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WO2008017840A1 - Dérivés de l'acide cyclopentanecarboxylique et leur utilisation pour traiter des maladies infectieuses d'origine bactérienne - Google Patents

Dérivés de l'acide cyclopentanecarboxylique et leur utilisation pour traiter des maladies infectieuses d'origine bactérienne Download PDF

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WO2008017840A1
WO2008017840A1 PCT/GB2007/003017 GB2007003017W WO2008017840A1 WO 2008017840 A1 WO2008017840 A1 WO 2008017840A1 GB 2007003017 W GB2007003017 W GB 2007003017W WO 2008017840 A1 WO2008017840 A1 WO 2008017840A1
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substituted
compound according
compound
formula
halo
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PCT/GB2007/003017
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Michael Glen Orchard
Mohammed Benghezal
Stéphanie BRAILLARD
Christine Burn
Christine Deuschel
Aurore Lucas
Emilio Valentino
Christian Janssen
Rustum S. Boyce
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Merlion Pharmaceuticals Sa
Merlion Pharmaceuticals Pte Ltd
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Publication of WO2008017840A1 publication Critical patent/WO2008017840A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/60—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/59—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—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
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • 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
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—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
    • 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
    • C07D295/182—Radicals derived from carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the invention relates to substituted cyclopentanecarboxylic acid derivatives and related compounds, processes for the preparation thereof, pharmaceutical compositions containing the same, the use thereof optionally in combination with one or more other pharmaceutically active compounds as anti-bacterial agents for the therapy of bacterial infectious diseases, and a method for the treatment of such diseases.
  • Antibiotics have been discovered by searching in vitro for substances with bactericidal or bacteriostatic activities. Although very successful, this approach has reached its limits: Despite the fact that hundreds of antibiotics have been discovered within the last 60 years, they all target only five different pathways in bacteria (Coates A., Hu Y., Bax R., Page C. (2002), Nature Reviews - Drug Discovery 1 :895-910). Vancomycin and the beta-lactam antibiotics (penicillins and cephalosporins) inhibit cell wall synthesis. Polymyxin B and amphotericin B increase membrane permeability.
  • Aminoglycosides irreversibly inhibit protein synthesis whereas chloramphenicol, erythromycin, clindamycin, and the tetracyclines are reversible inhibitors of protein synthesis.
  • the quinolones inhibit nucleic acid synthesis by inhibiting the DNA topoisomerases.
  • Sulfonamides inhibit nucleic acid synthesis by inhibiting ofe novo synthesis of purine bases among other actions so they are sometimes referred to as having antimetabolic activity. Noteworthy, all assays developed to search for anti-bacterial agents assessed compounds in vitro on artificial culture media, whereas bacteria are confronted with an entirely different environment within their host.
  • pathogenesis using the amoeba and the pathogenesis measured in an animal model are in excellent correlation (Cosson P. et al. (2002), J. Bact. 184/11 :3027-3033). This implies that the amoeba recreates some essential features of a mammalian host. Genes important for bacterial survival in the presence of the amoeba are also required for the bacteria to survive and disseminate in a mammalian host. Thus, this approach is integrating all of the potential host-pathogen based mechanisms of pathogenesis. Bacterial infections are among the largest health problems that the world has to face. For instance, infectious diseases are the third cause of death in the USA and bacterial infections account for more than 75% of these fatalities
  • the present invention aims at providing new compounds that selectively reduce the pathogenicity of bacteria within the host.
  • compounds according to the present invention have a new mode of action and therefore are useful in fighting bacterial infections that are resistant to current antibiotics.
  • the invention relates to novel compounds of formula (I) as defined hereinafter, to methods of synthesis of such compounds, to compounds of formula (I) for use as medicaments, in particular as antiinfective drugs, to pharmaceutical compositions containing compounds of formula (I), to the use of a compounds of formula (I) for the preparation of a pharmaceutical composition for the treatment of infective diseases, and to methods of treatment and prophylaxis of infective diseases using such compounds of formula (I) or of pharmaceutical compositions containing same.
  • Cyclopentanecarboxylic acid derivatives and related compounds of formula (I) are reducing selectively the pathogenicity of bacteria within the host, but without affecting the bacteria outside the host environment.
  • the invention relates to novel compounds of formula (I) wherein
  • R 1 represents substituted or non-substituted arylaminocarbonyl, substituted or non-substituted heteroarylaminocarbonyl, substituted or non-substituted aryl lower alkylaminocarbonyl, alkylaminocarbonyl, di-alkylaminocarbonyl, heterocyclylaminocarbonyl, substituted or non-substituted arylamino, substituted or non-substituted arylaminoalkyl, substituted or non-substituted arylaminocarbonylamino, substituted or non-substituted heteroarylaminocarbonylamino, substituted or non-substituted aryloxycarbonyl, substituted or non-substituted heteroaryloxycarbonyl, substituted or non-substituted arylsulfonylamino, substituted or non- substituted heteroarylsulfonylamino, substituted or non-sub
  • R 2 and R 5 independently represent hydrogen, methyl, hydroxy, lower alkyloxy, heterocyclyloxy, substituted or non-substituted aryloxy, substituted or non- substituted heteroaryloxy, lower alkylcarbonyloxy, heterocyclylcarbonyloxy, substituted or non-substituted arylcarbonyloxy, substituted or non-substituted heterocyclylcarbonyloxy, amino non-substituted or substituted by one or two substituents lower alkyl, heterocyclyl, substituted or non-substituted aryl, or substituted or non-substituted heteroaryl, lower alkylcarbonylamino, heterocyclylcarbonylamino, substituted or non-substituted arylcarbonylamino, substituted or non-substituted heteroarylcarbonylamino, aminocarbonylamino, lower alkylaminocarbonylamino, lower di-alkylaminocarbonyla
  • R 3 and R 4 independently represent hydrogen or lower alkyl, or together R 3 and R 4 form a C3-6 alkylene;
  • R 6 represents hydroxyl, lower alkyloxy, lower heterocyclyloxy, amino non- substituted or substituted by one or two substituents lower alkyl or heterocyclyl
  • R 1 is preferably arylaminocarbonyl, arylamino or arylaminoalkyl.
  • Arylaminocarbonyl is particularly preferred and will be referred to hereinafter in the context of substituted and unsubstituted aryls, however the discussion of aryls also applies to the aryl of an arylamino or arylaminoalkyl.
  • the aryl is substituted. It is particularly preferred that the aryl is substituted by at least one (preferably only one) alkyl or alkoxy group.
  • the alkyl or alkoxy group is itself substituted, preferably with one or more halo atoms.
  • R 1 is preferably a haloalkyl- or haloalkoxy-substituted aryl aminocarbonyl. Particularly preferred are haloalkyl- or haloalkoxy-substituted phenyl aminocarbonyls. Especially preferred are fluoro alkyl- or fluoro alkoxy-substituted phenyl aminocarbonyls. Also preferred are chloro and mixed fluoro/chloro alkyl- or chloro and mixed fluoro/chloro alkyloxy-substituted phenylaminocarbonyls.
  • the alkyl or alkoxy groups are lower alkyl or lower alkoxy, respectively.
  • the alkyl is methyl or tert-butyl.
  • the alkoxy is methoxy.
  • R 1 is alkyl- or alkoxy-substituted aryl aminocarbonyl
  • the alkyl or alkoxy are preferably selected from substituted methyl (preferably halo substituted methyl) and substituted methoxy (preferably halo substituted methoxy).
  • Trifluoroalkoxy preferably trifluor ⁇ methoxy
  • trifluoroalkyl preferably trifluoromethyl
  • difluorochloroalkoxy preferably difluorochloromethoxy
  • difluorochloroalkyl preferably difluorochloromethyl
  • unsubstituted alkyl and unsubstituted alkoxy are also suitable.
  • particularly preferred are methyl- or tert-butyl-substituted aryl aminocarbonyls, particularly methyl-substituted phenyl amino carbonyl (especially 4-methyl-phenyl aminocarbonyl).
  • halo-substituted aryl aminocarbonyls are also suitable. Mono or di substitution with a halo atom is preferred.
  • the halo substituents are preferably chosen from F, Cl and Br.
  • the aryl has more than one substituent, for example two substituents. In such cases, preferably the substituents are different.
  • Preferred combinations of substituents include two halo groups; a halo and a halo- substituted alkyl; a halo and a halo-substituted alkoxy; a halo and an unsubstituted alkyl; and a halo and an unsubstituted alkoxy.
  • Particularly preferred combinations include Br and F (especially 4-bromo-2-fluoro-phenyl aminocarbonyl); dichloro (especially 3,4-dichloro-phenyl aminocarbonyl); fluoroalkyl and halo (especially 4-chloro-3-trifluoromethyl-phenyl aminocarbonyl); and alkyl and F (especially 3-fluoro-4-methyl-phenyl aminocarbonyl).
  • the substitution of the phenyl can be at one or more (preferably only one) of the ortho (2-), meta (3-) and para (4-) positions. Substitution at the para position (i.e. 4-position) is preferred.
  • R 1 is a group according to formula (X)
  • R 7 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halo or cyano;
  • R 8 represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or halo.
  • R 7 is a haloalkyl or haloalkoxy, preferably a fluoro-, chloro- or mixed fluoro-chloro-substituted alkyl or alkoxy, as discussed above.
  • the alkyl or alkoxy are lower alkyl or lower alkoxy, respectively.
  • R 7 is selected from halo-lower alkyl and halo-lower alkoxy.
  • R 8 is preferably hydrogen or halo (suitably selected from F, Cl and Br).
  • R 8 is hydrogen (i.e. the phenyl is monosubstituted).
  • R 7 is at the para or meta position, preferably para.
  • R 8 when it is not hydrogen, is preferably para or meta.
  • R 8 when R 7 is at the meta position, R 8 is para.
  • R 7 and R 8 are both independently selected from unsubstituted alkyl and unsubstituted alkoxy
  • R 7 may be at the 2-position and R 8 at the 5-position. Indeed, 2,5-dimethyl and 2,5-dimethoxy substitution is possible.
  • R 7 is 2-methyl
  • R 8 is preferably not 5-methyl or vice versa
  • R 7 is 2-methoxy
  • R 8 is preferably not 5-methoxy or vice versa.
  • R 7 and R 8 are unsubstituted alkyl, preferably they are not methyl.
  • R 7 and R 8 are unsubstituted alkoxy, preferably they are not methoxy.
  • R 8 is not hydrogen if R 7 is para-methyl, para-methoxy, para-fluoro or ortho-methoxy carbonyl, R 8 is not hydrogen.
  • R 1 Preferred examples of R 1 are:
  • R 1 is an arylamino or arylaminoalkyl.
  • the aryl is phenyl, as discussed above.
  • R 1 is an arylaminoalkyl, preferably phenylaminomethyl.
  • R 1 is as defined above with respect to formula (X), except that the core structure is a phenylaminomethyl as follows:
  • a particularly preferred example is:
  • R 1 is a heteroarylaminocarbonyl, preferably a nitrogen- containing heteroaryl.
  • the heteroaryl is a bicyclic heteroaryl.
  • a particularly preferred bicyclic heteroaryl is benzimidazolyl.
  • the benzene portion of the benzimidazoyl is substituted, preferably with a lower alkyl. Di-substitution is particularly preferred, suitably 5,6-dimethyl substitution.
  • a preferred example of R 1 is:
  • R 2 is preferably methyl.
  • R 3 is preferably methyl.
  • R 4 is preferably methyl.
  • R 3 and R 4 are both methyl.
  • R 2 , R 3 and R 4 are methyl.
  • R 5 is preferably hydrogen.
  • R 6 is preferably hydroxyl or substituted amino.
  • substituted amino lower alkyl substitution is preferred, particularly methyl amino (-NHMe).
  • R 6 is most preferably hydroxyl or -NHMe, with hydroxyl being particularly preferred.
  • R 6 is hydroxyl or methylamino
  • R 1 is a substituted phenyl aminocarbonyl according to formula (X) or (X 1 ) above.
  • R 1 is a substituted phenyl aminocarbonyl according to formula (X).
  • R 6 is preferably hydroxyl.
  • the compound has a 1S, 3R configuration.
  • the present invention provides a compound according to formula (I) as defined above, wherein R 1 is a substituted arylaminocarbonyl wherein the aryl substituent comprises a halo-substituted alkyl or halo- substituted alkoxy.
  • the substituent comprises a halo-substituted lower alkyl or halo-substituted lower alkoxy, more preferably halomethyl or halomethoxy.
  • the present invention provides a compound according to formula (I) as defined above, wherein when R 2 , R 3 and R 4 are all Me, and R 5 is hydrogen, R 1 is not one of the following:
  • the present invention provides a compound according to formula (I) as defined above, wherein when R 1 is any one of:
  • R 5 is not hydrogen.
  • Aryl designates a mono- or bicyclic fused ring aromatic group with 5 to 10 carbon atoms, such as phenyl, 1-naphthyl or 2-naphthyl, or also a partially saturated bicyclic fused ring comprising a phenyl group, such as indanyl, dihydro- or tetrahydronaphthyl.
  • aryl is phenyl.
  • the aryl may be substituted by up to 3 substituents which are preferably lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, lower alkoxycarbonyl, methylenedioxy, halo-lower alkyl, halo-lower alkoxy, lower alkoxy-lower alkyl, halo, cyano, nitro, heterocyclyl, heteroaryl, aminosulfonyl where amino is non substituted or substituted by one or more substituents lower alkyl, amino non substituted or substituted by one or two substituents lower alkyl, or amino with one substituent lower alkylcarbonyl, aryl, heteroaryl or heterocyclyl.
  • substituents are preferably lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, lower alkoxycarbonyl, methylenedioxy, halo-lower alkyl, halo-lower alkoxy, lower alkoxy-lower alkyl,
  • Heteroaryl designates an aromatic group containing at least one heteroatom selected from nitrogen, oxygen and sulfur, and is mono- or bicyclic.
  • Monocyclic heteroaryl includes 5 or 6 membered heteroaryl groups containing 1 , 2, 3 or 4 heteroatoms selected from nitrogen, sulfur and oxygen.
  • Bicyclic heteroaryl includes 9 or 10 membered fused-ring heteroaryl groups.
  • Examples of monocyclic heteroaryl include pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Examples of bicyclic heteroaryl include indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl and purinyl.
  • the heteroaryl may be substituted by up to 3 substituents which are preferably lower alkyl, halo-lower alkyl, halo-lower alkoxy, lower alkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, halo, cyano, nitro, amino non substituted or substituted by one or two substituents lower alkyl, or amino with one substituent lower alkylcarbonyl, aryl, heteroaryl or heterocyclyl.
  • substituents are preferably lower alkyl, halo-lower alkyl, halo-lower alkoxy, lower alkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, halo, cyano, nitro, amino non substituted or substituted by one or two substituents lower alkyl, or amino with one substituent lower alkylcarbonyl, aryl, heteroaryl or heterocyclyl.
  • Heterocyclyl designates preferably a saturated, partially saturated or unsaturated, mono- or bicyclic ring containing 4-10 atoms comprising one, two or three heteroatoms selected from nitrogen, oxygen and sulfur, and may, unless otherwise specified, be carbon or nitrogen linked.
  • a ring nitrogen atom may also be substituted by a group selected from lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl and acyl, and a ring carbon atom may be substituted by lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl, heteroaryl, lower alkoxy, hydroxy or oxo.
  • heterocyclyl examples include pyrrolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxolanyl and tetrahydropyranyl.
  • Acyl designates, for example, alkylcarbonyl, cyclohexylcarbonyl, arylcarbonyl, aryl-lower alkylcarbonyl, or heteroarylcarbonyl.
  • Acyl is preferably lower alkylcarbonyl, in particular propionyl or acetyl.
  • Lower alkyl is preferably Ci to C 5 , more preferably Ci to C 3 , even more preferably C 1 to C 2 .
  • Particularly preferred examples are methyl, ethyl, isopropyl and tert-butyl.
  • Lower alkoxy is preferably Ci to C 5 alkoxy, more preferably Ci to C 3 , even more preferably Ci to C 2 .
  • Particularly preferred examples are methoxy, ethoxy, isopropyloxy and tert-butyloxy.
  • Halo designates halogens that are selected among fluoro, chloro, bromo, or iodo.
  • Halo-lower alkyl is preferably trifluoromethyl, pentafluoroethyl or 2,2,2- trifluoroethyl.
  • Halo-lower alkoxy is preferably trifluoromethoxy, difluorochloromethoxy, pentafluoroethoxy or 2,2,2-trifluoroethoxy.
  • a moiety that is covalently attached to a molecule or part of a molecule is defined as a substituent (where the moiety is not hydrogen). If the moiety is hydrogen, then the molecule or part of the molecule is described as being non substituted.
  • a pathogenic organism has been defined as an organism that causes, or is capable of causing disease. Pathogenic organisms propagate on or in tissues and may obtain nutrients and other essential materials from their hosts. As used herein, the term “pathogenicity” refers to a capability of causing disease and/or degree of capacity to cause disease to its host. The term is applied to parasitic micro-organisms in relation to their hosts.
  • pathogenicity encompass the general capability of causing disease as well as various mechanisms and structural and/or functional deviations from normal used in the art to describe the causative factors and/or mechanisms, presence, pathology, and/or progress of disease, such as virulence, host recognition, cell wall degradation, toxin production, infection hyphae, penetration peg production, appressorium production, lesion formation, sporulation, and the like.
  • infecting bacterium is meant a bacterium that has established infection in the host, and which may be associated with a disease or undesirable symptom as a result.
  • infecting bacteria of interest are pathogenic bacteria, and may include a culture of multiple bacteria which together act to cause the pathology. Treatment may require elimination of a single, or multiple types of bacteria.
  • drug-resistant bacteria or “antibiotic-resistant bacteria” is meant a bacterial strain that is resistant to growth inhibition or killing by an antibiotic. Multi-drug resistant bacteria are resistant to two or more antibiotics classes. Drug resistance can encompass, for example, ineffective killing of the infecting bacteria such that at least an infectious dose remains in the subject and the infection continues, resulting in continued symptoms of the associated infectious disease or later evidence of such symptoms.
  • Drug resistance can also encompass inhibiting growth of the drug- resistant bacteria until such time therapy is discontinued, after which the bacteria begin to replicate and further the infectious disease.
  • inhibiting growth of the drug- resistant bacteria in the context of infection of an incapacitated bacterial cell according to the invention is meant that, following infection of the bacteria, the bacterial host cell's normal transcriptional and/or translational mechanisms are compromised such that the infected bacteria does not undergo substantial cell division (replication) and is caused to enter a state of bacteriostasis. The stasis causes pathogenic effects to also regress.
  • an infectious disease or infectious disorder is a disease arising fm the presence of a microbial agent in the body.
  • the microbial agent may be an infectious bacteria or an infectious fungi, which gives rise to a bacterial infectious disease or a fungal infectious disease, respectively.
  • infectious bacteria include but are not limited to: Helicobacter pylons, Borelia burgdorferi, Legionella pneumophilia, Mycobacteria sps (e.g. M. tuberculosis, M. avium, M. intracellulare, M. kansaii, M. gordonae), Staphylococcus aureus, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Streptococcus pyogenes (Group A Streptococcus), Streptococcus agalactiae (Group B Streptococcus),
  • Streptococcus (viridans group), Streptococcus faecalis, Streptococcus bovis, Streptococcus (anaerobic sps.), Streptococcus pneumoniae, pathogenic Campylobacter sp., Enterococcus sp., Haemophilus influenzae, Bacillus antracis, corynebacterium diphtheriae, corynebacterium sp., Erysipelothrix rhusiopathiae, Clostridium perfringers, Clostridium tetani, Enterobacter aerogenes, Klebsiella pneumoniae, Pasturella multocida, Bacteroides sp., Fusobacterium nucleatum, Streptobacillus moniliformis, Treponema pallidium, Treponema permur, Leptospira, Rickettsia, Actinomyces israel
  • salts refers to a salt that retains the biological effectiveness of the free acids and bases of a specified compound and that is not biologically or otherwise undesirable.
  • salts are especially the pharmaceutically acceptable salts of compounds of formula (I).
  • Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula (I) with a basic nitrogen atom, especially the pharmaceutically acceptable salts.
  • Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantinecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2- hydroxyethanesulfonic acid, ethane-1 ,2-d
  • salts for isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates.
  • pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
  • the salts are prepared by reacting the free base with stoichiometric amounts or with an excess of the desired salt forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • the free base can be dissolved in a mixed aqueous solution of the appropriate acid and the salt recovered by standard techniques, for example, by evaporation of the solution.
  • the free base can be charged into an organic solvent such as a lower alkanol, symmetrical or asymmetrical ethers containing 2 to 10 carbon atoms, an alkyl ester, or mixtures thereof, and the like, and then it is treated with the appropriate acid to form the corresponding salt.
  • the salt is recovered by standard recovery techniques, for example, by filtration of the desired salt from the mixture, or it can be precipitated by the addition of a solvent in which the salt is insoluble and recovered there from.
  • acidic drugs or acidic prodrugs such as phosphates
  • inorganic bases are lithium, sodium, potassium, ammonium, calcium, magnesium, zinc and manganese. Production of phosphate salts are described in e.g. G. R. Pettit et al. Anti-Cancer Drug Design 16 (2001) 185-193.
  • Preferred salts also include those formed from acidic prodrugs and organic amines, including, but not limited to, imidazole and morpholine. Alkaline amino acid salts may also be used.
  • amino acids designates, according to the invention, in particular the [alpha]-amino acids occurring in nature, but moreover also includes their homologues, isomers and derivatives. Enantiomers can be mentioned as an example of isomers. Derivatives can be, for example, amino acids provided with protective groups.
  • Preferred alkaline amino acid are arginine, ornithine, diaminobutyric acid, lysine or hydroxy lysine and especially L-arginine, L-lysine or L-hydroxy lysine; an alkaline dipeptide or a pharmaceutically acceptable alkaline amino acid derivate.
  • any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.
  • the compound of the formula (I) may be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the formula (I).
  • pro-drugs include in vivo hydrolysable esters of a compound of the formula (I).
  • the present invention also relates to pro-drugs of a compound of formula (I) that in vivo convert to the compound of formula (I) as such. Any reference to a compound of formula (I) is therefore to be understood as referring also to the corresponding pro-drug of the compound of formula (I), as appropriate.
  • a "pro-drug” is an entity which either comprises an inactive form of an active drug (parent compound) or includes a chemical group which confers preferred characteristics on the drug.
  • it concerns a composition which has the potential of producing a desired physiological effect on bacteria, but is initially inert (i.e. does not produce said effect), and only after undergoing some modifications becomes physiologically active and produces said physiological effect on bacteria.
  • the derivative of the compound of formula (I) has a chemically or metabolically degradable group, and becomes pharmaceutically active after biotransformation.
  • Biotransformation of the prodrug or a salt thereof is carried out under physiological conditions (in vivo) and is a result of a reaction with an enzyme, or a body fluid such as gastric acid, blood etc., thus undergoing an enzymatic oxidation, reduction, hydrolysis etc. or a chemical hydrolysis convert into the active parent compound of formula (I).
  • parent compounds or “active parent compounds” or “active drugs” are used interchangeably herein to designate the compounds of formula (I) according to the present invention.
  • pro-drug derivatives designate phosphate derivatives, ester derivatives, carbonate derivatives (acyloxy derivatives of the parent compounds) and/or linked poly(ethylene glycol) derivatives as described below. Any other suitable derivatives known by those skilled in the art and considered as equivalents may also be used in the scope of the present invention.
  • the invention also encompasses chemical modifications of the compounds of formula (I) to prolong their circulating lifetimes.
  • suitable poly(ethylene glycol) derivatives that possess this property are described in e.g. US 2005171328 (NEKTAR THERAPEUTICS AL CORP) or US 6,713,454 (NOBEX CORP). Since the compounds of formula (I) are fairly lipophilic, the PEG-oligomer/polymer also increases the hydrophilicity of the pro-drugs and thereby their aqueous solubility.
  • the compounds of formula (I) have valuable pharmacological properties.
  • the invention also relates to compounds of formula (I) as defined hereinbefore for use as medicaments.
  • the compounds of formula (I) as defined hereinbefore may be used to selectively reduce the pathogenicity of bacteria within a host, but without affecting the bacteria outside the host environment.
  • a classical antibiotic kills bacteria (bactericidal antibiotics) or prevents its growth (bacteriostatic antibiotics) in all environments, i.e. within a host, on an agar plate, in culture broths, in soil, in drinking water, in a sewer and the like
  • the compounds of formula (I) are effective only when bacteria are within the host, during the infection process.
  • compounds of the invention cannot be identified by any simple in vitro methods - as are classical antibiotics - since their activity is expressed upon bacteria (and can be monitored) only within the context of a complex multicellular organism such as a mammal.
  • compounds of formula (I) have no or non significant inhibitory activity or weak effect on bacterial growth as measured in standard growth inhibition assays.
  • the compounds of the invention are identified using the method to determine that a particular composition reduces the pathogenicity of bacteria to a test host organism described in WO 02/101081 (from the same applicant), the content of which is incorporated herein by reference in its entirety.
  • the compounds of the invention are identified using the method to determine that a particular composition reduces the pathogenicity of bacteria to a test host organism.
  • the method comprises exposing a unicellular test host organism to a pathogen in the presence and in the absence of a candidate composition and then monitoring the growth of the unicellular test host organism and/or the growth of the pathogen.
  • a higher level of growth of the unicellular test host organism (or a lower level of growth of the pathogen) in the presence of the candidate composition when compared to growth in the absence of the candidate composition indicates that the candidate composition reduces the pathogenicity of bacteria to the unicellular test host organism.
  • Anti-virulence activities of compounds were determined by measuring the growth of Klebsiella pneumoniae in the presence of Tetrahymena pyriformis. Tetrahymena pyriformis feed phagocytically upon bacteria such as K. pneumoniae.
  • the assay is performed in wells of black 384-well microtitre plates in a final volume of 50 ⁇ l.
  • 22.5 ⁇ l of Tetrahymena pyriformis cells (50,000 cells/ml) and 22.5 ⁇ l Klebsiella pneumoniae cells (1.11 x10 7 cfu/ml) are mixed together in SM medium (1% w/v protease peptone, 0.22% w/v KH 2 PO 4 , 0.1% w/v K 2 HPO 4 , 0.1% w/v yeast extract, 0.03% w/v MgSO 4 ) in the presence of 5 ⁇ l of test compound (in no greater than 5% DMSO).
  • SM medium 1% w/v protease peptone, 0.22% w/v KH 2 PO 4 , 0.1% w/v K 2 HPO 4 , 0.1% w/v yeast extract, 0.03% w/v MgSO 4
  • the plates are incubated for 24h at 35 0 C and growth of the Klebsiella is quantified by measuring absorbance at OD 450 nm- Control wells in which the Klebsiella have been omitted are used to subtract the background OD 45 o nm of Tetrahymena and media from each assay well. Similarly, control wells in which the test compound is omitted, thereby the Klebsiella will outgrow the Tetrahymena, are included to obtain a OD 45 on m equivalent to 0% antivirulence. Antivirulence activities of test compounds are calculated as a function of these control values.
  • Duplicate assay plates in which the Tetrahymena have been omitted are also included to determine antibacterial activity. Compounds are only deemed to have antivirulence activity if they do not inhibit growth of the Klebsiella to greater than 10% of the untreated control.
  • the efficacy of the compounds of the invention can be shown in inhibiting the pathogenicity of bacteria such as Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella m
  • a compound of formula (I) according to the invention shows therapeutic efficacy especially against infectious diseases.
  • the compounds of the invention are active against nosocomial infections in general, community acquired and nosocomial urinary tract infections, community acquired and nosocomial pneumonia, ventilator associated pneumonia, chronic pseudomonas infections in cystic fibrosis patients, peritonitis, febrile neutropenia, burn infections, sepsis, skin and soft tissue infections, including surgical site infections and bones infections.
  • a compound of formula (I) or the pharmaceutical composition containing the same can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations, or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic agents.
  • Therapeutic agents for possible combination are selected from quinolones, aminoglycosides, antifungal antibiotics, antiprotozoal agents, beta-lactam antibiotics, cephalosporins, cephamycins, macrolides, penicillins streptogramins, sulphonamides, tetracyclines, acedapsone, bacitracin, chloramphenicol, clindamycin, clofazimine, colistimethate, colistin, cycloserine, daptomycin, enoxacin, ethionamide, fosfomycin, ftivazide, furazolidone, fusidic acid, isoniazid, lincomycin, moxalactam, mupirocin, nitrofurantoin, nitrofurazone, nitroxoline, novobiocine, para-amino salicylic acid, para-aminobenzoic acid, polymyxin B, pristinamycin, pro
  • a compound according to the invention is not only for the (prophylactic and preferably therapeutic) management of humans, but also for the treatment of other warm-blooded animals, for example of commercially useful animals, for example rodents, such as mice, rabbits or rats, or guinea-pigs. Such a compound may also be used as a reference standard in the test systems described above to permit a comparison with other compounds.
  • R 1 represents substituted or non-substituted arylaminocarbonyl, substituted or non-substituted heteroarylaminocarbonyl, substituted or non-substituted aryl lower alkylaminocarbonyl, alkylaminocarbonyl, di-alkylaminocarbonyl, heterocyclylaminocarbonyl, substituted or non-substituted arylamino, substituted or non-substituted arylaminoalkyl, substituted or non-substituted arylaminocarbonylamino, substituted or non-substituted heteroarylaminocarbonylamino, substituted or non-substituted aryloxycarbonyl, substituted or non-substituted heteroaryloxycarbonyl, substituted or non-substituted arylsulfonylamino, substituted or non- substituted heteroarylsulfonylamino, substituted or non-sub
  • R 2 and R5 independently represent hydrogen, methyl, hydroxy, lower alkyloxy, heterocyclyloxy, substituted or non-substituted aryloxy, substituted or non-substituted heteroaryloxy, lower alkylcarbonyloxy, heterocyclylcarbonyloxy, substituted or non-substituted arylcarbonyloxy, substituted or non-substituted heterocyclylcarbonyloxy, amino non-substituted or substituted by one or two substituents lower alkyl, heterocyclyl, substituted or non-substituted aryl, or substituted or non-substituted heteroaryl, lower alkylcarbonylamino, heterocyclylcarbonylamino, substituted or non-substituted arylcarbonylamino, substituted or non-substituted heteroarylcarbonylamino, aminocarbonylamino, lower alkylaminocarbonylaminocarbonylamino, lower di-
  • R 3 and R 4 independently represent hydrogen or lower alkyl, or together R 3 and R 4 form a C3-6 alkylene;
  • R 6 represents hydroxyl, lower alkyloxy, lower heterocyclyloxy, amino non- substituted or substituted by one or two substituents lower alkyl or heterocyclyl.
  • the present invention provides a process for manufacturing a compound or pharmaceutical composition of the present invention.
  • a compound of the invention may be prepared by processes that, though not applied hitherto for the new compounds of the present invention, are known perse, in particular
  • Compounds of the present invention can be made for instance by reacting compounds of the formula (II) or (Ha) with compounds of the formula (III).
  • compounds of formula (I) where R 2 , R 3 and R 4 are methyl, and R 5 is hydrogen can be prepared from camphoric acid (or its anhydride or derivatives thereof) to make compounds of formula (I) shown below.
  • compounds of formula (I) are prepared from L-camphoric acid. It should be noted that it should also be possible to make compounds of formula (I) described immediately above or their isomers shown below (where R 3 , R 4 and R 5 are methyl, and R 2 is hydrogen),
  • Reaction of compounds of formula (II), (Ma) or a derivative thereof, with compounds of formula (III) may be carried out with functional groups in a protected form, in the presence of an inert base and/or a suitable catalyst, and optionally in the presence of an inert solvent; and any protecting groups in an obtained protected derivative of a compound of the formula (I) are removed;
  • an obtainable compound of formula (I) is converted into another compound of formula (I)
  • a free compound of formula (I) is converted into a salt
  • an obtainable salt of a compound of formula (I) is converted into the free compound or another salt
  • a mixture of isomeric compounds of formula (I) is separated into the individual isomers.
  • one or more other functional groups for example carboxy, hydroxy or amino, are or may need to be protected in a compound of formulas (II), (Ma), (III), and (IV), because they should not take part in the reaction, these are such protecting groups as are usually applied in the synthesis of amides, in particular peptide compounds, cephalosporins, penicillins, nucleic acid derivatives and sugars.
  • the protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e.
  • functional groups of the starting compounds which should not take part in the reaction may be present in unprotected form or may be protected for example by one or more of the protecting groups mentioned hereinabove under "protecting groups".
  • the protecting groups are then wholly or partly removed according to one of the methods described there.
  • functional groups of the starting compounds which should not take part in the reaction may be present in unprotected form or may be protected for example by one or more of the protecting groups mentioned hereinabove under "protecting groups".
  • the protecting groups are then wholly or partly removed according to one of the methods described there. Salts may be present in all starting compounds and transients, if these contain salt-forming groups. Salts may also be present during the reaction of such compounds, provided the reaction is not thereby disturbed.
  • isomeric mixtures that occur can be separated into their individual isomers, e.g. diastereomers or enantiomers, or into any mixtures of isomers, e.g. racemates or diastereomeric mixtures.
  • a compound of formula (I) is prepared according to or in analogy to the processes and process steps defined in the Examples.
  • the compounds of formula (I), including their salts, are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallization, i.e. be present as solvates.
  • New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention.
  • such starting materials are used and reaction conditions so selected as to enable the preferred compounds to be obtained.
  • compositions that comprise a compound of formula (I) as active ingredient and that can be used especially in the treatment of the diseases mentioned above.
  • Compositions for enteral administration such as nasal, buccal, rectal or, especially, oral administration, and for parenteral administration, such as intravenous, intramuscular or subcutaneous administration, to warm-blooded animals, especially humans, are especially preferred.
  • the composition can also be used in the context of cold blood animals such as fish.
  • the compositions comprise the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier.
  • the dosage of the active ingredient depends upon the disease to be treated and upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration.
  • the present invention relates especially to pharmaceutical compositions that comprise a compound of formula (I), a tautomer, a prodrug or a pharmaceutically acceptable salt, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable carrier.
  • the invention relates also to pharmaceutical compositions for use in a method for the prophylactic or especially therapeutic management of the human or animal body, in particular in a method of treating or preventing bacterial infectious disease in patients suffering neoplastic disease, autoimmune disease, transplantation related pathology and/or degenerative disease, especially those mentioned hereinabove.
  • the invention relates also to processes and to the use of compounds of formula (I) thereof for the preparation of pharmaceutical preparations which comprise compounds of formula (I) as active component (active ingredient).
  • a pharmaceutical composition for the prophylactic or especially therapeutic management of an infective disease of a warm-blooded animal, especially a human or a commercially useful mammal requiring such treatment, comprising a novel compound of formula (I) as active ingredient in a quantity that is prophylactically or especially therapeutically active against the said diseases, is likewise preferred.
  • the pharmaceutical compositions comprise from approximately 1% to approximately 95% active ingredient, single-dose administration forms comprising in the preferred embodiment from approximately 20% to approximately 90% active ingredient and forms that are not of single-dose type comprising in the preferred embodiment from approximately 5% to approximately 20% active ingredient.
  • Unit dose forms are, for example, coated and uncoated tablets, ampoules, vials, suppositories, or capsules.
  • Further dosage forms are, for example, ointments, creams, pastes, foams, tinctures, lip-sticks, drops, sprays, dispersions, etc. Examples are capsules containing from about 0.05 g to about 1.0 g active ingredient.
  • the compounds of formula (I) may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semi permeable matrices of solid hydrophobic polymers containing the compounds of formula (I), which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No.
  • copolymers of L-glutamic acid and [gamma] ethyl-L-glutamate non-degradable ethylene-vinyl acetate
  • degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT(TM) (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.
  • compositions of the present invention are prepared in a manner known perse, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes. Preference is given to the use of solutions of the active ingredient, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilized compositions comprising the active ingredient alone or together with a carrier, for example mannitol, can be made up before use.
  • a carrier for example mannitol
  • compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known perse, for example by means of conventional dissolving and lyophilizing processes.
  • the said solutions or suspensions may comprise viscosity-increasing agents, typically sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatins, or also solubilizers, e.g. Tween 80 ® (polyoxyethylene(20)sorbitan mono-oleate).
  • Suspensions in oil comprise as the oil component the vegetable, synthetic, or semi-synthetic oils customary for injection purposes.
  • liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms.
  • the alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a monovalent or polyvalent, for example a mono-, di- or trivalent, alcohol, especially glycol and glycerol.
  • vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and groundnut oil are especially useful.
  • injectable preparations are usually carried out under sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the containers.
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxy methyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
  • Additional excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • Tablet cores can be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide
  • suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
  • Dyes or pigments may be added to the tablets or tablet coatings, for example for identification
  • compositions for oral administration also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers.
  • the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • compositions suitable for rectal administration are, for example, suppositories that consist of a combination of the active ingredient and a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • aqueous solutions of an active ingredient in water-soluble form for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers, are especially suitable.
  • the active ingredient can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents. Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.
  • Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.
  • the present invention relates furthermore to a method for the treatment of an infective disease, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the radicals and symbols have the meanings as defined above for formula (I), in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.
  • the compounds of formula (I) can be administered as such or especially in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in an amount effective against the said diseases, to a warmblooded animal, for example a human, requiring such treatment.
  • the daily dose administered is from approximately 0.005 g to approximately 1.5 g, preferably from approximately 0.01 g to approximately 0.5 g, of a compound of the present invention.
  • Treatment refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented. Hence, the mammal to be treated herein may have been diagnosed as having the disorder or may be predisposed or susceptible to the disorder. Subjects in need of the treatment are preferably warm-blooded animal, and most preferably mammals. "Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals or pet animals, such as dogs, horses, cats, cows, monkeys etc. Preferably, the mammal is human.
  • terapéuticaally effective amount refers to an amount of a drug effective to treat a disease or disorder in a mammal.
  • therapeutically effective amount is used herein to mean an amount sufficient to prevent, or preferably reduce by at least about 30 percent, preferably by at least 50 percent, preferably by at least 70 percent, preferably by at least 80 percent, preferably by at least 90%, a clinically significant change in the therapeutic management of an infective disease of a warm-blooded animal.
  • the present invention relates especially also to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, especially a compound of formula (I) which is said to be preferred, or a pharmaceutically acceptable salt thereof, as such or in the form of a pharmaceutical formulation with at least one pharmaceutically acceptable carrier for the therapeutic and also prophylactic management of one or more of the diseases mentioned hereinabove, in particular an infective disease.
  • a therapeutic agent i.e. anti-bacterial agents
  • this may be used in the form of a medicament containing a combination of these two agents, for simultaneous administration, or they may be used in the form of separate dosage forms, each containing one of the agents, and in the latter case the individual dosage forms may be used e.g. sequentially, i.e. one dosage form with the compound (I), followed by a dosage form containing the chemotherapeutic agent (or vice versa).
  • This embodiment of two separate dosage forms may be conceived and provided in the form of a kit or Articles.
  • the Kit comprises a container and a label or package insert on or associated with the container.
  • Suitable containers include, for example, bottles, vials, syringes, etc.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container holds the compound's composition or the pro-drug composition or pharmaceutically acceptable salts thereof that are effective for treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • the label or package insert indicates that the composition is used for treating the condition of choice, such as infective diseases.
  • the compounds (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of the pathogenicity of microorganisms in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search i.e. for new therapeutic agents.
  • the present invention provides a compound, a compound for use as a medicament, a compound for use as a medicament for treating an infective disease, use of a compound in the manufacture of a medicament for treating an infective disease, a pharmaceutical composition comprising a compound, use of a compound in a method of treating an infective disease, and method of manufacturing a compound, wherein the compound, composition containing the compound, use of the compound and manufacure of the compound is as defined above in any combination of aspects, including preferred and optional features therein.
  • DMSO dimethylsulfoxide
  • eq. equivalent(s)
  • LCMS (MH+) liquid chromatography mass spectrum (mass plus 1 - positive ion mode).
  • Examples 1-5 and 7-31 were prepared according to the procedure exemplified for example 6 starting from L-camphoric acid anhydride (example 1), D- camphoric acid anhydride (example 2) or (+/-) camphoric acid anhydride (3-5 and 7-31) and the respective nucleophiles.
  • Example 33 1 ,2,2-Trimethyl-cvclopentane-1 ,3-dicarboxylic acid 1- methylamide 3-[(4-trifluoromethoxy-phenyl)-amidel
  • mice The acute pneumonia model in mouse is described below.
  • Sets of 6 mice are infected with 1 million virulent Klebsiella pneumoniae bacteria. Each set of mice is either treated with the vehicle, or with the compounds of Example 1 or 4.
  • Repeated intraperitoneal injections start immediately after the infection with 6 hours interval.
  • Colony forming unit (CFU) are counted to determine the bacterial load in the lung of the mice.
  • Figure 1 shows the efficacy of compounds Example 1 and 4 in the acute pneumonia model with strain Kp52145.
  • Table 1 Antivirulence activity ICso values and characterisation of examples Assay method described above.

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Abstract

L'invention concerne des dérivés de l'acide cyclopentanecarboxylique et des composés apparentés de formule (I), dans laquelle R1, R2, R3, R4, R5, et R6 sont tels que décrits dans la description. L'invention concerne également des procédés de préparation de tels dérivés, des compositions pharmaceutiques les comprenant, leur utilisation (éventuellement combinés avec un ou plusieurs autres composés pharmaceutiquement actifs) en tant qu'agents antibactériens pour traiter des maladies infectieuses, et enfin un procédé de traitement de telles maladies. Les composés de formule (I) réduisent de façon sélective le caractère pathogène des bactéries chez l'hôte, sans affecter les bactéries en dehors de l'environnement hôte.
PCT/GB2007/003017 2006-08-08 2007-08-08 Dérivés de l'acide cyclopentanecarboxylique et leur utilisation pour traiter des maladies infectieuses d'origine bactérienne WO2008017840A1 (fr)

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US83612606P 2006-08-08 2006-08-08
US60/836,126 2006-08-08

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105902537A (zh) * 2016-04-26 2016-08-31 兰州大学 靶向人fkbp51蛋白的先导化合物及其筛选方法与应用
CN106008289A (zh) * 2016-04-26 2016-10-12 兰州大学 一种抗去势抵抗性前列腺癌先导化合物及其筛选和应用
WO2022160365A1 (fr) * 2021-01-28 2022-08-04 中山大学孙逸仙纪念医院 Petite molécule inhibitrice pour l'inhibition ciblée de pitpnm3 et son application

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105902537A (zh) * 2016-04-26 2016-08-31 兰州大学 靶向人fkbp51蛋白的先导化合物及其筛选方法与应用
CN106008289A (zh) * 2016-04-26 2016-10-12 兰州大学 一种抗去势抵抗性前列腺癌先导化合物及其筛选和应用
WO2022160365A1 (fr) * 2021-01-28 2022-08-04 中山大学孙逸仙纪念医院 Petite molécule inhibitrice pour l'inhibition ciblée de pitpnm3 et son application

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