JP2002522409A - 2-fluoromutilin derivative - Google Patents

Abstract

  (57) [Summary] The present invention provides a mutilin having a 2-fluoro substituent or a 14-acyloxy derivative of 19,20-dihydromutilin, represented by structural formulas (a) and (b),¹Is vinyl or ethyl;^aProvided is a compound wherein COO- is an acyloxy group. The acyloxy group is HOCH₂CO₂-, RX-CH ₂-CO₂-, R²− (CH₂)_m-X- (CH₂)_n-CH₂CO₂-Or carbamoyl. The compounds are useful for treating microbial infections in animals, especially humans and domestic mammals. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to novel compounds, their preparation, pharmaceutical compositions containing them and their use in medicine, especially in antimicrobial therapy.

BACKGROUND OF THE INVENTION Pleuromutilin, a compound of formula (A), is a natural antibiotic with anti-mycoplasma activity and mild antibacterial activity. Replacing the glycolic acid ester moiety at the 14-position with R—X—CH ₂ CO ₂ — (where R is an aliphatic or aromatic group and X is O, S or NR ′) improves its antibacterial activity. (H. Egger and H. Reinshagen, J. Antibiotics, 1976, 29, 922
3). Tiamulin, a compound of formula (B) used as a veterinary antibiotic
ulin) is a derivative of this type (G. Hogenauer, Antibiotics, Vol. V, part
1, ed. FE Hahn, Springer-Verlag, 1979, p.344).

[0003]

Embedded image

[0004] In this specification, a non-conventional numbering system commonly used in the literature (G. Hogenauer, supra) is used. WO 97/25309 (SmithKline Beecham) describes a further modification of the acyloxy group and describes the 14- of mutilin or 19,20-dihydromutilin.
O-carbamoyl derivatives are disclosed, wherein the N atom of the carbamoyl group is unsubstituted, mono- or di-substituted. WO98 / 05659 (SmithKline Beecham) is a mutilin or 1
Disclosed are 14-O-carbamoyl derivatives of 9,20-dihydromutilin,
The N atom of the carbamoyl group is acylated with a group containing an azabicyclo group.

[0005] WO 98/05659 (SmithKline Beecham) discloses mutilin or 1-acylation of the N-atom of a carbamoyl group with one group, including an azabicyclic group.
Disclosed are 14-O-carbamoyl derivatives of 9,20-dihydromutilin. The present inventors have now surprisingly found that a novel pleuromutilin analog having a fluorine substituent on its nucleus has good antibacterial activity combined with improved metabolic stability. . Thus, the present invention, in its broadest aspect, provides a mutilin having a 2-fluoro substituent or a 14-acyloxy derivative of 19,20-dihydromutilin.

The 2-fluoro compound of the present invention is a compound having a (2S) configuration, a (2R) configuration, or a mixture thereof. (2S) arrangement is preferred. The structures of the two isomers are as follows:

Embedded image (2S) -2-fluoro (2R) -2-fluoro wherein R ¹ is vinyl or ethyl, and R ^a COO- is an acyloxy group.

[0007] Acyloxy groups are known as HOCH, as in pleuromutilin.₂CO₂-
Or R-X-CH₂CO₂-. Where iger
(Rgger) and Reinshagen compounds, X is
O, S or NR ', wherein R and R' are each hydrogen or aliphatic or
It is an aromatic group. The acyloxy group is represented by R²− (CH₂)_m-X- (CH₂)_n-CH₂CO₂−
(Where n and m are independently 0 or 2); and X is -O-, -S-, -S (O)-, -SO₂-, -NH-, CONH-, -CH ₂ And R is selected from²Has one or two basic nitrogen atoms and is linked through a ring carbon atom.
It is an aromatic monocyclic or bicyclic group.

R ² represents up to 3 when the monocyclic group can contain 4 to 8 ring atoms and when the bicyclic group can contain 5 to 10 ring atoms in each ring. May be substituted at the carbon atom. Suitable substituents include alkyl, alkyloxy, alkenyl and alkenyloxy, each of which may be carried on either bridged or unbridged carbon atoms. In addition, it is clear that each nitrogen atom may be replaced with oxygen to form an N-oxide, or may be replaced with mono or dialkyl, in which case a quaternary cation may be formed. Will. The counter ion is a halide such as chloride or bromide,
Preferably it is chloride. In addition, the aza ring system may contain one or more bonds.

Preferably, the acyloxy group is a carbamoyl, especially R³R⁴NCO₂-
Where: R³And R⁴Are the same or different groups and are selected from the following groups: hydrogen; linear or branched, saturated or unsaturated, optionally substituted C₁-C₆Hydrocarbon
A saturated or unsaturated C which may be substituted₃-C₈A cyclic hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted aryl group; or
It may contain a terrorist atom, and is condensed with a hydrocarbon ring, a heterocyclic ring or an aromatic group.
To form an optionally substituted cyclic group of 3 to 8 ring atoms
Or R³Is a monovalent group described above,⁴Is SO₂R⁵, COR⁶, OR⁶and
NR⁷R⁸Where R is⁵Is a linear or branched, saturated or unsaturated, optionally substituted C₁-C ₆ Hydrocarbon group; saturated or unsaturated, optionally substituted C₃-C₈Cyclic hydrocarbon
An aryl group; an optionally substituted heterocyclic group; an optionally substituted aryl group;
C that may be₁-C₆An alkylamino group; and an optionally substituted
Selected from reelamino groups; R⁶Is hydrogen; linear or branched, saturated or unsaturated, optionally substituted C ₁ -C₆Hydrocarbon group; saturated or unsaturated, optionally substituted C₃-C₈Ring
A hydrocarbon group; an optionally substituted heterocyclic group; and an optionally substituted ant
R group; R⁷And R⁸Are the same or different and are hydrogen; linear or branched saturated or
Unsaturated, optionally substituted C₁-C₆Hydrocarbon group; saturated or unsaturated substitution
C that may be₃-C₈A cyclic hydrocarbon group; an optionally substituted heterocyclic group;
And an optionally substituted aryl group; or
, N, O and S.
And may be fused to a hydrocarbon ring, a heterocyclic ring or an aromatic group.
A group represented by to form a cyclic group which may be substituted with a ring atom.

Particularly suitable groups for R ³ and R ⁴ are hydrogen, hydroxy, methoxy, phenyl, methyl, isopropyl, phenylsulfonyl, methoxyphenyl, nitrophenyl, trichloroacetyl, benzyl, hydroxyiminobenzyl, benzylaminosulfonyl, dihydro Pyridinyl, hydroxyethyl, 2-phenylethyl, 1- (R) -phenyl-2-hydroxyethyl, 2- (methoxycarbonyl)
Benzoyl, furoyl optionally substituted by ethyl, 2-carboxyethyl, dimethylamino, dimethylaminopropyl, methanesulfonylamino, methanesulfonyl, benzylamino, trifluoromethyl, carboxy, methoxy, hydroxy, acetoxy, amino or nitro; Nicotinoyl, isonicotinoyl,
Acetyl, phenylacetyl and phenoxy. Particularly suitable groups for the cyclic group R ³ R ⁴ N are indolino and morpholino.

[0011] Advantageously, the N-atom of the carbamoyl group is represented by one group, including an azabicyclic group.
It is acylated. More particularly, the acyloxy group advantageously comprises R⁹CON
HCO₂-And R⁹Is the group R¹⁰, R¹⁰CH₂-Or R¹¹R¹²C =
CH-, where R¹⁰Is an azabicyclic ring system, or R¹¹And R ¹² Together with the carbon atom to which they are attached form an azabicyclic ring system. Azabicyclic ring systems are linked via bridged or unbridged ring carbon atoms and are
Bridged or fused containing one bridged nitrogen atom as one heterocyclic atom
It may be a non-aromatic ring system. The ring system has 5 to 10 ring atoms in each ring
And the carbon atom may be substituted with up to three substituents. Suitable place
Substituents include alkyl, alkyloxy, alkenyl and alkenyloxy
Each of which is held at either a bridged or unbridged carbon atom
Is also good. In addition, the bridged nitrogen atom is replaced by oxygen to form an N-oxide
Or may be substituted with alkyl to form a quaternary cation. Vs. A
On is a halide such as chloride or bromide, preferably chloride.
You.

The azabicyclic ring system is, for example, of the formula (I):

Embedded image Wherein R ⁰ is one or more of the optional substituents described above, and a, b, and c are each 0 to 0, such that any one ring has from 5 to 10 ring atoms. 4]. In addition, azabicyclic ring systems may contain one or more double bonds. Individual azabicyclic groups are azabicyclo [2.2.2] octyl, azabicyclo [2.
2.1] Heptyl, azabicyclo [3.2.1] octyl, azabicyclo [4.4.0] decyl, quinuclidinyl, azabicyclo [3.2.1] octenyl and azabicyclo
[3.3.1] non-5-yl.

Suitable C ₁ -C ₆ hydrocarbon groups include straight and branched chains containing 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl and isopropyl; being methyl Is preferred. Suitable C ₃ C ₈ to cyclic hydrocarbon groups include cyclopropyl, cycloalkyl such as cyclopentyl and cyclohexyl. As used herein, the term “heteroaryl” refers to a group in which each ring has up to four,
Encompasses aromatic monocyclic and fused rings containing heteroatoms selected from oxygen, nitrogen and sulfur, wherein the ring is unsubstituted or substituted, for example, with up to three substituents. Is also good. Each heteroaryl ring suitably has 6 or 6 ring atoms. The fused heteroaryl ring may include a carbocyclic ring and there may be only one heteroaryl ring. Substituents for the heteroaryl or heterocyclyl group, preferably halogen, _{(C 1-6)} alkyl, aryl _{(C 1-4)} alkyl, _{(C 1-6)} alkoxy, _{(C 1-6)} alkoxy _{(C 1
-6)} alkyl, halo _{(C 1-6)} alkyl, hydroxy, amino, mono- - and _{di-N-(C 1-6)} alkylamino, acylamino, carboxy salts, carboxy esters, carbamoyl, mono- - and di -N -(C _1-6 ) alkylcarbonyl, aryloxycarbonyl, (C _1-6 ) alkoxycarbonyl (C _1-6 ) alkyl, aryl, oxy, ureido, amidino, guanidino, sulfonylamino, aminosulfonyl, (C _{1 -6)} alkylamino, are selected from _{(C 1-6)} alkylsulfinyl, _{(C 1-6)} alkylsulfonyl, heterocyclyl and heterocyclyl _{(C 1-4)} alkyl.

The alkyl and alkenyl groups referred to herein have up to 6 carbon atoms.
Straight and branched chains containing aryl (C_1-6) Alkoxy, aryl
(C_1-6) Alkylthio, cycloalkyl, cycloalkenyl, carbonyl
And salts and esters thereof, halogen, hydroxy, (C_1-6) Alkoxy, a
Reeloxy, (C_1-6) Alkoxycarbonyl, carbamoyl, mono- or
Di- (C_1-6) Alkylcarbamoyl, sulfamoyl, mono- and di- (C
_1-6) Alkylsulfamoyl, amino, mono- and di- (C_1-6) Archi
Luamino, (C_1-6) Acylamino, ureido, (C_1-6) Alkoxycarboni
Ruamino, aryl, heterocyclyl, oxo, hydroxyimino, acyl,
(C_1-6) Alkylthio, arylthio, (C_1-6) Alkanesulfinyl, a
Reel sulfinyl, (C_1-6) Alkanesulfonyl, arylsulfonyl, a
Includes midino, amide oxime and guanidino. The cycloalkyl and cycloalkenyl groups referred to herein are from 3 to
It contains 8 carbon atoms and is as defined above for alkyl and alkenyl groups.
It may be substituted.

As used herein, the term “aryl” suitably refers to single and fused rings containing from 4 to 7, preferably 5 or 6, ring atoms in each ring. And each ring may be unsubstituted or substituted, for example, with up to three substituents. The fused ring system may contain aliphatic rings, and
It is sufficient if there are two aromatic rings. Suitable aryl groups include phenyl and naphthyl, for example, 1-naphthyl or 2-naphthyl. Suitably, any aryl group, including phenyl and naphthyl, may be substituted with up to 5, preferably up to 3 substituents. Suitable substituents are 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, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- - and _{di-N-(C 1-6)} alkylcarbamoyl, _{(C 1-6)} alkoxy carbonyl, aryloxycarbonyl, ureido, guanidino, sulfonylamino, aminosulfonyl, _{(C 1-6)} alkylthio, _{(C 1-6)} alkylsulfinyl, _{(C 1-6)} alkylsulfonyl, heterocyclyl and heterocyclyl
(C _1-6 ) alkyl. In addition, when two adjacent ring carbon atoms are ( _C3-
5 ) They can be linked by an alkenyl chain to form a carbocyclic ring.

As used herein, the terms “heterocyclyl” and “heterocyclic” are, where appropriate, unless otherwise specified, suitably up to four oxygen, nitrogen and sulfur atoms in each ring. Heteroaromatic, aromatic and non-aromatic, monocyclic and fused rings, wherein each ring is unsubstituted or substituted, for example, with up to three substituents. It may be. Each heterocyclic ring is suitably 4
It has from 7 to 7, preferably 5 or 6, ring atoms. The fused heterocyclic ring system may include a carbocyclic ring and need only have one heterocyclic ring. Substituents for a heterocyclyl group are preferably 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, hydroxy, amino, mono- - and _{di-N-(C 1-6)} alkylamino, acylamino,
Carboxy, carboxy salts, carboxyesters, carbamoyl, mono- and di-N- (Ci- ₆ ) alkylcarbamoyl, aryloxycarbonyl, (C1
-6) alkoxycarbonyl _{(C 1-6)} alkyl, aryl, aryloxy group, ureido, guanidino, sulfonylamino, aminosulfonyl, _{(C 1-6)} alkylthio, _{(C 1-6)} alkylsulfinyl, _{(C 1-6} ) Alkylsulfonyl, amidino, amidoxime, heterocyclyl and heterocyclyl ( _{Ci_6} ) alkyl.

In a further aspect, the present invention relates to a process for the preparation of a compound according to the invention, comprising a mutilin or a 14-acyloxy-2-diazo derivative of 19,20-dihydromutilin, preferably wherein the 11-hydroxy position is protected. Compounds, for example, of the formula:

Embedded image Wherein R ¹ is ethyl or vinyl, R ^a COO— is an acyloxy group, and Y is hydrogen or a removable hydroxy protecting group. Providing a method comprising:

[0018] Conveniently, the hydrogen fluoride source is an amine complex of hydrogen fluoride (eg, hydrogen fluoride-pyridine, hydrogen fluoride, 2,4,6-trimethylpyridine; triethylamine hydrogen fluoride; -4-vinylpyridinium poly (hydrogen fluoride)). The reaction can be performed in an anhydrous solvent (eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane) at a temperature of −15 ° C. to 25 ° C.

By this reaction, a (2S) -2-fluoro derivative is produced. The (2R) -2-fluoro-mutilin derivative can be produced by treating the (2S) -isomer with a base (eg, sodium hydroxide or potassium hydroxide in ethanol). This usually produces a mixture of (2S) and (2R) -isomers, which can be separated using conventional techniques such as chromatography and crystallization.

[0020] The 2-diazo-mutilin derivative can be obtained from H Berner, G Schulz, and G Fisher, Monats.
h. Using the method disclosed by Chem., 1981, 112, 1441, for example, 2-hydroxymethylene-14-acyloxy-mutilin or 2-hydroxymethylene-11-formate-14 at -10 ° C. under argon. By reacting a solution of the acyloxy-mucin derivative in dichloromethane with tosyl azide and triethylamine.

[0021] 2-Hydroxymethylene-14-acyloxy-mutilin and 11-formate were obtained from AJ Birch, CW Holzapfel and RW Rickards (Tet (Suppl) 1996 8
Using methods based on the method disclosed by part III 359), the corresponding 14-acyloxy-mutilin derivatives in toluene and methyl formate can be prepared by treating with sodium methoxide and stirring under argon. The format group is
If necessary, it can be removed by treatment with potassium hydroxide in methanol.

[0022] 14-acyloxy-mutilin derivatives are available from H Egger and H Reinshagen, J Anti
biotics, 1976, 29, 923 an acyloxy group pleuromutilin or 14 position prepared as disclosed are separate by _{R-X-CH 2 CO 2} - may be a compound which is substituted by.

Furthermore, the 14-acyloxy-mutilin derivative is a 14-O-carbamoyl derivative, more specifically the formula (1) produced in the same manner as in WO 97/25309 (SmithKline Beecham):

Embedded image Or a compound of formula (2) produced in a similar manner as in WO98 / 05659 (SmithKline Beecham):

Embedded image May be a compound represented by

Also, the 14-acyloxy-mutilin derivative has the formula (4) wherein Y is hydrogen or a hydroxyl protecting group, for example, an acyl group:

Embedded image Or a compound represented by the formula (5):

Embedded image A compound represented by the formula: R ^2- (CH ₂ ) _m -X- (CH ₂ ) _n -CH ₂ CO ₂ H Equation (3):

Embedded image May be a compound represented by

A general method for forming esters by this type of manufacturing method is described in IO Sutherland
in Comprehensive Organic Chemistry, Vol. 2, ed.IO Sutherland, pages 8
75-883 (Pergamon Press, Oxford, 1979). The formula R ^2- (C
_{H 2) m -X- (CH 2} ) acylating agent formed from a carboxylic acid represented by _n -CH ₂ CO ₂ H, the acid chloride, acid bromide, mixed acid anhydride, or N- acyl - imidazole May be. Preferred such acylating agents are acid chlorides. General methods for forming such acylating agents are disclosed in the chemical literature (see IO Sutherland, supra, and the references cited therein).

The ester forming reaction can be performed in the presence of an organic base, an inorganic base or an acid. Organic bases include pyridine, 2,6-lutidine, triethylamine, and N, N-dimethylaniline. Inorganic bases include sodium hydride, lithium hydride, potassium carbonate, lithium hexamethyldisilazide, and sodium hexamethyldisilazide. Acids include p-toluenesulfonic acid, benzenesulfonic acid, and sulfuric acid. Optionally, if the reaction is performed in the presence of a base, an acylation catalyst such as 4-dimethylamino-pyridine or 4-pyrrolidino-pyridine (G Hofle and W Steglich, Synthesis, 1
972, 619) can also be added to the reaction mixture. Solvents for the ester formation reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N,
N-dimethylformamide, diethyl ether, dichloromethane and chloroform. A preferred solvent is tetrahydrofuran.

The compound of formula (3) can be prepared by reaction with the 14-hydroxyl in the known compound mutilin (Y = H in formula (4)), but in fact the compound of formula (4) (Y ≠ H ) Or an intermediate having 11-hydroxyl protection such as a compound represented by the formula (5).

A preferred compound represented by the formula (4) is an 11-O-acylmutilin derivative such as mutilin 11-acetate (Y = Ac in the formula (4)) (AJ Birch, CW
Holzapfel, RW Richards, Tetrahedron (Suppl.), 1966, 8, Part II, 359) or mutilin 11-dichloroacetate or mutilin 11-trifluoroacetate. After formation of the 14-ester derivative, the 11-O-acyl group is
It can be removed by selective hydrolysis (eg using NaOH in MeOH).

Formula (5) is represented by (3R) -3-deoxopho 11-deoxy-3-methoxy-11
Oxo-4-epi-mutilin (H Berner, G Schulz and H Schneider, Tetrahed
ron, 19880, 36, 1807). After formation of the 14-ester, the intermediate was converted to concentrated HC
by treatment with l or Lucas (Lukas) reagent (conc. HCl saturated with ZnCl ₂₎ can be converted to (3).

Before or after esterification, the compound of formula (4) or (5)
To prepare the 20-dihydro analog (compound represented by the above formula where R ¹ = ethyl), the vinyl group R ¹ can be prepared by using a palladium catalyst (eg, 10% palladium) in a solvent such as ethyl acetate, ethanol, dioxane, or tetrahydrofuran. -Carbon) can be reduced by hydrogenation.

[0031] Suitable hydroxy, carboxy and amino protecting groups are well known in the art and can be removed under conventional conditions without splitting the remainder of the molecule. A comprehensive discussion of how hydroxy, carboxy and amino groups are protected and how the resulting protected derivatives are cleaved can be found, for example, in "Protective Groups in Organic Chemistry".
ry ”(TW Greene and PGM Wuts, Wiley-Interscience, New York, 2nd edi
tion, 1991). Particularly suitable hydroxy protecting groups include, for example, triorganosilyl groups such as trialkylsilyl and organocarbonyl and organooxycarbonyl groups such as acetyl, allyloxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxy. Carbonyl. Particularly suitable carboxy protecting groups include alkyl and aryl groups such as methyl, ethyl and phenyl. Particularly suitable amino protecting groups include alkoxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl.

When using an intermediate of formula (4) (eg, Y = acetyl), the base-labile protecting group can be conveniently removed at the same time that the group Y is deprotected. Equation (5)
When using an intermediate of formula (I), the acid-labile protecting group is conveniently converted to the compound (5
) Is converted to compound (3) and can be removed at the same time.

The compound of the formula (3) wherein X is O, S or NH and n is 0 is also represented by the formula (7):

Embedded image [Wherein, R ¹³ represents 4-MeC ₆ H ₄ SO ₂ O, MeSO ₂ O, F ₃ CSO ₂ O,
Or wherein R ² of the compound represented by leaving a radical such as Cl - and (CH ₂₎ a compound represented by _m -XH, typically it can be prepared by reacting under the following conditions: ( a) When X = O, the alcohol R ² — (CH ₂ ) _m —OH is reacted with a non-hydroxyl solvent such as N, N-dimethylformamide or tetrahydrofuran before reacting with the compound of formula (7). Conversion into an alkoxide by reaction with an inorganic base such as sodium hydride, lithium hydride, sodium hexamethyldisilazide or lithium hexamethyldisilazide; (b) when X = S, thiol R _² - (CH ²⁾ _m -SH, and 2-propanol, ethanol, methanol, N, solvents such as N- dimethylformamide or tetrahydrofuran Reacting with a compound represented by formula (7) in the presence of an inorganic base such as sodium methoxide, sodium ethoxide, sodium hydride, sodium hexamethyldisilazide, or lithium hexamethyldisilazide; (c ) When X = NH, the amine R ² — (CH ₂ ) _m —NH ₂ is optionally treated in a solvent such as N, N-dimethylformamide or tetrahydrofuran with potassium carbonate, pyridine, N, N-di- ( Reacting with a compound of formula (7) in the presence of a base such as (isopropyl) -ethylamine or triethylamine.

Compounds of formula (3) wherein X is CONH and n is 0 can also be prepared using one of the general amide formation methods described in the chemical literature, where R ¹³ is amino the compound represented by an expression (7) wherein R ² - (CH ₂₎ can be prepared by reacting the derived acylating agent compound or therefrom represented by _m -CO 2 _H. A common amide formation method is BC Challis and JA Challis in Comprehensive Org
anic Chemistry, Vol. 2, ed.IO Sutherland, pages 959-964 (Pergamon Pres
s, Oxford, 1979).

The compound of formula (7) is easily prepared from pleuromutilin or 19,20-dihydropleuromutilin. For example, chloride amines and tosylate are disclosed by K Riedl in J. Antibiotics, 1976, 29, 132; tosylate and mesylate are disclosed by H Egger and H Reinshagen in J. Antibiotics,
1976, 29, 915.

Compounds of formula (3) where X is S (O) or SO ₂ and R ¹ is ethyl can also be prepared by converting the corresponding compound where X = S to an oxidizing agent (eg, 3
-Chloroperoxybenzoic acid, or catalytic osmium tetroxide in tetrahydrofuran and tert-butanol + N-methylmorpholine N-oxide).

In a further aspect, the present invention provides an acylating agent, including a carbamoylating agent, comprising 2-fluoro-mutilin or 2-fluoro-19,20-dihydromutilin (
Preferably, the 11-hydroxy position is protected), for example, of the formula

Embedded image Wherein R ¹ is ethyl or vinyl, and Y is hydrogen or a removable hydroxy-protecting group.

For example, the acylating agent is an acid HOCH ₂ CO ₂ H, R—X—CH ₂ CO ₂ H (where X is O, S or NR ′, and R and R ′ are each an aliphatic group or an aromatic group) or ^{_{R 2 - (CH 2) m}} -X- (CH 2) n -CH 2 CO 2 H (
Wherein n and m are each independently 0 to 2; X is -O-, -S-,
_{-S (O) -, - SO} 2 -, - NH-, CONH -, - CH 2 - and a bond; ^{R 2} is a non-aromatic monocyclic or bicyclic group (1 or 2 bases Containing a neutral nitrogen atom and attached through a ring carbon atom).

A general method for forming esters by this type of method is described in IO Sutherland in
Comprehensive Organic Chemistry, Vol. 2, ed.IO Sutherland, pages 875-8
83 (Pergamon Press, Oxford, 1979). The acylating agent may be an acid chloride, acid bromide, mixed anhydride, or N-acyl-imidazole. Preferred acylating agents are acid chlorides. General methods of forming such acylating agents are disclosed in the chemical literature (see IO Sutherland, supra, and the references cited therein).

A more detailed method of forming a 14-acyloxy side chain is described in 14-acyloxy-
The formation of compounds that are precursors of 2-diazo-mutilin is described above. For example, carbamoylation can be performed as described in WO 97/15309 or WO 98/05659.

The 2-fluoro-mutilin used in the above-mentioned acylation reaction can be obtained by converting the latter compound from mutilin via 2-hydroxy-methylene-mutilin and 2-diazo-mutilin using the above-mentioned method. Can be produced by reacting Inevitably, the compounds of the present invention may be used before and after attachment to the 14-acyloxy group.
-The fluoro substituent can be prepared by introducing a mutilin nucleus.

The compounds of the present invention have a chiral center and therefore can give diastereomers or single diastereomers. Single diastereomers can be prepared by separating a mixture of diastereomers synthesized using the racemic starting material or by synthesizing using the optically pure starting material. The compounds of the invention may be in crystalline or non-crystalline form, and in crystalline form may be optionally hydrated or solvated. When some of the compounds of the present invention are crystallized or recrystallized from an organic solvent, a crystallization solvent may be present in the crystalline product. The present invention includes such solvates within the scope of the present invention. Similarly, some of the compounds of the present invention can be crystallized or recrystallized from a solvent containing water. In such cases, water of hydration may be present in the crystalline product. Compounds containing stoichiometric amounts of hydrates and varying amounts of water prepared by methods such as lyophilization are also within the scope of the invention. The compounds obtained by the process of the invention are suitably in substantially pure form, for example at least 50% pure, suitably at least 60% pure, advantageously at least 75% pure
Purity, preferably at least 85% purity, more preferably at least 95% purity, especially at least 98% purity (all percentages are calculated as w / w).
. The impure or impure forms of the compounds of the present invention can be used, for example, in the preparation of compounds of the same or related compounds (eg, the corresponding derivatives) which are more suitable for pharmaceutical purposes.

The present invention also includes pharmaceutically acceptable salts and derivatives within the scope of the present invention.
Where one of the substituents has an acidic or basic group, salt formation is possible. The salt can be prepared by a conventional salt exchange. The acid addition salt may or may not be pharmaceutically acceptable. In the latter case, such salts will be useful as isolation and purification of the compounds of the invention, or as intermediates thereof, and will subsequently be converted to pharmaceutically acceptable salts or free bases. Pharmaceutically acceptable acid addition salts include Berge, Bighley and Monkhous, J. Pharm.
Sci., 1977, 66, 1-19. Suitable salts include hydrochloride,
Includes malate and methanesulfonate, especially the hydrochloride. If the compounds of the present invention contain a free carboxy group, they can form zwitterions.

The compounds of the present invention and their pharmaceutically acceptable salts or derivatives have antibacterial properties and are therefore therapeutic, particularly bacterial infections of animals, including humans, especially humans and livestock (including herds). Useful for the treatment of sickness. The compounds of the present invention include, for example, Staphylococcus aureus, Staphylococcus aureus,
Epidermidis (Staphylococcus epidermidis), Enterococcus faecalis (Enterococcus faecalis), Streptococcus pyogenes (Streptoco)
ccus pyogenes, Streptococcus agala
ctiae), Streptococcus pneumoniae, Haemophilus sp., Neisseria sp.
eria sp.), Legionella sp., Chlamydia sp.
Pea (Chlamydia sp.), Moraxella catarrhalis,
It can be used to treat Gram-positive bacteria, including Mycoplasma pneumoniae and Mycoplasma gallisepticum, Gram-negative bacteria and infections caused by Mycoplasma.

The present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt or derivative thereof together with a pharmaceutically acceptable carrier or excipient. The present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof,
Also provided is a method of treating a microbial infection in animals, particularly humans and livestock, characterized by administering a derivative or solvate or a composition of the present invention. The present invention particularly provides a method for treating or preventing recurrent otitis media or recurrent sinusitis, and providing the compound of the present invention or a pharmaceutically acceptable salt or derivative thereof or a derivative thereof to a patient in need of such treatment and prevention. Includes a method of topically administering a composition according to the invention. The present invention provides a method of treating skin and soft tissue infections and acne, and provides a compound of the present invention or a pharmaceutically acceptable salt or derivative thereof or a composition according to the present invention to a patient in need thereof. Is administered locally.

More generally, the compounds and compositions of the present invention, as well as other antibiotics, may be formulated for administration in any conventional manner for human or veterinary medicine.

The compounds and compositions of the present invention can be formulated for administration by any route, for example, for oral, topical or parenteral administration. For example, the compositions may be tablets, capsules, powders, granules, lozenges, creams, syrups, sprays or liquid preparations, such as solutions or suspensions for oral or sterile formulation for parenteral administration by injection or infusion. It can be in the form. Tablets and capsules for oral administration may be in unit dosage form, with conventional excipients such as binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polypinylpyrrolidone; fillers such as lactose, sucrose, corn starch,
Tablets, such as magnesium stearate, talc, polyethylene glycol or silica; disintegrants, such as potato starch; and pharmaceutically acceptable wetting agents, such as sodium lauryl sulfate. Tablets may be coated according to methods well known in normal pharmaceutical practice.

[0048] Oral liquid formulations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be a dry product for reconstitution with water or other suitable vehicle before use. Good. Such liquid preparations contain conventional additives,
For example, suspending agents such as sorbitol, methylcellulose, glucose syrup,
Gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible oils and fats; emulsifiers such as lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (including edible oils and fats) such as almond oils, oily esters (eg. Glycerin), propylene glycol or ethyl alcohol; may contain conventional additives including preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavors and colorants. Can be.

The composition for topical administration of the present invention includes, for example, ointments, creams, lotions, eye ointments,
Eye drops, ear drops, nasal drops, impregnated bandages and aerosol forms,
It may contain suitable conventional additives including, for example, preservatives, solvents to aid drug preparation and emollients in ointments and creams. Such topical formulations may also contain compatible conventional carriers, for example cream and ointment bases, ethanol or oleyl alcohol for lotions. Such carriers may make up from about 1% to about 98% by weight of the formulation, and typically comprise up to about 80% by weight of the formulation. The composition for topical administration of the present invention may contain, in addition to the above, for example, a steroidal anti-inflammatory agent such as betamethasone. The compositions of the present invention may also be formulated as a suppository, and may contain conventional suppository bases such as cocoa butter or other glycerides.

The compositions for parenteral administration of the invention may conveniently be in liquid unit dosage form and may be prepared using a compound of the invention and a sterile vehicle, preferably water. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and then sealed. Advantageously, conventional additives including, for example, local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle. To enhance the stability of the solution, the composition is frozen after filling into the vial, the water is removed under vacuum, the resulting lyophilized powder is sealed in the vial, and the liquid is reconstituted before use. An accompanying water vial for injection can be supplied for use. Suspensions for parenteral administration can be prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. Instead, the compound
Sterilize by exposure to ethylene oxide before suspending in a sterile vehicle. Advantageously, such suspending agents include a surfactant or wetting agent to promote uniform distribution of the compound.

Suitably, the compounds and compositions of the present invention are administered parenterally in an antibacterial effective amount. The compositions of the present invention may suitably contain 0.1% by weight or more, preferably 10-60% by weight, of a compound of the present invention (based on the total weight of the composition), depending on the method of administration.

The compounds of the present invention are suitably administered in a daily dose of from 1.0 mg to 50 mg, depending on body weight.
Preferably it is administered to a patient in mg / kg. Adult human (weight about 70kg)
In this case, 50 mg to 3000 mg, for example, about 1500 mg of the compound of the present invention may be administered daily. Preferably the dosage for adult humans is between 5 mg / kg and 20 mg / kg daily. However, depending on normal treatment habits, amounts above or below such amounts may be used. When the compound of the present invention is in unit dosage form, it is preferred that any unit dose contains from 25 mg to 1000 mg, preferably from 50 mg to 500 mg, of the compound of the present invention.

Suitable intermittent therapies for the prevention of recurrent otitis media or recurrent sinusitis include S. aureus, H. influenza (H. in)
fluenzae), S. pneumonia and M. catalalis (M.ca)
It can also be used to remove or reduce nasal carriage of pathogenic bacteria such as tarrahlis). Thus, in the manufacture of a medicament for the elimination or reduction of nasal carriage of pathogenic organisms associated with recurrent sinusitis, the medicament is preferably adapted for nasal administration, especially for localized delivery to the nasopharynx. Used for Preferably, the drug is administered intermittently rather than continuously to reduce the risk of promoting the development of resistant organisms. The drug substance is administered for a short number of days, eg, 2-10 days, suitably 3-8 days. More suitably about daily for about 5 days, and then at intervals, for example for a period of several months,
For example, dosing is repeated on a monthly basis over a period of up to six months. Although less preferred, the drug substance may be administered for an extended period of time daily, for example, continuously for several months. Preferably, the drug substance is administered once or twice daily. Preferably, the drug substance is administered during the oral winter months when recurrent otitis media and recurrent sinusitis are prevalent. Preferably, the drug substance is present in each nostril 1 to 10 mg at a time, more preferably 3 to 10 mg.
-8 mg, typically about 5 mg. The drug substance is administered to the nasopharynx, especially the anterior nasopharynx.

Suitably, the drug substance is present for use in the present invention between 0.01 and 10%, more preferably between 0.1 and 5%, even more preferably between 1 and 5%. . Suitable amounts are 2 and 4% by weight, based on the weight of the composition.
. Low levels of drug substance should be avoided to reduce the risk of promoting the development of resistant organisms. Preferred compositions for administration are those that are suitable for centralized delivery to the nasopharynx and remain within the nasopharynx. The term "focused delivery" as used herein means that the composition is delivered to the nasopharynx rather than staying in the nares. "Stay" in the nasopharynx
The term means that the composition, once delivered to the nasopharynx, remains in the nasopharynx over the course of several hours, rather than being washed out more or less immediately. Such 2
One embodiment can be conveniently analyzed by gamma (gamma) wave scintigraphy. Suitably, such compositions include sprays and creams. The following examples illustrate the invention.

2- (3-R, 4S) -1-azabicyclo [2.2.1] hept-3-ylcarbonyl] carbamic acid
Luorumutilin 14-ester (mixture of (2R) and (2S)) Step 1 Formylated derivatives of mutilin AJ Brich, CW Holzapfel and RWRickards (Tet (Suppl) 1996 8 part III)
The reaction was carried out in the same manner as described in 359). Mutilin (6 g) in toluene (330 ml) and methyl formate (100 ml) was reacted with sodium methoxide (3 g) and stirred under argon for 8 hours. Add ice water (100 ml), then add 2
N HCl (220 ml) was added. The mixture was shaken and separated, and the aqueous layer was extracted with ether. The combined organic layers were dried, evaporated and the residue was chromatographed eluting with an ethyl acetate / hexane mixture. First, 2-hydroxymethylene mutilin 11,14-diformate (2.33 g): ¹ H NMR (CDCl ₃ )
2 (1H, d), 5.77 (1H, d), 6.94 (1H, s), 7.89 (1H, s), 8.10 (1H, s) eluted. The next eluted product was 2-hydroxymethylene mutilin 11-formate (3.0 g): ¹ H
NMR (CDCl ₃₎ inter alia, 4.40 (1H, d), 5.11 (1H, d), 7.06 (1H, s), 8.25 (H, d, J O.8Hz)
Met. The next elute was a mixture of 2-hydroxymethylene mutilin 14-formate and 2-hydroxymethylene mutilin (1.8 g) (2: 1).
Met.

[0056]Step 2 2-diazomutilin 11-formate Dichloromethane of 2-hydroxymethylene mutilin 11-formate (3.0 g)
The solution in tan (100 ml) was cooled to −10 ° C. under argon and triethylamine was added.
(3.3 ml) and tosyl azide (2.36 g). Mix 3
H at room temperature, 0.5N HCl (100 ml), water and aqueous NaHCO ₃ , Dried and evaporated. The title compound was obtained as yellow crystals (1.68 g)
); IR (CHCl_Three) 3635,2083,1714 and 1670.

Step 3 2- (S) -Fluoromutilin 11-formate A suspension of 2-diazomutilin 11-formate (1 g) in ether (15 ml) was cooled to -15 ° C. under argon and hydrogen fluoride-pyridine (2 ml). The cooling bath was removed and the mixture was stirred until it became colorless (about 1 hour). E
After dilution with tOAc (39 ml), the solution was washed with water (2 × 20 ml) and NaHCO ₃ solution (20 ml), dried and evaporated. Chromatography eluting with 5% EtOAc in CHCl ₃ afforded the title compound as white crystals (0.
4g): MS (-ve ion electrospray) m / z 365 (MH, 30%).

Step 4 [(3R, 4S) -1-azabicyclo [2.2.1] hept-3-ylcarbonyl] carbamine
Acid-2-fluoromutilin 14-ester 11-formate (3R, 4S) -ethyl 1 azabicyclo [2.2.1] heptane-3-carboxylate (2.0 g IF F Cottrell. D. Hand, DJ Kennedy , KJ Paul. SH
.B. Wright and K. Hoogsteen.j. Chem. Soc. Perkin Trans. 1.1991. 1091-
1097) was dissolved in concentrated hydrochloric acid and heated under reflux for 5 hours. After cooling, the solution was evaporated under reduced pressure and the residue was again evaporated from toluene (x3). Drying over phosphorus pentoxide and trituration with cold ethyl acetate / ethanol gave the hydrochloride salt of (3R, 4S) -1-azabicyclo [2.2.1] heptane-3-carboxylic acid (1.2 g). 300
mg of the compound were suspended in dichloromethane (9 ml) under argon and DMF
(2 drops) and oxalyl chloride (0.52 ml) and stirred for 4 hours.
The solution was evaporated, toluene (5 ml) was added and evaporated, and the residue was taken up in dry dichloromethane (10 ml). The solution under argon was reacted with 2- (S) -fluoromutilin 11-formate (0.3 g), gin cyanide (0.45 g) and triethylamine (0.21 ml) and stirred for 18 hours. Aqueous NaHCO ₃ (10 ml) was added and the mixture was stirred vigorously for 5 minutes and filtered through celite. The layers were separated and the organic layer was dried and evaporated. Chloroform / methanol / 0.
Chromatography eluting with 88 NH ₃ (aq) (19: 1: 0.1) gave the title compound as a foam (0.2 g); MS (+ ve ion electrospray m / z 533 (MH +, 60 %), 141 (100%).

Step 5 [(3R, 4S) -1-azabicyclo [2.2.1] hept-3-ylcarbonyl] carbamine
Acid-2-fluoromutilin 14-ester (mixture of (2R) and (2S)) The product (0.19 g) obtained in step 4 was dissolved in ethanol (6 ml),
A solution of M KOH in ethanol was added dropwise for about 1 hour. When 1.3 ml is added,
TLC indicated that the starting material had completely disappeared. The solution was washed with CHCl ₃ (30 ml
), Washed with water (30 ml), dried and evaporated. Chromatography eluting with chloroform / methanol / 0.88NH ₃ (aq) (92.5: 7.5: 0.75) gave the title mixture as a foam (0.11 g): MS (+ ve ion electrospray) m / z 505 (MH +, 20%), 141 (100%).

Example 2 [(3R, 4S) -1-Azabicyclo [2.2.1] hept-3-ylcarbonyl] carbamic acid-2- (
S) -Fluoromutilin 14-ester hydrochloride step 1 2-hydroxymethylene mutilin 2-hydroxymethylene mutilin 11,14-diformate (2.33 g) and [2-hydroxymethylene mutilin 14-formate + 2-hydroxymethylene Mutilin] (1.8 g) (see Example 1, Step 1) with ethanol (
30 ml) and reacted with 0.5 N KOH in ethanol (60 ml). After 1 hour, the solution was diluted with ethyl acetate (200 ml) and 0.2N HCl (1
20 ml) and water (100 ml), dried and evaporated to give 2-hydroxymethylene mutilin as a foam (3.6 g). ¹ H NMR (CDCl ₃ )
(1H, d), 4.37 (1H, d), 6.97 (1H, s).

Step 2 A solution of 2- diazomutilin 2-hydroxymethylenemutilin (3.6 g) in dichloromethane was cooled to -10 ° C. under argon and reacted with triethylamine (4.6 ml) and tosyl azide (3.55 g). And warmed to room temperature. After 6 hours, the solution was washed with 0.5N HCl (150 ml) and water (100 ml), dried and evaporated.
2-Diazomutilin was obtained as yellow crystals from ethyl acetate / hexane (1.7 g).
); IR (CHCl ₃₎ 3634,2082 and 1670 cm.

Step 3 2- (S) -Fluoromutilin 2-diazomutilin was treated with hydrogen fluoride-pyridine using the method of Step 3 of Example 1 to give the title compound as white crystals: MS (- ve ion ^{electrospray) 397 (M + OAc -,} 100%), 337 (MH -, 30%).

Step 4 2- (S) -Fluoromutilin 11-Trifluoractate A solution of 2- (S) -fluoromutilin (2.18 g) in THF (80 ml) was treated under argon with trifluoroacetylimidazole (0. 806 ml) and stirred for 22 hours. The mixture was concentrated to about 10 ml, diluted with ethyl acetate (50 ml) and water (50 ml) and shaken to separate the layers. The organic layer was dried and evaporated. The residue was chromatographed eluting with 15% EtOAc in hexane to give the title compound (1.80 g) as a white foam: ¹ H NMR (CDCl ₃ )
4.28 (1H, t, j 6.5Hz), 4.68 (1H, dt, j52 and 7.7Hz), 4.90 (1H, d, J6.7Hz).

Step 5 [(3R, 4S) -1-Azabicyclo [2.2.1] hept-3-ylcarbonyl] carbamine
Acid-2- (s) -fluoromutilin 14-ester 11-trifluoroacetate The product of Step 4 was reacted using the method of Step 4 of Example 1 to give the title compound as a white foam (62% ): MS (+ ve ion electrospray) 601 (MH ⁺ , 100%)
.

Step 6 [(3R, 4S) -1-azabicyclo [2.2.1] hept-3-ylcarbonyl] carbamine
Acid-2- (s) -fluoromutilin 14-ester hydrochloride The product of Step 4 (1.5 g) is dissolved in ethanol (150 ml), reacted with saturated aqueous NaHCO ₃ (150 ml) and vigorously for 2 hours. Stirred. Chloroform (400 ml) and water (400 ml) were added and the mixture was shaken to separate. The organic layer was dried and evaporated, and the residue was subjected to chloroform / methanol / 0.88N
H 3 _(aq) was chromatographed, eluting with (94: 6 0.6). After evaporation of the solvent, the product was redissolved in chloroform (100 ml) and reacted with 1 M HCl in diethyl ether (2 ml). Evaporate the solvent. The title compound was obtained as a white solid (1.31g): MS (+ ve ion ^{electrospray) 546 (MH + + MeCN,} 60%), 505 (MH +, 100%).

Example 3 p-methoxybenzoylcarbamic acid-2- (R) -fluoromutilin 14-e
Ster and p-methoxybenzoylcarbamic acid-2- (S) -fluoromuchi
Phosphorus 14-ester Step 1 p-Methoxybenzoylcarbamic acid-2-hydroxymethylenemutyl
14-ester 11-formate p-methoxybenzoylcarbamic acid mutilin 14-ester (PCT / EP
96/05874 (Example 31) was converted to the title compound using the method of Step 1 of Example 1.

Step 2 p-Methoxybenzoylcarbamic acid-2-diazomutilin 14-S
Ter 11-formate p-methoxybenzoylcarbamic acid-2-hydroxymethylene mutilin 14
-The ester 11-formate was converted to the title compound using the method of Step 2 of Example 1: MS (-ve ion electrospray) MH ⁺ , 100%).

Step 2 p-methoxybenzoylcarbamic acid-2- (S) fluoromutilin 14
-Ester 11-formate p-methoxybenzoylcarbamic acid-2-diazomutilin 14-ester 1
A suspension of 1-formate (0.276 g) in dimethyl ether (2.5 ml) was cooled to −15 ° C. under argon and hydrogen fluoride-pyridine (1 ml) was added dropwise. The cooling bath was removed and a colorless solution formed within 5 minutes. This was added to EtOAc (2
0 ml), washed with water (2 × 20 ml), dried and evaporated. The title compound was obtained as a white solid chromatographed eluting with 30% EtOAc in hexanes (0.11g): MS (-ve ion ^{electrospray) 542 (MH -, 100%} ), 365 (80% ).

Step 3 p-methoxybenzoylcarbamic acid-2- (R) fluoromutilin 14
-Esters and p-methoxybenzoylcarbamic acid-2- (S) -fluorome
The product of tilin 14-ester step 3 (0.11 g) was dissolved in THF (2 ml) / ethanol (2 ml) and 0.5 M KOH in ethanol (0.8 ml) was added dropwise over 1 hour. The solution was diluted with EtOAc (15 ml), washed with water (2 × 15 ml), dried and evaporated. Chromatographed eluting with 40% EtOAc in hexane. First, p-methoxybenzoylcarbamic acid-2- (S) fluoromutilin 14-ester (0.026 g) was eluted. MS (-ve ion ^{electrospray) 514 (MH -, 100%} ). Next, p-methoxybenzoylcarbamic acid-2- (R) -fluoromutilin 14
Eluted ester (0.055 g): MS (-ve ion electrospray) 514
(MH ^-, 100%).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 31/04 A61P 31/04 C07C 49/513 C07C 49/513 269/06 269/06 C07D 487/08 C07D 487/08 (72) Inventor Gerald Brooks C.M.19.5 Adablue, Essex, Harlow, Third Avenue, New Frontiers Science Park South, SmithKline Beecham Pharmaceutical (72) Inventor Eric Hunt, C.M. 19.5 ADB, Essex, Harlow, Third Avenue, New Frontiers Science Park South, Smith Clin Bee JAM Pharmaceuticals F-term (reference) 4C050 AA03 BB04 CC04 DD10 EE01 FF03 GG01 HH01 4C086 AA01 AA03 CB03 GA16 MA01 MA04 NA14 ZA34 ZA90 ZB35 4C206 AA01 AA03 HA22 KA08 KA17 A01 A03 A04 MA04 AB20 AC30 BE01 BJ30 BM20 BN20 BR80 EA14

Claims (16)

[Claims] 1. A 14-acyloxy derivative of mutilin or 19,20-dihydromutilin having a 2-fluoro substituent. 2. Structural formula: embedded image [Wherein, R ¹ is vinyl or ethyl, and R ^a COO— is an acyloxy group]. 3. The acyloxy group is HOCH ₂ CO ₂ — or R—X—CH ₂ CO ₂ —, wherein X is O, S or NR ′, and R and R ′ are each aliphatic or aromatic. The compound according to claim 2, which is a group. 4. An acyloxy group represented by R²− (CH₂)_m-X- (CH₂)_n-CH ₂ CO₂X (where n and m are independently 0 or 2);
Is -O-, -S-, -S (O)-, -SO₂-, -NH-, CONH-, -CH₂ And R is selected from²Contains one or two basic nitrogen atoms
Having a non-aromatic monocyclic or bicyclic group attached via a ring carbon atom.
Item 7. The compound according to Item 2. 5. The compound according to claim 2, wherein the acyloxy group is carbamoyl. 6. An acyloxy group represented by R³R⁴NCO₂-Where R³And R⁴Is the same or different and is hydrogen; linear or branched saturated or
Unsaturated, optionally substituted C₁-C₆Hydrocarbon group; saturated or unsaturated substitution
C that may be₃-C₈A cyclic hydrocarbon group; an optionally substituted heterocyclic group;
Optionally substituted aryl groups; or together they are N, O and
A hydrocarbon ring which may contain one further heteroatom selected from S
, Substituted with 3 to 8 ring atoms, which may be fused to a heterocyclic or aromatic group
Forming an optionally substituted cyclic group; or R³Is a monovalent group described above, and R⁴Is SO₂R⁵, COR⁶, OR⁶and
NR⁷R⁸Where R is⁵Is a linear or branched, saturated or unsaturated, optionally substituted C₁-C ₆ Hydrocarbon group; saturated or unsaturated, optionally substituted C₃-C₈Cyclic hydrocarbon
An aryl group; an optionally substituted heterocyclic group; an optionally substituted aryl group;
C that may be₁-C₆An alkylamino group; and an optionally substituted
Selected from reelamino groups; R⁶Is hydrogen; linear or branched, saturated or unsaturated, optionally substituted C ₁ -C₆Hydrocarbon group; saturated or unsaturated, optionally substituted C₃-C₈Ring
A hydrocarbon group; an optionally substituted heterocyclic group; and an optionally substituted ant
R group; R⁷And R⁸Is the same or different and is hydrogen; linear or branched saturated or
Unsaturated, optionally substituted C₁-C₆Hydrocarbon group; saturated or unsaturated substitution
C that may be₃-C₈A cyclic hydrocarbon group; an optionally substituted heterocyclic group;
And an optionally substituted aryl group; or
, N, O and S.
And may be fused to a hydrocarbon ring, a heterocyclic ring or an aromatic group.
The compound according to claim 5, which forms a cyclic group which may be substituted with a ring atom. 7. The compound according to claim 5, wherein the N-atom of the carbamoyl group is acylated with one group containing an azabicyclic group. 8. The acyloxy group is R ⁹ CONHCO ₂ — and R ⁹ is a group R ¹⁰ , R ¹⁰ CH ₂ — or R ¹¹ R ¹² C ＝ CH—, wherein R ¹⁰ is an azabicyclic or is a ring system, or R ¹¹ and R ¹² form a azabicyclic ring system together with the carbon atoms to which they are attached, 7. a compound according. 9. A bridged or fused non-aromatic ring system in which the azabicyclic ring system is linked via a bridged or unbridged ring carbon atom and contains one bridged nitrogen atom as a sole heterocyclic atom. 9. The compound according to claim 8, which is 10. An azabicyclic ring system comprising a compound of formula (I): Wherein R ⁷ is one or more of the optional substituents described above and a, b and c are each 0-, such that any one ring has 5-10 ring atoms. The compound of claim 9, which is a number of 4]. 11. A process for preparing a compound according to any one of claims 1 to 10, wherein the compound has the formula: Wherein R ¹ is ethyl or vinyl, R ^a COO— is an acyloxy group, and Y is hydrogen or a removable hydroxy protecting group. The method characterized by making it. 12. A process for preparing a compound according to any one of claims 1 to 10, wherein the acylating agent, including a carbamoylating agent, has the formula: Wherein R ¹ is ethyl or vinyl and Y is hydrogen or a removable hydroxy protecting group. 13. The formula: embedded image Wherein R ¹ is ethyl or vinyl and Y is hydrogen or a removable hydroxy protecting group. 14. A method for treating a microbial infection in an animal, particularly a human or a domestic mammal, comprising the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or derivative thereof, or the present invention. A method comprising administering a composition of the invention to a subject in need thereof. 15. A method for treating or preventing recurrent otitis media or recurrent sinusitis in a human, comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt or derivative thereof. Alternatively, the composition of the present invention is administered intranasally to a subject in need thereof. 16. A method for treating skin and soft tissue infections in humans and treating acne, wherein the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt or derivative thereof, or A method comprising topically administering a composition of the present invention to a subject in need thereof.