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WO2000027790A1 - Composes a base de mutiline - Google Patents

Composes a base de mutiline Download PDF

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Publication number
WO2000027790A1
WO2000027790A1 PCT/EP1999/008705 EP9908705W WO0027790A1 WO 2000027790 A1 WO2000027790 A1 WO 2000027790A1 EP 9908705 W EP9908705 W EP 9908705W WO 0027790 A1 WO0027790 A1 WO 0027790A1
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WO
WIPO (PCT)
Prior art keywords
mutilin
acetate
compound
ester
title compound
Prior art date
Application number
PCT/EP1999/008705
Other languages
English (en)
Inventor
Steven Dabbs
Susannah Davies
David Kenneth Dean
Colin Henry Frydrych
Alessandra Gaiba
Steven Howard
Eric Hunt
Francis David King
Antoinette Naylor
Andrew Kenneth Takle
Original Assignee
Smithkline Beecham P.L.C.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9824781.0A external-priority patent/GB9824781D0/en
Priority claimed from GBGB9827830.2A external-priority patent/GB9827830D0/en
Priority claimed from GBGB9827880.7A external-priority patent/GB9827880D0/en
Application filed by Smithkline Beecham P.L.C. filed Critical Smithkline Beecham P.L.C.
Publication of WO2000027790A1 publication Critical patent/WO2000027790A1/fr

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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07C205/43—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
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Definitions

  • the present invention relates to novel compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medical therapy, particularly antibacterial therapy.
  • Pleuromutilin the compound of formula (A), is a naturally occurring antibiotic which has antimycoplasmal activity and modest antibacterial activity. It has been shown that the antimicrobial activity can be improved by replacing the glycolic ester moiety at position 14 by another acyloxy group R-X-CH2CO2-, where R is an aliphatic or aromatic moiety and X is O, S, or NR' (H. Egger and H. Reinshagen, J. Antibiotics, 1976, 29, 923).
  • Tiamulin, the compound of formula (B), which is used as a veterinary antibiotic, is a derivative of this type (G. Hogenauer in Antibiotics, Vol. V, part 1, ed. F.E. Hahn, Springer- Verlag, 1979, p.344).
  • WO 97/25309 (SmithKline Beecham) describes further modification of the acyloxy group, disclosing 14-(9-carbamoyl derivatives of mutilin or 19, 20- dihydromutilin, in which the N-atom of the carbamoyl group is unsubstituted, mono- or di-substituted.
  • WO98/05659 discloses 14-O-carbamoyl derivatives of mutilin or 19, 20-dihydromutilin, in which the N-atom of the carbamoyl group is acylated by a group which includes an azabicyclic moiety.
  • the present invention is based on the unexpected discovery that novel mutilin derivatives having either a spirocyclic acylcarbamate, an (hetero)arylalkyl carboxylate or an arylalkoxyalkyl carboxylate substituent at the 14-position also have antimicrobial activity. Accordingly the present invention provides a compound of formula (IA) or (IB)
  • Rl is RA(CH 2 )nO(CH 2 )m, R A (CH 2 ) p , or
  • Y is -NH-, -CH 2 - or -CH 2 -CH 2 -;
  • R A is an optionally substituted aryl group or heteroaryl group linked via a carbon atom; m is 1, 2 or 3; n is 0, 1 or 2; and p is 1 to 4;
  • R 2 is vinyl or ethyl
  • R 3 is H, OH or F, and R 4 is H, or R 3 is H and R 4 is F.
  • R 2 is vinyl or ethyl
  • R 3 is H, OH or F
  • Y is -NH-, -CH 2 - or -CH 2 -CH 2 -; and R is a spiro-fused monocyclic or bicyclic ring containing one or two basic nitrogen atoms.
  • R is monocyclic it may contain from 4 to 8 ring atoms, and when bicyclic may contain from 5 to 10 ring atoms in each ring, and is optionally substituted on carbon by up to 3 substituents.
  • Suitable substituents include alkyl, alkyloxy, alkenyl and alkenyloxy, each of which may be carried by either a bridgehead or a non-bridgehead carbon atom.
  • the counterion may be a halide ion such as chloride or bromide, preferably chloride.
  • the aza ring system additionally may contain one or more double bonds.
  • the ring containing X , X 2 and Y is suitably pyrrolidinone, piperidinone or imidazolidone or the corresponding dione.
  • R ⁇ is an optionally substituted aryl group or heteroaryl group linked via a carbon atom;
  • R 2 is vinyl or;
  • n is 1 or 2, and especially 1.
  • R ⁇ when it is an aryl group include optionally substituted phenyl.
  • R ⁇ when it is a heteroaryl group include optionally substituted thienyl, pyridinyl, furyl, thiazolyl, isoxazolyl, benzimidazolyl, quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl and benzothienyl.
  • RZ is a group RY(CH 2 ) n O(CH 2 )m; in which:
  • RY is an optionally substituted aryl or heteroaryl group linked via a carbon atom; n is 0, 1 or 2; and m is 1, 2 or 3;
  • R 2 is vinyl or ethyl
  • R 3 is H, OH or F
  • R 4 is H or R 3 is H and R 4 is F.
  • R ⁇ is a group RY0CH - , i.e. n is 0 and m is
  • Representative values for R ⁇ when it is an aryl group include optionally substituted phenyl.
  • Representative values for RY when it is a heteroaryl group include optionally substituted thienyl, pyridinyl, furyl, thiazolyl, isoxazolyl, benzimidazolyl, quinolinyl,
  • the aryl or heteroaryl group is optionally substituted, typically by up to three substituents on carbon atoms.
  • Representative substituents include nitro; optionally substituted (C ⁇ _6)alkyl, such as methyl optionally substituted by di(C] ⁇ 6)alkylamino, cyano, carbamoyl, and N-containing non-aromatic heterocyclyl; and substituents containing primary, secondary and tertiary amines, including (C ⁇ _6)alkylarnino(C ⁇ _6)alkyl and di(C ⁇ _6)alkylamino(Cj.6)alkyl, such as dimethylaminomethyl, (Cj_6)alkyl-and di(C 6)alkyl-amino(C ⁇ _6)alkoxy, N- containing non-aromatic heterocyclyl, such as piperidinyl,
  • (C ⁇ _6)alkylpiperidinyl(C ⁇ _6)alkyloxy such as methylpiperidinylmethoxy
  • suitable substituents include alkyloxy, alkenyl and alkenyloxy.
  • nitrogen atoms in heterocylic groups may be substituted by oxygen to form an N-oxide, or by mono- or dialkyl, in which case it will be appreciated that a quaternary cation can be formed.
  • the counterion may be a halide ion such as chloride or bromide, preferably chloride.
  • Preferred substituents include those containing primary, secondary and tertiary amines.
  • Alkyl and alkenyl groups referred to herein may be straight and branched groups containing up to six carbon atoms and are optionally substituted by one or more groups selected from the group consisting of aryl(C ⁇ _6)alkoxy, aryl(C ⁇ _6)alkylthio, cycloalkyl, cycloalkenyl, carboxy and salts and esters thereof, halogen, hydroxy, (C ⁇ -g)alkoxy, aryloxy, (Ci-g)alkoxycarbonyl, carbamoyl, mono- or di(C ⁇ -6)alkylcarbamoyl, sulphamoyl, mono- and di(C ⁇ -6)alkylsulphamoyl, amino, mono- and di(C ⁇ -6)alkylamino, (C ⁇ - ⁇ )acylamino, ureido, (C ⁇ -5)alkoxycarbonylamino,
  • Cycloalkyl and cycloalkenyl groups referred to herein include groups having from three to eight ring carbon atoms and are optionally substituted as described hereinabove for alkyl and alkenyl groups.
  • aryl means single and fused rings suitably containing from 4 to 7, preferably 5 or 6, ring atoms in each ring which rings may each be unsubstituted or substituted by, for example, up to three substituents.
  • a fused ring system may include aliphatic rings and need include only one aromatic ring.
  • Suitable aryl groups include phenyl and naphthyl such as 1-naphthyl or 2-naphthyl.
  • any aryl group including phenyl and naphthyl, may be optionally substituted by up to five, preferably up to three substituents.
  • Suitable substituents include halogen, (Cj ⁇ alkyl, aryl, aryl(C ⁇ _6)alkyl, (C ⁇ _6)alkoxy, (C ⁇ _6)alkoxy(C ⁇ _6)alkyl, halo(C ⁇ _6)alkyl, aryl(C ⁇ _6)alkoxy, hydroxy, nitro, cyano, azido, amino, mono- and di-N- (C ⁇ _6)alkylamino, acylamino, arylcarbonylamino, acyloxy, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(C ⁇ _6)alkylcarbamoyl,
  • two adjacent ring carbon atoms may be linked by a (C3_5)alkylene chain, to form a carbocyclic ring.
  • heterocyclyl and “heterocyclic” suitably include, unless otherwise defined, aromatic and non-aromatic, single and fused, rings suitably containing up to four heteroatoms in each ring, each of which is selected from oxygen, nitrogen and sulphur, which rings, may be unsubstituted or substituted by, for example, up to three substituents.
  • Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
  • a fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.
  • heteroaryl refers to a mono- or bicyclic heteroaromatic ring system comprising up to four, preferably 1 or 2, heteroatoms each selected from oxygen, nitrogen and sulphur. Each ring may have from 4 to 7, preferably 5 or 6, ring atoms.
  • a bicyclic heteroaromatic ring system may include a carbocyclic ring.
  • a substituent for a heterocyclyl or a heteroaryl group is selected from halogen, (C ⁇ _6)alkyl, aryl(C ⁇ _6)alkyl, (C ⁇ _g)alkoxy, (C ⁇ _6)alkoxy(C ⁇ _6)alkyl, halo(C ⁇ _ 6)alkyl, hydroxy, amino, mono- and di-iV-(C ⁇ _6)alkyl-amino, acylamino, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(C ⁇ _6)alkylcarbonyl, aryloxycarbonyl, (C ⁇ _6)alkoxycarbonyl(C ⁇ _6 ' )alkyl, aryl, oxy groups, ureido, (C ⁇ _ 6)alkylguanidino, amidino, (C ⁇ _6)alkylamidino, sulphonylamino, aminosulphonyl
  • the 2-hydroxy-substituted compounds of formula (IA 2 ) and (LA 3 ) are of the (25) configuration.
  • the 2-F-substituted compounds of formula (IA 2 ) and (IA 3 ) may be of (25) configuration or (2R) configuration, or be provided as mixtures thereof.
  • the (25) configuration is however preferred.
  • Examples of compounds of the invention include: 2,8-diaza-8-methyl-l-oxospiro[4.5]decane-2-carboxylic acid mutilin 14-ester;
  • the compounds of this invention may be in crystalline or non-crystalline form and, if crystalline, may optionally be hydrated or solvated.
  • This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water.
  • the compounds according to the invention are suitably provided in substantially pure form, for example at least 50% pure, suitable at least 60% pure, advantageously at least 75% pure, preferably at least 85% pure, more preferably at least 95% pure, especially at least 98% pure, all percentages being calculated as weight/weight.
  • the compounds of the invention may be in the form of free bases or acid addition salts. Examples carrying a carboxy substituent may be in the form of zwitterions, or alkali metal salts (of the carboxy group). Pharmaceutically acceptable salts are preferred.
  • Acid-addition salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.
  • Suitable salts include the hydrochloride, maleate, and methanesulphonate; particularly the hydrochloride.
  • the present invention also provides methods for preparing the compounds of the invention, starting from mutilin or epi-mu lin and introducing the C-14 side chain by an appropriate coupling reaction.
  • the mutilin nucleus may be modified to introduce 2-F; 2- OH; 19, 20-dihydro; or 1, 2-dehydro substituents, before or after the coupling.
  • the present invention provides a method for preparing compounds of formula (IA 1 ) and (LB 1 ) which comprises reacting a compound of formula
  • R 2 A and R 3 A are R 2 and R 3 as defined for formulae (IA) and (IB) or groups convertible to R 2 and R 3 , with a lactam of formula (HI):
  • R, X 1 , X 2 and Y are as defined for compounds of formula (IA ) and (IB ) in the presence of a base (e.g. lithium di-wo-propylamide, lithium hexamethyl-disilazide), suitably in a non-protic solvent (e.g. tetrahydrofuran, 1,2-dimethoxyethane), typically at a temperature of -60°C to 0°C; and, where required or desired, converting P to hydrogen, converting an R 2A or R 3A group to a R 2 or R 3 group, and/or converting one R 2 or R 3 group to another R 2 or R 3 group.
  • a base e.g. lithium di-wo-propylamide, lithium hexamethyl-disilazide
  • a non-protic solvent e.g. tetrahydrofuran, 1,2-dimethoxyethane
  • the present invention also provides a process for preparing a compound of formula (IA 2 ) or (IB 2 ) which comprises reacting a compound of formula (IIA 2 ) or (LIB 2 ):
  • R A, R3A ⁇ d R4A are R 2 , R 3 and R 4 as defined for formulae (IA) and (IB) or groups convertible to R 2 , R 3 and R 4 ; with an active derivative of a carboxylic acid of formula (LV):
  • Compounds of formula (IA 2 ) and (IB 2 ) may also be prepared by coupling a mutilin having a carboxylate-forming group at position 14, such as the 14-chloroformate, with an appropriate organolithium compound, and if necessary converting the epz-mutilin to mutilin.
  • the present invention provides a process for preparing a compound of formula (LA 2 ) or (IB 2 ) which comprises reacting a compound of the formula (IIA 1 ) or (LLB ) as hereinbefore defined; with an organo-lithium compound of formula (VI):
  • (VI) suitably in a non-protic solvent, such as THF, typically at a temperature in the range -78 to 0°C; and where required or desired; converting P to hydrogen, converting an R ⁇ A R2A R3A or R4A g r0 up to a RY, R 2 , R 3 or R 4 group, and/or converting one R ⁇ , R 2 , R 3 or R 4 group to another R ⁇ , R 2 , R 3 or R 4 group.
  • a non-protic solvent such as THF
  • the present invention additionally provides a process for preparing a compound of formula (LA 3 ) or (LB 3 ) which comprises reacting a compound of formula (HA 3 ) or (EQ3 3 ):
  • R 2 A, R 3 A an R4A are R 2 , R 3 and R 4 as defined for formulae (IA) and (IB) or groups convertible to R 2 , R 3 and R 4 , and RL is a leaving group or OH , with: (a) when R ⁇ is a leaving group, a compound of the formula (VA):
  • RYA is RY as defined for formulae (LA 3 ) and (LB 3 ) or a group convertible to RY, and Q 2 is a leaving group;
  • Suitable leaving groups for R ⁇ and Q 2 include halogen, tosylate, mesylate, diazonium, etc.
  • Procedures for coupling the group R (CH 2 ) m CO.O- with a compound of formula (VA B) include the following: (a) when R is a leaving group, such as tosyl, mesyl, chloro or bromo, by reaction of R with an alkoxide anion RYA(CH 2 ) n O _ in a non-protic solvent (e.g. tetrahydrofuran or N,N dimethylformamide), typically by analogy to the method of H. Egger and H. Reinshagen, J. Antibiot., 1976, 29, 915, for example forming the anion in situ by reacting the corresponding alcohol with sodium hydride; L L L L
  • RYA(CH 2 ) n - such as an aralkyl halide or aryl- or aralkyl-diazonium using conventional conditions for electrophilic substitution
  • Compounds of the formula (IA 3 ) or (LB 3 ) may also be prepared by coupling a mutilin (having a protected hydroxy group at position 11), with an active derivative of a carboxylic acid R(CH 2 ) n O(CH 2 )mCOOH, such as an acid chloride.
  • the present invention provides a process for preparing a compound of formula (IA 3 ) or (LB 3 ) which comprises reacting a compound of formula (IIA 2 ) or (LIB 2 ) as hereinbefore defined; with an active derivative of a carboxylic acid of formula (VII):
  • n and m are as defined for compounds of formulae (LA 3 ) and (LB 3 ) and RYA is RY as defined for formulae (LA 3 ) and (IB 3 ) or a group convertible to RY; under ester forming conditions; and thereafter, where required or desired; converting P to hydrogen, converting an RYA, R 2 A R3A or R4A g r0 up to an RY, R 2 , R 3 or R 4 group, and/or converting one RY, R 2 , R 3 or R 4 group to another RY, R 2 , R 3 or R 4 group.
  • the active derivative used as an acylating agent may be an acid chloride, acid bromide, a mixed anhydride, or an N- acyl-imidazole.
  • the preferred agent is an acid chloride.
  • General methods for forming such acylating agents from the acid are described in the chemical literature (see LO. Sutherland, Comprehensive Organic Chemistry, Vol. 2, ed. LO. Sutherland, pages 875- 883 (Pergamon Press, Oxford, 1979), and references therein).
  • Useful methods for acylating the 14-hydroxyl in the present invention include the use of the following: acid chloride in NN-dimethylformamide at elevated temperature (e.g. 100°C to 120°C); acid chloride in the presence of an organic base (e.g. pyridine, 2,6-lutidine, 2,4,6- collidine, di-wo-propylethylamine) or an inorganic base (e.g. sodium or lithium hexamethyldisilazide); carboxylic acid in the presence of dicyclohexylcarbodiimide and an acylation catalyst (e.g.
  • an organic base e.g. pyridine, 2,6-lutidine, 2,4,6- collidine, di-wo-propylethylamine
  • an inorganic base e.g. sodium or lithium hexamethyldisilazide
  • carboxylic acid in the presence of dicyclohexylcarbodiimide and an acylation catalyst (e.g.
  • tertiary base e.g. triethylamine, di-wo-propyl-ethylamine
  • an acylation catalyst e.g. 4-dimethylamino- pyridine, 4-pyrrolidino-pyridine.
  • substituent groups in compounds ( U), (LV), (VA/B), (VI) and (VH) prior to the coupling reaction for example protecting ⁇ atoms with alkoxycarbonyl, for example t-butoxycarbonyl.
  • P is a hydroxyl protecting group such as an acyl group, for example so that -OP is trifluoroacetyl or dichloroacetyl.
  • R 3 A is also preferably acyloxy, for example acetyl or dichloroacetyl.
  • Hydroxyl groups at positions 11 and 2 may be protected using, for example, dichloroacetic anhydride and pyridine in tetrahydrofuran or N-trifluoroacetyl-imidazole in tetrahydrofuran at 0°C.
  • the protecting acyl groups may be removed to restore the hydroxyl groups by hydrolysis e.g. using ⁇ aOH in MeOH.
  • Suitable hydroxy, carboxy and amino protecting groups are those well known in the art and which may be removed under conventional conditions and without disrupting the remainder of the molecule.
  • a comprehensive discussion of the ways in which hydroxy, carboxy and amino groups may be protected and methods for cleaving the resulting protected derivatives is given in for example "Protective Groups in Organic Chemistry” (T.W. Greene, Wiley-Interscience, New York, 2nd edition, 1991).
  • Particularly suitable hydroxy protecting groups include, for example, triorganosilyl groups such as, for instance, trialkylsilyl and also organocarbonyl and organooxycarbonyl groups such as, for instance, acetyl, allyloxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl.
  • Particularly suitable carboxy protecting groups include alkyl and aryl groups, for instance methyl, ethyl and phenyl.
  • Particularly suitable amino protecting groups include alkoxycarbonyl, 4-methoxybenzyloxycarbonyl and 4- nitrobenzyloxycarbonyl.
  • R YA , R A ; R2A R 3A or R 4A group Conversions of an R YA , R A ; R2A R 3A or R 4A group to a R ⁇ , R 1 , R 2 , R 3 or R 4 group typically arise when a protecting group is needed during the above coupling reaction or during the preparation of the reactants by the procedures described below.
  • Intercon version of one RY, R , R 2 , R 3 or R 4 group to another typically arises when one compound of formula (I) is used as the immediate precursor of another compound of formula (I) or when it is easier to introduce a more complex or reactive substituent at the end of a synthetic sequence.
  • R 2A is typically the R 2 group vinyl, and this may be converted to the alternative
  • R 2 ethyl group by hydrogenating the vinyl group to form an ethyl group, typically by hydrogenation over a palladium catalyst (e.g. 10% palladium-on-carbon) in a solvent such as ethyl acetate, ethanol, dioxane, or tetrahydrofuran.
  • a palladium catalyst e.g. 10% palladium-on-carbon
  • a solvent such as ethyl acetate, ethanol, dioxane, or tetrahydrofuran.
  • R3A i s typically hydrogen, fluoro or protected hydroxyl, such as acyloxy.
  • protecting acyl groups may be removed to restore the hydroxyl groups by hydrolysis e.g. using NaOH in MeOH.
  • Compounds of formula (IA) may also be prepared from an ep/-mutilin starting material.
  • This invention also provides for the preparation of a compound of formula (LA 1 ) by the reaction of a compound of formula (IIC ) :
  • P and R A are as defined for formulae (HA 1 ); with the lactam of formula (III) as defined above under similar conditions to the coupling of the compounds of formulae (IIA 1 ) and (LLB ) with lactam (Ul), and then treating the product with an acid, and where required or desired converting an R 2A group to a R 2 group, and/or converting one R 2 group to another R 2 group.
  • a compound of formula (LA 2 ) may be prepared by reacting an epi-mutilin compound of formula (LJC 2 ):
  • R 2 A is as defined for formulae (HA 2 ) and (HB 2 ); with an active derivative of the acid of formula (LV) under ester forming conditions, as hereinbefore described, and then treating the product with an acid, and where required or desired converting an R A or R 2A group to a R 1 or R 2 group, and/or converting one R 1 or R 2 group to another R or R 2 group.
  • a compound of formula (LA 2 ) may be prepared by reacting an epi- mutilin compound of formula (HC 1 ) as defined above; with the organo-lithium compound of formula (NI) above, and then treating the product with an acid, and where required or desired converting an RYA or R 2A group to a RY or R 2 group, and/or converting one RY or R 2 group to another RY or R 2 group.
  • a compound of formula (LA 3 ) may also be prepared from an e /-mutilin starting material, for instance by reacting a compound of formula (HC 3 ):
  • R 2A and R ⁇ are as defined for formulae (HA 3 ) and (HB 3 ); with the active derivative (V) by the procedures (a), (b) or (c) set out above, and then; treating the product with an acid, and thereafter and where required or desired; converting an RYA or R 2A group to a RY or R 2 group, and/or converting one RY or R 2 group to another RY or R 2 group.
  • a compound of formula (LA 3 ) may also be prepared by reacting a compound of formula (HC 2 ) as defined above; with an active derivative of a carboxylate acid of formula (VH) under ester forming conditions, as described above; and then, treating the product with an acid, and thereafter and where required or desired; converting an RYA or R 2A group to an RY or R 2 group, and/or converting one RY or R 2 group to another RY or R 2 group.
  • R 2A is typically the R 2 group vinyl, and this may be converted to the alternative
  • R 2 group by hydrogenating the vinyl group to form an ethyl group.
  • substituent groups in compounds of formula (III), (IV), (VA/B), (VI) and (VII) prior to the coupling reaction, for example protecting N atoms with alkoxycarbonyl, for example t-butoxycarbonyl.
  • the compounds of formulae (IIA 1 ), (HB ! and (IIC 1 ) may be prepared by reacting the corresponding compounds of formula (IIA 2 ), (IEB 2 ) and (IIC 2 ) in which the substituent at position 11 is hydroxyl:
  • P, R 2A and R 3A are as defined for formulae (HA 1 ), (HB 1 ) and (HC 1 ); with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate or bis(trichloromethyl) carbonate, in the presence of an organic base in a suitable solvent , such as tetrahydrofuran.
  • Suitable bases include pyridine, 2,6-lutidine, triethylamine, and N,N-di-wo-propylethylamine.
  • the reaction typically is carried out at 0°C to 20°C.
  • OP and R A hydroxyl groups are suitably protected as described above.
  • Suitable compounds of formula (VHI) include 11-O-acyl mutilin derivatives, e.g. mutilin
  • R 2 A is vinyl. They may be converted into the corresponding compounds in which R A is ethyl by hydrogenation, typically by hydrogenation over a palladium catalyst (e.g. 10% palladium-on-carbon) in a solvent such as ethyl acetate, ethanol, dioxane, or tetrahydrofuran.
  • a palladium catalyst e.g. 10% palladium-on-carbon
  • a solvent such as ethyl acetate, ethanol, dioxane, or tetrahydrofuran.
  • Compounds of formula (HA 2 ) in which R 3 A is hydroxyl or fluoro may be prepared by first preparing 2-hydroxymethylene mutilin from a compound of formula (VIII). Using procedures based on that described by A.J. Birch, C.W. Holzapfel and
  • the product is a mixture of the desired 2-hydroxymethylene compound and corresponding compounds substituted by formate at position 11 (if OP is OH) and /or position 14.
  • the formate groups may be removed when desired by treatment with potassium hydroxide in methanol.
  • the product mixture may be used directly to prepare 2-diazo-mutilin derivatives using the method described by H. Berner, G. Schulz, and G. Fisher, Monatsh. Chem., 1981, 112, 1441, for example by reacting a solution of a 2-hydroxymethylene-mutilin and the formate derivatives in dichloromethane at -10 °C under argon with tosyl azide and triethylamine.
  • Compounds of formula (IIA 2 ) in which R 3 A is fluoro may be obtained by reacting 2-diazo-mutilin with a source of hydrogen fluoride.
  • the hydrogen fluoride source is an amine complex of hydrogen fluoride such as hydrogen fluoride- pyridine.
  • the reaction may be carried out in an anhydrous solvent (e.g. diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane) at a temperature of -15°C to 25°C.
  • (25)-2-fluoro derivatives (2R)-2-Fluoro-mutilin derivatives may be prepared by treating the (25)-isomer with a base (e.g. sodium hydroxide or potassium hydroxide in ethanol). This will usually produce a mixture of (25) and (2R)-isomers that may be separated using conventional techniques such as chromatography and crystallisation.
  • a base e.g. sodium hydroxide or potassium hydroxide in ethanol
  • 1,2-Didehydro-mutilins are either 1 ,2-didehydro-mutilin or obtainable therefrom by manipulation of OP and R 2 A as described above.
  • 1,2-Didehydro-mutilins can be prepared using the method described by G. Schulz and H. Berner in Tetrahedron, 1984, 40 j 905, by treating the 2-diazo compound with cone. HCl, to give the 2-chloro derivative and then eliminating HCl, by heating at 160°C in 2,6-lutidine.
  • the compounds of the present invention may contain a chiral centre, and therefore the above processes may produce a mixture of diastereoisomers.
  • a single diastereoisomer may be prepared by separating such a mixture of diastereoisomers which has been synthesised using a racemic starting material, or by synthesis using an optically pure starting material.
  • the compounds of this invention may be in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated.
  • solvent of crystallisation may be present in the crystalline product.
  • some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be present in the crystalline product. Crystallisation procedures will usually produce stoichiometric hydrates.
  • Compounds containing variable amounts of water may be produced by processes such as lyophilisation.
  • the compounds according to the invention are suitably provided in substantially pure form, for example at least 50% pure, suitable at least 60% pure, advantageously at least 75% pure, preferably at least 85% pure, more preferably at least 95% pure, especially at least 98% pure, all percentages being calculated as weight/weight.
  • An impure or less pure form of a compound according to the invention may, for example, be used in the preparation of a more pure form of the same compound or of a related compound (for example a corresponding derivative) suitable for pharmaceutical use.
  • the present invention also includes pharmaceutically acceptable salts and derivatives of the compounds of the invention. Salt formation may be possible when one of the substituents carries an acidic or basic group. Salts may be prepared by salt exchange in conventional manner.
  • Acid-addition salts may be pharmaceutically acceptable or non-pharmaceutically acceptable. In the latter case, such salts may be useful for isolation and purification of the compound of the invention, or intermediates thereto, and will subsequently be converted into a pharmaceutically acceptable salt or the free base.
  • the compounds of the present invention and their pharmaceutically acceptable salts or derivatives have antimicrobial properties and are therefore of use in therapy, in partiuclar for treating microbial infections in animals, especially mammals, including humans, in particular humans and domesticated animals (including farm animals).
  • the compounds may be used for the treatment of infections caused by, for example, Gram- positive and Gram-negative bacteria and mycoplasmas, including, for example, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Haemophilius sp., Neisseria sp., Legionella sp., Chlamydia sp., Moraxella catarrhalis, Mycoplasma pneumoniae, and Mycoplasma gallisepticum.
  • the present invention also provides a method of treating microbial infections in animals, especially in humans and in domesticated mammals, which comprises administering a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof, or a composition according to the invention, to a patient in need thereof.
  • the invention further provides the use of a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the preparation of a medicament for use in the treatment of microbial infections.
  • Compounds of the present invention may be used to treat skin and soft tissue infections and acne, by topical application. Accordingly, in a further aspect the present invention provides the use of a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the preparation of a medicament adapted for topical administration for use in the treatment of skin and soft tissue infections and also in the treatment of acne in humans. Compounds of the present invention may be also used for the elimination or reduction of nasal carriage of pathogenic bacteria such as 5. aureus, H. in ⁇ uenzae, 5. pneumonia and M. catarrhalis, in particular colonisation of the nasospharynx by such organisms, by the administration of a compound of the present invention thereto.
  • pathogenic bacteria such as 5. aureus, H. in ⁇ uenzae, 5. pneumonia and M. catarrhalis
  • the present invention provides for the use of a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the manufacture of a medicament adapted for administration to the nasal cavity, for reducing or eliminating the nasal carriage of pathogenic organisms.
  • the medicament is adapted for focussed delivery to the nasopharynx, in particular the anterior nasopharynx.
  • Such reduction or elimination of nasal carriage is believed to be useful in prophylaxis of recurrent acute bacterial sinusitis or recurrent otitis media in humans, in particular in reducing the number of episodes experienced by a patient over a given period of time or increasing the time .intervals between episodes.
  • the present invention provides for the use of a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the manufacture of a medicament adapted for administration to the nasal cavity, for prophylaxis of recurrent acute bacterial sinusitis or recurrent otitis media.
  • Compounds of the present invention are also useful in treating chronic sinusitis.
  • the present invention provides for the use of a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the manufacture of a medicament, for treating of chronic sinusitis.
  • the compounds according to the invention may suitably be administered to the patient at a daily dosage of from 1.0 to 50 mg/kg of body weight.
  • a daily dosage of from 1.0 to 50 mg/kg of body weight For an adult human (of approximately 70 kg body weight), from 50 to 3000 mg, for example about 1500 mg, of a compound according to the invention may be administered daily.
  • the dosage for adult humans is from 5 to 20 mg/kg per day. Higher or lower dosages may, however, be used in accordance with normal clinical practice.
  • drug substance is administered on a daily basis, for a small number of days, for instance from 2 to 10, suitably 3 to 8, more suitably about 5 days, the administration then being repeated after an interval, for instance, on a monthly basis over a period of months, for instance up to six months.
  • the drug substance may be administered on a continuing, daily basis, over a prolonged period, for instance several months.
  • drug substance is administered once or twice a day.
  • drug substance is administered during the winter months when bacterial infections such as recurrent otitis media and recurrent sinusitis tend to be more prevalent.
  • the drug substance may be administered at a dosage of from 0.05 to l.OOmg, typically about 0.1 to 0.2mg, in each nostril, once or twice a day.
  • the compounds and compositions according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics.
  • the present invention provides a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof together with a pharmaceutically acceptable carrier or excipient.
  • compositions according to the invention may be formulated for administration by any route, for example oral, topical or parenteral.
  • the compositions may, for example, be made up in the form of tablets, capsules, powders, granules, lozenges, creams, syrups, sprays or liquid preparations, for example solutions or suspensions, which may be formulated for oral use or in sterile form for parenteral administration by injection or infusion.
  • Tablets and capsules for oral administration may be in unit dosage form, and may contain conventional excipients including, for example, binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; and pharmaceutically acceptable wetting agents, for example sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or another suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, including, for example, suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters (for example glycerine), propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavouring and colour agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate
  • compositions according to the invention intended for topical administration may, for example, be in the form of ointments, creams, lotions, eye ointments, eye drops, ear drops, nose drops, nasal sprays, impregnated dressings, and aerosols, and may contain appropriate conventional additives, including, for example, preservatives, solvents to assist drag penetration, and emollients in ointments and creams.
  • Such topical formulations may also contain compatible conventional carriers, for example cream or ointment bases, ethanol or oleyl alcohol for lotions and aqueous bases for sprays.
  • Such carriers may constitute from about 1% to about 98% by weight of the formulation; more usually they will constitute up to about 80% by weight of the formulation.
  • compositions according to the invention intended for topical administration may also contain a steroidal anti-inflammatory agent; for example, betamethasone.
  • a steroidal anti-inflammatory agent for example, betamethasone.
  • compositions according to the invention may be formulated as suppositories, which may contain conventional suppository bases, for example cocoa-butter or other glycerides.
  • Compositions according to the invention intended for parenteral administration may conveniently be in fluid unit dosage forms, which may be prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, may be either suspended or dissolved in the vehicle.
  • the compound may be dissolved in water for injection and filter-sterilised before being filled into a suitable vial or ampoule, which is then sealed.
  • conventional additives including, for example, local anaesthetics, preservatives, and buffering agents can be dissolved in the vehicle.
  • the composition may be frozen after being filled into the vial, and the water removed under vacuum; the resulting dry lyophilised powder may then be sealed in the vial and a accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions may be prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound may instead be sterilised by exposure to ethylene oxide before being suspended in the sterile vehicle.
  • a surfactant or wetting agent is included in such suspensions in order to facilitate uniform distribution of the compound.
  • a compound or composition according to the invention is suitably administered to the patient in an antimicrobially effective amount.
  • a composition according to the invention may suitably contain from 0.001% by weight, preferably (for other than spray compositions) from 10 to 60% by weight, of a compound according to the invention (based on the total weight of the composition), depending on the method of administration.
  • each unit dose may suitably comprise from 25 to 1000 mg, preferable from 50 to 500 mg, of a compound according to the invention.
  • compositions of the present invention include those adapted for intranasal administration, in particular, those that will reach into the nasopharynx. Such compositions are preferably adapted for focussed delivery to, and residence within, the nasopharynx.
  • the term 'focussed delivery' is used to mean that the composition is delivered to the nasopharynx, rather than remaining within the nares.
  • the term 'residence' within the nasopharynx is used to mean that the composition, once delivered to the nasopharynx, remains within the nasopharynx over a course of several hours, rather than being washed away more or less immediately.
  • Preferred compositions include spray compositions and creams.
  • Representative spray compositions include aqueous compositions, as well as oily compositions which contain amphiphilic agents so that the composition increases in viscosity when in contact with moisture. Creams may also be used, especially creams having a rheology that allows the cream to spread readily in the nasopharynx.
  • Preferred aqueous spray compositions include, in addition to water, further excipients including a tonicity modifier such as a salt, for instance sodium chloride; preservative, such as benzalkonium salt; a surfactant such as a non-ionic surfactant, for instance a polysorbate; and buffer, such as sodium dihydrogen phosphate; present in low levels, typically less than 1%.
  • a tonicity modifier such as a salt, for instance sodium chloride
  • preservative such as benzalkonium salt
  • a surfactant such as a non-ionic surfactant, for instance a polysorbate
  • buffer such as sodium dihydrogen phosphate
  • Representative oily spray and cream compositions are described in WO 98/14189 (SmithKline Beecham).
  • Representative aqueous sprays are described in International Application no PCT/GB98/03211 (SmithKline Beecham).
  • the drug substance is present in compositions for nasal delivery in between 0.001 and 5%, preferably 0.005 and 3%, by weight of the composition. Suitable amounts include 0.5% and 1% by weight of the composition (for oily compositions and creams) and from 0.01 to 0.2% (aqueous compositions).
  • Spray compositions according to the present invention may be delivered to the nasal cavity by spray devices well known in the art for nasal sprays, for instance an air lift pump.
  • Preferred devices include those which are metered to provide a unit volume of composition, preferably about lOO ⁇ l, and optionally adpated for nasal administration by addition of a modified nozzle.
  • Step 1 Ethyl l-terM>utyloxycarbonyIpiperidine-4-carboxylate - Ethyl piperidine-4- carboxylate (10 g, 0.063 mole) in 1,2-dimethoxyethane (100 ml) and water (100 ml) at 0°C was treated with di-tert-butyldicarbonate (15.3 g, 0.07 mole) and triethylamine (9.7 ml, 0.07 mole) and then stirred at ambient temperature for 60 hours.
  • Step 2 Ethyl l-tert-butyloxycarbonyl-4-(2-chloroethyl)-piperidine-4-carboxylate - Ethyl l-tert-butyloxycarbonylpiperidine-4-carboxylate (10 g, 0.039 mole) in dry tetrahyrofuran (200 ml) at -60°C was treated with 2.0 molar lithium di-wo-propylamide (20 ml, 0.04 mole) and kept at -60°C for 2 hours. l-Bromo-2-chloroethane (3.3ml, 0.04 mole) was added and the mixture allowed to warm to ambient temperature over 18 hours.
  • Step 3 Ethyl l-ter ⁇ -butyloxycarbonyl-4-(2-azidoethyl)-piperidine-4-carboxylate - Ethyl l-tert-butyloxycarbonyl-4-(2-chloroethyl)-piperidine-4-carboxylate (3.5 g, 0.011 mole) in dimethylformamide (50 ml) was treated with sodium azide (1.0 g, 0.015 mole) and stirred at 90°C for 18 hours.
  • Step 4 2,8-Diaza-8-tert-butyloxycarbonyl-l-oxospiro[4.5]decane - Ethyl tert- butyloxycarbonyl-4-(2-azidoethyl)-piperidine-4-carboxylate (3.0 g, 0.009 mole) was hydrogenated at 1 atmosphere in ethanol (50 ml) over 20% palladium on carbon (0.2 g) at 25°C for 18 hours. The catalyst was filtered off on kieselguhr and the filtrate concentrated in vacuo. Trituration of the residue with 60-80 petroleum ether gave the title compound 0.72g (31%) as an off-white solid: M.S. (APCI) m/z 155 (MH+-BOC, 100%).
  • Step 5 2,8-Diaza-8-methyl-l-oxospiro[4.5]decane - 2,8-Diaza-8-tert- butyloxycarbonyl-l-oxospiro[4.5]decane (1.3 g, 0.005 mole) in dichloromethane (80 ml) was treated with trifluoroacetic acid and heated under reflux for 4 hours. The mixture was evaporated to dryness and the residue partitioned between saturated potassium carbonate and 10% methanol/chloroform (2 x 50 ml). The organics were dried (Na 2 5U4), filtered and evaporated to dryness.
  • Step 7 2,8-Diaza-8-methyl-l-oxospiro[4.5]decane-2-carboxylic acid mutilin 14-ester -
  • the title compound was prepared as in the method of Example 87, Step 4 of PCT/EP96/05874 from 2,8-Diaza-8-methyl-l-oxospiro[4.5]decane-2-carboxylic acid (3R)-3-deoxo-l l-deoxy-3-methoxy-l l-oxo-4-eptmutilin 14-ester (0.48 g, 0.0009 mole) to give 0.34 g (73%) as a foam: M.S. (+ve ion electrospray) m z 515 (MH+, 100%).
  • Example 102 2,9-Diaza-9-methyl-l-oxospiro[5.5]undecane-2-carboxylic acid mutilin 14-ester -
  • the title compound was prepared analogously to Example 101, Steps 1-7 except the alkylating agent used in step 2 was l-bromo-3-chloropropane. This gave 0.085 g (32% final step): M.S. (+ve electrospray) m/z 529 (MH+ 100%).
  • Step 1 2,4,8-Triaza-8-methyl-l,3-dioxospiro[4.5]decane-2-carboxylic acid (3R)-3- deoxo-ll-deoxy-3-methoxy-ll-oxo-4-e 7imutilin 14-ester - 2,4,8-Triaza-8-methyl-l,3- dioxospiro[4.5]decane (see Coursison, J.C. et al, Farmaco, Ed. Sci (1988), 43 (2), 153- 160) (0.1 g, 0.0005 mole) in dimethylformamide (2 ml) was treated with 60% sodium hydride in oil (0.025 g, 0.0006 mole) and stirred for 1 hour.
  • Example 104 2,8-Diaza-8-methyl-l,3-dioxaspiro[4.5]decane-2-carboxylic acid mutilin 14-ester -
  • the title compound was prepared in 2 steps by analogy with Example 103, Steps 1-2 from -2,8-diaza-8-methyl-l,3-dioxos ⁇ iro[4.5]decane [see Valenta et al, Collect. Czech. Chem. Commun. (1990), 55(9), 2304-2316] to give 0.016 g (4% 2 steps): M.S. (+ve ion electrospray) m/z 529 (MH+ 100%).
  • Example 105 2,8-Diaza-8-methyI-3-oxospiro[4.5]decane-2-carboxylic acid mutilin 14-ester -
  • the title compound was prepared by analogy to Example 101, Steps 6-7 from 2,8-diaza-8-methyl-3-oxospiro[4.5]decane [see Cignarella, G. et al, J. Heterocylic Chem., (1993) 30 (5) 1357-1389]. This gave 0.084 g (27%, 2 steps). M.S. (+ve ion electrospray) m/z 515 (MH+, 100%).
  • Example 106 2,8-Diaza-l-oxospiro [4.5]decane-2-carboxylic acid mutilin 14-ester Step 1 2,8-Diaza-8-t ⁇ rt-butyloxyxcarbonyI-l-oxospiro[4.5]decane-2-carboxylic acid (3R)-3-deoxo-ll-deoxy-3-methoxy-ll-oxo-4-ep ⁇ mutilin 14-ester - The title compound was prepared as in the method of Example 101, Step 6 from 2,8-diaza-8-tert- butyloxcarbonyl-oxospiro[4.5]decane (2.0 g, 0.0079 mole) to give 3.4 g (70%); *H NMR (CDC1 3 ) inter alia 0.78 (3H ,d, J 7Hz), 0.95 (3H, d, J 7Hz), 1.20 (3H, s), 1.35 (3H, s), 1.42 (9H, s), 3.21 (2H,
  • Step 2 2,8-Diaza-l-oxospiro [4.5]decane-2-carboxylic acid mutilin 14-ester
  • the title compound was prepared as in the method of Example 87, Step 4 of PCT/EP96/05874 from 2,8-Diaza-8-tert-butyloxyxcarbonyl-l-oxospiro[4.5]decane-2- carboxylic acid (3R)-3-deoxo-l l-deoxy-3-methoxy-l l-oxo-4-e tmutilin 14-ester (3.4 g, 0.0055 mole). This procedure also removes the tert-butyloxycarbonyl group to give 2.4 g (87%) M.S. (+ve ion electrospray) m/z 501 (MH+, 100%).
  • Example 107 2,8-Diaza-8-te/tf -butyloxy carbony lmethyl- 1 -oxospiro[4.5]decane-2- carboxylic acid mutilin 14-ester - 2,8-Diaza-8-oxospiro[4.5]decane-2-carboxylic acid mutilin 14-ester (Example 106) (1.2 g, 0.0024 mole) in dimethylformamide (20 ml) was treated with potassium carbonate (1.0 g, 0.0072 mole) and tert-butyl bromoacetate (0.43 ml, 0.0029 mole) and stirred at ambient temperature for 18 hours.
  • Example 108 (3R,45)-Spiro[(l-azabicyclo[2,2,l]heptane-3,3'-(2'-oxo-pyrrolidine)]-l'- carboxylic acid mutilin 14-ester -
  • the title compound was prepared as in the method of Example 101, Steps 2-4 and 6-7 from ethyl (3R,45)-l-azabicyclo[2,2,l]heptane-3- carboxylate (see Cottrell D. et al, J.Chem. Soc. Perkin Trans 1 (1991), 1091-1097) to give 0.16 g (74%, final step): M.S. (+ve ion electrospray) m/z 513 (MH+, 60%).
  • Step 1 Formylated derivatives of mutilin -
  • the reaction was carried out similarly to that described by A.J. Birch, C.W. Holzapfel and R.W. Rickards (Tet (Suppl) 1996 8 part III 359).
  • Mutilin (6 g) in toluene (330 ml) and methyl formate (100 ml) was treated with sodium methoxide (3 g) and stirred under argon for 8 hours. Ice-water (100 ml) was added, followed by 2N HCl (220 ml). The mixture was shaken and separated and the aqueous extracted with ether.
  • Step 3 2-Diazomutilin - A solution of 2-hydroxymethylenemutilin (3.6 g) in dichloromethane was cooled to -10°C under argon, treated with triethylamine (4.6 ml) and tosyl azide (3.55 g) and warmed to room temperature. After 6 hours the solution was washed with 0.5M HCl (150 ml) and water (100 ml), dried and evaporated. The 2- diazomutilin was obtained as yellow crystals (1.7 g) from ethyl acetate/hexane; LR (CHCI3) 3634, 2082 and 1670 cm' 1 .
  • Step 4 (25)-2-Dichloroacetoxy-mutilin -
  • a solution of 2-diazomutilin (1.7 g) in dichloromethane (40 ml) was ice-cooled and treated dropwise with dichloracetic acid (0.5 ml). The bath was removed and after 30 minutes the solution was colourless. It was washed with aqueous NaHCO3 (50 ml), dried and evaporated.
  • Step 5 (2S)-2-Dichloroacetoxy-ll-0-trifluoroacetyl-mutilin - (25)-2- Dichloroacetoxymutilin (5.8 g, 0.012 mole) in dry tetrahydrofuran (120 ml) was treated with trifluoroacetylimidazole (1.54 ml, 0.0135 mole) and stirred at ambient temperature for 18 hours. Ethyl acetate (200 ml) was added to the mixture which was then washed with dilute sodium chloride solution (2 x 200 ml). The organic layer was separated, dried (Na 2 S04), filtered and evaporated to dryness.
  • Step 7 (3R,45)-Spiro[(l-azabicyclo[2,2,l]-heptane)-3,3'-(2'-oxopyrrolidine)]-l'- carboxylic acid (25)-2-hydroxy-mutilin 14-ester -
  • the title compound was prepared from (3R,45)-spiro[(l-azabicyclo[2,2,l]heptane)-3,3'-(2'-oxopyrrolidine) (see Example 108 and Example 101, step 6 for details) and (25)-2-dichloroacetoxy-l l-O- trifluoroacetyl-mutilin 14-chloroformate.
  • Example 201 Mutilin 14-(4-nitrophenyl) acetate - Mutilin (0.32 g, 0.001 mole) was dissolved in dichloromethane (8 ml) and (4-nitrophenyl) acetyl chloride (0.239 g, 0.0012 mole) and pyridine (0.097 ml 0.0012 mole) were added. The resulting mixture was stirred under an argon atmosphere. After 1 hour additional (4-nitrophenyl) acetyl chloride (0.06 g, 0.0003 mole) and pyridine (0.024 ml, 0.0003 mole) were added.
  • Example 202 Mutilin 14-phenylacetate - The title compound (0.258 g, 19%) was prepared using the method of Example 201; MS (electron ionisation) m/z 438 (M + ).
  • Step 2 Mutilin 14-(2-thienyl) acetate-11-trifluoroacetate - Mutilin 11-trifluoroacetate (0.625 g, 0.0015 mole) and (2-thienyl) acetyl chloride (0.0025 mole theoretical, Step 1) were dissolved in N,N-dimethylformamide (5 ml) and the resulting solution heated at 110°C for 17 hours under an argon atmosphere. The reaction mixture was then diluted with ethyl acetate (100 ml) and washed with water (3 x 50 ml), saturated aqueous sodium hydrogen carbonate (1 x 50 ml) and brine (1 x 50 ml).
  • Step 3 Mutilin 14-(2-thienyl) acetate - Mutilin 14-(2-thienyl) acetate- 11- trifluoroacetate (0.41 g, 0.00076 mole) was dissolved in ethanol (20 ml) and the solution cooled in an ice bath. 0.5M Potassium hydroxide in ethanol (1.5 ml) was then added dropwise. After 5 minutes the mixture was concentrated in vacuo and the residue taken up in ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and brine, then dried over magnesium sulphate.
  • Triphenylphosphine (2.23 g, 0.0085 mole) in dry tetrahydrofuran was cooled to 0°C and treated dropwise with diethylazodicarboxylate (1.34 ml, 0.0085 mole) and the mixture stirred for 30 minutes.
  • l-Methylpiperidine-4-methanol (1.0 g, 0.0078 mole) and methyl 4-hydroxyphenylacetate (1.30 g, 0.00085 mole) in dry tetrahydrofuran were added dropwise to the mixture and stirred at room temperature overnight. The solvent was removed in vacuo and the residue partitioned between 1M hydrochloric acid and diethyl ether.
  • Step 2 4-(l-Methylpiperidin-4-ylmethyloxy) phenylacetic acid hydrochloride -
  • the product of Step 1 (1.1 g, 0.004 mole) in concentrated hydrochloric acid (10 ml) was heated under reflux overnight. The solvent was removed in vacuo, the residue was azeotroped with toluene to afford the title compound (1.2 g, 100%) as a cream solid; MS (+ve ion electrospray) m/z 264 (MH + ).
  • Step 3 4-(l-Methylpiperidin-4-ylmethyloxy) phenylacetyl chloride -
  • the product of Step 2 (0.30 g, 0.0014 mole) in dry dichloromethane was treated with oxalyl chloride (0.3 ml, 0.0034 mole) and DMF (0.05 ml). The mixture was stirred at room temperature for 4.5 hours. The solvent was removed in vacuo, and the residue azeotroped with toluene to afford the title compound (0.36g, 100%).
  • MS (+ve ion electrospray in methanol) m/z 278 (MH + methyl ester).
  • Step 4 (3R)-3-Deoxo-ll-deoxy-3-methoxy-ll-oxo-4-e/? ⁇ ' -mutilin 14[4-(1 methylpiperidin-4-ylmethyloxy)] phenylacetate -
  • the product of Step 3 (0.36 g, 0.0011 mole) in dry N,N-dimethylformamide was treated with (3R)-3-deoxo-l l-deoxy-3- methoxy-1 l-oxo-4-e/? -mutilin (0.38 g, 0.0011 mole) and heated at 110°C overnight.
  • Step 2 (3R)-3-Deoxo-3-methoxy-ll-oxo-4-epi-mutilin 14-(2-methylthiazoI-4-yI) acetate -
  • the product of Step 1 (3.4 g, 0.0075 mole), and thioacetamide (0.56 g, 0.0075 mole) were heated in ethanol under reflux for 3.5 hours.
  • the reaction mixture was diluted with water and extracted into ethyl acetate.
  • the ethyl acetate layer was washed with water and brine, dried (MgSO 4 ) and concentrated in vacuo.
  • Trimethylsilyl-diazomethane (18.75 ml, 0.038 mole) and triethylamine (4.3 ml, 0.031 mole) in 1 : 1 THF/acetonitrile (60ml) was cooled to 0°C and treated dropwise with 3-furoyl chloride (K. Kuhn, Chem. Ber., 1956, 89, 1473: 3.25g, 0.025 mole). The mixture was kept at 0°C for 48 hours.
  • Step 2 ( 3 R)-3-Deoxo-l 1 -deoxy-3 -methoxy- 11 -oxo-4-epi-mutilin 14-(2-dimethyl aminomethylfur-3-yl)acetate, and ( 3R)-3-deoxo-l 1 -deoxy-3-methoxy-l 1 -oxo-4-epi-mutilin 14-(5-dimethylaminomethylfur-3-yl)acetate - Glacial acetic (15 ml) was cooled in an ice bath and treated with 40% aqueous dimethylamine (0.32 ml, 0.0029 mole) and 37% aq. formaldehyde (0.23 ml, 0.0029 mole).
  • Step 2 This mixture was then added to the product of Step 1 (1.05g, 0.0024 mole) with stirring.
  • the reaction mixture was briefly warmed in a water bath, stirred at room temperature for 0.5 hours then and heated at 100°C for 50 minutes.
  • the reaction mixture was diluted with 2M sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine, dried (MgSO 4 ), and concentrated in vacuo.
  • the product was purified by column chromatography, eluting with 2-10% methanol in dichloromethane.
  • Example 210 Mutilin 14-(5-dimethylaminoethylfur-3-yl)acetate -
  • the title compound was prepared from Example 9, Step 2, Product B using the method described in Example 207 Step 5; MS (+ve ion electrospray) m/z 486 (MH+).
  • Step 1 (3R)-3-Deoxo-3-methoxy-ll-oxo-4-ep ⁇ -mutilin 14-(2-furyl) acetate -
  • the title compound was prepared from 2-furoyl chloride and (3R)-3-deoxo-l l-deoxy-3-methoxy- 1 l-oxo-4-e/? /-mutilin, using the method described in Example 209, Step 1; MS (-ve ion electrospray) m/z 441 ([M-H]-).
  • Example 212 Mutilin 14-(5-DimethylaminomethyI-2-furyI) acetate -
  • the title compound (0.0 lg, 16%) was prepared from Example 211 (0.056g, 0.00013mole) using the method described in Example 9, Step 2: MS (+ve ion electrospray) m/z 486 (MH+).
  • Step 2 Mutilin 14-(3-methylisoxazole-5-yl) acetate - The title compound (0.1 lg, 57%) was prepared from the product of Step 1, using the method described in Example 207, Step 5: MS (ammonia Cl) m/z 444 (MH+), 461 ([M+NH4]+).
  • Step 2 (3R)-3-Deoxo-ll-deoxy-3-methoxy-ll-oxo-4-e/w-mutiIin 14-(4- dimethylaminomethylphenyl) acetate -
  • the product of Step 1 (0.2 lg, O.OOlmol) in dry N,N-dimethylformamide was treated with (3R)-3-deoxo-l l-deoxy-3-methoxy-l l-oxo-4- ep -mutilin (0.267g, 0.0008mmol) and heated at 120°C overnight.
  • Step 3 Mutilin 14-(4-dimethyIaminomethylphenyl) acetate -
  • the title compound (0.1 lg, 63%) was prepared from the product of Step 2 using the method of Example 207 Step 5; ⁇ NMR (CDC1 3 ): inter alia 0.54 (3H, d, J 6.4Hz), 0.85 (3H, d, J 6.9Hz), 2.22 (6H, s), 3.35 (IH, m), 3.39 (2H, s), 3.53 (2H, s), 5.16 (IH, d, J 17.5Hz), 5.33 (IH, d, J 10.9Hz),5.70 (IH, d, J 8.5Hz), 6.49 (IH, dd, J 17.4Hz, 11.0Hz), 7.21 (4H, m).
  • Step 2 Mutilin 14-(2-cyanomethyl-thiazol-4-yl) acetate - The the title compound (0.9 lg, 73%) was obtained from the product of Step 1 using the method described in Example 207 Step 5; MS (-ve ion electrospray) m/z 483 ([M-H] " ).
  • Example 217 Mutilin 14-(2-carbamoylmethylthiazol-4-yl)-acetate - Hydrogen chloride gas was bubbled through a stirred solution of the product from Example 16 (0.4g, O.00083mol) and methanol (0.2ml) in dioxane (5ml). After 1 hour the solvent was evaporated and the residue triturated with diethyl ether giving a solid. The solid was dissolved in methanol (10ml) and ammonia gas was bubbled through the solution for 30 minutes. The mixture was then heated at 60°C for 16 hours under argon.
  • Step 1 (3R)-3-Deoxo-ll-deoxy-3-methoxy-ll-oxo-4-ep ⁇ ' -mutilin 14-(4- cyanophenyl) acetate -
  • the title compound (350mg, 15%) was prepared from 4-cyanobenzoyl chloride and (3R)-3-deoxo-l l-deoxy-3-methoxy-l l-oxo-4-ep /-mutilin using the method described in Example 209, Step 1; MS (-ve ion electrospray) m/z 476 ([M-H] " ).
  • Example 219 Mutilin 14-(4- carbamimidoyl-phenyl) acetate - The title compound was obtained from the mixture of (3R)-3-deoxo-l l-deoxy-3-methoxy-l l-oxo-4-ept-mutilin 14-(4-carbamimidoyl-phenyl) acetate and mutilin 14-(4-carbamimidoyl-phenyl) acetate, isolated from Example 18 Step 2, by treatment with concentrated hydrochloric acid in 1,4-dioxane as described in Example 207, Step 5; MS (+ve ion electrospray) m/z 481 (MH + ).
  • Example 220 Mutilin 14-[4-(2-dimethyIaminoethyl)-carbamoyl-phenyl]-acetate Step 1. Mutilin 14-(4-methoxycarbonylphenyl) acetate-11-trifluoroacetate -
  • Step 2 Mutilin 14-(4-carboxyphenyl) acetate -
  • the product from Step 1 (4.2g, 7mmol) was dissolved in 1,4-dioxane (20ml), 2M aqueous sodium hydroxide (10ml) added and the mixture stirred at room temperature overnight.
  • the dioxane was evaporated and the aqueous layer washed with ethyl acetate.
  • the aqueous layer was then acidified with 2M hydrochloric acid and extracted with ethyl acetate.
  • Example 221 Mutilin 14- ⁇ 4-[(2-dimethylaminoethyl)-methyl-carbamoyl]phenyI ⁇ - acetate -
  • the title compound (65mg, 30%) was prepared from the product of Example 220, Step 2 and N,N,N'-trimethylethylendiamine using the method described in Example 220, Step 3; MS (+ve ion electrospray) m/z 567 (MH+).
  • Example 222 Mutilin 14- ⁇ 4-[4-(3-hydroxypropyl)-piperazine-l-carbonyl]-phenyl ⁇ - acetate -
  • the title compound was prepared from the product of Example 220, Step 2 and l-(3-hydroxypropyl)piperazine using the method of Example 220, Step 3; MS (+ve ion electrospray) m/z 609 (MH+).
  • Step 2 3-(4-terf-Butoxycarbonyl-piperazin-l-yl-methyl)-5-methyl isoxazole -
  • the product from step 1 (180 mg, 0.99 mmol) and di-tert-butyl dicarbonate (327 mg 1.5 mmol) were dissolved in dichloromethane (15 ml) and stirred for 48 hours. The solvent was removed and the residue purified on silica gel eluting with ethyl acetate : hexane (4: 1) to afford the title compound (150 mg, 54%) as a crystalline solid.
  • MS (+ve ion, Cl) m/z: 282 (MH)+ Step 3.
  • Reagent 1 4-[(3-e o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy] phenol
  • Step 1 (3-enrf ⁇ )-3-Methanesulphonyloxy-8-methyl-8-aza-bicyclo[3.2.1]octane -
  • methanesulphonyl chloride 1.2 ml, 15.5 mmol
  • triethylamine 2.2 ml, 15.8 mmol
  • Reagent 2 N-(2-Dimethylaminoethyl)-3-hydroxyisoxazole-5-carboxamide - Methyl 3-hydroxyisoxazole-5-carboxylate (2.0g, 0.013 mole) was added portionwise to a mixture of N,N-dimethylethylenediamine (1.52 ml, 0.013 mole) and methanol. The reaction mixture was stirred at room temperature for 16 hours, and then heated at 60°C for 3 hours.
  • Example 323 Mutilin 14-(4-carbamidoylphenoxy)acetate - Anhydrous hydrogen chloride gas was bubbled through a stirred solution of mutilin 14-(4- cyanophenoxy)acetate (Example 3; 294mg, O. ⁇ lmmol) and methanol (0.5ml) in dioxane (3ml). After 1 hour the solvent was evaporated and the residue triturated with diethyl ether giving a solid. The solid was dissolved in methanol (20ml) and ammonia gas was bubbled through the solution for 30 minutes. The mixture was then heated at 60°C for 16 hours under argon.
  • Step 3 Mutilin 14-[4-(2-dimethylaminoethyl)phenoxy]acetate -
  • the product of Step 2 (320mg, 0.59mmol) was dissolved in dioxane (2ml) and treated with cone. HCl (2ml). The mixture was stirred for 2 hours at room temperature and then poured into ethyl acetate and water. The aqueous layer was washed with ethyl acetate and then basified with aqueous potassium hydroxide solution. The product was extracted into chloroform (x2), dried (MgSO4) and concentrated to yield a colourless foam (141 mg, 46%): MS(+ve ion electrospray) m/z 526 (MH+).
  • Example 325 Mutilin 14- ⁇ 4-[(35)-(l-aza-bicyclo[2.2.2]oct-3-yl)minomethyl]phenoxy ⁇ acetate -
  • the product from Example 11 (71 mg, 0.15 mmol) was dissolved in methanol (4 ml) and treated with (5)-(-)-3-aminoquinuclidine dihydrochloride (29 mg, 0.15 mmol) and triethylamine (0.021ml, 0.15 mmol). The mixture was stirred at room temperature for 6 hours and then treated with sodium triacetoxyborohydride (155 mg, 0.73 mmol). The reaction mixture was stirred for a further 14 hours and then diluted with dilute hydrochloric acid.
  • Example 326 Mutilin 14- ⁇ 4-[(3R)-(l-aza-bicyclo[2.2.2]oct-3-l)aminomethyl]phenoxy ⁇ acetate -
  • the title compound (50 mg, 24%) was prepared from (R)-(+)-3- aminoquinuclidine dihydrochloride using the method described in Example 325: MS (+ve ion electrospray) m/z 593 (MH + ).
  • Example 327 Mutilin 14-(2-dimethylaminomethyI-4-methanesulphonamido phenoxy) acetate -
  • the product from Example 16 (270 mg, 0.51 mmol) was dissolved in dichloromethane (10 ml) and cooled to 0°C.
  • Methanesulphonyl chloride (0.043ml, 0.55 mmol) was added, followed by triethylamine (0.079 ml, 0.56 mmol).
  • the reaction was allowed to warm to room temperature and stirred for a further 3 hours.
  • the mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulphate and concentrated in vacuo.
  • Example 328 Mutilin 14-benzyloxyacetate - Pleuromutilin (500mg, 1.3mmol) was dissolved in dry DMF (5ml), cooled to 0°C and treated portion-wise with sodium hydride (56mg of a 60% dispersion in oil, 1.4mmol). The mixture was stirred at room temperature for 30 minutes before the addition of benzyl bromide (0.17ml, 1.4mmol). After stirring overnight at room temperature, the reaction mixture was diluted with ethylacetate and washed with saturated aqueous sodium hydrogen carbonate, water and brine.
  • Example 329 Mutilin 14-(4-carboxyphenoxy)acetate -
  • the product of Example 20 (500mg, 0.98 mmole) in 5:1 tetrahydrofuran/water was treated dropwise with 2M sodium hydroxide solution and the reaction mixture stirred at room temperature for 48 hours. The solvent was removed in vacuo, and the residue dissolved in water. The aqueous phase was acidified with 5M hydrochloric acid and extracted with dichloromethane. The organic extracts were dried (MgSO 4 ) and concentrated in vacuo.
  • Example 330 Mutilin 14-(2-carboxy-5-methylthiazol-4-yloxy)acetate - The title compound (120mg, 18%) was prepared from the product of Example 321 using the method of Example 329: MS (-ve ion electrospray) m/z 518 (MH-).
  • Example 331 Mutilin 14-(2-carboxy-3-thienyloxy)acetate -
  • the title compound (118mg, 10%) was prepared from the product of Example 322 using the method of Example 329: l H NMR (CDC13) inter alia 7.52 (IH, d, J 7Hz), 6.73 (IH, d, J 7Hz), 6.44 (IH, dd, J 17, 12Hz), 5.89 (IH, d, J 8Hz), 5.36 (IH, dd, J 12, 2Hz), 5.20 (IH, dd, J 17, 2Hz), 4.70 (2H, s) 0.88 (3H, d, J 7Hz), 0.70 (3H, d, J 7Hz).
  • Example 332 Mutilin 14-[4-(2-dimethylaminoethyIaminosulphonyl)phenoxy]acetate -
  • the product from Example 315 (100 mg, 0.19 mmol) was dissolved in acetone (5 ml) and treated with 2-dimethylaminoethylchloride hydrochloride (27 mg, 0.19 mmol) and potassium carbonate (52 mg, 0.38 mmol).
  • the reaction mixture was heated to reflux for 48 hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine.
  • Example 333 Mutilin 14-(2-methoxycarbonylphenoxy)acetate - Methyl salicylate (5 g, 33 mmol) was dissolved in dry DMF (100 ml) and potassium tert-butoxide (3.69 g, 33 mmol) added. After stirring for 20 minutes, pleuromutilin-22-mesylate was added and the mixture stirred for 16 hours. The mixture was then partitioned between diethylether and water. The diethylether layer was then dried (sodium sulfate), filtered and the solvent removed in vacuo.
  • Example 334 Mutilin 14-(2-carbamoyIphenoxy)acetate -
  • the product from Example 333 400 mg, 0.78 mmol was dissolved in methanol (50 ml), cooled to -5 °C and then treated with gaseous ammonia for 5 minutes. The mixture was closed in a sealed tube and allowed to warm to room temperature, after which it was allowed to stand for 3 days. The solvent was removed in vacuo and the residue purified by silica gel chromatography eluting with ethyl acetate-hexane (1:1) to afford the title compound (172 mg, 44%) as a white foam: MS (-ve ion electrospray) m/z 556 [M + O 2 CCH3]-
  • Example 335 Mutilin 14-(2-carboxyphenoxy) acetate -
  • the product from Example 333 (1 g, 1.95 mmol) was dissolved in tetrahydrofuran-water (5: 1) to which was added 1.98 M sodium hydroxide (0.98 ml). After 48 hours the reaction mixture was partitioned between diethylether and 1 M aqueous sodium hydroxide. The aqueous layer was isolated and acidified with cone, hydrochloric acid until the product precipitated. The product was extracted into dichloromethane and the organic layer then washed with brine and dried (sodium sulfate).
  • Example 336 Mutilin 14-(isoquinoIin-5-yl-oxy) acetate - 5-Hydroxyisoquinoline (153 mg, 1.05 mmol), DMF (10ml) and sodium hydride (42 mg of a 60% suspension in oil, 1.05 mmol) were stirred at 0 °C for 30 minutes.
  • Pleuromutilin-22-mesylate 400 mg
  • Example 337 Mutilin 14-[4-(2-tert-butoxycarbonylamino-2-methoxycarbonylethyl)- phenoxy] acetate -
  • the title compound (1.44 g, 13%) was prepared from N-tert- butoxycarbonyl-D-tyrosine methyl ester using the method described in Example 333: ⁇ NMR (CDC1 3 ) inter alia 0.74 (3 H, d, J 6.5 Hz), 1.42 (9 H, s), 3.45 (1 H, dd, J 10.7, 6.5 Hz), 3.70 (3 H, s) 5.84 (1 H, d, J 8.2 Hz), 6.79 (2 H, d, J 8.7 Hz), 7.02 (2 H, d, J 8.7 Hz).
  • Example 338 Mutilin 14-[4-(2-tert-butoxycarbonylamino-2-carboxyethyl)-phenoxy] acetate, ammonium salt -
  • the product from Example 337 (1.68 g, 2.57 mmol) and lithium hydroxide hydrate (0.214 g, 7.71 mmol) were stirred in THF-H 2 O (4: 1) for 1 hour.
  • the reaction mixture was partitioned between dichloromethane and 0.5 M hydrochloric acid.
  • the organic layer was dried (sodium sulfate), filtered and the solvent removed in vacuo.
  • Example 339 Mutilin 14-[4-(2-amino-2-carboxyethyl)phenoxy] acetate, ammonium salt -
  • the product from Example 338 (1.42 g, 2.21 mmol) was dissolved in trifluoroacetic acid (36 ml).
  • Example 340 19,20-Dihydromutilin 14-[4-(2-carboxy-2-dimethyIaminoethyl) phenoxy] acetate, ammonium salt -
  • the product from Example 339 (0.78 g, 1.19 mmol), 37% aqueous formaldehyde (0.53 ml), DMF (1 ml), 5%-palladium/charcoal (50 mg) and ethanol (5ml) were stirred under a hydrogen atmosphere for 16 hours. The solution was then filtered and the solvent removed in vacuo. The residue was suspended in water which was adjusted to pH 7 using 2 M aqueous sodium hydroxide and the product then extracted with dichloromethane.
  • Example 341 Mutilin 14-[4-(2-amino-2-methoxycarbonylethyl)phenoxy] acetate hydrochlodide -
  • the product from Example 337 (1.51 g, 2.30 mmol) was dissolved trifluoroacetic acid (25 ml). After 15 minutes the mixture was evaporated to dryness and the residue partitioned between diethylether and 0.5 M hydrochloric acid. The aqueous layer was evaporated to dryness to afford the title compound (0.715 g, 53%) as a white solid: MS (+ve ion electrospray) m/z 556 (MH + ).
  • Example 342 19,20-Dihydromutilin 14-[4-(2-dimethylamino-2-methoxycarbonyl- ethyl)phenoxy] acetate -
  • the product from Example 341 (0.56 g, 0.957 mmol), 37% aqueous formaldehyde (0.43ml), 5% palladium/charcoal (50 mg) and methanol (15 ml) were stirred together under an atmosphere of hydrogen for 16 hours. The mixture was filtered and the solvent removed in vacuo. The residue was partitioned between dichloromethane and saturated aqueous sodium hydrogencarbonate. The organic fraction was dried (sodium sulfate), filtered and evaporated to dryness.
  • Step 1 5-(2-tert-butoxycarbonylaminoethyl)-2-methoxycarbonyl-phenol - 5-(2- aminoethyl)-2-methoxycarbonyl-phenol (S.F. Dyke et al; Tetrahedron 1973, 29, 857) (1 g, 4.3 mmol), triethylamine (0.6ml, 4.3 mmol), di tert-butyl dicarbonate (0.942 g, 4.3 mmol) and DMF (40 ml) were stirred together at -20°C. The mixture was allowed to warm to room temp and stirred for 16 hours.
  • Example 344 Mutilin 14-[5-(2-aminoethyI)-2-methoxycarbonylphenoxy] acetate -
  • the product from Example 343 (0.57 g, 0.97 mmol) and 1 :4 trifluoroacetic acid: dichloromethane, (15ml) were stirred for 1 hour after which the mixture was evaporated to dryness.
  • the residue was partitioned between dichloromethane and saturated aqueous sodium hydrogencarbonate. The organic fraction was dried (sodium sulfate), filtered and evaporated to dryness.
  • Example 345 Mutilin 14-[5-(2-aminoethyl)-2-carboxy-phenoxy] acetate, ammonium salt -
  • the product from Example 344 60 mg, 0.0896 mmol
  • sodium hydroxide 7.2 mg, 0.0896 mmol
  • the solvent was removed in vacuo and the residue purified on silica gel eluting with dichloromethane/ methanol/ 35% ammonia solution (85:14.5:0.5) to afford the title compound (4 mg, 8%) as a white solid: MS (-ve ion mode) m/z 540 (M - H) _ .
  • Example 346 19,20-Dihydromutilin 14-[5-(2-dimethyIaminoethyl)-2- methoxycarbonyl-phenoxy] acetate -
  • the title compound (212 mg, 55%) was prepared from the product of Example 344 (350 mg, 0.65 mmol) using the method described in Example 342.
  • the product was purified on silica gel eluting with dichloromethane- methanol (95:5): MS (+ve ion electrospray) m/z 586 (MH + ).
  • Example 347 19,20-Dihydromutilin 14-[5-(2-dimethylaminoethyl)-2-carboxy- phenoxy] acetate, ammonium salt -
  • the title compound (55 mg, 35%) was prepared from the product of Example 346 using the method described in Example 345. The product was purified by silica gel chromatography eluting with dichloromethane/ methanol/ 35% ammonia solution (90:9:1): MS (+ve ion electrospray) m/z 572 (MH+).
  • Example 348 19,20-dihydromutiIin-14-[5-aminomethyl-2-methoxycarbonyl- phenoxy] acetate, hydrochloride
  • Step 1 Methyl 4-azidomethyl-2-hydroxybenzoate - Methyl 4-bromomethyl-2- hydroxybenzoate (1.96 g, 8.0 mmol) (7. Am. Chem. Soc. 1994, 116, 2630), sodium azide (0.78 g, 12.0 mmol) and DMF (15 ml) were stirred together at 90 °C for 2.5 hours. The solvent was removed in vacuo and the residue partitioned between diethylether and water.
  • Example 349 19,20-Dihydromutilin-14-[5-dimethylaminomethyl-2- methoxy carbonyl-phenoxy] acetate -
  • the title compound (0.18 g, 68%) was prepared using from the product of Example 348 using the method described in Example 342.
  • the product was purified on silica gel eluting with methanol-dichloromethane (5:95): MS (+ve ion electrospray) m/z 572 (MH + ).

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Abstract

L'invention concerne un composé correspondant à la formule (IA) ou (IB) dans laquelle R?1 est RA(CH¿2)nO(CH2)m, RA(CH2)p, R se présentant comme un noyau fusionné en spirale ou bicyclique qui contient un ou deux atomes d'azote de base; et X1 et X2, qui peuvent être identiques ou différents sont chacun -CH¿2?- ou -C=O, à condition qu'au moins un de X?1 et X2¿ soit -C=O; Y est -NH-, -CH¿2?- ou -CH2-CH2-; R?A¿ est un groupe aryle ou hétéroaryle éventuellement substitué lié à travers un atome de carbone; m est 1, 2 ou 3; n est 0, 1 ou 2; et p est 1 à 4; R2 est vinyle ou éthyle; R3 est H, OH ou F, et R4 est H, ou R3 est H et R4 est F. Les composés sont utiles pour traiter des infections microbiennes chez les animaux, notamment chez les humains et les mammifères domestiqués.
PCT/EP1999/008705 1998-11-11 1999-11-09 Composes a base de mutiline WO2000027790A1 (fr)

Applications Claiming Priority (6)

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GB9824781.0 1998-11-11
GBGB9824781.0A GB9824781D0 (en) 1998-11-11 1998-11-11 Novel compounds
GBGB9827830.2A GB9827830D0 (en) 1998-12-17 1998-12-17 Novel compounds
GB9827830.2 1998-12-17
GBGB9827880.7A GB9827880D0 (en) 1998-12-17 1998-12-17 Novel compounds
GB9827880.7 1998-12-17

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WO2002022580A1 (fr) * 2000-09-13 2002-03-21 Biochemie Gesellschaft M.B.H. Mutilines antibacteriennes
US6753445B2 (en) 2000-07-11 2004-06-22 Biochemie Gesellschaft M.B.H. Pleuromutilin derivatives having antibacterial activity
WO2004113334A1 (fr) * 2003-06-24 2004-12-29 Neurosearch A/S Nouveaux derives de 8-aza-bicyclo[3.2.1]octane et utilisation en tant qu'inhibiteurs de la reabsorption des neurotransmetteurs monoamine
US6878704B2 (en) * 2000-08-03 2005-04-12 Smithkline Beecham P.L.C. Heterocyclic mutilin esters and their use as antibacterials
JP2006523195A (ja) * 2003-04-08 2006-10-12 グラクソ　グループ　リミテッド プレウロムチリン誘導体、その製法およびその使用
EP1666466A3 (fr) * 1999-07-30 2007-09-26 Nabriva Therapeutics Forschungs GmbH Derivés de mutilin et leur utilisation comme antimicrobiens
WO2008143343A1 (fr) 2007-05-24 2008-11-27 Kyorin Pharmaceutical Co., Ltd. Dérivé de la mutiline ayant une structure d'acide carboxylique à noyau aromatique hétérocyclique en substituant à la position 14
EP2014645A1 (fr) * 2007-07-13 2009-01-14 Nabriva Therapeutics AG Dérivés de pleuromutiline et leur application comme agents antimicrobiens
US7521473B2 (en) 2004-02-25 2009-04-21 Wyeth Inhibitors of protein tyrosine phosphatase 1B
US7556948B2 (en) 2002-08-09 2009-07-07 Glaxo Group Limited Method for producing crystallized pleuromutilins
JP2009531278A (ja) * 2006-01-16 2009-09-03 ナブリヴァ セラピュティクス アクチエンゲゼルシャフト ムチリン派生物および調合薬としてのそれらの使用
CN103709102A (zh) * 2012-09-28 2014-04-09 山东亨利医药科技有限责任公司 含有螺环的截短侧耳素类抗生素
JP2016525101A (ja) * 2013-07-11 2016-08-22 エベストラ インコーポレイテッド プロドラッグを生成する化合物
CN107324998A (zh) * 2017-07-31 2017-11-07 重庆华邦胜凯制药有限公司 一种制备外用抗生素类药物瑞他莫林的新方法
US11299495B2 (en) 2016-08-01 2022-04-12 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
CN114716384A (zh) * 2022-03-10 2022-07-08 中国农业科学院兰州畜牧与兽药研究所 一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其制备与应用
US11401233B1 (en) * 2021-02-12 2022-08-02 Shaanxi University Of Science And Technology Pleuromutilin salicylic acid ester with antibacterial activity and a method of preparing the same
US11427585B2 (en) 2016-08-01 2022-08-30 Aptinyx Inc. Spiro-lactam NMDA modulators and methods of using same
US11512051B2 (en) 2016-08-01 2022-11-29 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
US11578072B2 (en) 2018-01-31 2023-02-14 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof

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WO1999021855A1 (fr) * 1997-10-29 1999-05-06 Smithkline Beecham P.L.C. Derives de pleuromutiline utilises comme agents antimicrobiens

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* Cited by examiner, † Cited by third party
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EP1666466A3 (fr) * 1999-07-30 2007-09-26 Nabriva Therapeutics Forschungs GmbH Derivés de mutilin et leur utilisation comme antimicrobiens
JP2009108088A (ja) * 2000-07-11 2009-05-21 Nabriva Therapeutics Forschungs Gmbh 抗細菌活性を有するプレウロムチリン誘導体
US6753445B2 (en) 2000-07-11 2004-06-22 Biochemie Gesellschaft M.B.H. Pleuromutilin derivatives having antibacterial activity
US6878704B2 (en) * 2000-08-03 2005-04-12 Smithkline Beecham P.L.C. Heterocyclic mutilin esters and their use as antibacterials
US7169804B2 (en) 2000-09-13 2007-01-30 Gerd Ascher Antibacterial mutilins
US7569587B2 (en) 2000-09-13 2009-08-04 Nabriva Therapeutics Ag Antibacterial mutilins
WO2002022580A1 (fr) * 2000-09-13 2002-03-21 Biochemie Gesellschaft M.B.H. Mutilines antibacteriennes
US7556948B2 (en) 2002-08-09 2009-07-07 Glaxo Group Limited Method for producing crystallized pleuromutilins
JP2006523195A (ja) * 2003-04-08 2006-10-12 グラクソ　グループ　リミテッド プレウロムチリン誘導体、その製法およびその使用
WO2004113334A1 (fr) * 2003-06-24 2004-12-29 Neurosearch A/S Nouveaux derives de 8-aza-bicyclo[3.2.1]octane et utilisation en tant qu'inhibiteurs de la reabsorption des neurotransmetteurs monoamine
US7407970B2 (en) 2003-06-24 2008-08-05 Neurosearch A/S 8-aza-bicyclo[3.2.1]octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors
US7888358B2 (en) 2003-06-24 2011-02-15 Neurosearch A/S 8-aza-bicyclo[3.2.1]octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors
JP2009513491A (ja) * 2003-06-24 2009-04-02 ノイロサーチ アクティーゼルスカブ 新規な８−アザ−ビシクロ［３．２．１］オクタン誘導体、及びモノアミン神経伝達物質の再取り込み阻害剤としてのその使用
US7521473B2 (en) 2004-02-25 2009-04-21 Wyeth Inhibitors of protein tyrosine phosphatase 1B
JP2009531278A (ja) * 2006-01-16 2009-09-03 ナブリヴァ セラピュティクス アクチエンゲゼルシャフト ムチリン派生物および調合薬としてのそれらの使用
WO2008143343A1 (fr) 2007-05-24 2008-11-27 Kyorin Pharmaceutical Co., Ltd. Dérivé de la mutiline ayant une structure d'acide carboxylique à noyau aromatique hétérocyclique en substituant à la position 14
JP2010533131A (ja) * 2007-07-13 2010-10-21 ナブリヴァ セラピュティクス アクチエンゲゼルシャフト 有機化合物
KR101547543B1 (ko) * 2007-07-13 2015-08-26 나브리바 테라퓨틱스 아게 플루로뮤틸린 유도체 및 이의 항미생물제로서의 용도
WO2009009812A1 (fr) * 2007-07-13 2009-01-22 Nabriva Therapeutics Ag Dérivés de pleuromutiline et leur utilisation comme antimicrobiens
EP2014645A1 (fr) * 2007-07-13 2009-01-14 Nabriva Therapeutics AG Dérivés de pleuromutiline et leur application comme agents antimicrobiens
US8173685B2 (en) 2007-07-13 2012-05-08 Nabriva Therapeutics Ag Pleuromutilin derivatives and their use as antimicrobials
CN101801923A (zh) * 2007-07-13 2010-08-11 纳布里瓦治疗股份公司 截短侧耳素衍生物及其作为抗微生物剂的应用
EA019806B1 (ru) * 2007-07-13 2014-06-30 Набрива Терапьютикс Аг Производные плевромутилина и их применение в качестве антимикробных средств
CN103709102A (zh) * 2012-09-28 2014-04-09 山东亨利医药科技有限责任公司 含有螺环的截短侧耳素类抗生素
JP2016525101A (ja) * 2013-07-11 2016-08-22 エベストラ インコーポレイテッド プロドラッグを生成する化合物
US11427585B2 (en) 2016-08-01 2022-08-30 Aptinyx Inc. Spiro-lactam NMDA modulators and methods of using same
US11299495B2 (en) 2016-08-01 2022-04-12 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
US12084444B2 (en) 2016-08-01 2024-09-10 Tenacia Biotechnology (Hong Kong) Co., Limited Spiro-lactam NMDA modulators and methods of using same
US11530223B2 (en) 2016-08-01 2022-12-20 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
US11512051B2 (en) 2016-08-01 2022-11-29 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
CN107324998A (zh) * 2017-07-31 2017-11-07 重庆华邦胜凯制药有限公司 一种制备外用抗生素类药物瑞他莫林的新方法
US11578072B2 (en) 2018-01-31 2023-02-14 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
US20220259138A1 (en) * 2021-02-12 2022-08-18 Shaanxi University Of Science And Technology Pleuromutilin salicylic acid ester with antibacterial activity and a method of preparing the same
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CN114716384B (zh) * 2022-03-10 2023-09-26 中国农业科学院兰州畜牧与兽药研究所 一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其制备与应用
CN114716384A (zh) * 2022-03-10 2022-07-08 中国农业科学院兰州畜牧与兽药研究所 一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其制备与应用

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