, C₃ to C₈ cyclic hydrocarbon group;

an optionally substituted heterocyclic group;

an optionally substituted aryl group;

an optionally substituted C₁ to C₆ alkylamino group; and

an optionally substituted arylamino group;

R⁵ is selected from hydrogen;

a straight or branch chained, saturated or unsaturated, optionally substituted, C₁ to C₆ hydrocarbon group;

a saturated or unsaturated, optionally substituted, C₃ to C₈ cyclic hydrocarbon group;

an optionally substituted heterocyclic group; and

an optionally substituted aryl group;

R⁶ and R⁷ are the same or different groups selected from hydrogen;

a straight or branch chained, saturated or unsaturated, optionally substituted, C₁ to C₆ hydrocarbon group;

a saturated or unsaturated, optionally substituted, C₃ to C₈ cyclic hydrocarbon group;

an optionally substituted heterocyclic group, and an optionally substituted aryl group;

or together form an optionally substituted cyclic group of 3 to 8 ring atoms, optionally containing one additional heteroatom selected from N, O and S, and optionally fused to a hydrocarbon ring, a heterocyclic group or an aromatic group;

and are protected where appropriate, and where necessary deprotecting the group X to generate a hydroxyl group at position 11, deprotecting a protected group R² or R³ , converting one group R² or R³ to another group R² or R³, or hydrogenating the vinyl group at position 12 to form an ethyl group.

6. A process for the preparation of a compound according to claim 2, which comprises reacting a compound of formula (5) with

(a) a compound R² NCO,

(b) a compound R² R³ NCOCl, or

(c) phosgene or a chloroformate or a carbonate followed by a compound R² R³ NH,

where R² and R³ are the same or different groups selected from hydrogen;

a straight or branch chained, saturated or unsaturated, optionally substituted, C₁ to C₆ hydrocarbon group;

a saturated or unsaturated, optionally substituted, C₃ to C₈ cyclic hydrocarbon group;

an optionally substituted heterocyclic group;

an optionally substituted aryl group;

or together form an optionally substituted cyclic group of 3 to 8 ring atoms, optionally containing one additional heteroatom selected from N, O and S, and optionally fused to a hydrocarbon ring, a heterocyclic group or an aromatic group;

or

R² is one of the above monovalent groups and R³ is a group selected from SO₂ R⁴, COR⁵, OR⁵ and NR⁶ R⁷ where

R⁴ is selected from a straight or branch chained, saturated or unsaturated, optionally substituted, C₁ to C₆ hydrocarbon group;

a saturated or unsaturated, optionally substituted, C₃ to C₈ cyclic hydrocarbon group;

an optionally substituted heterocyclic group;

an optionally substituted aryl group;

an optionally substituted C₁ to C₆ alkylamino group; and

an optionally substituted arylamino

R⁵ is selected from hydrogen;

a straight or branch chained, saturated or unsaturated, optionally substituted, C₁ to C₆ hydrocarbon group;

a saturated or unsaturated, optionally substituted, C₃ to C₈ cyclic hydrocarbon group;

an optionally substituted heterocyclic group; and

an optionally substituted aryl group;

R⁶ and R⁷ are the same or different groups selected from hydrogen;

a straight or branch chained, saturated or unsaturated, optionally substituted, C₁ to C₆ hydrocarbon group;

a saturated or unsaturated, optionally substituted, C₃ to C₈ cyclic hydrocarbon group;

an optionally substituted heterocyclic group, and an optionally substituted aryl group;

or together form an optionally substituted cyclic group of 3 to 8 ring atoms, optionally containing one additional heteroatom selected from N, O and S, and optionally fused to a hydrocarbon ring, a heterocyclic group or an aromatic group;

and are protected where appropriate, treating the product with an acid, deprotecting a protected group R² or R³, converting one group R² or R³ to another group R² or R³, or hydrogenating the vinyl group at position 12 to form an ethyl group.