Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
  • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • 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
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
  • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
  • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
  • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
  • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
  • C07C255/28—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton containing cyano groups, amino groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with 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
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
  • C07D211/66—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having a hetero atom as the second substituent in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/56—Amides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D229/00—Heterocyclic compounds containing rings of less than five members having two nitrogen atoms as the only ring hetero atoms
  • C07D229/02—Heterocyclic compounds containing rings of less than five members having two nitrogen atoms as the only ring hetero atoms containing three-membered rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/90—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
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
• • 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
  • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/14—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D295/145—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/15—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• Novel albicidin derivatives their use and synthesis
• the present invention relates to albicidin derivatives according to claim 1 and claim 12.
• Albicidin is a natural product, isolated from Xanthomonas albilineans and heteroiogousiy expressed in Xanthomonas axonopodis pv vesicatoria. Its structure (see below) is based on peptides and amino acids, but it does not contain any proteinogenic amino acids.
• Albicidin is, on the one hand, a causative agent of the leaf scald disease in sugar cane and on the other hand a DNA-gyrase-inhibitor of prokaryotic cells (gram-positive and -negative).
• the mentioned properties make the natural product albicidin a potential antibiotic.
• the known molecular structure of albicidin and available synthetic routes allows the development of a plurality of novel derivatives that may exhibit potential antimicrobial activities.
• the problem underlying the present invention is the provision of new compounds, which comprise antibiotic properties, a method of their synthesis and their use. This problem is attained by the subject-matter of the independent claims.
• purity refers to the content of said compound relative to the sum of all compounds contained in the preparation.
• compound in this context is to be understood as a compound according to the general formula 1 (or any specific embodiments thereof) as well as any salts, hydrates or solvates thereof. Thus, the respective salts, hydrates or solvates are not considered as impurities according to the previous definition.
• the "purity" of a compound may be determined using elemental analysis, HPLC analysis using UV diode array detection also in combination with mass spectrometry detection, or quantitative NMR analysis.
• substituted refers to the addition of a substituent group to a parent moiety.
• Substituent groups can be protected or unprotected and can be added to one available site or to many available sites in a parent moiety. Substituent groups may also be further substituted with other substituent groups and may be attached directly or by a linking group such as an alkyl, an amide or hydrocarbyl group to a parent moiety.
• “Substituent groups” amenable herein include, without limitation, halogen, subst. oxygen, subst. nitrogen, subst.
• each R a , R b and R c is, independently, H or a further substituent group with a preferred list including without limitation, H, alkyl, alkenyl, alkynyl, cycloalkyi, alkoxy, acyl, aryl, heteroaryl, alicyclyl, heterocyclyl and heteroarylalkyl.
• alkyl refers to a saturated straight or branched hydrocarbon moiety containing up to 8, particularly up to 4 carbon atoms.
• alkyl groups include, without limitation, methyl, ethyl, propyl, butyl, isopropyl, n-hexyl, octyl, and the like.
• Alkyl groups typically include from 1 to about 8 carbon atoms (CrC 8 alkyl), particularly with from 1 to about 4 carbon atoms (CrC 4 alkyl).
• cycloalkyi refers to an interconnected alkyl group forming a saturated or unsaturated ring (whereby an unsaturated cycle can also be defined as “cycloalkenyl”) or polyring structure containing 3 to 10, particularly 5 to 10 carbon atoms.
• Examples of cycloalkyi groups include, without limitation, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, decalinyl or adamantyl (derived from tricyclo[3.3.1 .1 ]decane), and the like.
• Cycloalkyi groups typically include from 5 to 10 carbon atoms (C5-C10 cycloalkyi).
• Alkyl or cycloalkyi groups as used herein may optionally include further substituent groups.
• a substitution on the cycloalkyi group also encompasses an aryl, a heterocyclyl or a heteroaryl substituent, which can be connected to the cycloalkyl group via one atom or two atoms of the cycloalkyl group (like tetraline).
• haloalkyi refers to a saturated straight or branched hydrocarbon moiety containing 1 to 8, particularly 1 to 4, carbon atoms and at least one halogen atom, in particular CI or F, connected to a carbon atom.
• haloalkyi groups include, without limitation, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CHFCF 3 , CHFCHF 2 , CHFCH 2 F, CF 2 CF 3 , CF 2 CHF 2 , CF 2 CH 2 F and the like.
• Haloalkyi groups typically include 1 to 4 carbon atoms (C1 -C4 haloalkyi). More particularly haloalkyi groups comprise only F as halogen atoms.
• halo cycloalkyl refers to an interconnected alkyl group forming a saturated or unsaturated ring or polyring structure containing 3 to 10, particularly 5 to 10 carbon atoms and at least one halogen atom, in particular CI or F, connected to a carbon atom.
• halo cycloalkyl groups include, without limitation, fluorocyclopropyl, chlorocyclohexyl, dichlorocyclohexyl, chloroadamantyl, and the like.
• Halo cycloalkyl groups typically include from 5 to 10 carbon atoms (C5-C10 cycloalkyl). More particularly cyclohaloalkyl groups comprise only F as halogen atoms.
• Halo alkyl or halo cycloalkyl groups as used herein may optionally include further substituent groups.
• a substitution on the halo cycloalkyl group also encompasses an aryl, a heterocyclyl or a heteroaryl substituent, which can be connected to the halo cycloalkyl group via one atom or two atoms of the halo cycloalkyl group (like tetraline).
• alkenyl refers to a straight or branched hydrocarbon chain moiety containing up to 8 carbon atoms and having at least one carbon-carbon double bond.
• alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, 1 -methyl-2- buten-1 -yl, dienyl groups such as 1 ,3-butadienyl and the like.
• Alkenyl groups typically include from 2 to about 8 carbon atoms, more typically from 2 to about 4 carbon atoms. Alkenyl groups as used herein may optionally include further substituent groups.
• alkynyl refers to a straight or branched hydrocarbon moiety containing up to 8 carbon atoms and having at least one carbon-carbon triple bond.
• alkynyl groups include, without limitation, ethynyl, 1 -propynyl, 1 -butynyl, and the like.
• Alkynyl groups typically include from 2 to about 8 carbon atoms, more typically from 2 to about 4 carbon atoms.
• Alkynyl groups as used herein may optionally include further substituent groups.
• carboxy groups include without limitation, formate, acetate, lactate, citrate, oxalate and the like.
• Carboxy groups as used herein may optionally include further substituent groups.
• Non limiting examples are polyethylester or polyacrylate.
• alkoxy refers to an oxygen alkyl moiety containing 1 to 8, particularly 1 to 4 carbon atoms comprising at least one oxygen moiety, wherein the oxygen atom is used to attach the alkoxy group to a parent molecule.
• alkoxy groups include without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert- butoxy, n-pentoxy, neopentoxy, n-hexyloxy and the like.
• Alkoxy groups as used herein may optionally include further substituent groups.
• alkoxy groups include straight or branched polyalkoxy groups (polyether), which comprise several interconnected monomer alkoxy groups (e. g. -0-CH 2 -CH 2 -).
• polyether polyalkoxy groups
• Non limiting examples are groups derived from polyethyleneglycol (PEG) or polypropylenglycol (PPG).
• heterocyclyl refers to an interconnected alkyl group forming a saturated or unsaturated ring or polyring structure containing 3 to 10, particularly 5 to 10 carbon atoms in which at least one carbon atom is replaced with an oxygen, a nitrogen or a sulphur atom forming a non-aromatic structure.
• heterocyclyl groups include, without limitation, oxalanyl, pyrrolidinyl or piperidinyl.
• Heterocyclic groups as used herein may optionally include further substituent groups.
• a substitution on the heterocyclic group also encompasses an aryl, a cycloalkyl or a heteroaryl substituent, which can be connected to the heterocyclic group via one atom or two atoms of the heterocyclic group (comparable to indole or indoline).
• aryl refers to a hydrocarbon with alternating double and single bonds between the carbon atoms forming an aromatic ring structure, in particular a six (C 6 ) to ten (Cio) membered ring or polyring structure.
• heteroaryl refers to aromatic structures comprising a five to ten membered ring or polyring structure, comparable to aryl compounds, in which at least one member is an oxygen or a nitrogen or a sulphur atom. Due to simplicity reasons they are denominated C 5 to C10 heteroaryl, wherein at least one carbon atom is replaced with an oxygen, a nitrogen or a sulphur atom forming an aromatic structure.
• a C 5 heteroaryl comprises a five membered ring structure with at least one carbon atom being replaced with an oxygen, a nitrogen or a sulphur atom.
• Examples for such a C 5 heteroaryl are triazolyl, pyrazolyl, imidazolyl, thiophenyl, furanyl or oxazolyl.
• a C 6 heteroaryl can be pyridyl, pyrimidinyl or triazinyl.
• a C 9 heteroaryl can be indolyl and a Cio heteroaryl can be quinolinyl.
• Aryl or hetero aryl groups as used herein may optionally include further substituent groups.
• a substitution on the hetero aryl group also encompasses an aryl, a cycloalkyl or a heterocyclyl substituent, which can be connected to the hetero aryl via one atom or two atoms of the hetero aryl group (comparable to indole). The same applies to an aryl group.
• * indicates a stereo center of a L- or D- enantiomer, which is located on the tertiary carbon atom below the asterisk * , and wherein the compound of a general formula comprising " * " is an essentially pure L-enantiomer, an essentially pure D-enantiomer or a mixture of the L- and D-enantiomer of the same molecular formula, wherein in particular such a compound is an essentially pure L-enantiomer or an essentially pure D-enantiomer.
• the invention relates to compounds having a molecular structure as defined by formula (1 )
• BC being selected from
• Li being a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle, or -NHR d or -NR d 2 ;
• Rt being selected from H or CrC 4 alkyl
• Li and Rt forming a non-aromatic heterocycle, in particular a N-heterocyclic ring, which is optionally substituted,
• l_2 being selected from -H, -OH, -OR d , and substituted or unsubstituted -Ci-C 4 alkyl, CrC 6 alkoxycarbonyl and CrC 6 alkylaminocarbonyl,
• R d being selected from a substituted or unsubstituted C Ci 6 alkyl, , a substituted or unsubstituted C 2 -Ci 6 alkenyl, in particular a substituted or unsubstituted CrC 8 alkyl, a substituted or unsubstituted C 2 -C 8 alkenyl, a substituted or unsubstituted C3-C10 cycloalkyl, and all moieties optionally substituted with F,
• R 2 and R 3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyi, in particular with R 2 and R 3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, , - CH 3 , -CH 2 CH 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF3, -CH 2 CF 3 , - CHFCF3, -CF 2 CF 3 , -CHF 2 , -CH 2 F or -CF 3 , more particularly with R 2 and R 3 being selected independently from each other from -H, -F, -OCH 3 or -CH
• a substituted or unsubstituted C Ci 6 alkyl a substituted or unsubstituted C 2 - Ci6 alkenyl, a substituted or unsubstituted C 2 -Ci 6 alkynyl, in particular a substituted or unsubstituted CrC 8 alkyl, a substituted or unsubstituted C 2 -C 8 alkenyl, a substituted or unsubstituted C 2 -C 8 alkynyl, a substituted or unsubstituted C 3 -Cio cycloalkyl,
• At least one optional substituent may be in particular aryl, alkoxy, hydroxy or halogen; such as fluor;
• each R 8 being -H, or CrC 4 alkyl, optionally substituted with one or more F, in particular with each R 8 being selected independently from each other from H or CH 3 , more particularly R 8 being H, and
• n of R 0 n and n of R n being independently from each other 0, 1 , 2, 3 or 4, in particular n of R 0 n and n of R n being 0, 1 , 2 or 3, and
• each R 0 and R being selected independently from any other R 0 and R from -OH, -F, -CI, -Br, -I, -CCH, -CN, -N 3 , -OCi-C 6 alkyl, optionally substituted with OH or F, such as , -OCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -Ci-C 6 alkyl, in particular -CH 3 or -
• R a being selected from
• Ci 6 alkyl a substituted or unsubstituted C Ci 6 alkyl, a substituted or unsubstituted C 2 - Ci6 alkenyl, a substituted or unsubstituted C 2 -Ci 6 alkynyl, or a C Ci 6 haloalkyl, or
• m being selected from 0, 1 or 2, in particular 0 or 1 ,
• R 3 n 0, 1 , 2, 3 or 4, in particular n of R 3 n being 0, 1 , 2 or 3, and with each R 3 being selected independently from any other R 3 from -OH, substituted or unsubstituted -CrC 6 alkyl, substituted or unsubstituted CrC 6 alkoxy or fluoro, in particular -OH or -OCH 3 .
• the moiety L is a five membered or six membered aromatic heterocycle or 3-7 membered non-aromatic heterocycle, preferably a five membered or six membered aromatic N-heterocycle or non- aromatic N heterocycle that may be substituted or unsubstituted.
• - pyrazolone preferably 3H-pyrazol-3-ones, 4H-pyrazol-4-ones, 1 ,2-dihydro- 3H-pyrazol-3-ones, 2,4-dihydro-3H-pyrazol-3-ones, triazolones, preferably 1 ,2,4- triazol-3-one, imidazolones, pyrrolidones,
• thiadiazoles preferably 1 ,3,4-thiadiazoles, thiazoles, isothiazoles, thiazolidinediones;
• moiety L may not be -CH2(C 3 H 3 N2) (imidazole).
• the aromatic five membered heterocyles may be preferably substituted by a CrC 6 alkyl moiety, most preferably by a methyl or ethyl moiety. It is most preferred, if the N atom is substituted by a CrC 6 alkyl moiety, most preferably by a methyl or ethyl moiety.
• the moiety Li is a five membered non-aromatic N-heterocycle selected from a group comprising substituted or unsubstituted
• the moiety Li is a six membered aromatic N-heterocycle selected from a group comprising substituted or unsubstituted pyridines, pyridazines, pyrimidines, pyrazines, triazines and tetrazines.
• the moiety Li is a six membered non-aromatic N heterocycle selected from a group comprising substituted or unsubstituted piperidines and piperazines or morpholines.
• the non-aromatic 5 and 6 membered heterocyles may be preferably substituted by a CrC 6 alkyl moiety, most preferably by a methyl or ethyl moiety. It is most preferred, if the N atom is substituted by a CrC 6 alkyl moiety, most preferably by a methyl or ethyl moiety.
• a suitable substituted N-heterocycle may be N-methyl piperidine.
• the moiety Li is -NHR d or -NR d 2 wherein Rd is a methyl or ethyl moiety.
• the moiety L 2 may be selected from -H, -OH, -OR d , and -CH 3 , -C 2 H 6 or -C 3 H 7 , with R d being substituted or unsubstituted CrC 5 alkyl, preferably a CrC 3 alkyl.
• the present compound may be of the general formulae (2)
• the present compound may be of general formula (3)
• present compound may be of general formula (4a)
• present compound may be of general formula (4b)
• present compound may be of general formula (4c)
• the present compound may be of general formula (5)
• the present compound may be of general formula (6)
• the present compound may be of general formula (7)
• the present compound may be of general formula (8)
• X 1 , BC, R 8 , R 3 and T have the above meaning.
• X 1 is BA-CONHR 8 - , with BA being BA1 , with R 2 and R 3 having the same meaning as defined previously, and
• n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n being 1 , and
• each R independently from any other R being selected from -OH, -F, -CI, -Br, I,
• R is preferably -OH,-(CH 3 ) 2 , -CH 3 , -CH 2 -CH 3 , -CF 3 , -OCONH 2 , -N0 2 , -OCH 2 0-, -0-P0 3 H 2 , -0-P0 3 RaH -0-P0 3 Ra 2 or -(CH 2 ) m -OR a , with m and R a having the above meaning.
• R is preferably -OH,-
• OCHCCH -OCH 3 , -OC 2 H 5 , -F, most preferably - F, -OH and -OCHCCH.
• At least one optional substituent may be in particular aryl, phenyl, methoxyphenyl or halogen; such as fluor;
• E being with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n being 1 , and
• each R independently from any other R being selected from -OH, -F, -CI, -Br, I, -CCH, -CN, -N 3 , -OCH 3 ,-OC 2 H 5 , -OC 3 H 7 , in particular -OiPr, -OCF 3 , -OCHCCH, -NH 2 , - NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 -CH 3 , -CF 3 , -OCONH 2 , -N0 2 , -OCH 2 0-, -0-P0 3 H 2 , -0-P0 3 RaH -0-P0 3 Ra 2 or -(CH 2 ) m -OR a , with m and R a having the above meaning.
• R is preferably -OH,- OCHCCH, -OCH 3 , -OC 2 H 5 , -F most preferably -OH.
• R 8 being selected from H or CH 3 , in particular R 8 is H and with V being selected from O, NH or S, in particular from O or NH.
• X 1 is selected from
• R 8 being selected from H or CH 3 , in particular R 8 is H. It is to be understood that all possible optical isomers may be covered.
• R 8 being H.
• n of R 0 n and n of R n is 0, 1 , 2, 3 or 4, in particular n of R 0 n and n of R n is 0, 1 , 2 or 3, and with each R 0 and with each R independently from any other R 0 being selected from -OH, -F, -OCH 3 , -OC 2 H 5 , -OnC 3 H 7 , - OisoC 3 H 7 , -OCF3, -CF 3 or -(CH 2 )m-OR a ,
• R a being selected from hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , - CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -C6H5— CH 2 C6H5,
• n 1 or 2
• R 0 or R being -OH and the other R 0 or R being -OCH 3 , - OC 2 H 5 or -OiPr respectively.
• R a being selected from hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -
• T being in particular -C0 2 H.
• the invention relates to compounds having a molecular structure as defined by general formula (9)
• R a and R b being selected, where applicable, independently from each other from a substituted or unsubstituted Ci -C 4 alkyl, a substituted or unsubstituted Ci -C 4 carboxy, a substituted or unsubstituted C 2 -C 4 alkenyl, a substituted or unsubstituted C 2 -C 4 alkynyl, or a Ci -C 4 haloalkyl, or
• a substituted or unsubstituted C 3 -Ci o cycloalkyi or a substituted or unsubstituted C 3 -Ci o halo cycloalkyi or a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
• L 5 being selected from -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , a CrC 2 -fluoro alkyl, -
• each R 3 being selected independently from any other R 3 from -OH , substituted or unsubstituted -d-Ce alkyl or substituted or unsubstituted d-Ce alkoxy;
• n is 1 and R 3 is OH , wherein R 3 is preferably in 2-position (i.e. ortho position to -CO-) or in 3-position (i.e. ortho-position to -NR8-).
• L 5 being selected from -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -NH 2 ,
• BC is with Z being H and Y being CN,
• R 0 and R are -OH or -OCH 3 with the specific substitutional arrangement depicted in any of the formulas (4) - (8).
• the compounds of the present invention may be used in a method of treatment of diseases, in particular for use in a method of treatment of bacterial infections.
• the present compounds may be provided in a pharmaceutical acceptable form.
• Pharmaceutically acceptable salts of the present compounds mean both their organic and inorganic salts as described in Remington's Pharmaceutical Sciences (17th edition, page 1418 (1985)). Because of the physical and chemical stability and the solubility, preference is given for acidic groups inter alia to sodium, potassium, calcium and ammonium salts; preference is given for basic groups inter alia to salts of maleic acid, fumaric acid, succinic acid, malic acid, tartaric acid, methylsulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids, for example as hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malates, gluconates, and salts of amino acids, of natural bases or carboxylic acids.
• acidic groups inter alia to sodium, potassium, calcium and ammonium salts
• preference is given for basic groups inter alia to salt
• the present compounds form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts with basic reagents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine, diethanolamine or triethanolamine, trometamol or else basic amino acids, for example lysine, ornithine or arginine.
• basic reagents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine, diethanolamine or triethanolamine, trometamol or else basic amino acids, for example lysine, ornithine or arginine.
• stable acid addition salts can also be prepared with strong acids.
• Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid.
• the hydrochloride salt is a preferred salt.
• Salts with a pharmaceutically unacceptable anion such as, for example, trifluoroacetate likewise belong within the framework of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in non- therapeutic, for example in vitro, applications.
• the present invention furthermore relates to pharmaceutical preparations (or pharmaceutical compositions) which contain an effective amount of at least one of the present compounds and/or its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier, i. e. one or more pharmaceutically acceptable carrier substances (or vehicles) and/or additives (or excipients).
• a pharmaceutically acceptable carrier i. e. one or more pharmaceutically acceptable carrier substances (or vehicles) and/or additives (or excipients).
• the pharmaceuticals can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatine capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures.
• Administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
• compositions according to the invention are prepared in a manner known per se and familiar to one skilled in the art, pharmaceutically acceptable inert inorganic and/or organic carrier substances and/or additives being used in addition to the compound(s) of the formula (I) and/or its (their) pharmaceutically acceptable salts and/or its (their) prodrugs.
• pharmaceutically acceptable inert inorganic and/or organic carrier substances and/or additives being used in addition to the compound(s) of the formula (I) and/or its (their) pharmaceutically acceptable salts and/or its (their) prodrugs.
• pharmaceutically acceptable inert inorganic and/or organic carrier substances and/or additives being used in addition to the compound(s) of the formula (I) and/or its (their) pharmaceutically acceptable salts and/or its (their) prodrugs.
• for the production of pills, tablets, coated tablets and hard gelatine capsules it is possible to use, for example, lactose, corn starch or derivatives thereof, tal
• Suitable carrier substances for the production of solutions for example injection solutions, or of emulsions or syrups are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc.
• Suitable carrier substances for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.
• the pharmaceutical preparations normally contain about 0.5 to about 90 % by weight of the present compounds and/or their pharmaceutically acceptable salts and/or their prodrugs.
• the amount of the active ingredient of the formula (I) and/or its pharmaceutically acceptable salts and/or its prodrugs in the pharmaceutical preparations normally is from about 0.5 to about 1000 mg, preferably from about 1 to about 500 mg.
• a prodrug within the meaning of the present invention is a precursor chemical compound of a biological active compound of the present invention.
• a prodrug might be used instead to improve the absorption, distribution, metabolization and excretion.
• Prodrugs are often designed to improve bioavailability when a drug itself is poorly absorbed from the gastrointestinal tract.
• a prodrug may also be used to improve the selectively of the drug. This reduces adverse or unintended effects of a drug, especially important in treatments like chemotherapy, which can have severe unintended and undesirable side effects.
• the pharmaceutical preparations can contain one or more additives such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavourings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants. They can also contain two or more of the present compounds and/or their pharmaceutically acceptable salts.
• a pharmaceutical preparation contains two or more of the present compounds the selection of the individual compounds can aim at a specific overall pharmacological profile of the pharmaceutical preparation. For example, a highly potent compound with a shorter duration of action may be combined with a long-acting compound of lower potency.
• the flexibility permitted with respect to the choice of substituents in the present compounds allows a great deal of control over the biological and physico-chemical properties of the compounds and thus allows the selection of such desired compounds.
• the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients.
• the dose can vary within wide limits and, as is customary and is known to the physician, is to be suited to the individual conditions in each individual case. It depends, for example, on the specific compound employed, on the nature and severity of the disease to be treated, on the mode and the schedule of administration, or on whether an acute or chronic condition is treated or whether prophylaxis is carried out.
• An appropriate dosage can be established using clinical approaches well known in the medical art.
• the daily dose for achieving the desired results in an adult weighing about 75 kg is from about 0.01 to about 100 mg/kg, preferably from about 0.1 to about 50 mg/kg, in particular from about 0.1 to about 10 mg/kg, (in each case in mg per kg of body weight).
• the daily dose can be divided, in particular in the case of the administration of relatively large amounts, into several, for example 2, 3 or 4, part administrations. As usual, depending on individual behaviour it may be necessary to deviate upwards or downwards from the daily dose indicated.
• the compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention.
• the compounds of the present invention may be present as optical isomers or as mixtures thereof.
• the invention relates both to the pure isomers and all possible isomeric mixtures and is hereinafter understood as doing so, even if stereochemical details are not specifically mentioned in every case.
• Enantiomeric mixtures of compounds of the general formula 1 which are obtainable by the process or any other way, may be separated in known manner - on the basis of the physical-chemical differences of their components - into pure enantiomers, for example by fractional crystallisation, distillation and/or chromatography, in particular by preparative HPLC using a chiral HPLC column.
• One general procedure for the synthesis of albicidin-derivatives with variations of the central amino acid, in particular compounds of general formula (1 ) - (8), may comprises the steps according to the general reaction scheme 1 :
• the amine is reacted with the active ester in basic conditions, preferably in the presence of triethylamine. Specifically, the corresponding amine is dissolved in anhydrous N,N- dimethylformamide under an atmosphere of nitrogen. After the addition of triethylamine the active ester (see Figure 1 ) is added and the reaction mixture is stirred for 16 h in the dark. All volatiles were removed under high vacuum and the residue was purified by means of preparative HPLC.
• Reaction scheme 2 the corresponding protected albicidin is reacted with tetrakis(triphenylphosphine)palladium(0) and phenylsilane.
• the corresponding protected albicidin (BBA-BBF) is dissolved in anhydrous tetrahydrofuran under an atmosphere of nitrogen.
• the reaction mixture is stirred for 4 h in the dark.
• the reaction was quenched with acetic acid. All volatiles were removed in vacuo and the residue was dissolved in methanol, filtered and purified by means of preparative HPLC.
• the present compounds can also be obtained in the form of their hydrates and/or also can include other solvents used for example for the crystallization of compounds present in the solid form.
• the present compounds can be obtained in the free form or in the form of salts. Particularly in the form of salts of alkali metals, alkaline earth metals, ammonium or alkylammonium.
• Compound 1 (L-His-albicidin) is synthesized in a multistep synthesis route as follows:
• Tetrapeptide IV (1 eq, 0.16 mmol, 149.2 mg) was dissolved in THF (10 ml) and phenylsilane (8.04 eq, 1 .30 mmol, 160 ⁇ _) and tefra/as(triphenylphosphin)palladium(0) (0.1 eq, 0.016 mmol, 19 mg) were added. The mixture was stirred for 2.5 h shielded from light. All volatiles were removed in vacuo and the residue was purified via flash chromatography on silica gel eluting with 5-20% methanol in DCM. Compound V (46.0 mg, 0.057 mmol, 35%) was obtained as a brown solid.
• Tetrapeptide V (1 eq, 0.057 mmol, 46.0 mg) was dissolved in DCM (5 ml) and trifluoroacetic acid (2 ml) was added. After 3 h, all volatiles were removed in vacuo and compound VI (38.5 mg, 0.057 mmol, quant.) was used in the next step without further characterization.
• the described compound (5.00 mg, 0.017 mmol, 10%) was obtained as a fluffy white powder.
• the described compound (25 mg, 28.7 ⁇ , 68%) was obtained as a fluffy white powder.
• the tests were performed using the micro dilution method.
• the test was carried out for four different bacterial strains (E.coli DSM 1 1 16 [gram negative], B. subtilis DSM 10 [gram positive], M. luteus DSM 1790 [gram positive], S. typhimurium TA100 [gram negative]).
• 20 ⁇ - of cryo stock of each strain were inoculated in 20 mL of LB media (Lysogeny broth: 10 g/L peptone, 5 g/L yeast extract, 5 g/L NaCI) followed by incubation over night at 37 ⁇ C, 200 rpm.
• the test inoculum was adjusted by the 0.5 McFarland Standard (OD625 from 0.08 to 0.1 ).
• the adjusted inoculum suspension was diluted in MHBII media (BBL TM Mueller-Hinton Broth II, Becton, Dickinson and Company, New Jersey/USA) so that each well contained approximately 5 x 105 CFU/mL in a final volume of 100 ⁇ .
• MHBII media BBL TM Mueller-Hinton Broth II, Becton, Dickinson and Company, New Jersey/USA
• ATCC strains were obtained from the American Type Culture Collection (ATCC).
• PEG- strains are clinical isolates that were collected during a study of the Paul-Ehrlich-Society for Chemotherapie e.V. (PEG) in 2010 and 2013/14.
• the strains without any further designations such as 100-2-49 are further clinical isolates obtained from a lab in Germany.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Communicable Diseases (AREA)
• Animal Behavior & Ethology (AREA)
• Oncology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Pyridine Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Priority Applications (5)

Applications Claiming Priority (2)

Publications (1)

Family

ID=60972211

Family Applications (1)

Country Status (6)

Cited By (2)

Families Citing this family (1)

Citations (2)

Family Cites Families (3)

• 2017
  • 2017-12-21 EP EP17829200.9A patent/EP3655394B1/en active Active
  • 2017-12-21 CN CN201780093285.XA patent/CN110997641A/zh active Pending
  • 2017-12-21 US US16/631,737 patent/US11225465B2/en active Active
  • 2017-12-21 JP JP2020502295A patent/JP7257697B2/ja active Active
  • 2017-12-21 WO PCT/EP2017/084120 patent/WO2019015794A1/en not_active Ceased
  • 2017-12-21 CA CA3070240A patent/CA3070240A1/en active Pending

Patent Citations (2)

Non-Patent Citations (3)

Also Published As

Similar Documents

Legal Events