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WO2001014310A1 - β-CETOESTERS DE PLEUROMUTILINE - Google Patents

β-CETOESTERS DE PLEUROMUTILINE Download PDF

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Publication number
WO2001014310A1
WO2001014310A1 PCT/EP2000/007687 EP0007687W WO0114310A1 WO 2001014310 A1 WO2001014310 A1 WO 2001014310A1 EP 0007687 W EP0007687 W EP 0007687W WO 0114310 A1 WO0114310 A1 WO 0114310A1
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Prior art keywords
compound
group
mutilin
oxo
formula
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Inventor
David Kenneth Dean
Antoinette Naylor
Andrew Kenneth Takle
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Priority to AU72728/00A priority Critical patent/AU7272800A/en
Publication of WO2001014310A1 publication Critical patent/WO2001014310A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/70—Sulfur atoms
    • C07D277/76—Sulfur atoms attached to a second hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
    • C07C2603/80—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings
    • C07C2603/82—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings having three condensed rings with in total fourteen carbon atoms and having a having a [5.4.3.0(1,8)] ring structure, e.g. pleuromutiline

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 anti-mycoplasmal activity and modest antibacterial activity Mutihn and other compounds with a free OH at C-14 are inactive The impact of further modification at C- 14 on the activity of pleuromutilin has been investigated (H Egger and H Reinshagen, J Antibiotics, 1976, 29, 923) Replacing the hydroxy group of the glyco c ester moiety at position 14 by another O, S or N-hnked group was found to improve anti-microbial activity Thus, introducing a diethylaminoethylthio group gives the compound of formula (B). also known as Tiamulin, which is used as a veterinary antibiotic (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-O-carbamoyl derivatives of mutihn or 19,20-d ⁇ hydromut ⁇ l ⁇ n, in which the N-atom of the carbamoyl group is unsubstituted, mono- or di-substituted WO98/05659 (SmithKline Beecham) discloses 14-O-carbamoyl derivatives of mutihn or 19.20-d ⁇ hydromut ⁇ l ⁇ n. in which the N-atom of the carbamoyl group is acylated by a group which includes an azabicyc c moiety
  • WO 99/21855, WO 00/27790 and WO 00/37074 (SmithKline Beecham) describe new classes of mutihn or 19,20-d ⁇ hydromut ⁇ hn, in which the glyco c ester moiety at position 14 is further modified
  • the present invention is based on the unexpected discovery that novel mutihn derivatives having a ⁇ -ketoester substituent at the 14-pos ⁇ t ⁇ on also have potent antimicrobial activity
  • the present invention provides a compound of formula (LA) or (LB)
  • R 1 is a nitrogen containing heterocycle, an optionally substituted aryl or optionally substituted heteroaiyl group, or CH2R- ⁇ 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, in which
  • R ⁇ is halogen or SR°
  • R6 IS ammoalkyl, a nitrogen containing heterocycle, or an optionally substituted aryl or optionally substituted heteroaryl group Representative examples of R! or R ⁇ when an aryl group include phenyl
  • R ' or R° is aryl.
  • a preferred number ot substituents is up to three, more preferred is one
  • Representative substituents include C ⁇ .g ⁇ alkoxy. for example methoxy
  • heteroaryl groups for R ! or R" include 3-py ⁇ dyl, 4-py ⁇ dyl, py ⁇ m ⁇ d ⁇ n-2-yl, l,3,4-th ⁇ ad ⁇ azol-2-yl, benzoth ⁇ azol-2-yl, and 2H-l,2,4-t ⁇ azol-3-yl.
  • Representative examples of R ⁇ or R ⁇ include when an optionally substituted heteroaryl group include 3-py ⁇ dyl, 4-py ⁇ dyl, py ⁇ m ⁇ d ⁇ n-2-yl, 5-am ⁇ no-l,3.4-th ⁇ ad ⁇ azol-2-yl, 6- ethoxybenzoth ⁇ azol-2-yl. and 5-am ⁇ no-2H-l,2,4-t ⁇ azol-3-yl
  • nitrogen containing heterocycle refers to a saturated or partially saturated non-aromatic mono- or bicychc group linked via a ring carbon atom
  • the group may comprise one to three nitrogen atoms, preferably one or two, more preferably one nitrogen atom.
  • the group is monocychc it can contain between 4 and 8 ring atoms, and when bicychc it can contain between 5 and 10 ring atoms in each ring
  • the azabicyclic ring system may, for example, be represented by the formulae (X) or (Y)
  • each of a, b, c, d and e which may be the same or different, is for a, b and c an integer from 1 to 4, and for d and e 0 or an integer from 1 to 3, such that any one ring has between 5 and 10 ring atoms
  • the nitrogen containing heterocycle can be optionally substituted on carbon by up to 3 substituents. Suitable substituents include C(i _6)alkyl, C ⁇ j.g ⁇ alkyloxy. C(2-6) a lkenyl and C(2-6) a lkenyloxy. each of which may be carried by either a bridgehead or a non- bridgehead carbon atom.
  • each nitrogen atom may be substituted by oxygen, to form an N-oxide, or by mono- or di-C ⁇ .g ⁇ alkyl, in which case it will be appreciated that a quaternary cation can be formed.
  • Representative nitrogen substituents include C( i_6)alkyl, preferably methyl.
  • the counterion may be a halide ion such as chloride or bromide, preferably chloride.
  • the ring system additionally may contain one or more double bonds.
  • nitrogen containing heterocycles include optionally substituted azabicycloheptyl, azabicyclo-octyl and piperidinyl.
  • Preferred nitrogen containing heterocyclic moieties include optionally substituted l-aza-bicyclo[2.2.2]oct-4-yl, 1-aza- bicyclo[2.2.1]hept-4-yl, piperidin-4-yl.
  • the linking ring carbon in an azabicyclic system may be a bridgehead atom or a non-bridgehead atom.
  • R is halogen
  • a preferred value is chlorine
  • R-* When R-* is SR°, representative values for R ⁇ include dialkylaminoalkyl, aza- bicyclo[2.2.2]octyl. pyrimidinyl, aryl, amino-l,3,4-thiadiazolyl, alkoxybenzothiazolyl, and amino-2H-l,2,4-triazolyl.
  • R ⁇ examples include 2-diethylaminoethyl, 1- aza-bicyclo[2.2.2]oct-4-yl, pyrimidin-2-yl, phenyl, 5-amino-l,3,4-thiadiazol-2-yl, 6- ethoxybenzothiazol-2-yl, and 5-amino-2H-l,2,4-triazol-3-yl.
  • aminoalkyl refers to, unless otherwise defined, a mono- or di-C(i _6)alkylamino-C ⁇ _6)alkyl group.
  • Representative amino alkyl groups include di-
  • aminoalkyl groups include 2-diethylaminoethyl.
  • aryl refers to, unless otherwise defined, phenyl or naphthyl optionally substituted with up to five, preferably up to three substituents.
  • Suitable substituents for an aryl group include, for example, and unless otherwise defined, halogen, (Cj ⁇ alkyl, aryl, aryl(C ⁇ _6)alkyl. (C ⁇ _6)alkoxy,
  • aryl(C ⁇ _6) a lkoxy, 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, (C )alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, (C ⁇ .
  • alkyl and alkenyl refer to (individually or as part of alkoxy or alkenyloxy) 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, heteroaryl, heterocyclyl, (C ⁇ _6)alkoxy, (C ⁇ _6)alkylthio, aryl(C ⁇ 6)alkoxy, aryl(C ⁇ _6)alkylthio, amino, mono- or di-(C ⁇ _6)alkylamino, cycloalkyl, cycloalkenyl, carboxy and esters thereof, amide, ureido, guanidino, (C ⁇ .g)alkylguanidino, amidino,
  • cycloalkyl and “cycloalkenyl” refer to groups having from three to eight ring carbon atoms and are optionally substituted as described hereinabove for alkyl and alkenyl groups.
  • heterocyclyl and “heterocyclic” refer to, unless otherwise defined, 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 preferably 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.
  • a substituent for a heterocyclyl group is selected from oxo, and the group hereinbefore defined as suitable aryl substituents.
  • heteroaryl suitably includes, unless otherwise defined, 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 heteroaromatic ring system is selected from the group hereinbefore defined as suitable aryl substituents.
  • the present invention includes the individual diastereoisomers and mixtures thereof.
  • the 2-hydroxy-substituted compounds of formula (IA) are of the (2S) configuration.
  • the 2-F-substituted compounds of formula (IA) may of (2S) configuration or (2R) configuration, or be provided as mixtures thereof.
  • the (2S) configuration is however preferred.
  • Preferred compounds of the invention include:
  • 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.
  • Compounds of the invention that contain a basic group such as an amino substituent may be in the form of a free base or an acid addition salt.
  • Compounds having an acidic group such as a carboxy substituent may be in the form of a pharmaceutically acceptable salt.
  • Compounds of the invention having both a basic and an acidic centre may be in the form of zwitterions, acid addition salt of the basic centre or alkali metal salts (of the carboxy group).
  • Pharmaceutically acceptable salts are preferred. The present invention includes all such salts.
  • Acid-addition salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Set, 1977, 66, 1-19.
  • Suitable salts include the hydrochloride, maleate, and methanesulphonate; particularly the hydrochloride.
  • salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.
  • Suitable salts include alkali metal salts such as the sodium and potassium salts.
  • P is hydrogen or an hydroxy-protecting group
  • R 2A , R 3A and R 4A are R 2 , R3 and R 4 as defined for formulae (IA) and (IB) or a group convertible to R 2 , R3 and R 4 respectively; and is as hereinbefore defined; with a compound of formula (III).
  • RIA is R ! as defined for formulae (IA) and (IB) or a group convertible to R 1 ; and Z ⁇ s C(i_6)alkyl, in a trans-este ⁇ fication reaction and thereafter, and if so needed, converting P to hydrogen, and if necessary converting an R 2A , R ⁇ A or R4A g r0 up to an R 2 , R ⁇ or R 4 group
  • trans-este ⁇ fication conditions are well known in the art (e.g I.O Sutherland in
  • the present invention provides a process for preparing a compound of formula (IA) or ( IB) which comprises reacting a compound of formula (LVA) or (IVB)-
  • R 1 A 1S as hereinbefore defined, and M is S ⁇ (R 7 )3, magnesium or an alkali metal, in which each R 7 is independently selected from C(i _6)alkyl and phenyl; in a ⁇ -ketoester formation reaction and thereafter, and if so needed; converting P to hydrogen, and if necessary, converting an R 2A , R3A or R 4A group t0 an R 2 j R 3 or R 4 group .
  • M is preferably lithium.
  • Suitable ⁇ -ketoester formation conditions are well known in the art ⁇ e.g. J.M. Brown in Comprehensive Organic Chemistry, Vol. 2, ed. I.O Sutherland, p. 779, Pergamon, 1979) and include an organic solvent such as tetrahydrofuran, at a temperature of -100°C to 0°C (preferably -80°C to -60°C)
  • this invention also provides for the preparation of compounds of formula (IA) or (IB) m which R 1 is -CH2SR 6 and R 1 and R 6 are as hereinbefore defined, which comprises reacting a compound of formula (IA) or (IB), in which R is -CH2-halogen with a compound of formula (VI)
  • a preferred protecting group is acyl, for example so that -OP is t ⁇ fluoroacetoxy or dichloroacetoxy
  • R 3A 1S a j so preferably acyloxy, for example acetyl or dichloroacetyl Hydroxyl groups at positions 1 1 and 2 (as groups OP and R 3A ) may t, e pro tected using, for example, t ⁇ fluoroacetic anhydride or dichloroacetic anhydride and py ⁇ dine in tetrahydrofuran or N-t ⁇ fluoroacetyl-imidazole in tetrahydrofuran at 0°C
  • the protecting acyl groups may be removed to restore the hydroxyl groups, for instance by hydrolysis e g using NaOH in either MeOH or tetrahydrofuran/water solution Suitable hydroxy,
  • 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 and 4-methoxybenzyloxycarbonyl
  • Particularly suitable carboxy protecting groups include alkyl and aryl esters, for instance methyl, ethyl and phenyl.
  • Particularly suitable amino protecting groups include alkoxycarbonyl and 4-methoxybenzyloxycarbonyl.
  • R-A is typically the R ⁇ - 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.
  • R 3 A 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.
  • a compound of formula (IA) may also be prepared from an epi -mutilin starting material. Accordingly, in a further aspect, the present invention provides a process for preparing a compound of formula (IA) in which R 3 and R 4 are both hydrogen which comprises reacting an ep.-mutilin compound of formula (IIC):
  • the present invention provides a process for preparing a compound of formula (IA) in which R 3 and R 4 are both hydrogen which comprises reacting an epi- mutilin compound of formula (IVC):
  • JNC wherein R 2 A is as hereinbefore defined; with a compound (V), as hereinbefore defined; and then treating the product with an acid; and where required or desired converting an R A group to an R* group and an R 2 A group to an R 2 group.
  • the acid treatment indicated above converts the ep.-mutihn configuration to the usual mutihn nucleus of formula (IIA) Typically this conversion is carried out by treatment ith cone HC1 or Lukas reagent (cone HC1 saturated with ZnCb) in dioxane
  • R ⁇ R 2 , R 3 or R 4 group may be interconvert to another R ' , R-, R 3 or R 4 group This typically arises when one compound of formula (IA/B) is used as the immediate precursor of another compound of formula (IA B) or when it is easier to introduce a more complex or reactive substituent at the end of a synthetic sequence.
  • a substituent group in R ⁇ can be converted into another substituent group using one of the general methods for functional group transformation described in the literature (e g. a.
  • carboxyhc ester can be hydrolysed to a carboxyhc acid with base; an acid can be converted into an amide; a tert-butoxycarbonylamino group can be converted into an amine by treatment with trifluoroacetic acid; an amino group can be alkylated or acylated), provided that the method chosen is compatible with other functional groups in the molecule (e.g. the ketone at C-3 in the pleuromutilin nucleus).
  • the intermediate 2-diazo compound may be reacted with a carboxyhc acid to give a 2- acyloxy-mutilin derivative.
  • reaction with dichloroacetic acid gives a 2- dichloroacetoxy-mutilin derivative, which can be deprotected as described above to provide the (2S)-2-hydroxy derivative, at an appropriate stage.
  • Compounds of formula (IIA) in which R ⁇ 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.
  • This reaction produces (2S)-2-fluoro derivatives.
  • (2/?)-2-Fluoro-mutilin derivatives may be prepared by treating the (2S)-isomer with a base (e.g. sodium hydroxide or potassium hydroxide in ethanol). This will usually produce a mixture of (2S) and (2i?)-isomers that may be separated using conventional techniques such as chromatography and crystallisation.
  • Enolates of formula (V) may be readily prepared from the corresponding ketone by methods known to those skilled in the art.
  • Ketones may be prepared by adapting procedures well known in the art for preparing ketones (e.g. A.J. Waring in Comprehensive Organic Chemistry, Vol. 1. ed. J.F. Stoddart, p. 1017, Pergamon, 1979).
  • 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 by conventional techniques such as chromatography or fractional crystallisation.
  • 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 particular for treating microbial infections m 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, Staphvlococcus aureus, Staphylococcus epidermidis, Enterococcus faecahs, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Haemophilus sp , Neisseria sp , Legwnella sp , Chlamydia sp , Moraxella catarrhahs, 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
  • 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
  • the present invention provides for the use of a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof the manufacture of a medicament adapted for administration to the nasal cavity, for prophylaxis of recurrent acute bacterial sinusitis or recurrent otitis media
  • 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 1.OOrng, typically about 0.1 to 0.2mg, in each nostril, once or twice a day.
  • 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
  • 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 ma be formulated tor 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 polyvmylpyrrohdone, 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 /? -hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring and colour agents
  • 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 ma ⁇ contain appropriate conventional additives, including, for example, preservatives, solvents to assist drug 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 anti-microbially 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.
  • focussed delivery' is used to mean that the composition is delivered to the nasopharynx, rather than remaining within the nares.
  • 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 that 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 %.
  • the pH of the composition may also be adjusted, for optimum stability of the drug substance during storage. For compounds of the present invention, a pH in the range 5 to 6, preferably about 5.3 to 5.8, typically about 5.5 is optimal
  • Representative oily spray and cream compositions are described in WO 98/14189 (SmithKline Beecham). Representative aqueous sprays are described in International Application no PCT/GB98/0321 1 (SmithKline Beecham).
  • the drug substance is present in compositions for nasal delivery in between
  • compositions 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 that are metered to provide a unit volume of composition, preferably about lOO ⁇ l, and optionally adapted for nasal administration by addition of a modified nozzle.
  • Step 2 Mutilin-14-(3-oxo-3-phenyl-propionate)
  • the product of Step 1 (280 mg, 0.58 mmol) in dioxane (5 ml) was treated with concentrated HC1 (5 ml) and the reaction stirred at room temperature for 4 hours.
  • the solution was poured into ethyl acetate and saturated aqueous sodium hydrogen carbonate solution.
  • the aqueous phase was re-extracted with ethyl acetate and the combined organic phases were washed with brine.
  • the organic phase was dried (MgSO_
  • the title compound was isolated as a colourless foam (154 mg, 57%); MS(Electrospray) m/z 465 [M-H]".
  • Methylcyanoformate (1.02g, 1.0 ml, 12 mmol) was added and the mixture was stirred at -78°C for 30 minutes and then allowed to warm to 0°C. The mixture was poured into saturated ammonium chloride solution and the product extracted into chloroform. The organic phase was dried (MgSO. ) and evaporated. Purification of the residue by chromatography on silica gel eluting with chloroform-methanol-35% ammonia solution (20: 1 :0.1 v/v/v) gave the title compound as an off white solid (850 mg, 43%):MS(Electrospray) m/z 198 [M+H]+.

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Abstract

β-cétoesters de pleuromutiline de Formule (IA) ou (IB). Dans les formules, R1 représente un hétérocycle contenant azote, un aryle facultativement substitué ou un groupe hétéroaryle facultativement substitué, ou CH¿2R?5; R2 représente vinyle ou éthyle; R3 représente H, OH ou F; et R4 représente H; ou R3 représente H et R4 représente F; R5 représente halogène ou SR?6; et R6¿ représente aminoalkyle, un hétérocycle contenant azote, ou un aryle facultativement substitué ou encore un groupe hétéroaryle facultativement substitué. Ces composés sont utiles en thérapie en tant qu'agents antibactériens.
PCT/EP2000/007687 1999-08-20 2000-08-04 β-CETOESTERS DE PLEUROMUTILINE Ceased WO2001014310A1 (fr)

Priority Applications (1)

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AU72728/00A AU7272800A (en) 1999-08-20 2000-08-04 Pleuromutilin beta-ketoesters

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GBGB9919839.2A GB9919839D0 (en) 1999-08-20 1999-08-20 Novel compounds
GB9919839.2 1999-08-20

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002030929A1 (fr) * 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Nouveaux derives de pleuromutiline
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
US7556948B2 (en) 2002-08-09 2009-07-07 Glaxo Group Limited Method for producing crystallized pleuromutilins
CN103626693A (zh) * 2012-08-28 2014-03-12 中国科学院上海药物研究所 一类截短侧耳素衍生物、其药物组合物及其合成方法与用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999021855A1 (fr) * 1997-10-29 1999-05-06 Smithkline Beecham P.L.C. Derives de pleuromutiline utilises comme agents antimicrobiens

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999021855A1 (fr) * 1997-10-29 1999-05-06 Smithkline Beecham P.L.C. Derives de pleuromutiline utilises comme agents antimicrobiens

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002030929A1 (fr) * 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Nouveaux derives de pleuromutiline
US6900345B2 (en) 2000-10-10 2005-05-31 Smithkline Beecham P.L.C. Pleuromutilin derivatives
EP1538150A1 (fr) * 2000-10-10 2005-06-08 Smithkline Beecham Plc Nouveaux pleuromutilin derivate
US7160907B2 (en) 2000-10-10 2007-01-09 Smithkline Beecham P.L.C. Pleuromutilin derivatives
EP1889845A1 (fr) * 2000-10-10 2008-02-20 SmithKline Beecham P.L.C. Nouveaux dérivés de pleuromutiline
US7556948B2 (en) 2002-08-09 2009-07-07 Glaxo Group Limited Method for producing crystallized pleuromutilins
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
CN103626693A (zh) * 2012-08-28 2014-03-12 中国科学院上海药物研究所 一类截短侧耳素衍生物、其药物组合物及其合成方法与用途

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