ZA200502862B - Novel compounds with antibacterial activity - Google Patents

Novel compounds with antibacterial activity Download PDF

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ZA200502862B
ZA200502862B ZA200502862A ZA200502862A ZA200502862B ZA 200502862 B ZA200502862 B ZA 200502862B ZA 200502862 A ZA200502862 A ZA 200502862A ZA 200502862 A ZA200502862 A ZA 200502862A ZA 200502862 B ZA200502862 B ZA 200502862B
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ZA200502862A
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Jean-Philippe Surivet
Cornelia Zumbrunn
Christian Hubschwerlen
Annabelle Perez-Frutos Hoener
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Morphochem Ag Komb Chemie
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    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

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Description

i
Resistance to the antibiotics used currently has increased appreciably in many countries of the world in recent years and in some cases has assumed alarming proportions. The main problem is that those pathogens exhibit not just a single resistance but, as a rule, multiple resistance.
This 1s true especially of some gram-positive pathogen groups, such as staphylococci, pneumococci and enteroccccl @®- 10 (S. Ewig et al.; Antibiotika-Resistenz bei Erregern ambulant erworbener Atemwegsinfektionen (Antibiotic resistance in pathogens of outpatient-acquired respiratory tract infections); Chemother. J. 2002, 11, 12-26;
F. Tenover; Development and spread of bacterial resistance to antimicrobial agents: an overview; Clin. Infect. Dis. 2001 Sep 15, 33 Suppl. 3, 108-115)
A long-feared development has recently occurred: In the
USA, the first strain of Staphylococcus aureus has been described that is not only resistant to methicillin but also highly resistant to vancomycin (Centers for Disease ® Control and Prevention; Staphylococcus aureus resistant to vancomycin - United States, 2002; MMWR 2002, 51, 565-567).
In addition tc hygiene measures in hospitals, therefore, increased efforts are also required to find new anti- biotics that as far as possible have a novel structure and a novel mechanism of action so as to be effective against those problem bacteria.
The present invention describes new kinds of compounds having anti-bacterial activity.
The present invention relates to compounds of the general formula (I):
NN
A” "R’ 1
R X
1 N esx? NZ wherein ® A is an oxygen, sulphur or nitrogen atom or a C;_jalkylene, t
Cs-qalkenylene, C;4alkynylene or C;_jsheterocalkylene group,
Xi, X3, X3, X45 and Xs are each independently of the others nitrogen atoms or groups of formula CR?,
R' is a hydrogen atom, a halogen atom, a hydroxy group, an alkyloxy group or a heteroalkyloxy group,
R® is a hydrogen atom, a halogen atom, or a hydroxy, alkyl, alkenyl, alkynyl or heteroalkyl group,
L J R® is selected from the following groups:
Jen om Im : N-R® —N N-R° +N R® 4 4 4
R, R', R,
R® R® RS +N 0 +N 3 TN 4 4 4
R, R, R,
Ho) Er
R* RY, the radicals R*, each independently of any other(s), are a hydroxy group, a Cj-g¢alkyl group or a Ci-gsheteroalkyl group,
R> is an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, hetercalkyl- ® cycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical, n is 0, 1, 2 or 3 and m is 0 or 2, or a pharmacologically acceptable salt, solvate, hydrate or a pharmacologically acceptable formulation thereof.
The expression alkyl refers to a saturated, straight-chain ® or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 12 carbon atoms, especially from 1 to 8 or from 1 to 6 or from 1 to 4 carbon atoms, for example a methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, n-hexyl, 2,2-dimethyl- butyl or n-octyl group.
The expressions alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, preferably from 2 to 12 carbon atoms, especially from 2 to
6 carbon atoms, for example an ethenyl, allyl, acetylenyl, propargyl, 1i1soprenyl or hex-2-enyl group. Preferably, alkenyl groups have one or two (especially one) double bond (s) and alkynyl groups have one or two (especially one) triple bond(s).
Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl) such as, ® 10 for example, a 2,2,2-trichloroethyl or a trifluoromethyl group.
The expression heteroalkyl refers to an alkyl, alkenyl or alkynyl group in which one or more (preferably 1, 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulphur atom (preferably oxygen, sulphur or nitrogen). The expression heteroalkyl furthermore refers to a carboxylic acid or to a group derived from a carboxylic acid such as, for example, acyl, acylalkyl, alkoxycarbonyl, acyloxy, ® acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy.
Examples of heteroalkyl groups are groups of formulae
R%-0-Y?%-, R%-S-Y%-, R?-N (R®) -Yé-, R%-CO-Y%-, R%-0-CO-Y?-,
R*-CO-0-Y%-, R%-CO-N (R®) -Y®-, R?-N (RP) -CO-Y?-,
R%-0-CO-N(R®)-Y*-, R®-N(R”)-C0-0-Y?-, R®-N(RP)-CO-N (R®)-y?-,
R?-0-C0O-0-Y?%-, R®-N (R®) -C (=NR?) -N (R®) -Y2~, R*-CS-Y?-,
R*-0-CS-Y%-, R*-CS-0-Y?-, R*-CS-N(R")-Y%-, R®-N(RP)-CS-Y2-,
R%-0-CS-N (R®) -Y®-, R®-N(R")-CS-0-Y®-, R*-N(RP)-CS-N(R®)-Y?3-,
R*-0-CS-0-Y*-, R®-S-CO-Y®-, R®-CO-S-Y%-, R*-5-CO-N(R®)-v?3-,
R*-N (R”) -CO-S-Y?-, R*-5-CO-0-Y*-, R*-0-CO-S-Y°-,
R*-S-CO-S-Y®-, R?-S-CS-Y*-, R®-CS-S-Y®-, R®*-S-CS-N(RP)-Y3-,
R*-N (R) -CS-5-Y?-, R®*-5-CS-0-Y®-, R*-0-CS-S-Y*-, R?® being a hydrogen atom, a C;-Cg¢alkyl, a Cp-Cgalkenyl or a Cy-Ce- alkynyl group; R® being a hydrogen atom, a C;-Cgalkyl, a
C,-Cealkenyl or a C;-Cealkynyl group; R® being a hydrogen 5 atom, a C;-Cesalkyl, a C;-Cg¢alkenyl or a Cy-Cgalkynyl group;
RY being a hydrogen atom, a C;-Cgalkyl, a C,-Cgalkenyl or a
C2-Csalkynyl group and Y* being a direct bond, a Ci-Cg- alkylene, a Cz;-Csalkenylene or a C,-Cgalkynylene group, each heteroalkyl group containing at least one carbon atom ® 10 and it being possible for one or more hydrogen atoms to have been replaced by fluorine or chlorine atoms. Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropyloxy, tert- butyloxy, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino, dimethylamino, diethylamino, isopropylethylamino, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyl, enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, N-ethyl-N- methylcarbamoyl and N-methylcarbamoyl. Further examples @® of heteroalkyl groups are nitrile, isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups.
The expression cycloalkyl refers to a saturated or partially unsaturated (e.g. cycloalkenyl) cyclic group that contains one or more rings (preferably 1 or 2) containing from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms.
The expression cycloalkyl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0,
SH, =S, NH, =NH or NO; groups, thus, for example, cyclic ketones such as, for example, cyclohexanone, 2-cyclo- hexenone or cyclopentanone. Further specific examples of cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclo- pentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclo- pentenyl, cyclohexadienyl, decalinyl, cubanyl, bicyclo- [4.3.0])nonyl, tetralin, cyclopentylcyclohexyl, fluoro- cyclohexyl or cyclohex-2-enyl group. @® 10 The expression heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably 1, 2 or 3) ring carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulphur atom (preferably oxygen, sulphur or nitrogen). A heterocyclo- alkyl group has preferably 1 or 2 ring(s) containing from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms. The expression heterocycloalkyl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0,
SH, =S, NH;, =NH or NO, groups. Examples are a piperidyl, ) morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothio- phenyl, tetrahydropyranyl, tetrahydrofuryl, oxacyclo- propyl, azacyclopropyl or 2-pyrazolinyl group and also lactams, lactones, cyclic imides and cyclic anhydrides.
The expression alkylcycloalkyl refers to groups containing both cycloalkyl and also alkyl, alkenyl or alkynyl groups in accordance with the above definitions, for example alkylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two rings systems having from 3 to 10 (especially 3, 4,
5, 6 or 7) ring carbon atoms, and one or two alkyl, alkenyl or alkynyl groups having 1 or 2 to 6 carbon atoms.
The expression hetercalkylcycloalkyl refers to alkylcyclo- alkyl groups as defined above in which one or more (preferably 1, 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulphur atom (preferably oxygen, sulphur or nitrogen). A hetercalkylcycloalkyl group preferably contains 1 or 2 ® 10 ring systems having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups having 1 or 2 to 6 carbon atoms.
Examples of such groups are alkylheterocycloalkyl, alkyl- heterocycloalkenyl, alkenylheterocycloalkyl, alkynyl- heterocycloalkyl, heteroalkylcycloalkyl, heteroalkyl- hetecrocycloalkyl and heteroalkylheterocylcloalkenyl, the cyclic groups being saturated or mono-, di- or tri- unsaturated.
The expression aryl or Ar refers to an aromatic group that ® has one or more rings containing from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) carbon atoms. The expression aryl (or Ar) refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH; or NO, groups. Examples are a phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitro- phenyl or 4-hydroxyphenyl group.
The expression heteroaryl refers to an aromatic group that has one or more rings and is formed by a ring system that contains from 5 to 14 ring atoms, preferably from 5 to 10
(especially 5 or 6) ring atoms, and contains one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulphur ring atoms (preferably O, S or N). The expression heteroaryl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH, or NO, groups. Examples are 4-pyridyl, 2-imidazolyl, 3-phenyl- pyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, pyrid- ( 10 azinyl, quinolinyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3 -bifuryl, 3-pyrazolyl and isoquinolinyl groups.
The expression aralkyl refers to groups containing both aryl and also alkyl, alkenyl, alkynyl and/or cycloalkyl groups in accordance with the above definitions, such as, for example, arylalkyl, arylalkenyl, arylalkynyl, aryl- cycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydro- ® naphthalene, indanone, phenylcyclopentyl, cumene, cyclo- hexylphenyl, fluorene and indan. An aralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing 1 or 2 to 6 carbon atoms and/or a cycloalkyl group containing 5 or © ring carbon atoms.
The expression heteroaralkyl refers to an aralkyl group as defined above in which one or more (preferably 1, 2, 3 or 4) carbon atoms have been replaced by an oxygen, nitrogen,
silicon, selenium, phosphorus, boron or sulphur atom (preferably oxygen, sulphur or nitrogen), that is to say to groups containing both aryl or heteroaryl and also alkyl, alkenyl, alkynyl and/or heteroalkyl and/or cyclo- alkyl and/or heterocycloalkyl groups in accordance with the above definitions. A heteroaralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) containing 5 or 6 to 10 carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing 1 or 2 to 6 ® 10 carbon atoms and/or a cycloalkyl group containing 5 or 6 ring carbon atoms, 1, 2, 3 or 4 or those carbon atoms having been replaced by oxygen, sulphur or nitrogen atoms.
Examples are arylheterocalkyl, arylheterocycloalkyl, aryl- heterocycloalkenyl, arylalkylheterocycloalkyl, aryl- alkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heterocarylalkyl, heteroaryl- alkenyl, heterocarylalkynyl, heteroarylheteroalkyl, hetero- arylcycloalkyl, heteroarylcycloalkenyl, hetercarylhetero- cycloalkyl, heterocarylheterocycloalkenyl, heterocarylalkyl- ® cycloalkyl, heteroarylalkylheterocycloalkenyl, heteroaryl- heteroalkylcycloalkyl, heteroarylheterocalkylcycloalkenyl and heterocarylheteroalkylheterocycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri- unsaturated. Specific examples are a tetrahydroiso- quinolyl-, benzoyl-, 2- or 3-ethylindolyl-, 4-methyl- pyridino-, 2-, 3- or 4-methoxyphenyl-, 4-ethoxyphenyl-, 2-, 3- or 4-carboxyphenyl-alkyl group.
The expressions cycloalkyl, heterocycloalkyl, alkyl- cycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl refer to groups in which one or more hydrogen atoms of such groups have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0,
SH, =S, NH;, =NH or NO, groups.
The expression “optionally substituted” refers to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0,
SH, =S, NH;, =NH or NO; groups. The expression refers furthermore to groups that are substituted by ® 10 unsubstituted C.1-Cealkyl, C,-Cgsalkenyl, C,-Cgalkynyl,
Ci1-Cg¢heteroalkyl, C3-Cipcycloalkyl, C,-Cgheterocycloalkyl,
C¢~Cioaryl, C;-Coheteroaryl, C;-Cjraralkyl or C;-Cj;hetero- aralkyl groups.
Owing to their substitution, compounds of formula (I) may contain onc or more centres of chirality. The present invention therefore includes both all pure enantiomers and all pure diastereoisomers and also mixtures thereof in any mixing ratio. The present invention moreover also includes all cis/trans-isomers of the compounds of the ® general formula (I) and also mixtures thereof. The present invention moreover includes all tautomeric forms of the compounds of formula (I).
Preferred are compounds of formula (I) wherein A is an oxygen atom or a group of formula CH; or CH(OH).
Also preferred are compounds of formula (I) wherein one of the groups X;, Xz, X3, Xs and Xs {especially X; or X,) is a nitrogen atom and the others are CH groups, or all of the groups Xi, Xz, X3, X4 and Xs are CH groups.
Furthermore, R® is preferably one of the following groups:
RS
] ( 5 . nl '
R' is especially preferably a halogen atom, a C;-galkyloxy group (for example methoxy or ethoxy), a methyl group or an ethyl group; especially a methoxy group. ® Also preferably, R*? is a C).g¢heteroalkyl group, as defined hereinabove, having one or two oxygen atoms as individual hetero atoms.
R' is especially preferably a group of formula -COOH, -CH,COOH, -CH,CH,COOH, -CH,COOCHj3, -CH,CHs;, -CH,0H, -CH,CH,0H, -OH, -0OCH;, -CH,OCONH,;, -CH,CH,COOCH3, -COOCHj;, -CHj; or —- (CH) 30H.
Also preferably, n is 0 or 1. ® Also preferably, R° is an aralkyl or a hetero-aralkyl group.
Again preferably, R®> is a group of formula -Y-Cy, Y being a C;-Cgalkylene, C,-Cg¢alkenylene or C;-Cgheterocalkylene group, wherein optionally a hydrogen atom may have been replaced by a hydroxy group or two hydrogen atoms may have been replaced by an =0 group, and Cy being an optionally substituted phenyl, naphthyl or heteroaryl group contain- ing 1 or 2 rings and from 5 to 10 ring atoms, or an optionally substituted arylheterocycloalkyl or heteroaryl-
heterocycloalkyl group containing two rings and 9 or 10 ring atoms.
The therapeutic use of compounds of formula (I), their pharmacologically acceptable salts or solvates and hydrates and also formulations and pharmaceutical compositions also lie within the scope of the present invention. ® 10 The pharmaceutically compositions according to the present invention comprise at least one compound of formula (I) as active ingredient and, optionally, carrier substances and/or adjuvants.
Examples of pharmacologically acceptable salts of the compounds of formula (I) are salts of physiologically acceptable mineral acids, such as hydrochloric acid, sulphuric acid and phosphoric acid, and salts of organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, lactic acid, acetic acid, trifluoroacetic acid, ® citric acid, succinic acid, fumaric acid, oxalic acid, maleic acid and salicylic acid. Further examples of pharmacologically acceptable salts of the compounds of formula (I) are alkali metal and alkaline earth metal salts such as, for example, sodium, potassium, lithium, calcium and magnesium salts, ammonium salts and salts of organic bases such as, for example, methylamine, dimethylamine, triethylamine, piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine and arginine salts. Compounds of formula (I) can be solvated, especially hydrated. The hydration may take place, for example, during the preparation process or as a consequence of the hygroscopic nature of the initially anhydrous compounds of formula (I). When the compounds of formula (I) comprise asymmetric carbon atoms, they may be either in the form of achiral compounds, diastereoisomeric mixtures, mixtures of enantiomers or in the form of optically pure compounds.
The pro-drugs to which the present invention also relates consist of a compound of formula (I) and at least one @® 10 pharmacologically acceptable protecting group that is removed under physiological conditions, for example an alkoxy, aralkyloxy, acyl or acyloxy group, such as, for example, an ethoxy, daloxate, benzyloxy, acetyl or acetyloxy group or a group of formula COOCH,0OCOC(CHs3)3 or
COOCH,0C0O0~-cyclohexyl.
The present invention relates also to the use of those active ingredients in the preparation of medicaments. In general, compounds of formula (I) are administered either individually, or in combination with any other desired o therapeutic agent, using the known and acceptable methods.
Such therapeutically useful agents may be administered, for example, by one of the following routes: orally, for example in the form of dragées, coated tablets, pills, semi-solid substances, soft or hard capsules, solutions, emulsions or suspensions; parenterally, for example in the form of an injectable solution; rectally in the form of suppositories; by inhalation, for example in the form of a powder formulation or spray, transdermally or intranasally. For the preparation of such tablets, pills, semi-solid substances, coated tablets, dragées and hard gelatin capsules, the therapeutically usable product can be mixed with pharmacologically inert, inorganic or organic pharmaceutical carrier substances, for example with lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof, talcum, stearic acid or salts thereof, skimmed milk powder and the like. For the preparation of soft capsules, pharmaceutical carrier substances such as, for example, vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols can be used. For the preparation of liquid solutions and
C 10 syrups, pharmaceutical carrier substances such as, for example, water, alcohols, aqueous saline solution, aqueous dextrose, polyols, glycerol, vegetable oils, petroleum and animal or synthetic oils can be used. For suppositories, pharmaceutical carrier substances such as, for example, vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols can be used. For aerosol formulations, compressed gases that are suitable for the purpose can be used, such as, for example, oxygen, nitrogen and carbon dioxide. The pharmaceutically acceptable agents may also comprise additives for preserving and stabilising, ® emulsifiers, sweeteners, flavourings, salts for altering the osmotic pressure, buffers, encapsulation additives and anti-oxidants.
Combinations with other therapeutic agents may comprise other antimicrobial and anti-fungal active ingredients.
For the prevention and/or treatment of bacterial infections, the dose of the biologically active compound according to the invention can vary within wide limits and can be adjusted to individual requirements. Generally, a dose of from 10 mg to 4000 mg per day is suitable, a preferred dose being from 50 to 3000 mg per day. In suitable cases, the dose may also be below or above the stated values. The daily dose can be administered as a single dose or in a plurality of doses. A typical individual dose contains approximately 50 mg, 100 mg, 250 mg, 500 mg, 1 g or 2 g of the active ingredient.
EXAMPLES
@® 10
Example 1: 2-((3RS)-{[(2,3-Dihydro-benzo[l,4]dioxin-6-yl- methyl)amino]methyl}piperidin-1-yl)-(1RS)- (6-methoxy- quinolin-4-yl)ethanol. 1.a) Benzyl (3RS)-azidomethylpiperidine-l-carbamate:
A ee h ® At 00°C, triethylamine (5.6 ml, 40.1 mmol) and then methanesulphonyl chloride (2 ml, 25.7 mmol) were added to a solution of benzyl 3-hydroxymethylpiperidine-1l-carbamate (5 g, 20.05 mmol) in dichloromethane (100 ml). After the solution had been stirred for 20 min., the reaction mixture was cooled to -60°C and a solution of benzyl 4-oxopiperidine-l-carbamate (2.33 g, 10 mmol) in diethyl ether (10 ml) was added. The reaction mixture was heated to room temperature in the course of 30 minutes and water (40 ml) was added. The two phases were separated and the aqueous phase was extracted twice using 50 ml of ethyl acetate each time. The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSQO4, filtered and concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (EtOAc). The resulting oil was dissolved in DMF (45 ml), and sodium azide (2.6 gq, 40 mmol) was added. The reaction mixture was further stirred for 3 hours at 80°C and then diluted with water (100 ml) and ethyl acetate (200 ml). The two phases were @ 10 separated and the aqueous phase was extracted twice using 50 ml of ethyl acetate each time. The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSO,, filtered and concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (hexane/EtOAc 1/1).
Yield: 6.1 g (18.6 mmol)
H-NMR (CDCl,, 300 MHz: 1.28 (m, 1H); 1.51 (m, 1H); 1.60-1.87 (m, 3H); 2.74 (br s, 1H); 2.91 (m, 1H); 3.23 (br d, J= 4.5 Hz, 2H); 3.98 (td, J= 4.1, 13.2 Hz, 1H); 4.06 (br s, 1H); 5.15 (s, 2H); 7.28-7.38 (m, 5H). ® Benzyl 3-hydroxymethyl-piperidine-l-carbamate has already been described in Arch. Pharm. (Weinheim, Germany) 1990 p. 9-12. 1.b) Benzyl (3RS)-aminomethyl-piperidine-l-carbamate:
H,N~ je
Op i
Triphenylphosphine (8 g, 30 mmol) was added to a solution of benzyl 3-azidomethylpiperidine-l-carbamate (6.1 gq,

Claims (13)

Patent Claims
1. Compounds of formula (I): PS AR 1 R X 1 <N ) SR -X ® wherein A is an oxygen, sulphur or nitrogen atom or a Ci-salkylene, Cy-qalkenylene, C,-4alkynylene or C,-sheterocalkylene group, Xi, X,, X3, X54 and Xs are each independently of the others nitrogen atoms or groups of formula CR?, R! is a hydrogen atom, a halogen atom, a hydroxy group, an alkyloxy group or a heteroalkyloxy group, R?> is a hydrogen atom, a halogen atom, or a hydroxy, alkyl, alkenyl, alkynyl or heteroalkyl group, R} is selected from the following groups: mn , Nm Im N-R° -—N N-R +N R® 4 4 4 R, R, R,
R® R® R® +N © +N N iN 4 4 4 R°, R, R, Hm HT 4 4 R' Ro, the radicals RY, each independently of any other(s), are a hydroxy group, a Cj-galkyl group or a C,-gsheteroalkyl group, R> is an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkyl- cycloalkyl, heterocycloalkyl, aralkyl or hetero- aralkyl radical, n is 0, 1, 2 or 3 and ® = mis 0 or 2, or a pharmacologically acceptable salt, solvate, hydrate or a pharmacologically acceptable formulation thereof.
2. Compounds according to claim 1, wherein A is an - oxygen atom or a group of formula CH; or CH (OH) .
3. Compounds according to claim 1 or 2, wherein one of the groups Xi, X2, X3, Xi and Xs 1s a nitrogen atom and the others are CH groups, or all of the groups X1, Xu», X3, X4 and Xs are CH groups.
4. Compounds according to any one of claims 1 to 3, wherein R!' is a halogen atom, a Ci-galkyloxy group, a methyl group or an ethyl group.
5. Compounds according to any one of claims 1 to 4, wherein R' is a methoxy group. ® 10
6. Compounds according to any one of claims 1 to 5, wherein R? is a C;.¢heteroalkyl group having one or two oxygen atoms as individual hetero atoms.
7. Compounds according to any one of claims 1 to 0, wherein R? is a group of formula -COOH, -CH,COOQH, -CH,CH,COCH, -CH,COOCH3, -CH,CH3;, -CH,0H, —-CH,CH,;0H, -OH, -0OCHs3, -CH,OCONH,, -CH,CH,COOCH3, -COOCH3, -CHj3 or — (CH2) 30H.
8. Compounds according to any one of claims 1 to 7, ® wherein n is 0 or 1.
9. Compounds according to any one of claims 1 to 8, wherein R® is an aralkyl group or a heteroaralkyl group.
10. Compounds according to any one of claims 1 to 9, wherein R® is a group of formula -Y-Cy, Y being a - C,-Cgsalkylene, C,-Cgsalkenylene or C,-C¢heterocalkylene group, wherein optionally a hydrogen atom may have been replaced by a hydroxy group or two hydrogen atoms may have been replaced by an =0 group, and Cy being an optionally substituted phenyl, naphthyl or heteroaryl group containing 1 or 2 rings and from 5 to 10 ring atoms, or an optionally substituted arylheterocycloalkyl or heteroarylheterocycloalkyl group containing two rings and 9 or 10 ring atoms.
11. Compounds according to any one of claims 1 to 10, wherein R3 is selected from the following groups: eo K [} 5 . HOw +)
10 .
12. Pharmaceutical compositions that comprise a compound according to any one of claims 1 to 11 and, optionally, carrier substances and/or adjuvants.
13. Use of a compound or of a pharmaceutical composition according to any one of claims 1 to 12 in the treatment of bacterial infections. \
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