HK1125624B

HK1125624B - Mutilin derivatives adn their use as pharmaceutical

Info

Publication number: HK1125624B
Application number: HK09104021.6A
Authority: HK
Inventors: K．瑟林; G．阿舍尔; S．鲍尔科纳; W．黑尔梅尔; R.诺瓦克
Original assignee: 纳布里瓦治疗股份公司
Priority date: 2006-01-16
Filing date: 2007-01-11
Publication date: 2015-01-30

Description

Mutilin derivatives and their use

The present invention relates to organic compounds, such as pleuromutilins.

Pleuromutilins, i.e. compounds of the general formula

Are naturally occurring antibiotics, for example prepared from basidiomycetes pleuroticus (basidomycetes sporoeurotius mutilus) and p.paseckerianus, see for example The merck index, 12 th edition, item 7694. A number of other pleuromutilins have been developed, such as antibacterial agents, which contain a ring structural element of pleuromutilin and are substituted at the hydroxyl group.

We have now found pleuromutilins with advantageous activity.

In one aspect, the invention provides a compound, such as pleuromutilin, selected from the group consisting of:

14-O-[(((C_1-6) Alkoxy radical- (C_1-6) Alkyl) -phenylsulfanyl) -acetyl]Mutilins (the term is herein interpreted as "mutilins"),

14-O-[(((C_1-6) Mono-or dialkylamino- (C)_1-6) Alkyl) -phenylsulfanyl) -acetyl]-a source of mutilin,

14-O- [ ((hydroxy- (C)_1-6) -alkyl) -phenylsulfanyl) -acetyl]-a source of mutilin,

14-o- [ ((formyl- (C)_0-5) -alkyl) -phenylsulfanyl) -acetyl]-a source of mutilin,

14-O- [ ((guanidino-imino (C)_1-6) Alkyl) -phenylsulfanyl) -acetyl]-a source of mutilin,

14-O- [ ((ureido-imino- (C)_1-6) Alkyl) -phenylsulfanyl) -acetyl]-a source of mutilin,

14-O- [ ((thioureido-imino- (C)_1-6) Alkyl) -phenylsulfanyl) -acetyl]-a source of mutilin,

14-O- [ ((isothioureido-imino- (C)_1-6) Alkyl) -phenylsulfanyl) -acetyl]-a source of mutilin,

14-O- [ ((cyano- (C)_0-5) -alkyl) -phenylsulfanyl) -acetyl]-a source of mutilin,

14-O- [ ((azido- (C)_0-5) -alkyl) -phenylsulfanyl) -acetyl]-a source of mutilin,

14-O-[(((C_1-6) Acyloxy- (C)_1-6) Alkyl) -phenylsulfanyl) -acetyl]-a source of mutilin,

14-O- [ ((benzoyloxy- (C)_1-6) Alkyl) -phenylsulfanyl) -acetyl]-a source of mutilin,

wherein the phenyl-or 5-or 6-membered heteroaryl-ring is optionally further substituted with up to four groups independently selected from: halogen, (C)_1-6) Alkyl, aryl (C)_1-6) Alkyl radicals, (C)_1-6) Alkoxy group, (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, sulfonylamino, aminosulfonyl, (C)_1-6) Alkyl sulfur, (C)_1-6) -alkylsulfinyl, (C)_1-6) Alkyl sulfonyl radicalGroup, heterocyclic group, heteroaryl group, heterocyclic group (C)_1-6) Alkyl and heteroaryl (C)_1-6) The alkyl group, or two adjacent ring carbon atoms, may be substituted by (C)_3-5) The alkylene chains are linked to form a carbocyclic ring.

Preferably, the invention relates to

14-O-[(((C_1-6) Alkoxy radical- (C_1-6) Alkyl) -phenylsulfanyl) -acetyl]-a source of mutilin,

14-O-[(((C_1-6) Amido- (C)_1-6) Alkyl) -phenylsulfanyl) -acetyl]-a source of mutilin,

14-O- [ ((guanidino-imino- (C)_1-6) Alkyl) -phenylsulfanyl) -acetyl]-mutilin.

More preferably, the present invention provides compounds of the general formula

Wherein

n is 1 to 6;

x is oxygen, or NR₂Wherein R is₂Is hydrogen or linear or branched (C)_1-6) -alkyl, or hydroxy- (C)_1-6) Alkyl or (C)_1-6) Alkoxy radical- (C_1-6) An alkyl group, a carboxyl group,

R₁is hydrogen, linear or branched (C)_1-6) Alkyl, mono-or dihalo (C)_1-6) Alkyl, amino (C)_1-6) Alkyl, hydroxy (C)_1-6) Alkyl, phenyl (C)_1-6) Alkyl radicals, (C)_1-6) Alkenyl, furyl (C)_1-6) Alkyl radicals, (C)_3-6) Cycloalkyl and the corresponding ammonium salts, e.g. chloride, or

R₁And R₂Together with the nitrogen atom to which they are attached form a 5-to 7-membered heterocyclic ring containing at least one nitrogen atom, or

XR₁Is piperazinyl or morpholinyl.

In another aspect, the invention provides compounds of the general formula

Wherein

n is a number of 0 to 5,

y is oxygen or NR₃，

R₃Is that

(ii) a X is oxygen, sulfur, NH or NR₇；

Or

And the corresponding anions, such as chloride,

R₄、R₅、R₆、R₇is hydrogen, linear or branched C_1-6Alkyl or C_3-8A cycloalkyl group,

R₈is C_1-4Alkyl radical。

Preferably, the present invention provides a compound of formula II,

wherein

Y is NR₃X is NR₇，R₃Is that

And R₄And R₇Together with the nitrogen atom to which they are attached form a 5-to 7-membered heterocyclic ring containing at least 2 nitrogen atoms, and R₅And R₆As defined above, in the above-mentioned manner,

or R₅And R₆Together with the nitrogen atom to which they are attached form a 5-to 7-membered heterocyclic ring containing at least 2 nitrogen atoms, and R₄And R₇As defined above, in the above-mentioned manner,

or R₄And R₅Together with the nitrogen atom to which they are attached form a 5-to 7-membered heterocyclic ring containing one or more nitrogen atoms, and R₆And R₇As defined above.

More preferably, the present invention provides compounds of the following general formula II,

wherein

Y is NR₃X is NR₇，R₃Is that

R₆And R₇As defined above, in the above-mentioned manner,

R₉is hydrogen, linear or branched C_1-6Alkyl or acyl radicals, e.g. C_1-6An acyl group.

Pleuromutilins provided by the present invention include pleuromutilins having the basic structural elements of the mutilin ring system as given by the general formula

Wherein R is_PLEUIs vinyl or ethyl, and the dotted line is a bond or no bond.

The following numbering system is used in this application:

the dotted line between positions 19 and 20 (and between positions 1 and 2) is a bond or no bond. In the compounds of formula a or of formula PLEU, the hydrogen atoms in the 4, 7 and/or 8 positions of the ring system may be replaced by deuterium, and if the dotted line between the 1 and 2 positions is not a bond (single bond between the 1 and 2 positions), the ring system may be further substituted in the 1 and/or 2 positions, for example by halogen, deuterium or hydroxy. The group-O-in position 14 is further substituted, preferably with a substituted carbonyl group.

It has been shown that the antibacterial activity of said pleuromutilin derivatives against clinically relevant bacterial pathogens (Staphylococcus aureus), Enterococcus faecalis (Enterococcus faecalis), Streptococcus pneumoniae (Streptococcus pneumoniae), Moraxella catarrhalis (Moraxella catarrhalis) and Escherichia coli (Escherichia coli), see Table 1 below, is especially improved when the phenyl ring carries the following atoms

a) Carrying a saturated or unsaturated carbon atom in the meta position relative to the sulphur bound to the phenyl ring, or

b) Carrying a saturated or unsaturated carbon atom in an ortho position with respect to the sulphur bonded to the phenyl ring, with the proviso that the phenyl ring is further substituted by up to four radicals mentioned in claim 1.

Thus, wherein the (CH)₂)_nCompounds in which the radical is in the meta position relative to the sulfur bonded to the phenyl ring are preferred. Also preferred are compounds wherein the (CH)₂)_n-the group is in an ortho position relative to the sulphur bonded to the phenyl ring, with the proviso that the phenyl ring is further substituted with up to four groups independently selected from: halogen, (C)_1-6) Alkyl, aryl (C)_1-6) Alkyl radicals, (C)_1-6) Alkoxy group, (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, sulfonylamino, aminosulfonyl, (C)_1-6) Alkyl sulfur, (C)_1-6) -alkylsulfinyl, (C)_1-6) Alkylsulfonyl group, heterocyclic group, heteroaryl group, heterocyclic group (C)_1-6) Alkyl and heteroaryl (C)_1-6) The alkyl radical, or two adjacent ring carbon atoms, may be substituted by (C)_3-5) The alkylene chains are linked to form a carbocyclic ring.

In another aspect, the present invention provides a compound selected from

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

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

14-O- [ (3- { [ (aminoimino-methyl) -hydrazinoidenyl ] methyl } -phenylsulfanyl) -acetyl ] -mutiline,

14-O- [ (3- { [2- (imino-N-piperazinyl-methyl) -2-methyl-hydrazinoylidene ] methyl } -phenylsulfanyl) -acetyl ] -mutiline,

14-O- [ (3- [ (3-ethyl-2-methylimino-imidazolidin-1-yl-imino) -methyl ] -phenylsulfanyl) acetyl ] -mutilin,

14-O- [ (3- { [ (imino-N-piperazinyl-methyl) -hydrazinoidene ] -methyl } -phenylsulfanyl) -acetyl ] -mutilin,

for example in the form of a salt, for example the hydrochloride salt.

In another aspect, the present invention provides a compound selected from the group consisting of:

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

14-O- { [3- (aminoimino-methyl) -hydrazinoidenemethyl-phenylsulfanyl ] -acetyl } -mutilin,

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

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

14-O- [ {3- [ (1-piperazineiminomethyl) -hydrazinoidemethyl ] -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-allylaminoethyl-phenylsulfanyl) -acetyl ] -mutilin,

14-O- [3- { [ (furan-2-ylmethyl) -amino ] -methyl } -phenylsulfanyl-acetyl ] -mutiline,

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

for example in the form of a salt, for example the hydrochloride salt.

The compounds provided by the present invention are also herein designated "(according to) the compounds of the present invention". The compounds of the invention include mutilin-14-yl acetates, such as those specifically defined above, and compounds of formula I or II. The compounds of the invention include compounds in any form, for example, in free form, in salt form, in solvate form and in salt and solvate form.

The compounds of the invention may be in crystalline or amorphous form, and if crystalline, may optionally be hydrated or solvated. When some compounds of the invention are allowed to crystallize or recrystallize from organic solvents, the solvent of crystallization may be present in the crystallized product.

The present invention includes within its scope such solvates. Similarly, some compounds of the invention may be crystalline or recrystallized from aqueous solvents. In this case, water of hydration may be present in the crystalline product. The present invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water, which may be prepared by methods such as lyophilization.

In another aspect, the invention provides a compound of the invention in the form of a salt.

These salts preferably include pharmaceutically acceptable salts, but include pharmaceutically unacceptable salts, for example for preparation/isolation/purification purposes.

Salts of the compounds of the present invention include metal salts or acid addition salts. Metal salts include, for example, alkali or alkaline earth metal salts; acid addition salts include compounds of the present invention with acids such as hydrogen fumarate (hydrogen fumarate), fumaric acid, naphthalene-1, 5-sulfonic acid, hydrochloric acid, tritialchloric acid; salts of hydrochloric acid are preferred.

The compounds of the invention in free form can be converted into the corresponding compounds in salt form; and vice versa. The compounds of the invention in free form or in salt form and in solvate form can be converted into the corresponding compounds in salt form in free form or in unsolvated form; and vice versa.

Accordingly, the compounds of the present invention, if substituted, may be in the form of isomers and mixtures thereof; for example in the form of optical isomers, diastereoisomers, cis/trans conformers. The compounds of the invention may, for example, contain asymmetric carbon atoms and may therefore exist as enantiomers or diastereomers and mixtures thereof, e.g., racemates. The substituents at any asymmetric carbon atom may be present in the (R) -, (S) -or (R, S) -configuration, preferably in the (R) -or (S) -configuration. For example, if in the compounds of the formula I R₁Is a substituted alkyl group and the substituent is attached to a carbon atom of a side chain of such alkyl group, then the carbon atom attached to such substituent is an asymmetric carbon atom and such substituent may be in the (R) -and (S) -configurations, including mixtures thereof. The configuration of the substituents attached to the asymmetric carbon atom of the mutilin ring is preferably the same as in the native pleuromutilins.

The isomer mixtures can be separated as appropriate, for example, according to, for example, methods analogous to conventional methods to obtain pure isomers. The present invention includes the compounds of the present invention in any isomeric form and in any isomeric mixture.

Where tautomers may exist, the invention also includes tautomers of the compounds of the invention.

Any of the compounds described herein, e.g., the compounds of the invention and intermediates in their preparation, may be prepared as appropriate, e.g., according to, e.g., analogous to, conventional methods, e.g., or as specified herein.

In another aspect, the present invention provides a method of making:

14-O-[(((C_1-6) Alkoxy radical- (C_1-6) Alkyl) -phenylsulfanyl) -acetyl]Mutilin, 14-O- [ (((C)_1-6) Mono-or dialkylamino- (C)_1-6) Alkyl) -phenylsulfanyl) -acetyl]Mutilin, 14-O- [ ((hydroxy- (C)_1-6) -alkyl) -phenylsulfanyl) -acetyl radical]Mutilin, 14-O- [ ((formyl- (C)_0-5) -alkyl) -phenylsulfanyl) -acetyl]Mutilin, 14-O- [ ((guanidino-imino (C))_1-6) Alkyl) -phenylsulfanyl) -acetyl]Mutilin, 14-O- [ ((ureido-imino- (C)_1-6) Alkyl) -phenylsulfanyl) -acetyl]Mutilin, 14-O- [ ((thioureido-imino- (C)_1-6) Alkyl) -phenylsulfanyl) -acetyl]Mutilin, 14-O- [ ((isothioureido-imino- (C)_1-6) Alkyl) -phenylsulfanyl) -acetyl]Mutilin, 14-O- [ (((C)_1-6) Alkoxy radical- (C_1-6) Alkyl) -5-or 6-membered heteroarylsulfanyl) -acetyl]Mutilin, 14-O- [ ((hydroxy- (C)_1-6) -alkyl) -5-or 6-membered heteroarylsulfanyl) -acetyl]Mutilin, 14-O- [ ((formyl- (C)_0-5) -alkyl) -5-or 6-membered heteroarylsulfanyl) -acetyl]Mutilin, 14-O- [ ((guanidino-imino- (C)_1-6) Alkyl) -5-or 6-membered heteroarylsulfanyl) -acetyl]Mutilin, 14-O- [ (((C)_1-6) Alkylguanidino-imino- (C)_1-6) Alkyl) -5-or 6-membered heteroarylsulfanyl) -acetyl]Mutilin, 14-O- [ ((ureido-imino- (C)_1-6) Alkyl) -5-or 6-membered heteroarylsulfanyl) -acetyl]Mutilin, 14-O- [ ((thioureido-imino- (C)_1-6) Alkyl) -5-or 6-membered heteroarylsulfanyl) -acetyl]Mutilin, 14-O- [ ((isothioureido-imino- (C)_1-6) Alkyl) -5-or 6-membered heteroarylsulfanyl) -acetyl]-mutilin, comprising

a. Reacting 14-O-pleuromutilin tosylate (14-O-pleuromutilin mesylate) with hydroxy- (C) in the presence of a base_1-6) -alkyl-thiophenols or 5-or 6-membered hydroxy- (C)_1-6) Alkyl-thioheteroaryl compound reaction (if no further conversion is required, the final compound is isolated and purified in a suitable manner),

b1. the hydroxyl group is selectively oxidized to the formyl group using a suitable oxidizing agent (if no further conversion is required, the final compound is isolated and purified in a suitable manner),

b2. the hydroxyl group is converted into the corresponding mesylate,

c1. by condensing compounds having formyl groups with compounds containing free amino groups

c2. Replacement of the mesylate with an azide

c2a replacement of methanesulfonate with a substituted primary or secondary amine

d2. Reduction of the azide to an amine

e2. The amine is acylated.

Compounds having substituents not intended to participate in the reaction step may be used in protected form. The protecting group can be removed later without interfering with the rest of the molecule.

The compounds obtained by the process provided by the present invention can be converted into the corresponding salts according to, e.g. analogously to conventional methods, e.g. by treatment with an acid, or a metal base (metal base), respectively, to obtain acid addition salts or metal salts, and vice versa, the compounds in salt form obtained by the process provided by the present invention can be converted into the corresponding compounds in free base (free base) form according to, e.g. analogously to conventional methods, e.g. by treatment with an acid if a metal salt is obtained and a metal base, e.g. a metal hydroxide, if an acid addition salt is obtained.

The compounds of the present invention, for example, including the above-described phenylsulfanyl-or 5-6-membered heteroarylsulfanyl-mutilins provided by the present invention, and the compounds of the general formula I or II show pharmacological activity and are therefore useful as medicaments.

For example, the compounds of the present invention exhibit antimicrobial activity, such as antibacterial activity, against: gram-positive bacteria, such as coagulase-positive and coagulase-negative Staphylococci (staphyloccci), e.g. Staphylococcus aureus, Streptococcus hemolyticus (staphyloccocus haemolyticus), Streptococcus (streptococci), e.g. Streptococcus pyogenes (Streptococcus pyogenenes), Streptococcus pneumoniae (Streptococcus pneumoniae), Streptococcus agalactiae (Streptococcus agalactiae), Enterococci (Enterococci), Enterococci and Moraxellaceae (Moraxellaceae), e.g. moraxella catarrhalis, Pasteurellaceae (pasteurella), e.g. Haemophilus influenzae (Haemophilus influenzae), and anti-mycoplasmaceae, Chlamydiaceae (chlamydiae), e.g. chlamydophila chlamydomonas, chlamydia trachomatis, and chlamydia difficile, e.g. chlamydia pneumoniae, chlamydia pneumoniae and anaerobic chlamydia difficile (Clostridium difficile), e.g. chlamydia pneumoniae, chlamydia pneumoniae (Clostridium difficile); the activities were measured in vitro in an agar dilution test or microdilution test according to the Clinical and laboratory Standards Institute (CLSI, formerly National Committee for Clinical Laboratory Standards (NCCLS)2006, Document M7-A7 Vol.26, No. 2: "Methods for dilution of Antimicrobial reactivity Tests for bacterial growth Aerobically-derived Edition, applied Standard", and in vitro in an anti-septic model according to the National Committee for Clinical Laboratory Standards (NCCLS) VOL.24, No.2, M11-A5, Methods for Antimicrobial reactivity Testing of Staphylococcus aureus; in vitro in a model for anti-septic activity of Staphylococcus aureus (CLSI, mouse) and in a micro-dilution test.

The compounds of the invention are therefore suitable for the treatment and prevention of diseases mediated by microorganisms, for example by bacteria. Diseases which may also be treated include, for example, diseases mediated by Helicobacter (Helicobacter pylori), such as Helicobacter pylori (Helicobacter pylori), and by Mycobacterium tuberculosis (Mycobacterium tuberculosis), diseases mediated by legionella pneumophila (legionella) or Neisseriaceae (Neisseriaceae), and also diseases which may also be treated generally include inflammatory diseases in which a microorganism is mediating said inflammation, including, for example, acne.

The compounds of the invention are preferably useful for the treatment of skin and soft tissue infections, for example, infections of the epidermis such as impetigo, bullous impetigo or deep pustule, infections of the dermis such as erysipelas, cellulitis, erythrasma or necrotizing fasciitis, follicular infections such as folliculitis, furunculosis or carbuncle disease, other infections such as paronychia, dactylitis, staphylococcal disease, mastitis, secondarily infected skin lesions, secondarily infected skin diseases, for the eradication of bacterial carriers (decolonization), for example of nasal staphylococcus aureus carriers, and for the treatment of acne by topical application. Thus, in another aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt or derivative or solvate thereof, for the manufacture of a medicament suitable for topical administration for the treatment of skin and soft tissue infections and for the treatment of acne in humans. The invention also provides the use of a compound of the invention, or a pharmaceutically acceptable derivative thereof, for the manufacture of a medicament for the treatment of a skin or soft tissue infection.

In another aspect, the present invention provides a compound of the invention for use as a medicament, preferably as an antimicrobial, e.g. antibacterial, e.g. anti-anaerobic.

In another aspect, the present invention provides a compound of the present invention for the treatment of acne.

In another aspect, the invention provides a compound of the invention for use in the preparation of a medicament for the treatment of a disease mediated by a microorganism, e.g. a bacterium, e.g.

-diseases mediated by bacteria, for example bacteria selected from staphylococci, streptococci, enterococci;

diseases mediated by helicobacter antibodies

-diseases mediated by Legionella (Legionella), Neisseria, Moraxella, Pasteurellaceae, Corynebacteria,

-diseases mediated by Mycobacterium tuberculosis,

diseases mediated for example by Mycoplasmataceae, Chlamydiaceae and obligate anaerobes,

-for the treatment of acne,

and for eliminating colonization in individuals colonized by bacteria.

In another aspect, the present invention provides a method of treating a disease mediated by a microorganism, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention, e.g., in the form of a pharmaceutical composition.

In another aspect, the present invention provides a method of treating acne comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention, e.g., in the form of a pharmaceutical composition

Treatment includes both treatment and prevention.

For antimicrobial and acne treatment, the appropriate dosage will of course depend upon, for example, the chemical nature and pharmacokinetic data of the compound of the invention employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, for satisfactory results in larger mammals, such as humans, a recommended daily dosage is about 0.01-3g of a compound of the present invention, for example, suitably administered in divided doses up to four times per day.

The compounds of the invention may be administered by any conventional route, for example, by invasive, including, for example, nasal, buccal, rectal, oral; parenteral, including, for example, intravenous, intramuscular, subcutaneous administration; or topically, for example including transdermal, intranasal, intratracheal administration, for example in the form of coated or uncoated tablets, capsules, injectable solutions or suspensions, for example in the form of ampoules, vials, in semisolid preparations, for example ointments, creams, gels, pastes, in the form of inhalation powders, foams, tinctures, lipsticks, foundations (concealer sticks), drops, sprays or in the form of suppositories, for example in a manner similar to that of macrolides, for example erythromycin, such as clarithromycin or azithromycin (azithromycin).

The compounds of the invention may be administered in the form of: pharmaceutically acceptable salts, such as acid addition salts or metal salts; or in free form; optionally in the form of a solvate. The compounds of the invention in salt form are shown in free form; optional compound in solvate form with the same level of activity.

The compounds of the present invention may be used in the pharmaceutical treatment according to the present invention, either alone or in combination with one or more other pharmaceutically active agents. These other pharmaceutically active agents include, for example, other antibiotics and anti-inflammatory agents, and, if the compounds of the present invention are used to treat acne, other pharmaceutical agents also include agents that are anti-acne active or are used to decolonize/sterilize bacterial carriers. Combinations include fixed combinations wherein two or more pharmaceutically active agents are in the same formulation; kits in which two or more pharmaceutically active agents in separate formulations are sold in the same package, e.g., with instructions for co-administration; and free combinations in which the pharmaceutically active agents are packaged separately but instructions for simultaneous or sequential administration are given.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (i) in free form or in pharmaceutically acceptable salt form; the compounds of the invention, for example in the form of and/or solvates, for example comprising a compound of the general formula I, together with at least one pharmaceutical excipient, for example a carrier or diluent, for example comprising fillers, binders, disintegrants, flow-regulating agents, lubricants, sugars and sweeteners, flavorants, preservatives, stabilizers, wetting and/or emulsifying agents, solubilizers, salts for regulating the osmotic pressure and/or buffers.

In another aspect, the present invention provides a pharmaceutical composition according to the invention, further comprising another pharmaceutically active agent.

Such pharmaceutical compositions may be manufactured according to, e.g., similar to conventional processes, e.g., by mixing, granulating, coating, dissolving or lyophilizing processes.

The unit dosage form may contain, for example, from about 0.01mg to about 3000mg, such as from 1mg to about 100 mg.

The compounds of the invention are also suitable as veterinary agents, e.g. veterinary active compounds, e.g. for the prevention and treatment of microbial, e.g. bacterial diseases, in animals such as poultry, pigs and cattle; for example and for diluting fluids for artificial insemination and for egg dipping techniques.

In another aspect, the invention provides a compound of the invention for use as a veterinary agent.

In another aspect, the invention provides a compound of the invention for use in the preparation of a veterinary composition which is useful as a veterinary agent.

In another aspect, the present invention provides a veterinary method of preventing and treating microbial, e.g. bacterial, diseases, which comprises administering to a subject in need of such treatment an effective amount of a compound of the present invention, e.g. in the form of a veterinary composition.

For the use of the active compounds of the invention as veterinary agents, the dosage will of course vary depending on the size and age of the animal and the effect desired; for example, for prophylactic treatment, lower doses may be administered over a longer period, e.g., 1-4 weeks. Preferred dosages in drinking water are from 0.0125 to 0.05 weight by volume, especially from 0.0125 to 0.025; for foodstuffs, 20-400 g/metric ton, preferably 20-200 g/metric ton. The active compounds according to the invention are preferably administered to hens as veterinary agents in drinking water, to pigs in food and to cattle orally or parenterally, for example in the form of oral or parenteral preparations.

The invention is further described with reference to the following examples. These examples are provided for illustrative purposes only and are not intended to limit the invention in any way.

Examples

Example 1: 14-O- [ (3-hydroxymethyl-phenylsulfanyl) -acetyl ] -mutilin

Step 1: pleuromutilin tosylate

To a solution of 18.63g (49.2mmol) of pleuromutilin and 9.39g (49.2mmol) of tosyl chloride in 1400mL of methyl ethyl ketone is slowly added a solution of 4.98g (49.2mmol) of triethylamine in 300mL of methyl ethyl ketone at ambient temperature. The reaction was stirred at ambient temperature for 24 hours, the precipitate formed was filtered off and 2800mL of water were added to the solution. The solution was extracted three times with ethyl acetate and Na₂SO₄The organic phase was dried and evaporated to dryness under reduced pressure. The crude product was used in the next step without further purification.

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.49(d, 3H, J ═ 7Hz, CH)₃-16)；0.8(d，3H，J＝7Hz，CH₃-17)；1.02(s，3H，CH₃-18)；1.29(s，3H，CH₃-15); 2.38(bs, 1H, H-4); AB-system (upsilon)_A＝4.75，υ_B＝4.62，J＝50Hz，CH₂-22); 5,00(m, 2H, H-20); 5.52(d, 1H, J ═ 8Hz, H-14); 6.04(dd, 1H, J ═ 11 and 18Hz, H-19); 7.46(d, 2H, J ═ 8Hz, H-24); 7.79(d, 2H, J ═ 8Hz, H-23).

Step 2: 14-O- [ (3-hydroxymethyl-phenylsulfanyl) -acetyl ] -mutilin

To 1.96g (14mmol) of (3-mercapto-phenyl) -methanol in 90mL of anhydrous ethanol [ prepared from 3-mercaptobenzoic acid according to: chemistry Express, volume 7, No.11, pp.865-868(1992)]To this solution, 322mg (14mmol) of sodium was added. After stirring the reaction for 30min at ambient temperature, a solution of 7.45g (14mmol) of pleuromutilin tosylate in 130mL of methyl ethyl ketone was added and the reaction stirred for 16h at ambient temperature. The reaction mixture was evaporated to dryness under reduced pressure, dissolved in ethyl acetate and extracted three times with water. With Na₂SO₄The organic phase is dried, evaporated to dryness under reduced pressure and applied to silica gel using dichloromethane/methanol 100: 1.5 asThe mobile phase chromatographically separates the residue.

The material obtained is crystalline (Fp.139-141 ℃ C.).

¹H-NMR(500MHz，CDCl₃δ, ppm, characteristic signal): 0.68(d, 3H, J ═ 7Hz, CH)₃-16)；0.88(d，3H，J＝7Hz，CH₃-17)；1.12(s，3H，CH₃-18)；1.42(s，3H，CH₃-15)；2.06(bs，1H，H-4)；3.32(t，1H，J＝6Hz，H-11)；3.59(s，2H，CH₂-22)；4.66(s，2H，CH₂-27); 5.15 and 5.30(2xm, 2H, H-20); 5.72(d, 1H, J ═ 8Hz, H-14); 6.41(dd, 1H, J ═ 11 and 17Hz, H-19); 7.19 and 7.28(2xm, 3H, H-24, 25 and 26); 7.38(s, 1H, H-23).

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.56(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.98(s，3H，CH₃-18)；1.30(s，3H，CH₃-15); 3.37(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.81，υ_B＝3.74，J＝29Hz，CH₂-22)；4.44(d，2H，J＝6Hz，CH₂-27); 4.95(m, 2H, H-20); 5.49(d, 1H, J ═ 8Hz, H-14); 6.04(m, 1H, H-19), 7.10-7.27(4xm, 4H, H-23, 24, 25 and 26).

The following compounds were prepared in a similar manner:

example 2 (comparative): 14-O- [ (4-methyl-phenylsulfanyl) -acetyl ] -mutilin

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.55(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.98(s，3H，CH₃-18)；1.30(s，3H，CH₃-15)；2.24(s，3H，CH₃-27); 2.35(bs, 1H, H-4); 3.37(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.75，υ _B＝3.68，J＝28Hz，CH₂-22); 4.96(m, 2H, H-20); 5.48(d, 1H, J ═ 8Hz, H-14); 6.03(dd, 1H, J ═ 11, and 20Hz, H-19); 7.09 and 7.23(2xd, 4H, J ═ 8Hz, arom-H).

Example 3: 14-O- [ (5-hydroxymethyl-2-fluoro-phenylsulfanyl) -acetyl ] -mutilin

¹H-NMR(400MHz，CD₃OD, δ, ppm, characteristic signal): 0.67(d, 3H, J ═ 7Hz, CH)₃-16)；0.89(d，3H，J＝7Hz，CH₃-17)；1.18(s，3H，CH₃-18)；1.35(s，3H，CH₃-15); 2.29(bs, 1H, H-4); 3.42(d, 1H, J ═ 7Hz, H-11); AB-system (upsilon)_A＝3.70，υ_B＝3.60，J＝39Hz，CH₂-22)；4.53(s，2H，CH₂-26); 5.07(m, 2H, H-20); 5.64(d, 1H, J ═ 8Hz, H-14); 6.19(dd, 1H, J ═ 7 and 19Hz, H-19); 7.08, 7.27 and 7.44(3xm, 3H, H-23, 24 and 25).

The required (4-fluoro-3-mercapto-phenyl) -methanol was prepared in two steps from 3-chlorosulfonyl-4-fluoro-benzoic acid following the procedure for preparing (3-mercapto-phenyl) -methanol described in chemistry express, volume 7, No.11, pp.865-868.

Example 4: 14-O- [ (2-hydroxymethyl-4-fluoro-phenylsulfanyl) -acetyl ] -mutilin

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.51(d, 3H, J ═ 7Hz, CH)₃-16)；0.78(d，3H，J＝7Hz，CH₃-17)；0.97(s，3H，CH₃-18)；1.27(s，3H，CH₃-15); 2.34(bs, 1H, H-4); 3.37(d, 1H, J ═ 7Hz, H-11); AB-system (upsilon)_A＝3.78，υ_B＝3.70，J＝29Hz，CH₂-22)；4.56(d，2H，J＝5Hz，CH₂-26); 4.92(m, 2H, H-20); 5.45(d, 1H, J ═ 8Hz, H-14); 6.19(dd, 1H, J ═ 11 and 18Hz, H-19); 7.02 and 7.44(2xm, 2H, H-24 and 25); 7.20(m, 1H, H-23).

The required (5-fluoro-2-mercapto-phenyl) -methanol was prepared from 5-fluoro-2-mercapto-benzoic acid following the procedure for preparing (3-mercapto-phenyl) -methanol described in Chemistry Express, volume 7, No.11, pp.865-868.

Example 5: 14-O- [ (3-cyano-phenylsulfanyl) -acetyl ] -mutilin

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.55(d, 3H, J ═ 7Hz, CH)₃-16)；0.78(d，3H，J＝7Hz，CH₃-17)；0.97(s，3H，CH₃-18)；1.28(s，3H，CH₃-15); 2.35(bs, 1H, H-4); 3.36(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝4.00，υ_B＝3.93，J＝31Hz，CH₂-22); 4.97(m, 2H, H-20); 5.48(d, 1H, J ═ 8Hz, H-14); 6.01(dd, 1H, J ═ 11 and 18Hz, H-19); 7, 45-7.86(3xm, 4H, H-23, 24, 25 and 26).

The desired 3-mercapto-benzonitrile is prepared from 3-cyano-benzenesulfonyl chloride following the procedure described in Journal of heterocyclic chemistry (1982), 19(4), 961-5 for 3-mercaptobenzoic acid.

Example 6: 14-O- [ (4-hydroxymethyl-phenylsulfanyl) -acetyl ] -mutilin

¹H-NMR(400MHz，CDCl₃δ, ppm, characteristic signal): 0.68(d, 3H, J ═ 7Hz, CH)₃-16)；0.86(d，3H，J＝7Hz，CH₃-17)；1.12(s，3H，CH₃-18)；1.40(s，3H，CH₃-15); 2.06(bs, 1H, H-4); 3.32(dd, 1H, J ═ 7 and 11Hz, H-11); 3.56(s, 2H, CH)₂-22)；4.66(d，2H，J＝4Hz，CH₂-25); 5.16 and 5.30(2xm, 2H, H-20); 5.73(d, 1H, J ═ 8Hz, H-14); 6.41(dd, 1H, J ═ 11 and 17Hz, H-19); 7.28 and 7.38(2xd, 4H, J ═ 8Hz, H-23 and 24); 9.91(s, 1H, H-25).

The required (4-mercapto-phenyl) -methanol was prepared from 4-mercapto-benzoic acid following the procedure for preparing (3-mercapto-phenyl) -methanol described in Chemistry Express, volume 7, No.11, pp.865-868.

Example 7: 14-O- [ (2-hydroxymethyl-phenylsulfanyl) -acetyl ] -mutilin

¹H-NMR(500MHz，CDCl₃δ, ppm, characteristic signal): 0.60(d, 3H, J ═ 7Hz, CH)₃-16)；0.85(d，3H，J＝7Hz，CH₃-17)；1.09(s，3H，CH₃-18)；1.39(s，3H，CH₃-15); 2.04(bs, 1H, H-4); 3.30(t, 1H, J ═ 7Hz, H-11); AB-system (upsilon)_A＝3.62，υ_B＝3.58，J＝21Hz，CH₂-22); AB-system (upsilon)_A＝4.82，υ_B＝4.78，J＝19Hz，CH₂-27); 5.12 and 5.28(2xm, 2H, H-20); 5.67(d, 1H, J ═ 8Hz, H-14); 6.35(dd, 1H, J ═ 11 and 18Hz, H-19); 7.24 and 7.42(2xm, 4H, arom-H).

The required (2-mercapto-phenyl) -methanol was prepared from 2-mercapto-benzoic acid following the procedure for preparing (3-mercapto-phenyl) -methanol described in Chemistry Express, volume 7, No.11, pp.865-868.

Example 8: 14-O- [ (2-hydroxy-5-hydroxymethyl-phenylsulfanyl) -acetyl ] -mutilin

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.57(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.99(s，3H，CH₃-18)；1.29(s，3H，CH₃-15); 2.34(bs, 1H, H-4); 3.36(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.70，υ_B＝3.59，J＝26Hz，CH₂-22)；4.32(d，2H，J＝5Hz，CH₂-26); 4.95(m, 2H, H-20); 5.47(d, 1H, J ═ 8Hz, H-14); 6.03(dd, 1H, J ═ 11 and 18Hz, H-19); 6.75(d, 1H, J ═ 8Hz, H-25); 6.98(dd, 1H, J ═ 2 and 8Hz, H-24); 7.11(d, 1H, J ═ 2Hz, H-23).

The required 4-hydroxymethyl-2-mercapto-phenol was prepared from 3-chlorosulfonyl-4-hydroxybenzoic acid following the procedure for the preparation of (3-mercapto-phenyl) -methanol described in Chemistry Express, volume 7, No.11, pp.865-868.

Example 9: 14-O- [ (3-formyl-phenylsulfanyl) -acetyl ] -mutilin

To 2.38g (4.75mmol) of 14-O- [ (3-hydroxymethyl-phenylsulfanyl) -acetyl ] -mutilin in 70mL of dichloromethane was added 2.02g (4.75mmol) of Dess-Martin reagent. After stirring the reaction at ambient temperature for 60min, the reaction mixture was filtered, evaporated to dryness under reduced pressure and chromatographed on silica gel using dichloromethane/methanol 100: 1 as mobile phase.

¹H-NMR(400MHz，CDCl₃δ, ppm, characteristic signal): 0.68(d, 3H, J ═ 7Hz, CH)₃-16)；0.86(d，3H，J＝7Hz，CH₃-17)；1.11(s，3H，CH₃-18)；1.39(s，3H，CH₃-15)；2.06(bs，1H，H-4)；3.32(m，1H，H-11)；3.64(s，2H，CH₂-22); 5.12 and 5.26(2xm, 2H, H-20); 5.74(d, 1H, J ═ 8Hz, H-14); 6.36 and 6.40(dd, 1H, J ═ 11 and 17Hz, H-19); 7.45(t, 1H, J ═ 8Hz, H-25); 7.62(m, 1H, H-26); 7.71(m, 1H, H-24); 7.85(m, 1H, H-23); 9.97(s, 1H, H-27).

The following compounds were prepared in a similar manner:

example 10: 14-O- [ (2-formylphenylsulfanyl) -acetyl ] -mutilin

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.54(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.97(s，3H，CH₃-18)；1.32(s，3H，CH₃-15); 2.35(bs, 1H, H-4); 3.37(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.95，υ_B＝3.88，J＝21Hz，CH₂-22); 4.92(m, 2H, H-20); 5.50(d, 1H, J ═ 8Hz, H-14); 6.02(dd, 1H, J ═ 11 and 18Hz, H-19); 7.38 and 7.57(2xt, 2H, J ═ 8Hz, H-24 and 25); 7.50 and 7.89(2xd, 2H, J ═ 8Hz, H-23 and 26); 10.19(s, 1H, H-27).

Example 11: 14-O- [ (4-formylphenylsulfanyl) -acetyl ] -mutilin

¹H-NMR(500MHz，DMSO-d₆δ, ppm, characteristic signal): 0.57(d, 3H, J ═ 7Hz, CH)₃-16)；0.78(d，3H，J＝7Hz，CH₃-17)；0.96(s，3H，CH₃-18)；1.30(s，3H，CH₃-15); 2.36(bs, 1H, H-4); 3.37(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝4.03，υ_B＝3.98，J＝24Hz，CH₂-22); 4.95(m, 2H, H-20); 5.51(d, 1H, J ═ 8Hz, H-14); 6.02(dd, 1H, J ═ 11 and 18Hz, H-19); 7.49 and 7.78(2xd, 4H, J ═ 8Hz, H-23 and 24); 9.91(s, 1H, H-25).

Example 12: 14-O- { [3- (aminoimino-methyl) -hydrazinoidenemethyl-phenylsulfanyl ] -acetyl } -mutilin hydrochloride

To 381mg (0.61mmol) of 14-O- [ (3-formyl-phenylsulfanyl) -acetyl ] -mutilin in 4mL of N, N-dimethylacetamide is added 83mg (0.61mmol) of aminoguanidine-dihydrocarbonate and 0.61mL of 2N HCl. After stirring the reaction at ambient temperature for 12h, the reaction mixture was evaporated to dryness under reduced pressure and chromatographed on silica gel using dichloromethane/methanol/isopropyl ether 4: 1 with 1% acetic acid as mobile phase.

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.55(d, 3H, J ═ 7Hz, CH)₃-16)；0.78(d，3H，J＝7Hz，CH₃-17)；0.95(s，3H，CH₃-18)；1.27(s，3H，CH₃-15); 2.33(bs, 1H, H-4); 3.36(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.94，υ_B＝3.85，J＝36Hz，CH₂-22); 4.90(m, 2H, H-20); 5.48(d, 1H, J ═ 8Hz, H-14); 6.00(dd, 1H, J ═ 11 and 18Hz, H-19); 7.32(m, 1H, H-25); 7.32 and 7.58(2xm, 2H, H-24 and 26); 7.83(s, 1H, H-23); 8.05(s, 1H, H-27).

The following compounds were prepared in a similar manner:

example 13: 14-O- [ {3- [ ((1-piperazineiminomethyl) -methylhydrazinylidene) -methyl ] -phenylsulfanyl } -acetyl ] -mutilin hydrochloride

¹H-NMR(500MHz，CD₃OD, δ, ppm, characteristic signal): 0.65(d, 3H, J ═ 7Hz, CH)₃-16)；0.89(d，3H，J＝7Hz，CH₃-17)；1.03(s，3H，CH₃-18)；1.37(s，3H，CH₃-15)；3.34(s，3H，N-CH₃)；3.41-3.58(m，8H，N-CH₂) (ii) a AB-system (upsilon)_A＝3.78，υ_B＝3.73，J＝24Hz，CH₂-22); 5.01(m, 2H, H-20); 5.64(d, 1H, J ═ 8Hz, H-14); 6.15(dd, 1H, J ═ 11 and 18Hz, H-19); 7.40, 7,48 and 7, 64(3xm, 3H, H-24, 25 and 26); 7.86(s, 1H, H-23); 8.14(bs, 1H, H-27).

Example 14: 14-O- [ {3- [ (3-ethyl- (2-ethylimino) -imidazolidin-1-ylimino) -methyl ] -phenylsulfanyl } -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，CDCl₃δ, ppm, characteristic signal): 0.66(d, 3H, J ═ 7Hz, CH)₃-16)；0.87(d，3H，J＝7Hz，CH₃-17)；1.10(s，3H，CH₃-18)；1.32(t，3H，J＝7Hz，CH₃-31)；1.39(s，3H，CH₃-15)；2.06(bs，1H，H-4)；3.46(d，3H，J＝5Hz，CH₃-32)；3.62(s，2H，CH₂-22); 3.85 and 4.05(2xm, 4H, CH)₂-28 and 29); 3.97(q, 2H, J ═ 7Hz, CH₂-30); 5.12 and 5.25(2xm, 2H, H-20); 5.70(d, 1H, J ═ 8Hz, H-14); 6.37(dd, 1H, J ═ 11 and 17Hz, H-19); 7.30-7.55(3xm, 3H, H-24, 25 and 26); 7.56(s, 1H, H-23); 7.64(s, 1H, H-27).

Example 15: 14-O- [ {3- [ (1-piperazinyliminomethyl) -hydrazinoidenemethyl ] -phenylsulfanyl } -acetyl ] -mutilin hydrochloride

¹H-NMR(500MHz，CDCl₃δ, ppm, characteristic signal): 0.63(d, 3H, J ═ 7Hz, CH)₃-16)；0.87(d，3H，J＝7Hz，CH₃-17)；1.04(s，3H，CH₃-18)；1.35(s，3H，CH₃-15)；2.25(bs，1H，H-4)；3.05(m，4H，N-CH₂)；3.64(m，6H，N-CH₂H-22); 5.02 and 5.12(2xm, 2H, H-20); 5.65(d, 1H, J ═ 8Hz, H-14); 6.21(dd, 1H, J ═ 11 and 17Hz, H-19); 7.31(t, 1H, H-25); 7.38 and 7.52(2xm, 2H, H-24 and 26); 7.77(bs, 1H, H-23); 8.26(s, 1H, H-27).

Example 16: 14-O- [ {3- [ (2-morpholin-4-yl-ethoxyimino) -methyl ] -phenylsulfanyl } -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.55(d, 3H, J ═ 7Hz, CH)₃-16)；0.78(d，3H，J＝7Hz，CH₃-17)；0.95(s，3H，CH₃-18)；1.28(s，3H，CH₃-15)；2.34(bs，1H，H-4)；2.40(m，4H，CH₂-30)；2.60(t，2H，J＝6Hz，CH₂-29)，3.42(t，1H，J＝6Hz，H-11)；3.55(t，4H，J＝5Hz，CH₂-31); AB-system (upsilon)_A＝3.88，υ _B＝3.70，J＝30Hz，CH₂-22)；4.21(t，2H，J＝6Hz，CH₂-28); 4.90(m, 2H, H-20); 5.48(d, 1H, J ═ 8Hz, H-14); 6.00(dd, 1H, J ═ 11 and 18Hz, H-19); 7.30-7.90(m, 4H, H-23, 24, 25 and 26); 8.17(s, 1H, H-27).

Example 17: 14-O- [3- { [ (2-pyrrolidin-1-yl-ethoxyimino) -methyl ] -phenylsulfanyl } -acetyl ] -mutilin hydrochloride

¹H-NMR(500MHz，DMSO-d₆δ, ppm, characteristic signal): 0.55(d, 3H, J ═ 7Hz, CH)₃-16)；0.78(d，3H，J＝7Hz，CH₃-17)；0.96(s，3H，CH₃-18)；1.28(s，3H，CH₃-15)；2.34(bs，1H，H-4)；2.60-3.00(bm，10H，CH₂-29, 30 and 31); 3.36(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.88，υ_B＝3.70，J＝35Hz，CH₂-22)；4.26(t，2H，J＝6Hz，CH₂-28); 4.90(m, 2H, H-20); 5.48(d, 1H, J ═ 8Hz, H-14); 6.00(dd, 1H, J ═ 11 and 18Hz, H-19); 7.30-7.43(m, 3H, H-24, 25 and 26); 7.58(s, 1H, H-23); 8.19(s, 1H, H-27).

Example 18: 14-O- [ {4- [ (1-piperazinyliminomethyl) -hydrazinoidenemethyl } -phenylsulfanyl } -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.51(d, 3H, J ═ 7Hz, CH)₃-16)；0.77(d，3H，J＝7Hz，CH₃-17)；0.97(s，3H，CH₃-18)；1.24(s，3H，CH₃-15)；2.33(bs，1H，H-4)；3.18(m，4H，CH₂-29)；3.36(t，1H，J＝6Hz，H-11)；3.81(m，4H，CH₂-28); AB-system (upsilon)_A＝3.90，υ_B＝3.81，J＝34Hz，CH₂-22); 4.91(m, 2H, H-20); 5.47(d, 1H, J ═ 8Hz, H-14); 6.00(dd, 1H, J ═ 11 and 18Hz, H-19); 7.10-7.51(m, 5H, H-23, 24, 25, 26 and 27).

Example 19: 14-O- [ {2- [ (aminoiminomethyl) -hydrazinoidenemethyl ] -phenylsulfanyl } -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.52(d, 3H, J ═ 7Hz, CH)₃-16)；0.75(d，3H，J＝7Hz，CH₃-17)；0.96(s，3H，CH₃-18)；1.27(s，3H，CH₃-15); 2.33(bs, 1H, H-4); 3.36(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.87，υ_B＝3.78，J＝26Hz，CH₂-22); 4.92(m, 2H, H-20); 5.47(d, 1H, J ═ 8Hz, H-14); 5.99(m, 1H, H-19); 7.25(m, 2H, H-24 and 25); 7.44 and 7.96(2xm, 2H, H-23, and 26); 8.54(s, 1H, H-27).

Example 20: 14-O- [ {4- [ (aminoiminomethyl) -hydrazinoidenemethyl ] -phenylsulfanyl } -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.56(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.97(s，3H，CH₃-18)；1.30(s，3H，CH₃-15); 2.36(bs, 1H, H-4); 3.37(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.94，υ_B＝3.88，J＝24Hz，CH₂-22)；4.96(m，2H，H-20)；5.50(d，1H，J＝8Hz，H-14)；6.03(dd，1H, J ═ 11 and 18Hz, H-19); 7.38 and 7.78(2xd, 4H, J ═ 8Hz, H-23 and 24); 8.10(s, 1H, H-25).

Example 21: 14-O- [ {4- [ (1-piperazinyliminomethyl) -hydrazinoidenemethyl ] -phenylsulfanyl } -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.56(d, 3H, J ═ 7Hz, CH)₃-16)；0.78(d，3H，J＝7Hz，CH₃-17)；0.98(s，3H，CH₃-18)；1.29(s，3H，CH₃-15)；2.36(bs，1H，H-4)；3.22(m，4H，CH₂-27)；3.37(t，1H，J＝6Hz，H-11)；3.85(m，4H，CH₂-26); AB-system (upsilon)_A＝3.95，υ_B＝3.89，J＝24Hz，CH₂-22); 4.94(m, 2H, H-20); 5.49(d, 1H, J ═ 8Hz, H-14); 6.03(dd, 1H, J ═ 11 and 18Hz, H-19); 7.40 and 7.79(2xd, 4H, J ═ 8Hz, H-23 and 24); 8.54(s, 1H, H-25).

Example 22: 14-O- [ {4- [ (1-piperazinyliminomethyl) -methylhydrazidenemethyl ] -phenylsulfanyl } -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.55(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.99(s，3H，CH₃-18)；1.30(s，3H，CH₃-15)；2.36(bs，1H，H-4)；3.24(m，4H，CH₂-28)；3.37(s，3H，CH₃-26)，3.37(t，1H，J＝6Hz，H-11)；3.70(m，4H，CH₂-27); AB-system (upsilon)_A＝3.94，υ_B＝3.88，J＝21Hz，CH₂-22); 4.95(m, 2H, H-20); 5.51(d, 1H, J ═ 8Hz, H-14); 6.04(dd, 1H, J ═ 11 and 18Hz, H-19); 7.40 and 7.73(2xd, 4H, J ═ 8Hz, H-23 and 24); 8.10(s, 1H, H-25).

Example 23: 14-O- [ {3- [ (1-acetylpiperazineiminomethyl) -hydrazinoidenemethyl ] -phenylsulfanyl } -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，CD₃OD, δ, ppm, characteristic signal): 0.63(d, 3H, J ═ 7Hz, CH)₃-16)；0.87(d，3H，J＝7Hz，CH₃-17)；1.04(s，3H，CH₃-18)；1.34(s，3H，CH₃-15)；2.13(s，3H，CH₃-30), AB-system (upsilon)_A＝3.51，υ_B＝3.33，J＝67Hz，CH₂-22)；3.50(t，1H，J＝6Hz，H-11)；3.55-3.69(m，8H，CH₂-28 and 29); 5.01 and 5.12(2xm, 2H, H-20); 5.65(d, 1H, J ═ 8Hz, H-14); 6.21(dd, 1H, J ═ 11 and 17Hz, H-19); 7.28(m, 1H, H-25); 7.33 and 7.48(2xm, 2H, H-24 and 26); 7.74(m, 1H, H-23); 8.18(s, 1H, H-27).

The required 1-acetylpiperazineiminomethyl-hydrazine is prepared analogously to the 1-formylpiperazineiminomethyl-hydrazine described hereinbefore (WO 9635692).

Example 24: 14-O- [ (3-acetoxymethyl-phenylsulfanyl) -acetyl ] -mutilin

To 1g (2mmol) of 14-O- [ (3-hydroxymethyl-phenylsulfanyl) -acetyl]Mutilin in 10mL CH₂Cl₂To the solution in (1) was added 351. mu.L (3.2mmol) of N-methylmorpholine and 302. mu.L (3.2mmol) of acetic anhydride, together with a catalytic amount of 4-dimethylaminopyridine. The reaction mixture was allowed to stand at ambient temperature for 16h, concentrated under reduced pressure and CH was used on silica₂Cl₂The mobile phase used was/MeOH 100: 0.5 → 100: 1 for chromatographic separation.

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.56(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.98(s，3H，CH₃-18)；1.30(s，3H，CH₃-15)；2.05(s，3H，CH₃-28); 2.35(bs, 1H, H-4); 3.37(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.85，υ _B＝3.78，J＝29Hz，CH₂-22)；4.97(m，2H，H-20)；5.00(s，2H，CH₂-27); 5.49(d, 1H, J ═ 8Hz, H-14); 6.03(dd, 1H, J ═ 11 and 18Hz, H-19); 7.13-7.28(m, 3H, H-24, 25, and 26); 7.33(bs, 1H, H-23).

Example 25: 14-O- { [3- (2-hydroxyphenylcarbonyl) -hydroxymethyl-phenylsulfanyl ] -acetyl } -mutilin

To be suspended in 15mL of CH₂Cl₂122mg (1mmol) of 4-dimethylaminopyridine (276 mg, 2mmol) of salicylic acid to which 500mg (1mmol) of 14-O- [ (3-hydroxymethyl-phenylsulfanyl) -acetyl ] acetyl]Mutilin and 515mg (2.5mmol) dicyclohexylcarbodiimide. Allowing the reaction mixture to reactLet stand at ambient temperature for 24 h. After concentration under reduced pressure, water and ethyl acetate were added and the organic phase was washed several times with water and brine. After concentration under reduced pressure, CH was used₂Cl₂The residue is chromatographed as mobile phase with MeOH 100: 1.

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.53(d, 3H, J ═ 7Hz, CH)₃-16)；0.77(d，3H，J＝7Hz，CH₃-17)；0.95(s，3H，CH₃-18)；1.27(s，3H，CH₃-15); 2.30(bs, 1H, H-4); 3.34(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.88，υ_B＝3.79，J＝26Hz，CH₂-22)；4.92(m，2H，H-20)；5.46(d，1H，J＝8Hz，H-14)；6.02(m，1H，H-19)；6.88-7.80(m，8H，arom-H).

Example 26: 14-O- [ (3-mercaptomethyl-phenylsulfanyl) -acetyl } -mutilin

Step 1: 14-O- [ (3-methanesulfonyloxymethyl-phenylsulfanyl) -acetyl ] -mutilin

To 6g (12mmol) of 14-O- [ (3-hydroxymethyl-phenylsulfanyl) -acetyl ] -mutilin in 250mL of dry THF were added 2.17mL (20mmol) of N-methylmorpholine and 3.06g (18mmol) of methanesulfonic anhydride along with a catalytic amount of 4-dimethylaminopyridine. The reaction mixture was allowed to stand at ambient temperature for 2 h. After addition of water, the mixture was extracted with ethyl acetate and the organic phase was washed several times with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was used in the next step without further purification.

¹H-NMR(400MHz，CDCl₃Delta, ppm, characteristic signal)：0.68(d，3H，J＝7Hz，CH₃-16)；0.87(d，3H，J＝7Hz，CH₃-17)；1.12(s，3H，CH₃-18)；1.40(s，3H，CH₃-15)；2.08(bs，1H，H-4)；2.96(s，3H，CH₃-28)； 3.34(d，1H，J＝6Hz，H-11)；3.59(s，2H，CH₂-22); 5.15 and 5.30(2xm, 2H, H-20); 5.72(d, 1H, J ═ 8Hz, H-14); 6.40(dd, 1H, J ═ 11 and 17Hz, H-19); 7.23-7.43(m, 4H, arom-H).

Step 2: 14-O- [ (3-tritylsulfanylmethyl-phenylsulfanyl) -acetyl ] -mutiline

To 118mg (1.73mmol) of NaOEt in 5mL of anhydrous ethanol was added 478mg (1.73mmol) of triphenylmethanethiol in 8mL of anhydrous ethanol and the resulting solution was stirred at ambient temperature. After 45 minutes, 1g (1.73mmol) of 14-O- [ (3-methanesulfonyloxymethyl-phenylsulfanyl) -acetyl ] -mutilin in 9mL of acetone was added and the reaction was kept at ambient temperature for 3 h. After concentration under reduced pressure, water and ethyl acetate were added and the organic phase was washed several times with water and brine. After concentration under reduced pressure, the crude product was used in the next step without further purification.

¹H-NMR(400MHz，CDCl₃δ, ppm, characteristic signal): 0.66(d, 3H, J ═ 7Hz, CH)₃-16)；0.85(d，3H，J＝7Hz，CH₃-17)；1.07(s，3H，CH₃-18)；1.38(s，3H，CH₃-15)；2.03(bs，1H，H-4)；3.26(s，2H，CH₂-27)；3.29(d，1H，H-11，J＝6Hz)；3.54(d，2H，J＝8Hz，CH₂-22); 5.09 and 5.26(2xm, 2H, H-20); 5.68(d, 1H, J ═ 8Hz, H-14); 6.38(dd, 1H, J ═ 11 and 18Hz, H-19); 6.95, and 7.20(2xm, 2H, H-24, and 26); 7.10(m, 1H, H-23); 7.13(t, 1H, J ═ 7Hz, H-25); 7.22-7.30(m, 15H, trityl-H).

And step 3: 14-O- [ (3-mercaptomethyl-phenylsulfanyl) -acetyl ] -mutilin

To dissolve in 15ml of LTFA/CH₂Cl₂600mg (0.79mmol) of 14-O- [ (3-tritylsulfanylmethyl-phenylsulfanyl) -acetyl ] mixture in a 1: 1 mixture]630. mu.L (3.95mmol) of triethylsilane was added to mutilin. The reaction mixture was allowed to stand at ambient temperature for 2 h. After concentration under reduced pressure, the residue is chromatographed on silica using cyclohexane/ethyl acetate 7: 3 as mobile phase.

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.57(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.98(s，3H，CH₃-18)；1.30(s，3H，CH₃-15)；2.37(bs，1H，H-4)；3.38(t，1H，J＝6Hz，H-11)；3.66(d，2H，J＝8Hz，CH₂-27); AB-system (upsilon)_A＝3.84，υ_B＝3.77，J＝27Hz，CH₂-22); 4.95(m, 2H, H-20); 5.49(d, 1H, J ═ 8Hz, H-14); 6.03(dd, 1H, J ═ 11 and 18Hz, H-19); 7.12-7.26(m, 3H, H-24, 25 and 26); 7.31(bs, 1H, H-23).

Example 27: 14-O- [ (3-acetylthiomethyl-phenylsulfanyl) -acetyl ] -mutilin

To 579mg (1mmol) of 14-O- [ (3-methanesulfonyloxymethyl-phenylsulfanyl) -acetyl ] in 100mL of THF]-mutilin to 114mg thioethylAnd (4) potassium salt. After stirring at ambient temperature for 24h, the reaction mixture was concentrated under reduced pressure. Ethyl acetate and water were added and the organic phase was washed several times with water and brine. After concentration under reduced pressure, CH was used₂Cl₂The residue is chromatographed as mobile phase with MeOH 100: 1.

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.55(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.98(s，3H，CH₃-18)；1.29(s，3H，CH₃-15)；2.33(s，3H，CH₃-28); 2.35(bs, 1H, H-4); 3.37(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.82，υ _B＝3.76，J＝26Hz，CH₂-22)；4.04(s，2H，CH₂-27); 4.94(m, 2H, H-20); 5.49(d, 1H, J ═ 8Hz, H-14); 6.03(dd, 1H, J ═ 11 and 18Hz, H-19); 7.08(m, 1H, H-25); 7.22(m, 2H, H-24 and 26); 7.26(bs, 1H, H-23).

Example 28: 14-O- [ (3-azidomethyl-phenylsulfanyl) -acetyl ] -mutilin

To 1g (1.73mmol) of 14-O- [ (3-methanesulfonyloxymethyl-phenylsulfanyl) -acetyl ] in 10mL of DMF]-mutilin added with 449mg NaN₃. The resulting suspension was stirred at 50 ℃ for 4.5h and kept at ambient temperature overnight. Water and ethyl acetate were added and the organic phase was washed several times with water and brine. After concentration under reduced pressure, CH was used on silica₂Cl₂The residue is chromatographed as mobile phase with MeOH 100: 1.

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.56(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；1.00(s，3H，CH₃-18)；1.30(s，3H，CH₃-15); 2.34(bs, 1H, H-4); 3.37(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.85，υ_B＝3.78，J＝27Hz，CH₂-22)；4.39(s，2H，CH₂-27); 4.95(m, 2H, H-20); 5.49(d, 1H, J ═ 8Hz, H-14); 6.04(dd, 1H, J ═ 11 and 18Hz, H-19); 7.18(m, 1H, H-25); 7,32(m, 2H, H-24 and 26); 7,34(bs, 1H, H-23).

Example 29: 14-O- [ (3 aminomethyl-phenylsulfanyl) -acetyl ] -mutilin hydrochloride

1g (1.9mmol) of 14-O- [ (3-azidomethyl) -phenylsulfanyl-acetyl]Mutilin was dissolved in 30mL THF, 900mg Lindlar-catalyst was added and the reaction mixture was hydrogenated for 6 h. The reaction mixture was filtered through celite, concentrated under reduced pressure and CH was used on silica₂Cl₂The residue was chromatographed as mobile phase with MeOH 10: 1. The hydrochloride salt was obtained as follows: 125mg of 14-O- [ (3-aminomethyl) -phenylsulfanyl-acetyl]-mutilin dissolved in 3ml CH₂Cl₂To which was added 2mL of HCl-saturated Et₂And O. After 45 minutes, the reaction was evaporated to dryness under reduced pressure.

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.57(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；1.00(s，3H，CH₃-18)，1.31(s，3H，CH₃-15); 2.38(bs, 1H, H-4); 3.38(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.89，υ_B＝3.82，J＝26Hz，CH₂-22)；3.95(s，2H，CH₂-27)；4.98(m，2H，H-20)；5.51(d，1H，J＝8Hz，H-14)；6.05(dd, 1H, J ═ 11 and 18Hz, H-19); 7,30(m, 3H, H-24, 25 and 26); 7,48(s, 1H, H-23).

Example 30: 14-O- [ (3-acetylaminomethyl-phenylsulfanyl) -acetyl ] -mutilin

To 3mL CH₂Cl₂300mg (0.6mmol) of 14-O- [ (3-aminomethyl) -phenylsulfanyl-acetyl]To mutilin was added 106. mu.L (0.96mmol) of N-methylmorpholine, 91. mu.L (0.96mmol) of acetic anhydride and a catalytic amount of 4-dimethylaminopyridine. The resulting solution was allowed to stand at ambient temperature for 5 h. After evaporation to dryness under reduced pressure, CH was used₂Cl₂The residue was chromatographed as mobile phase/MeOH 100: 1 → 100: 1.2.

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.56(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.99(s，3H，CH₃-18)；1.30(s，3H，CH₃-15)；1,85(s，3H，CH₃-28); 2.35(bs, 1H, H-4); 3.38(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.82，υ _B＝3.75，J＝28Hz，CH₂-22)；4，18(d，2H，J＝6Hz，CH₂-27); 4.95(m, 2H, H-20); 5.49(d, 1H, J ═ 8Hz, H-14); 6.04(dd, 1H, J ═ 11 and 19Hz, H-19); 7.03-7.26(m, 4H, H-23, 24, 25 and 26).

The following examples were prepared in a similar manner using acetic anhydride:

example 31: 14-O- [ (3-formylaminomethyl-phenylsulfanyl) -acetyl ] -mutilin

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.57(d, 3H, J ═ 7Hz, CH)₃-16)；0.80(d，3H，J＝7Hz，CH₃-17)；1.00(s，3H，CH₃-18)；1.30(s，3H，CH₃-15); 2.35(bs, 1H, H-4); 3.37(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.85，υ_B＝3.77，J＝26Hz，CH₂-22)；4,24(d，2H，J＝6Hz，CH₂-27); 4.95(m, 2H, H-20); 5.49(d, 1H, J ═ 8Hz, H-14); 6.05(dd, 1H, J ═ 11 and 19Hz, H-19); 7,03-7.38(m, 4H, H-23, 24, 25 and 26), 8.11(s, 1H, H-28).

Example 32: 14-O- [ {3- [ (2-hydroxy-ethylamino) -methyl ] -phenylsulfanyl } -acetyl ] -mutilin hydrochloride

To 579mg (1mmol) of 14-O- [ (3-methanesulfonyloxymethyl-phenylsulfanyl) -acetyl ] in 20mL of THF]To mutilin 112mg (2mmol) of 2-amino-ethanol was added and the reaction was stirred at ambient temperature for 16 h. After concentration under reduced pressure, ethyl acetate and water were added and the organic phase was washed several times with water and brine. The organic phase is dried over anhydrous sodium sulfate, evaporated under reduced pressure and CH is used on silica₂Cl₂/MeOH/NH₃The residue was chromatographed using an aqueous solution 100: 5: 0.05 as the mobile phase. The hydrochloride salt as exemplified for example 29 was obtained.

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.57(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.98(s，3H，CH₃-18)；1.30(s，3H，CH₃-15)；2.35(bs，1H，H-4)；2.53(t，2H，J＝6Hz，CH₂-28)；3.38(m，5H，H-11，CH₂-28 and 29); 3.44(q, 2H, J ═ 6 and 10Hz, CH₂-29)；3.65(S，3H，CH₂-27); AB-system (upsilon)_A＝3.82，υ_B＝3.74，J＝27Hz，CH₂-22); 4.95(m, 2H, H-20); 5.49(d, 1H, J ═ 8Hz, H-14); 6.04(dd, 1H, J ═ 11 and 18Hz, H-19); 7.18(m, 3H, H-24, 25 and 26); 7.29(s, 1H, H-23).

The following compounds were prepared in a similar manner:

example 33: 14-O- [ {3- [ (3-amino-propylamino) -methyl ] -phenylsulfanyl } -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.56(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.98(s，3H，CH₃-18)；1.30(s，3H，CH₃-15); 2.35(bs, 1H, H-4); 2.48 and 2.57(2xm, 4H, CH)₂-28 and 30); 3.36(t, 1H, J ═ 6Hz, H-11); 3.60(s, 2H, CH)₂-27); AB-system (upsilon)_A＝3.81，υ_B＝3.743，J＝28Hz，CH₂-22); 4.95(m, 2H, H-20); 5.49(d, 1H, J ═ 8Hz, H-14); 6.03(dd, 1H, J ═ 11 and 17Hz, H-19); 7.10-7.23(m, 3H, H-24, 25 and 26); 7.28(s, 1H, H-23).

Example 34: 14-O- [ (3- { [3- (3-amino-propylamino) -propylamino ] -methyl } -phenylsulfanyl) -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.57(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；1.00(s，3H，CH₃-18)；1.31(s，3H，CH₃-15)；2.38(s，1H，H-4)；2.86-3.05(m，8H，CH₂-28, 30, 31 and 33); 3.76(bt, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.92，υ_B＝3.84，J＝27Hz，CH₂-22)；4.06(bs，2H，CH₂-27); 4.97(m, 2H, H-20); 5.51(d, 1H, J ═ 8Hz, H-14); 6.04(dd, 1H, J ═ 11 and 18Hz, H-19); 7,36(m, 3H, H-24, 25 and 26); 7,60(s, 1H, H-23).

Example 35: 14-O- [ {3- [ (2, 2-difluoro-ethylamino) -methyl ] -phenylsulfanyl } -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.55(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.97(s，3H，CH₃-18)；1.29(s，3H，CH₃-15)；2.34(bs，1H，H-4)；2.79(bt，2H，J＝16Hz，CH₂-28)；3.48(t，1H，J＝6Hz，H-11)；3.68(s，2H，CH₂-27); AB-system (upsilon)_A＝3.83，υ_B＝3.77，J＝30Hz，CH₂-22); 4.94(m, 2H, H-20); 5.49(d, 1H, J ═ 8Hz, H-14); 5,97(tt, 1H, J ═ 4 and 56Hz, H-29); 6.03(dd, 1H, J ═ 11 and 18Hz, H-19); 7,10-7.28(m, 3H, H-24, 25 and 26); 7,30(s, 1H)，H-23).

Example 36: 14-O- [ (3-benzylaminomethyl-phenylsulfanyl) -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.56(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；1.00(s，3H，CH₃-18)；1.30(s，3H，CH₃-15); 2.35(bs, 1H, H-4); 3.37(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.89，υ_B＝3.83，J＝26Hz，CH₂-22)；4.09(m，4H，CH₂-27 and 28); 4.95(m, 2H, H-20); 5.50(d, 1H, J ═ 8Hz, H-14); 6.04(dd, 1H, J ═ 8 and 20Hz, H-19); 7,32-7,56(m, 9H, arom-H).

Example 37: 14-O- [ (3-allylaminoethyl-phenylsulfanyl) -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.56(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；1.00(s，3H，CH₃-18)；1.30(s，3H，CH₃-15)；2.35(bs，1H，H-4)；3.37(t，1H，J＝6Hz，H-11)；3.54(d，2H，J＝7Hz，CH₂-28); AB-system (upsilon)_A＝3.90，υ_B＝3.83，J＝26Hz，CH₂-22)；4.04(s，2H，CH₂-27)；4.97(m，2H，H-20)(ii) a 5.43(m, 2H, H-30); 5.50(d, 1H, J ═ 8Hz, H-14); 5,90(m, 1H, H-29); 6.04(dd, 1H, J ═ 11 and 18Hz, H-19); 7,35(m, 3H, H-24, 25 and 26); 7,53(d, 1H, J ═ 1Hz, H-23).

Example 38: 14-O- { [3- (2-methoxy-ethylamino) -methyl-phenylsulfanyl ] -acetyl } -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.57(d, 3H, J ═ 7Hz, CH)₃-16)；0.80(d，3H，J＝7Hz，CH₃-17)；0.99(s，3H，CH₃-18)；1.30(s，3H，CH₃-15)；2.36(bs，1H，H-4)；3,01(t，2H，J＝5Hz，CH₂-28)；3.28(s，3H，CH₃-30); 3.38(t, 1H, J ═ 6Hz, H-11); 3.59(t, 2H, J ═ 5Hz, H-29); AB-system (upsilon)_A＝3.89，υ_B＝3.83，J＝26Hz，CH₂-22)；4.07(s，2H，CH₂-27); 4.97(m, 2H, H-20); 5.50(d, 1H, J ═ 8Hz, H-14); 6.04(dd, 1H, J ═ 10 and 21Hz, H-19); 7,34(m, 3H, H-24, 25 and 26); 7,56(bs, 1H, H-23).

Example 39: 14-O- [ (3- { [2- (2-amino-ethylamino) -ethylamino ] -methyl } -phenylsulfanyl) -acetyl ] -mutilin hydrochloride

¹H-NMR(500MHz，DMSO-d₆δ, ppm, characteristic signal): 0.57(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；1.00(s，3H，CH₃-18)；1.31(s，3H，CH_3-15)；2.37(bs，1H，H-4)；3,13-3,36(m，8H，CH₂-28, 29, 30 and 31); 3.37(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.92，υ_B＝3.84，J＝32Hz，CH₂-22)；4.15(s，2H，CH₂-27); 4.96(m, 2H, H-20); 5.52(d, 1H, J ═ 8Hz, H-14); 6.06(dd, 1H, J ═ 11 and 18Hz, H-19); 7,37(m, 3H, H-24, 25 and 26); 7,59(s, 1H, H-23).

Example 40: 14-O- [3- { [ (furan-2-ylmethyl) -amino ] -methyl } -phenylsulfanyl-acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.57(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.99(s，3H，CH₃-18)；1.31(s，3H，CH₃-15); 2.36(bs, 1H, H-4); 3.37(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.90，υ_B＝3.83，J＝26Hz，CH₂-22); 4.07 and 4.18(2xs, 4H, CH)₂-27 and 28); 4.95(m, 2H, H-20); 5.50(d, 1H, J ═ 8Hz, H-14); 6.05(dd, 1H, J ═ 11 and 18Hz, H-19); 6.53 and 6.63(2xm, 2H, H-30 and 31); 7,34(m, 3H, H-24, 25 and 26); 7,52(s, 1H, H-23); 7.76(m, 1H, H-32).

Example 41: 14-O- [ (3-methylaminomethyl-phenylsulfanyl) -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.57(d, 3H, J ═ 7Hz, CH)₃-16)；0.81(d，3H，J＝7Hz，CH₃-17)；0.99(s，3H，CH₃-18)；1.31(s，3H，CH₃-15)；2.36(bs，1H，H-4)；2,50(s，3H，CH₃-28); 3.38(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.90，υ _B＝3.83，J＝26Hz，CH₂-22)；4.07(s，2H，CH₂-27); 4.95(m, 2H, H-20); 5.50(d, 1H, J ═ 8Hz, H-14); 6.05(dd, 1H, J ═ 11 and 18Hz, H-19); 7,33(m, 3H, H-24, 25 and 26); 7,53(s, 1H, H-23).

Example 42: 14-O- [ (3-cyclopropylaminomethyl-phenylsulfanyl) -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.57(d, 3H, J ═ 7Hz, CH)₃-16)；0.70，0.85(2xm，4H，CH₂-29，30)；0.79(d，3H，J＝7Hz，CH₃-17)；1.00(s，3H，CH₃-18)；1.31(s，3H，CH₃-15); 2.37(bs, 1H, H-4); 2.60(m, 1H, H-28); 3.37(t, 1H, J ═ 6Hz, H-11); AB-system (upsilon)_A＝3.90，υ_B＝3.83，J＝27Hz，CH₂-22)；4,14(s，2H，CH₂-27); 4.95(m, 2H, H-20); 5.51(d, 1H, J ═ 8Hz, H-14); 6.05(dd, 1H, J ═ 11 and 18Hz, H-19); 7.34(s, 3H, H-24, 25 and 26); 7.53(s, 1H, H-28).

Example 43: 14-O- [ (3-morpholin-4-yl-methyl-phenylsulfanyl) -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.56(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.99(s，3H，CH₃-18)；1.29(s，3H，CH₃-15)；2.35(bs，1H，H-4)；2.98-3.23(m，4H，CH₂-28 and 31); 3.35(t, 1H, J ═ 6Hz, H-11); 3.70-3.96(m, 6H, CH)₂-22, 29 and 30); 4,27(m, 2H, CH)₂-27); 4.95(m, 2H, H-20); 5.50(d, 1H, J ═ 8Hz, H-14); 6.03(dd, 1H, J ═ 11 and 19Hz, H-19); 7.40(m, 3H, H-24, 25 and 26), 7.63(s, 1H, H-28).

Example 44: 14-O- [ (3-piperazin-1-ylmethyl-phenylsulfanyl) -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.56(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；1.00(s，3H，CH₃-18)；1.28(s，3H，CH₃-15); 2.23 and 2.66(m, t, 8H, J ═ 5Hz, CH₂-28, 29, 30 and 31); 2.34(bs, 1H, H-4); 3.35(m, 3H, H-11, CH)₂-27); AB-system (upsilon)_A＝3.80，υ_B＝3.73，J＝24Hz，CH₂-22)；4,27(m，2H，CH₂-27); 4.95(m, 2H, H-20); 5.49(d, 1H, J ═ 8Hz, H-14); 6.02(dd, 1H, J ═ 11 and 18Hz, H-19); 7.08-7.27(m, 4H, H-23, 24, 25 and 26).

Example 45: 14-O- {3- [ (2-dimethylamino-ethylamino) -methyl ] -phenylsulfanyl-acetyl } -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.56(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；1.00(s，3H，CH₃-18)；1.31(s，3H，CH₃-15)；2.37(bs，1H，H-4)；2.82(s，6H，CH₃-30 and 31); 3.38(m, 5H, H-11, CH)₂-28 and 29); AB-system (upsilon)_A＝3.92，υ_B＝3.83，J＝27Hz，CH₂-22)；4，13(m，2H，CH₂-27); 4.97(m, 2H, H-20); 5.51(d, 1H, J ═ 8Hz, H-14); 6.05(dd, 1H, J ═ 11 and 18Hz, H-19); 7.38(m, 3H, H-24, 25 and 26); 7.59(s, 1H, H-23).

Example 46: 14-O- {3- [ (2-amino-ethylamino) -methyl ] -phenylsulfanyl } -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.56(d, 3H, J ═ 7Hz, CH)₃-16)；0.80(d，3H，J＝7Hz，CH₃-17)；0.97(s，3H，CH₃-18)；1.30(s，3H，CH₃-15); 2.35(bs, 1H, H-4); 2.45 and 2.58(2xm, 4H, CH)₂-28 and 29); 3.34(d, 1H, J ═ 6Hz, H-11); 3.62(s, 2H, CH)₂-27); AB-system (upsilon)_A＝3.82，υ_B＝3.73，J＝27Hz，CH₂-22); 4.95(m, 2H, H-20); 5.49(d, 1H, J ═ 8Hz, H-14); 6.03(dd, 1H, J ═ 11 and 18Hz, H-19); 7.18(m, 3H, H-24, 25 and 26); 7.29(s, 1H, H-23).

Example 47: 14-O- [ (3- { [ bis- (2-hydroxy-ethyl) -amino ] -methyl } -phenylsulfanyl) -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.56(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.99(s，3H，CH₃-18)；1.30(s，3H，CH₃-15)；2.36(bs，1H，H-4)；2.53(t，2H，J＝6Hz，CH₂-28); 3.13 and 3.23(2xm, 4H, CH)₂-28 and 30); 3.38(bt, 1H, H-11, J ═ 6 Hz); 3.78(m, 4H, CH)₂-29 and 31); AB-system (upsilon)_A＝3.92，υ_B＝3.84，J＝31Hz，CH₂-22)；4.48(bd，2H，J＝4Hz，CH₂-27); 4.95(m, 2H, H-20); 5.50(d, 1H, J ═ 8Hz, H-14); 6.04(dd, 1H, J ═ 11 and 18Hz, H-19); 7.38(m, 4H, arom-H).

Example 48: 14-O- [ (3-dimethylaminomethyl-phenylsulfanyl) -acetyl ] -mutilin hydrochloride

¹H-NMR(400MHz，DMSO-d₆δ, ppm, characteristic signal): 0.55(d, 3H, J ═ 7Hz, CH)₃-16)；0.79(d，3H，J＝7Hz，CH₃-17)；0.97(s，3H，CH₃-18)；1.29(s，3H，CH₃-15)；2.11(s，6H，CH₃-28 and 29); 2.36(bs, 1H, H-4); 3.31(s, 2H, CH)₂-27); 3.37(t, 1H, H-11, J ═ 6 Hz); AB-system (upsilon)_A＝3.80，υ_B＝3.74，J＝25Hz，CH₂-22); 4.95(m, 2H, H-20); 5.49(d, 1H, J ═ 8Hz, H-14); 6.03(m, 1H, H-19); 7.08 and 7.22(2xm, 4H, arom-H).

Antibacterial activity of novel pleuromutilin derivatives:

the antimicrobial activity expressed as the Minimum Inhibitory Concentration (MIC) was determined according to the approved standard reference recommendation for CLSI (formerly NCCLS).

The compound of example 1 and other claimed compounds show very good activity against at least one of the clinically relevant bacterial pathogens staphylococcus aureus, enterococcus faecalis, streptococcus pneumoniae, moraxella catarrhalis and escherichia coli (see table 1). This in vitro activity was significantly better than the comparator compound 2, since the MIC of example 1 was at least one-half lower than the MIC of example 2 for at least one of the strains shown in table 1 (see table 1).

Table 1. example 1 and comparator compounds example 2 show antibacterial activity against selected bacterial pathogens as the minimum inhibitory concentration (MIC, [ μ g/ml ]).

Claims

1. A compound of the general formula (I)

Wherein

n is 1 to 6;

x is oxygen or NR₂Wherein R is₂Is hydrogen or linear or branched (C)_1-6) -alkyl, or hydroxy- (C)_1-6) Alkyl or (C)_1-6) Alkoxy radical- (C_1-6) Alkyl radical，

R₁Is hydrogen, linear or branched (C)_1-6) Alkyl, mono-or dihalo (C)_1-6) Alkyl, amino (C)_1-6) Alkyl, hydroxy (C)_1-6) Alkyl, phenyl (C)_1-6) Alkyl radicals, (C)_1-6) Alkenyl, furyl (C)_1-6) -alkyl or (C)_3-6) Cycloalkyl and the corresponding ammonium salt, or

XR₁Is piperazinyl or morpholinyl.

2. A compound of the general formula (II)

Wherein

n is a number of 0 to 5,

y is oxygen or NR₃，

R₃Is that

X is oxygen, sulfur, NH or NR₇；

Or

And the corresponding anion,

R₄、R₅、R₆、R₇is hydrogen, linear or branched C_1-6Alkyl or C_3-8Cycloalkyl, and with the proviso that if R is₃Is that

And R₄And R₇Together with the nitrogen atom to which they are attached form a 5-to 7-membered heterocyclic ring containing at least 2 nitrogen atoms,

and/or R₅And R₆Together with the nitrogen atom to which they are attached form a 5-to 7-membered heterocyclic ring containing at least 2 nitrogen atoms,

and/or R₄And R₅Together with the nitrogen atom to which they are attached form a 5-to 7-membered heterocyclic ring containing one or more nitrogen atoms, and

R₈is C_1-4An alkyl group.

3. A compound of the general formula (II)

Wherein

n is a number of 0 to 5,

y is NR₃，R₃Is that

X is oxygen, sulfur, NH or NR₇；

R₄And R₇Together with the nitrogen atom to which they are attached form a 5-to 7-membered heterocyclic ring containing at least 2 nitrogen atoms, and R₅And R₆As defined in claim 2, the first and second,

or R₅And R₆Together with the nitrogen atom to which they are attached form a 5-to 7-membered heterocyclic ring containing at least 2 nitrogen atoms, and R₄And R₇As defined in claim 2, the first and second,

or R₄And R₅Together with the nitrogen atom to which they are attached form a 5-to 7-membered heterocyclic ring containing one or more nitrogen atoms, and R₈Is C_1-4An alkyl group.

4. A compound according to claim 2 or 3, wherein

Y is NR₃X is NR₇，R₃Is that

And R is₄、R₅、R₆、R₇As defined in claim 2 or 3.

5. A compound according to claim 4, wherein

Y is NR₃X is NR₇，R₃Is that

R₆And R₇As defined in claim 2, the first and second,

R₉is hydrogen, linear or branched C_1-6Alkyl or C_1-6An acyl group.

6. A compound according to claim 2 or 3, wherein said (CH)₂)_nThe radical is in the meta position relative to the sulphur bonded to the phenyl ring.

7. A compound selected from the following:

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

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

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

14-O- [3- { [ (furan-2-ylmethyl) -amino ] -methyl } -phenylsulfanyl-acetyl ] -mutilin, and

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

14-O- [ (3-hydroxymethyl-phenylsulfanyl) -acetyl ] -mutilin of the general formula:

9. a compound according to any one of claims 1 to 8 in the form of a salt.

10. The use of a compound according to any one of claims 1-9 for the preparation of a medicament for the treatment of a disease mediated by microorganisms.

11. Use according to claim 10, wherein the microbial mediated disease is a microbial infection, which is a skin or soft tissue infection.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, and at least one pharmaceutical excipient.

13. The pharmaceutical composition according to claim 12, further comprising another pharmaceutically active agent.

14. A compound according to claim 1, wherein for R₁And the ammonium salt is chloride.