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WO2010003197A1 - Morpholine derivatives used as antifungal compounds - Google Patents

Morpholine derivatives used as antifungal compounds Download PDF

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Publication number
WO2010003197A1
WO2010003197A1 PCT/BE2009/000033 BE2009000033W WO2010003197A1 WO 2010003197 A1 WO2010003197 A1 WO 2010003197A1 BE 2009000033 W BE2009000033 W BE 2009000033W WO 2010003197 A1 WO2010003197 A1 WO 2010003197A1
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Prior art keywords
alkyl
heterocycle
alkynyl
cycloalkyl
cycloalkenyl
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PCT/BE2009/000033
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French (fr)
Inventor
Dorothée BARDIOT
Bruno Cammue
Patrick Chaltin
Arnaud Didier Marie Marchand
Karin Thevissen
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Katholieke Universiteit Leuven
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Katholieke Universiteit Leuven
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    • 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
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

Definitions

  • the present invention relates to a series of novel compounds which have been shown to possess antifungal activity, in particular against Candida, Aspergillus and Fusarium species.
  • the invention therefore relates to the new compounds, methods for their preparation, pharmaceutical compositions comprising them and to the compounds for use as a medicament, more in particular antifungal medicament.
  • fungi Occurring worldwide, most fungi are largely invisible to the naked eye, living for the most part in soil, dead matter, and as symbionts of plants, animals, or other fungi. However, several species of the fungi are significant pathogens of humans and other animals or crops. The most commonly known human pathogens are part of the Candida, Aspergillus and/or Fusarium species.
  • Candida albicans is among the gut flora, the many organisms which live in the human mouth and gastrointestinal tract. Under normal circumstances, C. albicans lives in 80% of the human population with no harmful effects, although overgrowth results in candidiasis.
  • Candida albicans is a causal agent of opportunistic oral and genital infections in humans. Systemic fungal infections have emerged as important causes of morbidity and mortality in immunocompromised patients (e.g., AIDS, cancer chemotherapy, organ or bone marrow transplantation). In addition, hospital-related infections in patients not previously considered at risk (e.g. patients in an intensive care unit) have become a cause of major health concern.
  • C. glabrata was thought to be a primarily non-pathogenic organism.
  • C. glabrata was thought to be a highly opportunistic pathogen of the urogenital tract, and of the bloodstream. It is especially prevalent in HIV positive people, and the elderly.
  • a major phenotype and potential virulence factor that C. glabrata possesses is low-level intrinsic resistance to the azole drugs, which are the most commonly prescribed antifungal (antimycotic) drugs.
  • Candida kr ⁇ sei falls under the same umbrella as C.
  • Aspergillus is a genus of around 200 moulds found throughout much of nature worldwide. Some Aspergillus species cause serious disease in humans and animals, and can be pathogenic. The most common species causing invasive disease are Aspergillus fumigatus and Aspergillus flavus. Aspergillus flavus produces aflatoxin which is both a toxin and a carcinogen, and which can potentially contaminate foods such as nuts. The most common species causing allergic disease are Aspergillus fumigatus and Aspergillus clavatus.
  • Aspergillosis is the group of diseases caused by Aspergillus and includes paranasal sinus infections (fever, cough, chest pain or breathlessness), allergic bronchopulmonary aspergillosis or ABPA, acute invasive aspergillosis and disseminated invasive aspergillosis.
  • the polyenes e.g. amphotericin B 1 nystatin, natamycin
  • the azoles e.g. fluconazole, itraconazole, voriconazole
  • allylamines e.g. terbinafine
  • the newly introduced echinocandins e.g. caspofungin.
  • the polyenes, azoles and echinocandins are used to treat systemic fungal infections, not the allylamines.
  • the prior art describes different anti-fungal compound classes, including but not limited to the polyenes, the azoles, allylamines and echinocandins (e.g. caspofungin), but no antifungal compound class relates to the compounds of the invention.
  • new antifungal compounds are provided.
  • the compounds have a substituted morpholin-2-one structure and it has been shown in the present invention that they possess antifungal (fungicidal) activity, more specifically against Candida,
  • Aspergillus and Fusarium species The present invention demonstrates that the compounds inhibit the replication of fungi. Therefore, these compounds constitute a new potent class of antifungal agents that can be used in the treatment and prevention of fungal infections in animals, mammals and humans, more specifically for the treatment and prevention of (topical or systemic) infections with Candida, Aspergillus and/or
  • the present invention provides novel compounds which have fungistatic or fungicidal properties.
  • the invention also provides methods for preparation of all such compounds and provides pharmaceutical compositions comprising the compounds.
  • the invention further relates to the novel compounds for use as a medicament and for the prevention and/or treatment of fungal infections in subjects (including animals, mammals and humans).
  • the invention also relates to the use of the compounds in or for the manufacture of a medicament for the prevention or treatment of subjects suffering from a fungal infection, more in particular for treatment of subjects infected with Candida species (e.g. C. albicans, C. glabrata, C. krusei), Aspergillus species (e.g. A. flavus, A. fumigatus, A. clavatus), Fusarium species (e.g. F. oxysporum, F. culmorum) or other fungi.
  • the invention also provides methods of treatment or prevention of a fungal infection in a subject, including animals, mammals and humans.
  • One aspect of the present invention is the provision of novel compounds which are unsubstituted or substituted 2-(2-oxo-morpholin-3-yl)-acetamides, in an embodiment of this invention having a structure according to the formula (I): wherein:
  • R 1 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cydoalkyl; cycloalkenyl; cycloalkynyl; cycloalkylaikyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl;
  • alkyl, alkenyl, alkynyl, cydoalkyl, cycloalkenyl, cycloalkynyl, cycloalkylaikyl, cycloalkenylalkyl, cycloalkynylalkyl, aryl, heterocycle, arylalkyl, and heterocycle-alkyl can each independently be substituted with one or more R s ; and • wherein the alkyl, alkenyl, alkynyl, cydoalkyl, cycloalkenyl, cydoalkynyl, cycloalkylaikyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycl
  • each of R 2 and R 3 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cydoalkyl; cycloalkenyl; cycloalkynyl; cycloalkylaikyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
  • alkyl, alkenyl, alkynyl, cydoalkyl, cydoalkenyl, cycloalkynyl, cycloalkylaikyl, cycloalkenylalkyl, cycloalkynylalkyl, aryl, heterocycle, arylalkyl, and heterocycle-alkyl can each independently be substituted with one or more R s ;
  • alkyl, alkenyl, alkynyl, cydoalkyl, cycloalkenyl, cycloalkynyl, cycloalkylaikyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, the heteroatom selected from O, S and N; and
  • each R s is independently selected from halogen; hydroxyl; SR 4 ; S(O)R 5 ; S(O) 2 R S ; SO 2 NR 6 R 7 ; trifluoromethyl; nitro; NR 6 R 7 ; cyano; COOR 8 ; C(O)NR 6 R 7 ; C(O)R 5 ; alkyl; cycloalkyl; cyclalkyloxy; alkoxy; alkenyl; cycloalkenyl; cycoalkenyloxy; alkenyloxy; alkynyl; cycloalkynyl; cycloalkynyloxy; alkynyloxy; cycloalkylalkyi; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; and heterocycle- oxy; and • wherein the alkyl, alkenyl,
  • each R" is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyi; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyi, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, the heteroatom selected from O, S and N; and
  • each R 5 is independently selected from hydroxyl; alkyl; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; alkenyloxy; alkynyl; cycloalkynyl; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; and heterocycle-oxy; and
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, the heteroatom selected from O, S and N; and
  • each R 6 and R 7 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, the heteroatom selected from O, S and N; and
  • R 6 and R 7 can be taken together in order to form a (5-, 6-, or 7- membered) heterocycle which can be substituted or unsubstftuted;
  • each R 8 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and • wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and • wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalky
  • R 1 is selected from alkyl, more preferable C 1 -C 6 alkyl, more particularly ethyl.
  • one of R 2 and R 3 is hydrogen and the other of R 2 and R 3 is selected from unsubstituted or substituted (particularly with one or more R s ) aryl, arylalkyl, heterocycle or heterocycle-alkyl.
  • said substituted aryl, arylalkyl, heterocycle or heterocycle-alkyl is selected from aryl, arylalkyl, heterocycle or heterocycle-alkyl substituted independently with one or more halogen, hydroxy I, thiol, CF 3 , nitro, cyano, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl and/or alkynyloxy.
  • R 2 is selected from hydrogen and R 3 is selected from unsubstituted or substituted with one or more R s aryl and heterocycle. Chemical moieties substituted with one or more R s can be substituted with 1 , 2, 3, 4 or 5 independently selected R s .
  • the compound of present invention is NOT a compound having a structure according to the formula (I) wherein:
  • R 1 is C 6 H 5 and R 2 is hydrogen and R 3 is C 6 H 5 ;
  • R 1 is ethyl and R 2 is hydrogen and R 3 is (i-methylethyl)phenyl;
  • R 1 is ethyl and R 2 is hydrogen and R 3 is 4-methylphenyl
  • - R 1 is ethyl and R 2 is hydrogen and R 3 is 4-fluorophenyl
  • R 1 is phenylmethyl and R 2 is hydrogen and R 3 is 4-bromophenyl;
  • R 1 is phenylmethyl and R 2 is hydrogen and R 3 is (i-methylethyl)phenyl.
  • the compounds of the present invention are selected from the list of compounds in table 1 (encoded from compound number C 1 to C 18 ).
  • the compounds are selected from the list of.
  • the invention relates to the compounds as described herein, more specifically the compounds according to formula (I) and embodiments thereof, for use as a medicament, more in particular for use as an antifungal medicament and for the use in the prevention or treatment of a fungal infection in or on a subject (animal, mammal or human).
  • the present invention also relates to the use of the compounds of formula (I) and embodiments thereof as antifungal compounds, more particularly as compounds active against Candida species (e.g. C. albicans, C. glabrata, C. krusei), Aspergillus species (e.g. A. flavus, A. fumigatus, A. clavatus), Fusarium species (e.g. F. oxysporum, F. culmorum) or other fungi.
  • Candida species e.g. C. albicans, C. glabrata, C. krusei
  • Aspergillus species e.g. A. flavus, A. fumigatus, A. clavatus
  • Fusarium species e.g. F. oxysporum, F. culmorum
  • the invention also relates to the use of compounds of the formulae and claims herein for the manufacture of a medicament or as a pharmaceutically active ingredient, especially as a fungal replication inhibitor or fungicidal compound, for instance for the manufacture of a medicament or pharmaceutical composition having antifungal activity for the prevention and/or treatment of fungal infections in humans, mammals and animals in general.
  • the present invention further relates to a method of prevention or treatment of a fungal infection, preferably a Candida species, Aspergillus species or Fusarium species infection in an animal, including mammals, including a human, comprising administering to the animal in need of such treatment a therapeutically effective amount of a compound of the formulae and claims herein as an active ingredient, preferably in admixture with at least a pharmaceutically acceptable carrier.
  • the invention relates to the compounds as described herein, more specifically the compounds according to formula (I) and embodiments thereof, for use as plant antifungals, more in particular for use as an antifungal in the prevention, reduction or eradication of a fungal infection in or on plants (e.g. in agriculture).
  • the invention relates to methods to prevent, reduce or eradicate fungal infection in or on plants (e.g. in agriculture), or on materials for industrial or medical use, for example by inhibiting biofilm formation such as fungal biofilm formation.
  • Another aspect of the invention further relates to methods for the preparation of compounds of formulae and claims herein, more specifically the compounds according to formula (I) and embodiments thereof.
  • the intermediates [N-substituted ethanolamine, N-substituted-2-(2-hydroxyethylamino)acetate esters, N-substituted- morpholin-2-one, 2-(4-ethyl-2-oxomorpholin-3-yl)acetate esters] used in the preparation methods described herein are aspects of the present invention.
  • the method of preparation of the compounds of the invention comprises the following steps:
  • the method may further comprise, prior to step 1 , the following steps: i) Condensating an N-substituted-ethanolamine with an alpha halogen acetate ester in the presence of a base to obtain an N-substituted-2-(2-hydroxyethylamino)acetate ester; ii) Obtaining an N-substituted-morpholin-2-one by intramolecular lactonisation of said N- substituted-2-(2-hydroxyethylami ⁇ o)acetate ester in acidic medium; and iii) Condensating said N-substituted-morpholin-2-one with an alpha halogen acetate ester in the presence of a base.
  • compositions comprising the compounds of the invention according to formulae and claims herein; more specifically the compounds according to formula (I) and embodiments thereof, in admixture with at least a pharmaceutically acceptable earner, the active ingredient preferably being in a concentration range of about 0.1 to 100% by weight, and to the use of these derivatives namely as drugs useful for the treatment of subjects suffering from a fungal infection, in particular a Candida species, Aspergillus species or Fusarium species infection.
  • the invention further relates to the use of a composition
  • a composition comprising (a) one or more derivatives of formulae and claims herein, more specifically the compounds according to formula (I) and embodiments thereof, and (b) one or more fungistatic or fungicidal compounds as biologically active agents in respective proportions such as to provide a synergistic effect against a fungal infection in a mammal, for instance in the form of a combined preparation for simultaneous, separate or sequential use in fungal infection therapy.
  • the inhibitors used as a therapeutically active ingredients (b) may belong to categories already known in the art.
  • the invention relates to the compounds of formulae and claims herein, more specifically the compounds according to formula (I) and embodiments thereof, being useful as agents having biological activity or as diagnostic agents.
  • the invention also relates to the use of these compounds of formulae and claims herein more specifically the compounds according to formula (I) and embodiments thereof, as agents having biological activity or as diagnostic agents.
  • Any of the uses mentioned with respect to the present invention may be restricted to a non-medical use, a non-therapeutic use, a non-diagnostic use, or exclusively an in vitro use, or a use related to cells remote from an animal.
  • the compounds of present invention can be used to eradicate or reduce or prevent fungal infections on plants or materials (e.g. biofilm formation).
  • the number of carbon atoms represents the maximum number of carbon atoms generally optimally present in the substituent or linker; it is understood that where otherwise indicated in the present application, the number of carbon atoms represents the optimal maximum number of carbon atoms for that particular substituent or linker.
  • alkyl refers to C 1 -C 18 normal, preferably primary, secondary, or tertiary hydrocarbon chains. Examples are methyl, ethyl, 1-propyl, 2- propyl, 1-b ⁇ rtyl, 2-methyl-1-propyl(i-Bu), 2-butyl (s-Bu), 2-methyl-2-propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1 -butyl, 2- methyl-1 -butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl- 2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, /7-pentyl,
  • heteroalkyl which can contain a heteroatom in or at the end of the group (e.g. hydrocarbon group), said heteroatom selected from O, S, and N
  • said heteroatom selected from O, S, and N refers to a group where one or more carbon atoms are replaced by an oxygen, nitrogen or sulphur atom and thus includes, depending on the group to which is referred, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl, heteroaryl, arylheteroalkyl, heteroarylalkyl, heteroarylheteroalkyl, arylheteroalkenyl, heteroarylalkenyl, heteroarylheteroalkenyl, heteroarylheteroalkenyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkynyl, heteroarylheter
  • alkoxy alkenyloxy, alkynyloxy, alkyl-O-alkyl, alkenyl-O-alkyl, arylalkoxy, benzyloxy, heterocycle- heteroalkyl, heterocycle-alkoxy, among others.
  • alkyl can contain a heteroatom in or at the end of the alkyl chain, said heteroatom selected from O 1 S and N", than any carbon atom of the alkyl can be exchanged for a heteroatom selected from O, S and N when chemically feasible (and refers to heteroalkyl).
  • heteroalkyl examples include CH 3 -CH 2 -O-; CH 3 -O-CH 2 -; CH 3 -CH 2 -CH 2 - NH-CH 2 -, methoxy, methylthio, propoxy, CH 3 -S-CH 2 -, CH 3 -CH 2 -O-CH 2 -, CH 3 -NH-, (CHs) 2 -N-, (CHa) 2 -CH 2 -NH-CH 2 -CH 2 -, among many other examples.
  • arylalkyl which can contain a heteroatom in or at the end of the alkyl group, said heteroatom selected from O, S, and N therefore refers to arylheteroalkyl, meaning an arylalkyl which comprises one or more heteroatoms in the alkyl hydrocarbon chain, whereas the heteroatoms may be positioned at the beginning of the hydrocarbon chain, in the hydrocarbon chain or at the end of the hydrocarbon chain.
  • Arylheteroalkyl thus includes aryloxy, arylalkoxy, aryl-alkyl-NH- and the like and examples are phenyloxy, benzyloxy, 8PyI-CH 2 -S-CH 2 -, aryl-CH 2 -O-CH 2 -, aryl-NH-CH 2 - among many other examples.
  • cycloalkyl means a monocyclic saturated hydrocarbon monovalent radical having from 3 to 10 carbon atoms, such as for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, or a C 7-10 polycyclic saturated hydrocarbon monovalent radical having from 7 to 10 carbon atoms such as, for instance, norbornyl, fenchyl, trimethyltricycloheptyl or adamantyl.
  • alkenyl and cycloalkenyl as used herein is C 2 -C 18 normal, preferably primary, secondary or tertiary and respectively C 3 -C 10 cyclic hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, i.e. a carbon-carbon, sp2 double bond.
  • sites usually 1 to 3, preferably 1 of unsaturation, i.e. a carbon-carbon, sp2 double bond.
  • the double bond may be in the cis or trans configuration.
  • alkynyl and cycloalkynyl refer respectively to C 2 -C 18 normal, preferably primary, secondary, tertiary hydrocarbon or to the C 3 -C 13 cyclic hydrocarbon (more particularly to respectively C 2 -C 18 normal, preferably primary, secondary, tertiary hydrocarbon or the C 8 -C 13 cyclic hydrocarbon), with at least one site (usually 1 to 3, preferably 1) of unsaturation, i.e. a carbon-carbon, sp triple bond. Examples include, but are not limited to: acetylenic (-C ⁇ CH) and propargyl (-CH 2 C ⁇ CH).
  • aryi as used herein means an aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of hydrogen from a carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to 1 ring, or 2 or 3 rings fused together, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like.
  • Arylalkyl refers to an arylalkylene which is an alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
  • the arylalkyl group comprises 6 to 20 carbon atoms, preferably 7 to 20 carbon atoms, preferably 6 to 14 carbon atoms.
  • the "arylalkyl" radical may itself be substituted and thereby includes for example 4-chlorobenzyl, 4-fluorobenzyl, 2-fluorobenzyl, 3,4-dichlorobenzyl, 2,6- dichlorobenzyl, 3-methyIbenzyl, 4-methylbenzyl, 4-ter-butylbenzyl, 1-amino-2- phenylethyl and 1-amino-2-[4-hydroxyl-phenyl]ethyl.
  • heterocycle refers to a saturated, unsaturated or aromatic ring system including at least one N, O, or S. Heterocycle thus include heteroaryl groups which refers to aromtic heterocycles. Heterocycle as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A. "Principles of Modern Heterocyclic Chemistry” (WA Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; 'The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, CW. and Scriven, E.
  • heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrol inyl, tetrahydrofuranyl, bis-t
  • ⁇ eteroaryl includes by way of example and not limitation pyridyl, dihydropyridyl, pyridazi ⁇ yl, pyrimidinyf, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl.
  • carbon bonded heterocycles are bonded at position 2, 3, 4,
  • carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4- pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5- pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboli ⁇ e.
  • nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1- pyrazolyl, and 1-piperidinyl.
  • ⁇ eterocycle-alkyl refers to a heterocycle-alkylene which is an alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heterocycle radical.
  • Typical heterocycle- alkyl groups include, but are not limited to (pyridin-3-yl)methyl, (pyrrolidin-2-yl)methyl, (thien-2-yl)methyl, (1H-imidazol-2-yl)ethan-1-yl.
  • the heterocycle-alkylene group comprises 6 to 20 carbon atoms, e.g.
  • Cycloalkylalkyf refers to a cycloalkylalkylene which is an alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a cycloalkyl radical.
  • Cycloalkenylalkyl refers to a cycloalkenylalkylene which is an alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a cycloalkenyl radical.
  • Cycloalkynylalkyl refers to a cycloalkynylalkylene which is an alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a cycloalkynyl radical.
  • substituted aryl, substituted heterocycle, substituted arylalkyl, substituted heterocycle-alkyl and the like refer to the chemical structures defined above, and wherein the said aliphatic group and/or the said aryl or heterocycle may be optionally substituted with one or more substituents, in a particular embodiment said substituents being independently selected from the group consisting of halogen, amino, hydroxyl, sutfhydryl, alkyl, trifluoromethyl, nitro, cyano, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy.cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, aryl, heterocycle, arylalkyl, and heterocycle-alkyl, such as but not limited
  • alkoxy refers to substituents wherein an alkyl group, respectively a cycloalkyl, aryl, arylalkyl or heterocycle (each of them such as defined herein), are attached to an oxygen atom or a sulfur atom through a single bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy, mercaptobenzyl and the like.
  • halogen means any atom selected from the group consisting of fluorine (F) 1 chlorine (Cl), bromine (Br) and iodine
  • Substituents optionally are designated with or without bonds. Regardless of bond indications, if a substituent is polyvalent (based on its position in the structure referred to), then any and all possible orientations of the substituent are intended.
  • the present invention relates to a series of novel compounds which have been shown to possess antifungal activity, in particular against fungi of the family of the Candida, Aspergillus or Fusarium species.
  • the invention therefore relates to the new compounds, methods for their preparation, pharmaceutical compositions comprising them, the use of the compounds for the preparation of a medicament, and to the compounds for use as a medicament, more in particular as antifungal medicament.
  • Present invention also relates to methods to treat or to prevent a fungal infection.
  • the present invention provides novel compounds which are unsubstituted or substituted 2-(2-oxo-morpho!in-3-yl)-acetamides and which are in particular embodiments described herein.
  • the present invention provides novel compounds having a structure according to the formula (I):
  • R 1 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; alkylcycloalkyl; alkylcycloalkenyl; alkylcycloalkynyl; aryl; heterocycle; arylalkyl (such as benzyl); or heterocycle-alkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl can independently be substituted with one or more halogen, hydroxyl, thiol, CF 3 , nitro, cyano, alkyl, alkoxy, alkenyl, alkenyloxy, alken
  • each of R 2 and R 3 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; alkylcycloalkyl; alkylcycloalkenyl; alkylcycloalkynyl; aryl; heterocycle; arylalkyl (such as benzyl); or heterocyde-alkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl can independently be substituted with one or more halogen, hydroxy I, thiol, CF 3 , nitro, cyano, alkyl, alkoxy, alkenyl,
  • the compounds of the present invention are selected from the list of compounds in table 1 (encoded from compound number C 1 to C 18 ).
  • the compounds are selected from the list of:
  • the invention relates to the compounds as described herein, more specifically the compounds according to formula (I) and embodiments thereof, for use as a medicament, more in particular for use as an antifungal medicament and for the use in the prevention or treatment of a fungal infection in or on a subject (animal, mammal or human).
  • the present invention provides compounds having a structure according to the formula (I):
  • R 1 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; or heterocycle-alkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl, can independently be substituted with one or more R s ; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,
  • each of R 2 and R 3 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; alkylcycloalkyl; alkylcycloalkenyl; alkylcycloalkynyl; aryl; heterocycle; arylalkyl; or heterocycle-alkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, aryl, heterocycle, arylalkyl, or heterocycle-alky!
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, arylalkyl, or heterocycle-alkyl can contain a heteroatom in or at the end of hydrocarbon, said heteroatom selected from O, S and N; and wherein R 2 and R 3 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which can be substituted with one or more R s ;
  • each R s is independently selected from halogen; hydroxyl; SR 4 ; S(O)R 5 ; S(O) 2 R 5 ; SO 2 NR 6 R 7 ; trifluoromethyl; nitro; NR 6 R 7 ; cyano; COOR 8 ; C(O)NR 8 R 7 ; C(O)R 5 ; alkyl; cycloalkyl; cyclalkyloxy; alkoxy; alkenyl; cycloalkenyl; cycoalkenyloxy; alkenyloxy; alkynyl; cycloalkynyl; cycloalkynyloxy; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; heterocycle-oxy; and wherein said alkyl, alkenyl, alkyn
  • each R 4 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, or heterocycle-alkyl can contain a heteroatom in or at the end of the hydrocarbon alkyl, alkenyl or alkynyl, said heteroatom selected from O 1 S and N;
  • each R 5 is independently selected from hydroxyl; alkyl; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; alkenyloxy; alkynyl; cycloalkynyl; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; heterocycle-oxy; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, or heterocycle-alkyl can contain a heteroatom in or at the end of the hydrocarbon alkyl, alkenyl or alkynyl, said heterocycle
  • each R 8 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, or heterocycle-alkyl can contain a heteroatom in or at the end of the hydrocarbon alkyl, alkenyl or alkynyl, said heteroatom selected from O, S and N; and isomers (in particular stereoisomers or tautomers), solvates
  • R 1 is selected from alkyl, more preferable Ci-C 6 alkyl, while one of R 2 and R 3 is hydrogen and the other of R 2 and R 3 is selected from substituted aryl or substituted heterocycle.
  • said substituted aryl is selected from aryl substituted independently with one or more halogen, hydroxyl, thiol, CF 3 , nitro, cyano, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy; and wherein said substituted heterocycle is selected from heterocycle substituted independently with one or more halogen, hydroxyl, thiol, CF 3 , nitro, cyano, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy.
  • the compounds are selected from the list of
  • the invention relates to the compounds described above for use as a medicament for the prevention or treatment of a fungal infection in an animal or human, more particularly, wherein the fungal infection is caused by Candida or Aspergillus species. Yet more particularly, said fungal infection is a systemic infection or is a topical infection. Still more particularly, the compounds are for the treatment of a fungal infection in an animal or mammal.
  • the present invention also relates in another embodiment to the use of the compounds of formula (I) and embodiments thereof as antifungal compounds, more particularly as compounds active against Candida species (e.g. C. albicans, C. glabrata, C. krusei), Aspergillus species (e.g. A. flavus, A. fumigatus, A. clavatus), Fusarium species (e.g. F. oxysporum, F. culmorum) or other fungi.
  • Candida species e.g. C. albicans, C. glabrata, C. krusei
  • Aspergillus species e.g. A. flavus, A. fumigatus, A. clavatus
  • Fusarium species e.g. F. oxysporum, F. culmorum
  • the invention also relates to the use of compounds of the formulae and claims herein for the manufacture of a medicament or as a pharmaceutically active ingredient, especially as a fungal replication inhibitor or fungicidal compound, for instance for the manufacture of a medicament or pharmaceutical composition having antifungal activity for the prevention and/or treatment of fungal infections in humans, mammals and animals in general.
  • the present invention further relates to a method of prevention or treatment of a fungal infection, preferably a Candida species, Aspergillus species or Fusarium species infection in an animal, including mammals, including a human, comprising administering to the animal in need of such treatment a therapeutically effective amount of a compound of the formulae and claims herein as an active ingredient, preferably in admixture with at least a pharmaceutically acceptable carrier.
  • the invention relates to the compounds as described herein, more specifically the compounds according to formula (I) and embodiments thereof, for use as plant antifungals, more in particular for use as an antifungal in the prevention, reduction or eradication of a fungal infection in or on plants (e.g. in agriculture).
  • Another embodiment of the invention further relates to methods for the preparation of compounds of formulae and claims herein, more specifically the compounds according to formula (I) and embodiments thereof.
  • One embodiment relates to a method for the preparation of the compounds of the invention, the method comprising the steps of:
  • step 2 Coupling the acid obtained in step 1 with an appropriated amine in the presence of a coupling agent.
  • the method of preparation of the compounds of the invention comprises the following steps: 1) Condensation of an N-substituted-ethanolamine with an alpha halogen acetate ester in the presence of a base;
  • step 5 Coupling the acid obtained in step 4 and an appropriated amine in the presence of a coupling agent.
  • compositions comprising the compounds of the invention according to formulae and claims herein; more specifically the compounds according to formula (I) and embodiments thereof, in admixture with at least a pharmaceutically acceptable carrier, the active ingredient preferably being in a concentration range of about 0.1 to 100% by weight, and to the use of these derivatives namely as drugs useful for the treatment of subjects suffering from a fungal infection, in particular a Candida species, Aspergillus species or Fusarium species infection.
  • the invention further relates to the use of a composition
  • a composition comprising (a) one or more derivatives of formulae and claims herein, more specifically the compounds according to formula (I) and embodiments thereof, and (b) one or more fungistatic or fungicidal compounds as biologically active agents in respective proportions such as to provide a synergistic effect against a fungal infection in a mammal, for instance in the form of a combined preparation for simultaneous, separate or sequential use in fungal infection therapy.
  • the inhibitors used as a therapeutically active ingredients (b) may belong to categories already known in the art.
  • the invention relates to the compounds of formulae and claims herein, more specifically the compounds according to formula (I) and embodiments thereof, being useful as agents having biological activity or as diagnostic agents.
  • Any of the uses mentioned with respect to the present invention may be restricted to a nonmedical use, a non-therapeutic use, a non-diagnostic use, or exclusively an in vitro use, or a use related to cells remote from an animal.
  • the compounds of the invention are employed for the treatment or prophylaxis of fungal infections, more particularly Candida, Aspergillus or Fusarium species infections.
  • fungal infections more particularly Candida, Aspergillus or Fusarium species infections.
  • the active ingredients of the compound(s) may be administered to the mammal (including a human) to be treated by any means well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermal ⁇ , intravenously, intra- arterially, parenterally or by catheterization.
  • the therapeutically effective amount of the preparation of the compound(s), especially for the treatment of fungal infections in humans and other mammals corresponds to an amount which ensures a plasma level of between 1 ⁇ g/ml and 100 mg/ml, optionally of 10 mg/ml.
  • the effective amount may be divided into several sub-units per day or may be administered at more than one day intervals.
  • the present invention further relates to a method for preventing or treating a fungal infection in a subject or patient by administering to the patient in need thereof a therapeutically effective amount of the compounds of the present invention.
  • the therapeutically effective amount of the preparation of the compound(s), especially for the treatment of fungal infections in humans and other mammals preferably is a fungicidal amount. More preferably, it is a fungal replication inhibiting amount of the compounds of the formulae as defined herein.
  • the effective amount may be divided into several sub-units per day or may be administered at more than one day intervals.
  • Synergistic activity of the pharmaceutical compositions or combined preparations of this invention against fungal infection may also be readily determined by means of one or more tests such as, but not limited to, the isobologram method, as previously described by Elion et al. in J. Biol. Chem. (1954) 208:477-488 and by Baba et al. in A ⁇ microb. Agents Chemother. (1984) 25:515-517, using EC 50 for calculating the fractional inhibitory concentration (hereinafter referred as FIC).
  • the combination When the minimum FIC index corresponding to the FIC of combined compounds (e.g., FIC x + FIC y ) is equal to 1.0, the combination is said to be additive; when it is between 1.0 and 0.5, the combination is defined as subsynergistic, and when it is lower than 0.5, the combination is defined as synergistic. When the minimum FIC index is between 1.0 and 2.0, the combination is defined as subantagonistic and, when it is higher than 2.0, the combination is defined as antagonistic.
  • This principle may be applied to a combination of different antifungal drugs of the invention or to a combination of the antifungal drugs of the invention with other drugs that exhibit antifungal activity, or with drugs that exhibit other medicinal or health promoting activity.
  • the invention thus relates to a pharmaceutical composition or combined preparation having synergistic effects against a fungal infection and containing: either (A) a combination of two or more of the compounds of the present invention, and optionally one or more pharmaceutical excipients or pharmaceutically acceptable carriers, for simultaneous, separate or sequential use in the treatment or prevention of a fungal infection; or (B) one or more antifungal agents, and at least one of the compounds of the present invention, and optionally one or more pharmaceutical excipients or pharmaceutically acceptable carriers, for simultaneous, separate or sequential use in the treatment or prevention of a fungal infection.
  • the pharmaceutical composition or combined preparation with synergistic activity against fungal infection may contain compounds of the present invention, compounds according to the formulae of the application, over a broad content range depending on the contemplated use and the expected effect of the preparation.
  • the content of the compounds of the present invention of the combined preparation is within the range of 0.1 to 99.9% by weight, preferably from 1 to 99% by weight, more preferably from 5 to 95% by weight.
  • the compounds of the invention can be used for the treatment or prevention of infection by Candida species (e.g. C. albicans, C. glabrata, C. krusei), Aspergillus species (e.g. A. flavus, A. fumigatus, A. clavatus), Fusarium species (e.g. F. oxysporum, F. culmorum) or other fungi. More in particular, the compounds of present invention can be used as a medicament for treating or preventing fungal infections in a subject in need thereof.
  • Candida species e.g. C. albicans, C. glabrata, C. krusei
  • Aspergillus species e.g. A. flavus, A. fumigatus, A. clavatus
  • Fusarium species e.g. F. oxysporum, F. culmorum
  • the compounds of present invention can be used as a medicament for treating or preventing fungal infections in a subject in need thereof
  • the present invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
  • the present invention further provides agricultural compositions comprising at least one active ingredient as above defined together with a suitable carrier therefore. More generally, the invention relates to the compounds according to the formulae of the application being useful as agents having biological activity (particularly antifungal activity) or as diagnostic agents. Any of the uses mentioned with respect to the present invention may be restricted to a non-medical use, a non-therapeutic use, a nondiagnostic use, or exclusively an in vitro use, or a use related to cells remote from an animal.
  • the compounds of present invention can be used to eradicate or reduce or prevent fungal infections on plants or materials, or can be used to eradicate or reduce or prevent biofilm formation, e.g. a biofilm wherein fungi are attached or prevail or contribute to the biofilm formation.
  • the compounds of the invention optionally are bonded covalently to an insoluble matrix and used for affinity chromatography (separations, depending on the nature of the groups of the compounds, for example compounds with aryl are useful in hydrophobic affinity separations.
  • the compounds of the invention may exist in many different protonation states, depending on, among other things, the pH of their environment. While the structural formulae provided herein depict the compounds in only one of several possible protonation states, it will be understood that these structures are illustrative only, and that the invention is not limited to any particular protonation state, any and all protonated forms of the compounds are intended to fall within the scope of the invention.
  • the term "pharmaceutically acceptable salts" as used herein means the therapeutically active non-toxic salt forms which the compounds according to the formulae of the application are able to form. Therefore, the compounds of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na + , Li + , K + , Ca +2 and Mg +2 .
  • Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid.
  • the compounds of the invention may bear multiple positive or negative charges. The net charge of the compounds of the invention may be either positive or negative.
  • any associated counterions are typically dictated by the synthesis and/or isolation methods by which the compounds are obtained.
  • Typical counterions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counter ion is not a critical feature of the invention, and that the invention encompasses the compounds in association with any type of counter ion.
  • the invention is intended to encompass not only forms of the compounds that are in association with counterions (e.g., dry salts), but also forms that are not in association with counterions (e.g., aqueous or organic solutions).
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention.
  • metal salts which are prepared in this way are salts containing Li + , Na + , and K + .
  • a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • salts may be formed from acid addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups. Examples of such appropriate acids include, for instance, inorganic acids such as hydrohalic acids, e.g.
  • hydrochloric or hydrobromic acid sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxylacetic, 2- hydroxylpropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic (i.e.
  • compositions herein comprise compounds of the invention in their unionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • the salts of the parental compounds with one or more amino acids are included within the scope of this invention.
  • the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • the compounds of the invention also include physiologically acceptable salts thereof.
  • physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX 4 + (wherein X is C 1 -C 4 alkyl).
  • Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • Physiologically acceptable salts of a compound containing a hydroxyl group include the anion of said compound in combination with a suitable cation such as Na + and NX 4 + (wherein X typically is independently selected from H or a C 1 -C 4 alkyl group).
  • a suitable cation such as Na + and NX 4 + (wherein X typically is independently selected from H or a C 1 -C 4 alkyl group).
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
  • the compounds of the present invention can have different isomeric forms or can be a mixture of isomers.
  • enantiomer means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e. at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.
  • isomers as used herein means all possible isomeric forms, including tautomeric and sterochemical forms (“stereoisomers”) and including positional isomers, which the compounds according to the formulae of the application may possess. In a particular embodiment, the term “isomers” excludes positional isomers.
  • the structures shown herein exemplify only one tautomeric or resonance form of the compounds, but the corresponding alternative configurations are contemplated as well.
  • the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, including stereoisomers and tautomers, said mixtures containing all diastereomers and enantiomers (since the compounds according to the formulae of the application may have at least one chiral center) of the basic molecular structure, as well as the stereochemically pure or enriched compounds. More particularly, stereogenic centers may have either the R- or S-configuration, and multiple bonds may have either cis- or trans-configuration. Pure isomeric forms of the said compounds are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure.
  • stereoisomerically pure or “chirally pure” relates to compounds having a stereoisomers excess of at least about 80% (i.e. at least 90% of one isomer and at most 10% of the other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%.
  • enantiomerically pure and diastereomerically pure should be understood in a similar way, having regard to the enantiomeric excess, respectively the diastereomeric excess, of the mixture in question. Separation of stereoisomers is accomplished by standard methods known to those skilled in the art.
  • One enantiomer of a compound of the invention can be separated substantially free of its opposing enantiomer by a method such as formation of diastereomers using optically active resolving agents ("Stereochemistry of Carbon Compounds,” (1962) by E. L Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302).
  • Separation of isomers in a mixture can be accomplished by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure enantiomers, or (3) enantiomers can be separated directly under chiral conditions.
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair
  • a diastereomeric pair Eliei, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched compounds of the invention.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, a-methoxy-a- (trifluoromethyl)phenyl acetate (Jacob 111. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers.
  • Stable diastereomers can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111).
  • a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase.
  • Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives.
  • Commercially available polysaccharide based chiral stationary phases are ChiralCelTM CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and ChiralpakTM AD, AS, OP(+) and 0T(+).
  • Appropriate eluents or mobile phases for use in combination with said polysaccharide chiral stationary phases are hexane and the like, modified with an alcohol such as ethanol, isopropanol and the like.
  • Tautomers are organic compounds that are interconvertible by a chemical reaction called tautomerization. As most commonly encountered, this reaction results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on everal factors, including temperature, solvent, and pH.
  • the compounds of the invention may be formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Formulations optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxylalkylcellulose, hydroxylalkylmethyicellulose, stearic acid and the like.
  • the term "pharmaceutically acceptable carrier” as used herein means any material or substance with which the active ingredient is formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness.
  • the pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the compositions of this invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets or powders.
  • Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art, and there is no particular restriction to their selection within the present invention. They may also include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals.
  • additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals.
  • compositions of the present invention may be prepared in any known manner, for instance by homogeneously mixing, coating and/or grinding the active ingredients, in a one-step or multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents may also be prepared by inicronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 gm, namely for the manufacture of microcapsules for controlled or sustained release of the active ingredients.
  • Suitable surface-active agents also known as emulgent or emulsifier, to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and/or anionic materials having good emulsifying, dispersing and/or wetting properties.
  • Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface-active agents.
  • Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (Ci 0 -C 22 ), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable form coconut oil or tallow oil.
  • Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and alkylarylsulphonates.
  • Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alky) or acyl radical having from 8 to 22 carbon atoms, e.g.
  • Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms.
  • alkylarylsulphonates are the sodium, calcium or alcanolamine salts of dodecylbenzene sulphonic acid or dibutyl-naphtalenesulphonic acid or a naphtalene-sulphonic acid/forrnaldehyde condensation product.
  • corresponding phosphates e.g. salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and/or propylene oxide, or phospholipids.
  • Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g.
  • phosphatidylethanolamine phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl-choline, dipalmitoylphoshatidyl -choline and their mixtures.
  • Suitable non-ionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol.
  • non-ionic surfactants are water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups.
  • Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit.
  • non-ionic surfactants are nonylphenol -polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol and octylphenoxypolyethoxyethanol.
  • Fatty acid esters of polyethylene sorbitan such as polyoxyethylene sorbitan trioleate
  • glycerol glycerol
  • sorbitan sucrose and pentaerythritol are also suitable non-ionic surfactants.
  • Suitable cationic surfactants include quaternary ammonium salts, particularly halides, having 4 hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxyl; for instance quaternary ammonium salts containing as N- substituent at least one C 8 -C 22 alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxyl-lower alkyl radicals.
  • quaternary ammonium salts particularly halides, having 4 hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxyl
  • quaternary ammonium salts containing as N- substituent at least one C 8 -C 22 alkyl radical (e.g. cetyl, lauryl, palmityl,
  • compositions thereof may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).
  • suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).
  • the preferred route of administration may vary with for example the condition of the recipient.
  • the formulations both for veterinary and for human use, of the present invention comprise at least one active ingredient, as above described, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic ingredients.
  • the camer(s) optimally are "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. For infections of the eye or other external tissues e.g.
  • the formulations are optionally applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredients) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
  • the active ingredients may be employed with either a parafMnic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyll groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. [Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax
  • the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should optionally be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is optionally present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid earner.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc), which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient
  • Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit- dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Prefe ⁇ ed unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods.
  • Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino acids, polyvinyl pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate and the like.
  • the rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxylmethylcellulose, polyethyl methacryiate and the other above-described polymers.
  • Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on.
  • the pharmaceutical composition may require protective coatings.
  • Pharmaceutical forms suitable for injectionable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol and the like and mixtures thereof.
  • each active ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g. one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.
  • pro-drug forms of the compounds of the present invention. It may be desirable to formulate the compounds of the present invention in the form of a chemical species which itself is not significantly biologically-active, but which when delivered to the animal or human will undergo a chemical reaction catalysed by the normal function of the body, inter alia, enzymes present in the stomach or in blood serum, said chemical reaction having the effect of releasing the compound of present invention as defined herein.
  • prodrug thus relates to these species which are converted in vivo into the active pharmaceutical ingredient.
  • the pro-drugs of the present invention can have any form suitable to the formulator, for example, esters are non-limiting common pro-drug forms.
  • the pro-drug may necessarily exist in a form wherein a covalent bond is cleaved by the action of an enzyme present at the target locus.
  • a C-C covalent bond may be selectively cleaved by one or more enzymes at said target locus and, therefore, a pro-drug in a form other than an easily hydrolysable precursor, inter alia an ester, an amide, and the like, may be used.
  • the counterpart of the active pharmaceutical ingredient in the pro-drug can have different structures such as an amino acid or peptide structure, alkyl chains, sugar moieties and others as known in the art.
  • therapeutically suitable pro-drug is defined herein as "a compound of present invention modified in such a way as to be transformed in vivo to the therapeutically active form, whether by way of a single or by multiple biological transformations, when in contact with the tissues of the animal or human to which the pro-drug has been administered, and without undue toxicity, irritation, or allergic response, and achieving the intended therapeutic outcome ".
  • the compounds of the invention according to the formulae of the application can be prepared while using a series of chemical reactions known to those skilled in the art, altogether making up the process for preparing said compounds and exemplified further.
  • the processes described further are only meant as examples and by no means are meant to limit the scope of the present invention.
  • the compound of this invention can be prepared by the following general methods: One of the key steps in the preparation of compounds having the general formula (6) is the synthesis of the intermediate (2) as outlined in scheme 1.
  • This intermediate can be converted into the desired compound (2) by using an strong acid (e.g. p-toluenesulfonic acid, hydrochloric acid) in various (polar, apolar, protic aprotic) solvents (e.g. dichloromethane, toluene, ethanol) at a temperature of 0 0 C to about 11O 0 C 1 a process known as intramolecular lactonisation.
  • an strong acid e.g. p-toluenesulfonic acid, hydrochloric acid
  • various solvents e.g. dichloromethane, toluene, ethanol
  • the substituted ethanolamines (1) can be obtained via commercial sources or by synthesis. Many references are available in the literature using ethanolamine or a appropriated substituted amine as starting materials.
  • Compound (2) can then be deprotonated on position 3 with a strong base (e.g. lithium or sodium hexamethyldisilazane, n-buthyl lithium) in a polar aprotic solvent (e.g. THF, DME) at a temperature of -78 ⁇ C to about O 0 C (preferably -78°C).
  • a strong base e.g. lithium or sodium hexamethyldisilazane, n-buthyl lithium
  • a polar aprotic solvent e.g. THF, DME
  • the resulting enolate can be condensed with an alpha halogen acetate ester at a temperature of - 78 0 C to about 2O 0 C (preferably -78 ⁇ C) to yield the desired compound (3).
  • an alpha halogen acetate ester at a temperature of - 78 0 C to about 2O 0 C (preferably -78 ⁇ C) to yield the desired compound (3).
  • Ester (3) can then be hydrolyzed to the carboxylic acid (5) under acidic (e.g. hydrochloric acid, trifluoroacetic acid) or basic (e.g. lithium or sodium hydroxide) conditions in various polar, apolar, protic aprotic solvents (e.g. methanol, water, dichloromethane) depending on the nature of the ester group.
  • acidic e.g. hydrochloric acid, trifluoroacetic acid
  • basic e.g. lithium or sodium hydroxide
  • polar, apolar, protic aprotic solvents e.g. methanol, water, dichloromethane
  • Compound (5) can finally be reacted with different mono or di-substituted amines in the presence of a coupling agent such as a carbodiimide (e.g. DCC, DIC) or an uronium salts (e.g. TBTU, HATU) in polar aprotic solvents (e.g. DMF, dichloromethane) at room temperature over a period of time going from 1 to 24 hours.
  • a coupling agent such as a carbodiimide (e.g. DCC, DIC) or an uronium salts (e.g. TBTU, HATU) in polar aprotic solvents (e.g. DMF, dichloromethane)
  • Table 1 Structures of example compounds of the invention and their respective codes.
  • Candida species e.g. C. albicans, C. glabrata, C. krusei
  • antifungal activity e.g. C. albicans, C. glabrata, C. krusei
  • YPD agar 1% yeast extract, 2% peptone, 2% glucose, 1,5% agar
  • YPD 1% yeast extract, 2% peptone, 2% glucose, 1,5% agar
  • a square petridish (12 cm x 12 cm).
  • compounds were assessed for their growth-inhibitory potential by measurement of the inhibitory halo of the compounds. The majority of the compounds showed a growth-inhibitory halo of > 6 mm for Candida albicans.
  • MFC Minimal Fungicidal Concentration
  • MIC Minimal Inhibitory concentration
  • MFC filamentous fungi
  • the majority of the compounds of the invention showed an antifungal activity against Candida, Aspergillus as well as against Fusarium species, while some compounds were less broad spectrum and showed activity against only one or two of Candida, Aspergillus or Fusarium species.
  • the MICs ranged between 0.8 ⁇ g/mL and 25 ⁇ g/mL, while the MFCs ranged between 3 ⁇ g/mL and 50 ⁇ g/mL.
  • EXAMPLE 2 CELLULAR CYTOTOXICITY
  • MDBK Madin-Darbey Bovine Kidney
  • DMEME-FCS Dulbecco's modified Eagle medium
  • the effect of the compounds on exponentially growing MDBK cells can be assessed as follows. Cells are seeded at a density of 5000 cell/well in 96 well plates in MEM medium (Gibco) supplemented with 10% fetal calf serum, 2mM L-glutamine (Life Technologies) and bicarbonate (Life Technologies). Cells are cultured for 24 hr after which serial dilutions of the test compounds are added. Cultures are then again further incubated for 3 days after which the effect on cell growth is quantified by means of the MTS method (Promega). The concentration that results in 50% inhibition of cell growth is defined as the 50 % cytostatic concentration (CC 50 )
  • Huh-5-2 cells [a cell line with a persistent HCV replicon l389luc-ubi-neo/NS3- 375.1 ; replicon with firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein and an EMCV-IRES driven NS3-5B HCV polyprotein used here to investigate the cytostatic / cytotoxic effect of the compounds] were cultured in RPMI medium (Gibco) supplemented with 10% fetal calf serum, 2mM L-glutamine (Life Technologies), 1x nonessential amino acids (Life Technologies); 100 IU/ml penicillin and 100 ⁇ g/ml streptomycin and 250 ⁇ g/ml G418 (Geneticin, Life Technologies).
  • Cells were seeded at a density of 7000 cells/ well of classical 96- well cell culture plates (Becton-Dickinson) in medium containing the components as described above, except for G418. Cells are allowed to adhere and proliferate for 24 hr. At that time, culture medium is removed and 5 serial dilutions (5-fold dilutions starting at 100 ⁇ g/ml or 100 ⁇ M) of the compounds are added in culture medium lacking G418. Plates are further incubated at 37 ⁇ C and 5% CO 2 for 72 hours.
  • the effect of the compounds on the proliferation of the cells was measured 3 days after addition of the various compounds by means of The CellTiter 96 8 AQ u60Us Non- Radioactive Cell Proliferation Assay (MTS, Promega).
  • MTS Non- Radioactive Cell Proliferation Assay
  • MTS is bioreduced by cells into a formaza ⁇ that is soluble in tissue.
  • the number of cells correlates directly with the production of the formazan.
  • the MTS stained cultures were quantified in a plate reader at 498nm.
  • the 50% cytostatic concentrations (EC 50 ) were calculated from these datasets.
  • a selection of the compounds of the invention was tested and did not show a cytostatic activity on Huh-5-2 cells at 50 ⁇ g/mL.
  • EXAMPLE 3 IN VIVO EFFICACY AND TOXICITY MEASUREMENT
  • C. elegans model for Candida infection which was developed by Breger et al., 2007 (PLoS Pathog 2007, 3: e18).
  • Mini-host models are more and more used as simple experimental systems to study pathogenesis and immune responses of the host (Chamilos G et al., Lancet Infect. Dis. 2007, 7:42-55).
  • Medically important fungal pathogens, like Candida sp. have been shown to infect nematodes (Mylonakis E et al. Infect Immun. 2005, 73:3833-3841).
  • L4 larvae of a double mutant (glp-4 ⁇ sek-1 ⁇ ) of C. elegans are used which at 25 0 C are unable to produce eggs and die after reaching maturity.
  • the larvae are fed for 4-8 h on either E. coli OP50 (standard feeding source) agar plates for toxicity testing of the compounds or on C. albicans agar plates for efficacy testing of the compounds.
  • the percentage survival of the worms in the presence or absence of antifungal compounds is subsequently determined.
  • amphotericin B (10 ⁇ g/ml) and miconazole (10 ⁇ g/ml) in DMSO are used as positive controls for efficacy testing.
  • Control groups are treated with 10mg/Kg doses of fluconazole or saline following the same protocol.
  • Mice are sacrificed 5 days after fungal infection. Kidneys are excised, weighted, homogenized and the pellets are resuspended in PBS (1ml). 100 ⁇ l-samples are plated onto solid brain heart infusion (BHI) plates and C. albicans CFU (colony forming units) are counted after 2 days.
  • BHI solid brain heart infusion
  • Varian Mercury-400 100 MHz spectrometer by use of chloroform-d and dimethylsulfoxide-c/is as solvents. Carbon-13 chemical shifts are referenced to the center of the CDCI3 triplet ( ⁇ 77.0 ppm) and DMSO-d ⁇ pentet ( ⁇ 39.54 ppm). Multiplicities are recorded by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; J, coupling constant (Hz).
  • Lithium bis(trimethylsilyl)amide (1M solution in THF/ethylbenzene; 2,5 mL; 2,5 mmol) was added dropwise to a solution of 4-ethyl-2-morpholinone (300 mg; 2,32 mmol) in dry THF (15 mL) at -7O 0 C. After 1h at -7O 0 C, methyl bromoacetate (231 ⁇ L; 2,43 mmol) was added dropwise. The mixture was stirred at -70 0 C for 1,5h and overnight at room temperature. The reaction was quenched with saturated NH 4 CI and the solvents were evaporated under reduced pressure.
  • Lithium bis(trimethylsilyl)amide (1M solution in THF; 15,5 ml_; 15,500 mmol) was added dropwise to a solution of 4-ethyl-2-morpholi ⁇ one (2,000 g; 15,485 mmol) in dry THF (100 mL) at -7O 0 C. After 1h at -70 ⁇ C, methyl bromoacetate (1,610 mL; 17,007 mmol) was added dropwise. The mixture was stirred at -70 0 C for 3,5 h and the reaction was quenched with saturated NH 4 CI. After warming to room temperature, the reaction mixture was filtered and concentrated under reduced pressure.
  • EXAMPLE 8 GENERAL PROCEDURE FOR SYNTHESIS OF COMPOUNDS ACCORDING TO COMPOUND STRUCTURE (6): The crude acid (obtained in example 7) was suspended in DMF (e.g. 1 ,5 mL) and the mixture was cooled at 0 ⁇ C. 0-(7-Azabenzotriazol-1-yl)- ⁇ /, ⁇ /, ⁇ / I , ⁇ / I -tetramethyluronium hexafluorophosphate (e.g. 167 mg; 0,44 mmol) and diisopropylethylamine (e.g. 103 ⁇ L; 0,59 mmol) were added. After 1 hour at OT, the amine (e.g.
  • This compound was obtained by using the procedure of example 8 with 4- isopropylanili ⁇ e (34 ⁇ L; 0,25 mmol) to give 46 mg of desired product (76%).
  • An example of a reaction mixture is: 2-(4-ethyl-2-oxomorpholin-3-yl)acetic acid (0,200 mmol), HATU (0,167 mg; 0,439 mmol), diisopropylethylamine (0,103 mL; 0,590 mmol) and 4- isopropylaniline (0,034 mL; 0,249 mmol) in DMF (2 mL).
  • EXAMPLE 10 SYNTHESIS OF 2-(4-ETHYL-2-OXOMORPHOLIN-3-YL)-N-(4-
  • reaction mixture 2-(4-ethyl-2-oxomorpholin-3-yl)acetic acid (0,200 mmol), HATU (0,167 mg;
  • EXAMPLE 12 SYNTHESIS OF 2-(4-ETHYL-2-OXOMORPHOLIN-3-YL)- ⁇ /-(THIOPHEN- 2-YLMETHYL)ACETAMIDE (C19)
  • EXAMPLE 13 SYNTHESIS OF ⁇ /-(4-CHLOROBENZYL)-2-(4-ETHYL-2-
  • EXAMPLE 14 SYNTHESIS OF 2-(4-ETHYL-2-OXOMORPHOLIN-3-YL)- ⁇ /-(5- METHYLISOXAZOL-3-YL)ACETAMIDE (C21) This compound was obtained according to the procedure of example 8 from 2-(4- ethyi-2-oxomorpholin-3-yl)acetic acid (0,497 mmol), HATU (0,418 mg; 1,099 mmol), diisopropylethylamine (0,258 ml_; 1,477 mmol) and 3-amino-5-methylisoxazole (0,064 mg; 0,652 mmol) in DMF (5 mL) to give 14 mg of desired product (11%).
  • EXAMPLE 15 SYNTHESIS OF 2-(4-ETHYL ⁇ -OXOMORPHOLIN-S-YL)-N-(PYRIDIN-S- YL)ACETAMIDE (C22)
  • EXAMPLE 16 SYNTHESIS OF 2-(4-ETHYL ⁇ -OXOMORPHOLIN-S-YL)-N-(I-METHYL- 1H-INDOL-5-YL)ACETAMIDE (C23)

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Abstract

The present invention relates to a series of novel compounds (I) which have been shown to possess antifungal activity. The invention therefore relates to the new compounds, methods for their preparation, pharmaceutical compositions comprising them and to the compounds for use as a medicament, more in particular antifungal medicament.

Description

MORPHOLINE DERIVATIVES USED AS ANTIFUNGAL
COMPOUNDS
FIELD OF THE INVENTION
The present invention relates to a series of novel compounds which have been shown to possess antifungal activity, in particular against Candida, Aspergillus and Fusarium species. The invention therefore relates to the new compounds, methods for their preparation, pharmaceutical compositions comprising them and to the compounds for use as a medicament, more in particular antifungal medicament.
BACKGROUND OF THE INVENTION
Occurring worldwide, most fungi are largely invisible to the naked eye, living for the most part in soil, dead matter, and as symbionts of plants, animals, or other fungi. However, several species of the fungi are significant pathogens of humans and other animals or crops. The most commonly known human pathogens are part of the Candida, Aspergillus and/or Fusarium species.
Candida albicans is among the gut flora, the many organisms which live in the human mouth and gastrointestinal tract. Under normal circumstances, C. albicans lives in 80% of the human population with no harmful effects, although overgrowth results in candidiasis. Candida albicans is a causal agent of opportunistic oral and genital infections in humans. Systemic fungal infections have emerged as important causes of morbidity and mortality in immunocompromised patients (e.g., AIDS, cancer chemotherapy, organ or bone marrow transplantation). In addition, hospital-related infections in patients not previously considered at risk (e.g. patients in an intensive care unit) have become a cause of major health concern.
Until recently, C. glabrata was thought to be a primarily non-pathogenic organism. However, with the ever increasing population of immunocompromised individuals, trends have shown C. glabrata to be a highly opportunistic pathogen of the urogenital tract, and of the bloodstream. It is especially prevalent in HIV positive people, and the elderly. A major phenotype and potential virulence factor that C. glabrata possesses is low-level intrinsic resistance to the azole drugs, which are the most commonly prescribed antifungal (antimycotic) drugs. Candida krυsei falls under the same umbrella as C. glabrata in the meaning that this fungus has recently emerged as a human pathogen responsible for mortality in immunocompromised patients and is not sensitive to the azole antimycotics. Aspergillus is a genus of around 200 moulds found throughout much of nature worldwide. Some Aspergillus species cause serious disease in humans and animals, and can be pathogenic. The most common species causing invasive disease are Aspergillus fumigatus and Aspergillus flavus. Aspergillus flavus produces aflatoxin which is both a toxin and a carcinogen, and which can potentially contaminate foods such as nuts. The most common species causing allergic disease are Aspergillus fumigatus and Aspergillus clavatus. Other species are important as agricultural pathogens. Aspergillosis is the group of diseases caused by Aspergillus and includes paranasal sinus infections (fever, cough, chest pain or breathlessness), allergic bronchopulmonary aspergillosis or ABPA, acute invasive aspergillosis and disseminated invasive aspergillosis.
Today, there are 4 classes of established antifungal drugs on the market: (1) the polyenes (e.g. amphotericin B1 nystatin, natamycin), (2) the azoles (e.g. fluconazole, itraconazole, voriconazole), (3) allylamines (e.g. terbinafine), and (4) the newly introduced echinocandins (e.g. caspofungin). Of these classes, only the polyenes, azoles and echinocandins are used to treat systemic fungal infections, not the allylamines. All the currently marketed antifungal drugs have major drawbacks, including no broad-spectrum activity, no per oral absorption, side-effects, low antifungal activity, no fungicidal activity, drug-drug interactions and high costs. Therefore, there is still a stringent need in the art for potent antifungals for topical or systemic infections, especially with a broad spectrum activity against multiple species, per oral absorption, lower amount of side-effects, fungicidal activity, no drug-drug interactions or lower costs or a combination of these. Therefore a goal of the present invention is to satisfy this urgent need by identifying efficient and non-harmful pharmaceutically active ingredients and combination of ingredients for the treatment of (systemic) fungal infections in animals and in humans.
The prior art describes different anti-fungal compound classes, including but not limited to the polyenes, the azoles, allylamines and echinocandins (e.g. caspofungin), but no antifungal compound class relates to the compounds of the invention. SUMMARY OF THE INVENTION
In the present invention, new antifungal compounds are provided. The compounds have a substituted morpholin-2-one structure and it has been shown in the present invention that they possess antifungal (fungicidal) activity, more specifically against Candida,
Aspergillus and Fusarium species. The present invention demonstrates that the compounds inhibit the replication of fungi. Therefore, these compounds constitute a new potent class of antifungal agents that can be used in the treatment and prevention of fungal infections in animals, mammals and humans, more specifically for the treatment and prevention of (topical or systemic) infections with Candida, Aspergillus and/or
Fusarium species.
The present invention provides novel compounds which have fungistatic or fungicidal properties. The invention also provides methods for preparation of all such compounds and provides pharmaceutical compositions comprising the compounds. The invention further relates to the novel compounds for use as a medicament and for the prevention and/or treatment of fungal infections in subjects (including animals, mammals and humans). The invention also relates to the use of the compounds in or for the manufacture of a medicament for the prevention or treatment of subjects suffering from a fungal infection, more in particular for treatment of subjects infected with Candida species (e.g. C. albicans, C. glabrata, C. krusei), Aspergillus species (e.g. A. flavus, A. fumigatus, A. clavatus), Fusarium species (e.g. F. oxysporum, F. culmorum) or other fungi. The invention also provides methods of treatment or prevention of a fungal infection in a subject, including animals, mammals and humans.
One aspect of the present invention is the provision of novel compounds which are unsubstituted or substituted 2-(2-oxo-morpholin-3-yl)-acetamides, in an embodiment of this invention having a structure according to the formula (I):
Figure imgf000005_0001
wherein:
- R1 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cydoalkyl; cycloalkenyl; cycloalkynyl; cycloalkylaikyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl;
• wherein the alkyl, alkenyl, alkynyl, cydoalkyl, cycloalkenyl, cycloalkynyl, cycloalkylaikyl, cycloalkenylalkyl, cycloalkynylalkyl, aryl, heterocycle, arylalkyl, and heterocycle-alkyl, can each independently be substituted with one or more Rs; and • wherein the alkyl, alkenyl, alkynyl, cydoalkyl, cycloalkenyl, cydoalkynyl, cycloalkylaikyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, the heteroatom selected from O, S and N; and • wherein two or more hydrogen atoms on a carbon atom or heteroatom of the alkyl, alkenyl, alkynyl, cydoalkyl, cycloalkenyl, cycloalkynyl, cycloalkylaikyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S1 N=O, N=S, S=O, or S(O)2;
- each of R2 and R3 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cydoalkyl; cycloalkenyl; cycloalkynyl; cycloalkylaikyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
• wherein the alkyl, alkenyl, alkynyl, cydoalkyl, cydoalkenyl, cycloalkynyl, cycloalkylaikyl, cycloalkenylalkyl, cycloalkynylalkyl, aryl, heterocycle, arylalkyl, and heterocycle-alkyl can each independently be substituted with one or more Rs; and
• wherein the alkyl, alkenyl, alkynyl, cydoalkyl, cycloalkenyl, cycloalkynyl, cycloalkylaikyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, the heteroatom selected from O, S and N; and
• wherein R2 and R3 can be taken together in order to form a (5-, 6-, or 7- membered) heterocycle which can be substituted with one or more Rs; and • wherein two or more hydrogen atoms on a carbon atom or heteroatom of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyi, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O1 C=S, N=O1 N=S, S=O, or S(O)2;
- each Rs is independently selected from halogen; hydroxyl; SR4; S(O)R5; S(O)2RS; SO2NR6R7; trifluoromethyl; nitro; NR6R7; cyano; COOR8; C(O)NR6R7; C(O)R5; alkyl; cycloalkyl; cyclalkyloxy; alkoxy; alkenyl; cycloalkenyl; cycoalkenyloxy; alkenyloxy; alkynyl; cycloalkynyl; cycloalkynyloxy; alkynyloxy; cycloalkylalkyi; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; and heterocycle- oxy; and • wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyi, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, the heteroatom selected from O, S and N; and • wherein two or more hydrogen atoms on a carbon atom or heteroatom of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyi, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2;
- each R" is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyi; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
• wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyi, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, the heteroatom selected from O, S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyi, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O1 C=S1 N=O1 N=S, S=O, Or S(O)2;
- each R5 is independently selected from hydroxyl; alkyl; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; alkenyloxy; alkynyl; cycloalkynyl; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; and heterocycle-oxy; and
• wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, the heteroatom selected from O, S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2;
- each R6 and R7 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
• wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, the heteroatom selected from O, S and N; and
• wherein R6 and R7 can be taken together in order to form a (5-, 6-, or 7- membered) heterocycle which can be substituted or unsubstftuted; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2; - each R8 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and • wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, the heteroatom selected from O, S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O1 or S(O)2; and isomers (in particular stereoisomers or tautomers), solvates, pharmaceutically acceptable salts or prodrugs thereof.
Preferably R1 is selected from alkyl, more preferable C1-C6 alkyl, more particularly ethyl. In another particular embodiment, one of R2 and R3 is hydrogen and the other of R2 and R3 is selected from unsubstituted or substituted (particularly with one or more Rs) aryl, arylalkyl, heterocycle or heterocycle-alkyl. Particularly, said substituted aryl, arylalkyl, heterocycle or heterocycle-alkyl is selected from aryl, arylalkyl, heterocycle or heterocycle-alkyl substituted independently with one or more halogen, hydroxy I, thiol, CF3, nitro, cyano, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl and/or alkynyloxy. In another particular embodiment, R2 is selected from hydrogen and R3 is selected from unsubstituted or substituted with one or more Rs aryl and heterocycle. Chemical moieties substituted with one or more Rs can be substituted with 1 , 2, 3, 4 or 5 independently selected Rs.
In a particular embodiment, the compound of present invention is NOT a compound having a structure according to the formula (I) wherein:
- R1 is C6H5 and R2 is hydrogen and R3 is C6H5;
- R1 is ethyl and R2 is hydrogen and R3 is (i-methylethyl)phenyl;
- R1 is ethyl and R2 is hydrogen and R3 is 4-methylphenyl; - R1 is ethyl and R2 is hydrogen and R3 is 4-fluorophenyl;
- R1 is phenylmethyl and R2 is hydrogen and R3 is 4-bromophenyl; and/or
- R1 is phenylmethyl and R2 is hydrogen and R3 is (i-methylethyl)phenyl. In a particular embodiment, the compounds of the present invention are selected from the list of compounds in table 1 (encoded from compound number C1 to C18).
Yet in a more particular embodiment, the compounds are selected from the list of.
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(4-isopropylphenyl)acetamide; - N-(4-bromophenyl)-2-(4-ethyl-2-oxomoφholin-3-yl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-m-tolylacetamide;
- 2-(4-ethyl-2-oxornoφho!iπ-3-yl)-N-p-tolylacetamide;
- N-(3-chlorophenyl)-2-(4-ethyl-2-oxomoφholin-3-yl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(4-methoxyphenyl)acetamide; - 2-(4-benzyl-2-oxomoφholin-3-yl)-N-(2,4-dibromophenyl)acetamide;
- 2-(4-ethyl-2-oxomorpholin-3-yl)-N-(4-fluorophenyl)acetamide;
- 2-(4-benzyt-3-oxomorpholin-2-yl)-N-(3-chlorophenyl)acetamide;
- 2-(4-ethyl-2-oxomorpholin-3-yl)-N-(3-methoxyphenyl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(3-(trifluoromethyl)phenyl)acetamide; - 2-(4-ethyl-2-oxomoφholin-3-yl)-N-o-tolylacetamide;
- 2-(4-benzyl-2-oxomoφholin-3-yJ)-N-(4-fluorophenyl)acetamide;
- 2-(4-benzyl-2-oxomorpholin-3-yl)-N-m-tolylacetamide;
- 2-(4-benzyl-2-oxomorpholin-3-yl)-N-(3-methoxyphenyl)acetamide;
- 2-(4-methyl-2-oxomoφholin-3-yl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)acetamide; - 2-(2-oxo-4-propylmoφholin-3-yl)-N-phenylacetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide;
- 2-(4-ethyl-2-oxomorpholin-3-yl)-N-(thiophen-2-ylmethyl)acetamide;
- N-(4-chlorobenzyl)-2-(4-ethyl-2-oxomoφholin-3-yl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(5-methylisoxazol-3-yl)acetamide; - 2-(4-etiiyl-2-oxomoφholin-3-yl)-N-(pyridin-3-yl)acetamide; and
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(1 -methyl-1 H-indol-5-yl)acetamide.
According to a second aspect, the invention relates to the compounds as described herein, more specifically the compounds according to formula (I) and embodiments thereof, for use as a medicament, more in particular for use as an antifungal medicament and for the use in the prevention or treatment of a fungal infection in or on a subject (animal, mammal or human).
The present invention also relates to the use of the compounds of formula (I) and embodiments thereof as antifungal compounds, more particularly as compounds active against Candida species (e.g. C. albicans, C. glabrata, C. krusei), Aspergillus species (e.g. A. flavus, A. fumigatus, A. clavatus), Fusarium species (e.g. F. oxysporum, F. culmorum) or other fungi. The invention also relates to the use of compounds of the formulae and claims herein for the manufacture of a medicament or as a pharmaceutically active ingredient, especially as a fungal replication inhibitor or fungicidal compound, for instance for the manufacture of a medicament or pharmaceutical composition having antifungal activity for the prevention and/or treatment of fungal infections in humans, mammals and animals in general. The present invention further relates to a method of prevention or treatment of a fungal infection, preferably a Candida species, Aspergillus species or Fusarium species infection in an animal, including mammals, including a human, comprising administering to the animal in need of such treatment a therapeutically effective amount of a compound of the formulae and claims herein as an active ingredient, preferably in admixture with at least a pharmaceutically acceptable carrier. According to another aspect, the invention relates to the compounds as described herein, more specifically the compounds according to formula (I) and embodiments thereof, for use as plant antifungals, more in particular for use as an antifungal in the prevention, reduction or eradication of a fungal infection in or on plants (e.g. in agriculture). According to another aspect, the invention relates to methods to prevent, reduce or eradicate fungal infection in or on plants (e.g. in agriculture), or on materials for industrial or medical use, for example by inhibiting biofilm formation such as fungal biofilm formation.
Another aspect of the invention further relates to methods for the preparation of compounds of formulae and claims herein, more specifically the compounds according to formula (I) and embodiments thereof. Also the intermediates [N-substituted ethanolamine, N-substituted-2-(2-hydroxyethylamino)acetate esters, N-substituted- morpholin-2-one, 2-(4-ethyl-2-oxomorpholin-3-yl)acetate esters] used in the preparation methods described herein are aspects of the present invention. In a particular embodiment of this invention, the method of preparation of the compounds of the invention comprises the following steps:
1) Hydrolysing of an N-substituted or unsubstituted morpholin-2-one-3-acetate ester under acidic or basic conditions leading to the free carboxylic acid; and 2) Coupling said free carboxylic acid with an appropriated amine in the presence of a coupling agent.
The method may further comprise, prior to step 1 , the following steps: i) Condensating an N-substituted-ethanolamine with an alpha halogen acetate ester in the presence of a base to obtain an N-substituted-2-(2-hydroxyethylamino)acetate ester; ii) Obtaining an N-substituted-morpholin-2-one by intramolecular lactonisation of said N- substituted-2-(2-hydroxyethylamiπo)acetate ester in acidic medium; and iii) Condensating said N-substituted-morpholin-2-one with an alpha halogen acetate ester in the presence of a base.
Yet another aspect of the present invention relates to pharmaceutical compositions comprising the compounds of the invention according to formulae and claims herein; more specifically the compounds according to formula (I) and embodiments thereof, in admixture with at least a pharmaceutically acceptable earner, the active ingredient preferably being in a concentration range of about 0.1 to 100% by weight, and to the use of these derivatives namely as drugs useful for the treatment of subjects suffering from a fungal infection, in particular a Candida species, Aspergillus species or Fusarium species infection.
The invention further relates to the use of a composition comprising (a) one or more derivatives of formulae and claims herein, more specifically the compounds according to formula (I) and embodiments thereof, and (b) one or more fungistatic or fungicidal compounds as biologically active agents in respective proportions such as to provide a synergistic effect against a fungal infection in a mammal, for instance in the form of a combined preparation for simultaneous, separate or sequential use in fungal infection therapy. Within the framework of this embodiment of the invention, the inhibitors used as a therapeutically active ingredients (b) may belong to categories already known in the art.
More generally, the invention relates to the compounds of formulae and claims herein, more specifically the compounds according to formula (I) and embodiments thereof, being useful as agents having biological activity or as diagnostic agents. The invention also relates to the use of these compounds of formulae and claims herein more specifically the compounds according to formula (I) and embodiments thereof, as agents having biological activity or as diagnostic agents. Any of the uses mentioned with respect to the present invention may be restricted to a non-medical use, a non-therapeutic use, a non-diagnostic use, or exclusively an in vitro use, or a use related to cells remote from an animal. For example, as described herein, the compounds of present invention can be used to eradicate or reduce or prevent fungal infections on plants or materials (e.g. biofilm formation).
DI=TAILED DESCRIPTION OF THE INVENTION
The present invention will be described with respect to particular embodiments but the invention is not limited thereto. It is to be noticed that the term "comprising", used in the claims, should not be interpreted as being restricted to the means listed thereafter; it does not exclude other elements or steps.
Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances, of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure, in one or more embodiments. Where an indefinite or definite article is used when referring to a singular noun e.g. "a" or "an", "the", this includes a plural of that noun unless something else is specifically stated.
Similarly it should be appreciated that in the description of exemplary embodiments of the invention, various features of the invention are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects.
In each of the following definitions, the number of carbon atoms represents the maximum number of carbon atoms generally optimally present in the substituent or linker; it is understood that where otherwise indicated in the present application, the number of carbon atoms represents the optimal maximum number of carbon atoms for that particular substituent or linker.
The term "alkyl" as used herein refers to C1-C18 normal, preferably primary, secondary, or tertiary hydrocarbon chains. Examples are methyl, ethyl, 1-propyl, 2- propyl, 1-bιrtyl, 2-methyl-1-propyl(i-Bu), 2-butyl (s-Bu), 2-methyl-2-propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1 -butyl, 2- methyl-1 -butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl- 2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, /7-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, π-decyl, n-undecyl, π-dodecyl, /j-tridecyl, n- tetradecyl, /7-pentadecyl, /7-hexadecyl, n-heptadecyl, /7-octadecyl, /7-nonadecyl and n- icosyl. In a particular embodiment, reference is made to "C1-C6 alkyl", which refers to C1- C6 normal, preferably primary, secondary, or tertiary hydrocarbon chains.
The terminology "which can contain a heteroatom in or at the end of the group (e.g. hydrocarbon group), said heteroatom selected from O, S, and N" as used herein, refers to a group where one or more carbon atoms are replaced by an oxygen, nitrogen or sulphur atom and thus includes, depending on the group to which is referred, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl, heteroaryl, arylheteroalkyl, heteroarylalkyl, heteroarylheteroalkyl, arylheteroalkenyl, heteroarylalkenyl, heteroarylheteroalkenyl, heteroarylheteroalkenyl, arylheteroalkynyl, heteroarylalkynyl, heteroarylheteroalkynyl, among others. This term therefore comprises, depending on the group to which is referred, as an example alkoxy, alkenyloxy, alkynyloxy, alkyl-O-alkyl, alkenyl-O-alkyl, arylalkoxy, benzyloxy, heterocycle- heteroalkyl, heterocycle-alkoxy, among others. As an example, when reference is made to "alkyl can contain a heteroatom in or at the end of the alkyl chain, said heteroatom selected from O1 S and N", than any carbon atom of the alkyl can be exchanged for a heteroatom selected from O, S and N when chemically feasible (and refers to heteroalkyl). .Examples of such heteroalkyl are CH3-CH2-O-; CH3-O-CH2-; CH3-CH2-CH2- NH-CH2-, methoxy, methylthio, propoxy, CH3-S-CH2-, CH3-CH2-O-CH2-, CH3-NH-, (CHs)2-N-, (CHa)2-CH2-NH-CH2-CH2-, among many other examples. Furthermore, as an example, the terminology "arylalkyl which can contain a heteroatom in or at the end of the alkyl group, said heteroatom selected from O, S, and N" therefore refers to arylheteroalkyl, meaning an arylalkyl which comprises one or more heteroatoms in the alkyl hydrocarbon chain, whereas the heteroatoms may be positioned at the beginning of the hydrocarbon chain, in the hydrocarbon chain or at the end of the hydrocarbon chain. "Arylheteroalkyl" thus includes aryloxy, arylalkoxy, aryl-alkyl-NH- and the like and examples are phenyloxy, benzyloxy, 8PyI-CH2-S-CH2-, aryl-CH2-O-CH2-, aryl-NH-CH2- among many other examples. The terminology regarding a chemical group "wherein optionally two or more hydrogen atoms on a carbon atom or heteroatom of said group can be taken together to form a C=O, C=S, N=O, N=S, S=O or S(O)2" as used herein, refers to a group where two or more hydrogen atoms on a carbon atom or heteroatom of said group are taken together to form C=O, C=S1 N=O, N=S, S=O or S(O)2. As an example, the terminology refering to "an alkyl wherein optionally two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O or S(O)2", includes among other examples CH3-C(O)-CH2-, CH3-C(O)-, CH3-C(S)-CHr and (CH3J2-CH2-C(O)-CH2-CHr. The combination for a group "which optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms consisting of O, S, and N" and "wherein optionally two or more hydrogen atoms on a carbon atom or heteroatom of said group can be taken together to form a C=O, C=S1 N=O, N=S, S=O or S(O)2" can combine the two aspects described herein above and includes, if the group referred to is alkyl, among other examples CH3-COO-, CH3-COO-CHr, CH3-NH-CO-, CH3-NH-CO-CH2-, CH3-NH- CS-CH2-, CH3-NH-CS-NH-CH2-, CH3-NH-S(OJr and CH3-NH-S(O)2-NH-CH2-
As used herein and unless otherwise stated, the term "cycloalkyl" means a monocyclic saturated hydrocarbon monovalent radical having from 3 to 10 carbon atoms, such as for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, or a C7-10 polycyclic saturated hydrocarbon monovalent radical having from 7 to 10 carbon atoms such as, for instance, norbornyl, fenchyl, trimethyltricycloheptyl or adamantyl.
The terms "alkenyl" and "cycloalkenyl" as used herein is C2-C18 normal, preferably primary, secondary or tertiary and respectively C3-C10 cyclic hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, i.e. a carbon-carbon, sp2 double bond. Examples include, but are not limited to: ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), cyclohexenyl (-C6H9) and 5-hexenyl (-CH2 CH2CH2CH2CH=CH2). The double bond may be in the cis or trans configuration.
The terms "alkynyl" and "cycloalkynyl" as used herein refer respectively to C2-C18 normal, preferably primary, secondary, tertiary hydrocarbon or to the C3-C13 cyclic hydrocarbon (more particularly to respectively C2-C18 normal, preferably primary, secondary, tertiary hydrocarbon or the C8-C13 cyclic hydrocarbon), with at least one site (usually 1 to 3, preferably 1) of unsaturation, i.e. a carbon-carbon, sp triple bond. Examples include, but are not limited to: acetylenic (-C≡CH) and propargyl (-CH2C≡CH). The term "aryi" as used herein means an aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of hydrogen from a carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to 1 ring, or 2 or 3 rings fused together, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like.
"Arylalkyl" as used herein refers to an arylalkylene which is an alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. The arylalkyl group comprises 6 to 20 carbon atoms, preferably 7 to 20 carbon atoms, preferably 6 to 14 carbon atoms. If described as sych, the "arylalkyl" radical may itself be substituted and thereby includes for example 4-chlorobenzyl, 4-fluorobenzyl, 2-fluorobenzyl, 3,4-dichlorobenzyl, 2,6- dichlorobenzyl, 3-methyIbenzyl, 4-methylbenzyl, 4-ter-butylbenzyl, 1-amino-2- phenylethyl and 1-amino-2-[4-hydroxyl-phenyl]ethyl.
The term "heterocycle" refers to a saturated, unsaturated or aromatic ring system including at least one N, O, or S. Heterocycle thus include heteroaryl groups which refers to aromtic heterocycles. Heterocycle as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A. "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; 'The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, CW. and Scriven, E. "Comprehensive Heterocyclic Chemistry" (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566. Examples of heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrol inyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H.6H-1 ,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenaπthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, benzothienyl, benzothiazolyl and isatinoyl. Ηeteroaryl" includes by way of example and not limitation pyridyl, dihydropyridyl, pyridaziπyl, pyrimidinyf, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl. By way of example, carbon bonded heterocycles are bonded at position 2, 3, 4,
5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline and the like. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4- pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5- pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
By way of example, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboliπe. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1- pyrazolyl, and 1-piperidinyl.
Ηeterocycle-alkyl" as used herein refers to a heterocycle-alkylene which is an alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heterocycle radical. Typical heterocycle- alkyl groups include, but are not limited to (pyridin-3-yl)methyl, (pyrrolidin-2-yl)methyl, (thien-2-yl)methyl, (1H-imidazol-2-yl)ethan-1-yl. The heterocycle-alkylene group comprises 6 to 20 carbon atoms, e.g. the alkylene moiety of the heterocycle-alkyl group is 1 to 6 carbon atoms and the heterocycle moiety is 5 to 14 carbon atoms. "Cycloalkylalkyf as used herein refers to a cycloalkylalkylene which is an alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a cycloalkyl radical.
"Cycloalkenylalkyl" as used herein refers to a cycloalkenylalkylene which is an alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a cycloalkenyl radical.
"Cycloalkynylalkyl" as used herein refers to a cycloalkynylalkylene which is an alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a cycloalkynyl radical. As used herein with respect to a substituting group, and unless otherwise stated, the terms substituted aryl, substituted heterocycle, substituted arylalkyl, substituted heterocycle-alkyl and the like refer to the chemical structures defined above, and wherein the said aliphatic group and/or the said aryl or heterocycle may be optionally substituted with one or more substituents, in a particular embodiment said substituents being independently selected from the group consisting of halogen, amino, hydroxyl, sutfhydryl, alkyl, trifluoromethyl, nitro, cyano, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy.cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, aryl, heterocycle, arylalkyl, and heterocycle-alkyl, such as but not limited to 1-amino-2-pndol-2-yl]ethyl, styryl, pyridylmethyl (including all isomers thereof), pyridylethyl, 2-(2-pyridyl)isopropyl, oxazolylbutyl, 2-thienylmethyl, pyrrolylethyl, morpholinyl-ethyl, imidazol-1-yl-ethyl, benzodioxolylmethyl and 2-furylmethyl.
As used herein and unless otherwise stated, the terms "alkoxy", "cyclo-alkoxy", "aryloxy", "arylalkyloxy", "heterocycleoxy", "alkylthio", "cycloalkylthio", "arylthio", "arylalkylthio" and "heterocyclethio" refer to substituents wherein an alkyl group, respectively a cycloalkyl, aryl, arylalkyl or heterocycle (each of them such as defined herein), are attached to an oxygen atom or a sulfur atom through a single bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy, mercaptobenzyl and the like.
As used herein and unless otherwise stated, the term halogen means any atom selected from the group consisting of fluorine (F)1 chlorine (Cl), bromine (Br) and iodine
(I).
Any substituent designation that is found in more than one site in a compound of this invention shall be independently selected.
Substituents optionally are designated with or without bonds. Regardless of bond indications, if a substituent is polyvalent (based on its position in the structure referred to), then any and all possible orientations of the substituent are intended.
Detailed description
The present invention relates to a series of novel compounds which have been shown to possess antifungal activity, in particular against fungi of the family of the Candida, Aspergillus or Fusarium species. The invention therefore relates to the new compounds, methods for their preparation, pharmaceutical compositions comprising them, the use of the compounds for the preparation of a medicament, and to the compounds for use as a medicament, more in particular as antifungal medicament. Present invention also relates to methods to treat or to prevent a fungal infection.
The present invention provides novel compounds which are unsubstituted or substituted 2-(2-oxo-morpho!in-3-yl)-acetamides and which are in particular embodiments described herein.
In a yet more particular embodiment, the present invention provides novel compounds having a structure according to the formula (I):
Figure imgf000018_0001
wherein:
- R1 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; alkylcycloalkyl; alkylcycloalkenyl; alkylcycloalkynyl; aryl; heterocycle; arylalkyl (such as benzyl); or heterocycle-alkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl can independently be substituted with one or more halogen, hydroxyl, thiol, CF3, nitro, cyano, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, arylalkyl, or heterocycle-alkyl can contain a heteroatom in or at the end of hydrocarbon, said heteroatom selected from O, S and N;
- each of R2 and R3 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; alkylcycloalkyl; alkylcycloalkenyl; alkylcycloalkynyl; aryl; heterocycle; arylalkyl (such as benzyl); or heterocyde-alkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl can independently be substituted with one or more halogen, hydroxy I, thiol, CF3, nitro, cyano, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, arylalkyl, or heterocycle-alkyl can contain a heteroatom in or at the end of hydrocarbon, said heteroatom selected from O, S and N; and isomers (in particular stereoisomers or tautomers), solvates, pharmaceutically acceptable salts or prodrugs thereof. Preferably R1 is selected from alkyl, more preferable C1-C6 alkyl, while one of R2 and R3 is hydrogen and the other of R2 and R3 is selected from substituted aryl or substituted heterocycle.
In another particular embodiment, the compounds of the present invention are selected from the list of compounds in table 1 (encoded from compound number C1 to C18).
Yet in a more particular embodiment, the compounds are selected from the list of:
- 2-(4-ethyl-2-oxomorpholin-3-yl)-N-(4-isopropylphenyl)acetamide;
- N-(4-bromophenyl)-2-(4-ethyl-2-oxomoφho!in-3-yl)acetamide;
- 2-(4-ethyl-2-oxornoφholin-3-yl)-N-m-tolylacetamide; - 2-(4-ethyl-2-oxomoφholin-3-yl)-N-p-tolylacetamide;
- N-(3-chlorophenyl)-2-(4-ethyl-2-oxomorpholin-3-yl)acetamide;
- 2-(4-ethyl-2-oxomoφhoIin-3-yl)-N-(4-methoxyphenyl)acetamide;
- 2-(4-benzyl-2-oxomorpholin-3-yl)-N-(2,4-dibromophenyl)acetamide;
- 2-(4-ethyl-2-oxomorpholin-3-yl)-N-(4-fluorophenyl)acetamide; - 2-(4-benzyl-3-oxomoφholin-2-yl)-N-(3-chlorophenyl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(3-methoxyphenyl)acetamide;
- 2-(4-ethyl-2-oxomorpholin-3-yl)-N-(3-(trifluoromethyl)phenyl)acetamide;
- 2-(4-ethyl-2-oxomorpholin-3-yl)-N-o-tolylacetamide;
- 2-(4-benzyl-2-oxomorpholin-3-yl)-N-(4-fluorophenyl)acetamide; - 2-(4-benzyl-2-oxomoφholin-3-yl)-N-m-tolylacetamide;
- 2-(4-benzyl-2-oxomoφholin-3-yl)-N-(3-methoxyphenyl)acetamide;
- 2-(4-methyl-2-oxomoφholin-3-yl)-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)acetamide;
- 2-(2-oxo-4-propylmoφholin-3-yl)-N-phenylacetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide;
According to another embodiment, the invention relates to the compounds as described herein, more specifically the compounds according to formula (I) and embodiments thereof, for use as a medicament, more in particular for use as an antifungal medicament and for the use in the prevention or treatment of a fungal infection in or on a subject (animal, mammal or human).
In a particular embodiment, the present invention provides compounds having a structure according to the formula (I):
Figure imgf000020_0001
wherein:
- R1 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; or heterocycle-alkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl, can independently be substituted with one or more Rs; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, or heterocycle-alkyl can contain a heteroatom in or at the end of the hydrocarbon alkyl, alkenyl or alkynyl, said heteroatom selected from O, S and N;
- each of R2 and R3 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; alkylcycloalkyl; alkylcycloalkenyl; alkylcycloalkynyl; aryl; heterocycle; arylalkyl; or heterocycle-alkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, aryl, heterocycle, arylalkyl, or heterocycle-alky! can independently be substituted with one or more R8; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, arylalkyl, or heterocycle-alkyl can contain a heteroatom in or at the end of hydrocarbon, said heteroatom selected from O, S and N; and wherein R2 and R3 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which can be substituted with one or more Rs;
- each Rs is independently selected from halogen; hydroxyl; SR4; S(O)R5; S(O)2R5; SO2NR6R7; trifluoromethyl; nitro; NR6R7; cyano; COOR8; C(O)NR8R7; C(O)R5; alkyl; cycloalkyl; cyclalkyloxy; alkoxy; alkenyl; cycloalkenyl; cycoalkenyloxy; alkenyloxy; alkynyl; cycloalkynyl; cycloalkynyloxy; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; heterocycle-oxy; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, or heterocycle-alkyl can contain a heteroatom in or at the end of the hydrocarbon alkyl, alkenyl or alkynyl, said heteroatom selected from O, S and N;
- each R4 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, or heterocycle-alkyl can contain a heteroatom in or at the end of the hydrocarbon alkyl, alkenyl or alkynyl, said heteroatom selected from O1 S and N;
- each R5 is independently selected from hydroxyl; alkyl; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; alkenyloxy; alkynyl; cycloalkynyl; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; heterocycle-oxy; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, or heterocycle-alkyl can contain a heteroatom in or at the end of the hydrocarbon alkyl, alkenyl or alkynyl, said heteroatom selected from O, S and N; - each R6 and R7 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, or heterocycle-alkyl can contain a heteroatom in or at the end of the hydrocarbon alkyl, alkenyl or alkynyl, said heteroatom selected from O, S and N; and wherein R6 and R7 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which can be substituted or unsubstituted;
- each R8 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, or heterocycle-alkyl can contain a heteroatom in or at the end of the hydrocarbon alkyl, alkenyl or alkynyl, said heteroatom selected from O, S and N; and isomers (in particular stereoisomers or tautomers), solvates, pharmaceutically acceptable salts or prodrugs thereof, for use as a medicament.
Preferably, R1 is selected from alkyl, more preferable Ci-C6 alkyl, while one of R2 and R3 is hydrogen and the other of R2 and R3 is selected from substituted aryl or substituted heterocycle. Preferably, said substituted aryl is selected from aryl substituted independently with one or more halogen, hydroxyl, thiol, CF3, nitro, cyano, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy; and wherein said substituted heterocycle is selected from heterocycle substituted independently with one or more halogen, hydroxyl, thiol, CF3, nitro, cyano, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy. Yet more particularly, the compounds are selected from the list of
- 2-(4-ethyl-2-oxomorpholin-3-yl)-N-(4-isopropylphenyl)acetamide;
- N-(4-bromophenyl)-2-(4-ethyI-2-oxomoφholin-3-yl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-m-tolylacetarnide;
- 2-(4-ethyl-2-oxomorpholin-3-yl)-N-p-tolylacetarnide; - N-(3-chlorophenyl)-2-(4-ethyl-2-oxomoφholin-3-yl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(4-methoxyphenyl)acetamide;
- 2-(4-benzyl-2-oxomorpholin-3-yl)-N-(2,4-dibromophenyl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(4-fluorophenyl)acetamide;
- 2-(4-benzyl-3-oxomoφholin-2-yl)-N-(3-chlorophenyl)acetamide; - 2-(4-ethyl-2-oxomorpholin-3-yl)-N-(3-methoxyphenyl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(3-(trifluoromethyl)phenyl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-o-tolylacetamide;
- 2-(4-benzyl-2-oxomorpholin-3-yl)-N-(4-fluorophenyl)acetamide;
- 2-(4-benzyl-2-oxomoφholin-3-yl)-N-m-tolylacetamide; - 2-(4-benzyl-2-oxomoφholin-3-yl)-N-(3-methoxyphenyi)acetamide; - 2-(4-methyl-2-oxomoφholin-3-yl)-N-(4-(6-methylbenzo[d]thiazoI-2-yl)phenyl)acetamide; - 2-(2-oxo-4-propylmoφholin-3-yl)-N-phenylacetamide; and - 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(3,4,5-trinnethoxyphenyl)acetamide. In another embodiment, the invention relates to the compounds described above for use as a medicament for the prevention or treatment of a fungal infection in an animal or human, more particularly, wherein the fungal infection is caused by Candida or Aspergillus species. Yet more particularly, said fungal infection is a systemic infection or is a topical infection. Still more particularly, the compounds are for the treatment of a fungal infection in an animal or mammal.
The present invention also relates in another embodiment to the use of the compounds of formula (I) and embodiments thereof as antifungal compounds, more particularly as compounds active against Candida species (e.g. C. albicans, C. glabrata, C. krusei), Aspergillus species (e.g. A. flavus, A. fumigatus, A. clavatus), Fusarium species (e.g. F. oxysporum, F. culmorum) or other fungi.
The invention also relates to the use of compounds of the formulae and claims herein for the manufacture of a medicament or as a pharmaceutically active ingredient, especially as a fungal replication inhibitor or fungicidal compound, for instance for the manufacture of a medicament or pharmaceutical composition having antifungal activity for the prevention and/or treatment of fungal infections in humans, mammals and animals in general. The present invention further relates to a method of prevention or treatment of a fungal infection, preferably a Candida species, Aspergillus species or Fusarium species infection in an animal, including mammals, including a human, comprising administering to the animal in need of such treatment a therapeutically effective amount of a compound of the formulae and claims herein as an active ingredient, preferably in admixture with at least a pharmaceutically acceptable carrier. According to another embodiment, the invention relates to the compounds as described herein, more specifically the compounds according to formula (I) and embodiments thereof, for use as plant antifungals, more in particular for use as an antifungal in the prevention, reduction or eradication of a fungal infection in or on plants (e.g. in agriculture). Another embodiment of the invention further relates to methods for the preparation of compounds of formulae and claims herein, more specifically the compounds according to formula (I) and embodiments thereof. Also the intermediates [N-substituted ethanolamine, N-substituted-2-(2-hydroxyethylamino)acetate esters, N- substituted-morpholin-2-one, 2-(4-ethyl-2-oxomorpholin-3-yl)acetate esters] used in the preparation methods described herein are aspects of the present invention.
One embodiment relates to a method for the preparation of the compounds of the invention, the method comprising the steps of:
1) Hydrolysis of an N-substituted or unsubstituted morpholin-2-one-3-acetate ester under acidic or basic conditions leads to the free carboxylic acid;
2) Coupling the acid obtained in step 1 with an appropriated amine in the presence of a coupling agent.
In a particular embodiment of this invention, the method of preparation of the compounds of the invention comprises the following steps: 1) Condensation of an N-substituted-ethanolamine with an alpha halogen acetate ester in the presence of a base;
2) Intramolecular lactonisation reaction of the N-substituted-2-(2- hydroxyethylamino)acetate ester in acidic medium;
3) Condensation of the resulting N-substituted-morpholin-2-one of step 2 with an alpha halogen acetate ester in the presence of a base;
4) Hydrolysis of the morpholin-2-one-3-acetate ester obtained in step 3 under acidic or basic conditions leads to the free carboxylic acid;
5) Coupling the acid obtained in step 4 and an appropriated amine in the presence of a coupling agent.
Yet another embodiment of the present invention relates to pharmaceutical compositions comprising the compounds of the invention according to formulae and claims herein; more specifically the compounds according to formula (I) and embodiments thereof, in admixture with at least a pharmaceutically acceptable carrier, the active ingredient preferably being in a concentration range of about 0.1 to 100% by weight, and to the use of these derivatives namely as drugs useful for the treatment of subjects suffering from a fungal infection, in particular a Candida species, Aspergillus species or Fusarium species infection. The invention further relates to the use of a composition comprising (a) one or more derivatives of formulae and claims herein, more specifically the compounds according to formula (I) and embodiments thereof, and (b) one or more fungistatic or fungicidal compounds as biologically active agents in respective proportions such as to provide a synergistic effect against a fungal infection in a mammal, for instance in the form of a combined preparation for simultaneous, separate or sequential use in fungal infection therapy. Within the framework of this embodiment of the invention, the inhibitors used as a therapeutically active ingredients (b) may belong to categories already known in the art. More generally, the invention relates to the compounds of formulae and claims herein, more specifically the compounds according to formula (I) and embodiments thereof, being useful as agents having biological activity or as diagnostic agents. Any of the uses mentioned with respect to the present invention may be restricted to a nonmedical use, a non-therapeutic use, a non-diagnostic use, or exclusively an in vitro use, or a use related to cells remote from an animal.
The compounds of the invention are employed for the treatment or prophylaxis of fungal infections, more particularly Candida, Aspergillus or Fusarium species infections. When using one or more compounds according to the formulae of the application as defined herein:
- the active ingredients of the compound(s) may be administered to the mammal (including a human) to be treated by any means well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermal^, intravenously, intra- arterially, parenterally or by catheterization.
- the therapeutically effective amount of the preparation of the compound(s), especially for the treatment of fungal infections in humans and other mammals, corresponds to an amount which ensures a plasma level of between 1μg/ml and 100 mg/ml, optionally of 10 mg/ml. Depending upon the pathologic condition to be treated and the patient's condition, the effective amount may be divided into several sub-units per day or may be administered at more than one day intervals.
The present invention further relates to a method for preventing or treating a fungal infection in a subject or patient by administering to the patient in need thereof a therapeutically effective amount of the compounds of the present invention. The therapeutically effective amount of the preparation of the compound(s), especially for the treatment of fungal infections in humans and other mammals, preferably is a fungicidal amount. More preferably, it is a fungal replication inhibiting amount of the compounds of the formulae as defined herein. Depending upon the pathologic condition to be treated and the patient's condition, the effective amount may be divided into several sub-units per day or may be administered at more than one day intervals.
As is conventional in the art, the evaluation of a synergistic effect in a drug combination may be made by analyzing the quantification of the interactions between individual drugs, using the median effect principle described by Chou et al. in Adv. Enzyme Reg. (1984) 22:27. Briefly, this principle states that interactions (synergism, additivity, antagonism) between two drugs can be quantified using the combination index (hereinafter referred as CI) defined by the following equation:
Figure imgf000026_0001
wherein EDx is the dose of the first or respectively second drug used alone (1a, 2a), or in combination with the second or respectively first drug (1c, 2c), which is needed to produce a given effect. The said first and second drug have synergistic or additive or antagonistic effects depending upon CI < 1, CI = 1, or CI > 1, respectively. Synergistic activity of the pharmaceutical compositions or combined preparations of this invention against fungal infection may also be readily determined by means of one or more tests such as, but not limited to, the isobologram method, as previously described by Elion et al. in J. Biol. Chem. (1954) 208:477-488 and by Baba et al. in Aπϋmicrob. Agents Chemother. (1984) 25:515-517, using EC50 for calculating the fractional inhibitory concentration (hereinafter referred as FIC). When the minimum FIC index corresponding to the FIC of combined compounds (e.g., FICx + FICy) is equal to 1.0, the combination is said to be additive; when it is between 1.0 and 0.5, the combination is defined as subsynergistic, and when it is lower than 0.5, the combination is defined as synergistic. When the minimum FIC index is between 1.0 and 2.0, the combination is defined as subantagonistic and, when it is higher than 2.0, the combination is defined as antagonistic.
This principle may be applied to a combination of different antifungal drugs of the invention or to a combination of the antifungal drugs of the invention with other drugs that exhibit antifungal activity, or with drugs that exhibit other medicinal or health promoting activity.
The invention thus relates to a pharmaceutical composition or combined preparation having synergistic effects against a fungal infection and containing: either (A) a combination of two or more of the compounds of the present invention, and optionally one or more pharmaceutical excipients or pharmaceutically acceptable carriers, for simultaneous, separate or sequential use in the treatment or prevention of a fungal infection; or (B) one or more antifungal agents, and at least one of the compounds of the present invention, and optionally one or more pharmaceutical excipients or pharmaceutically acceptable carriers, for simultaneous, separate or sequential use in the treatment or prevention of a fungal infection.
The pharmaceutical composition or combined preparation with synergistic activity against fungal infection according to this invention may contain compounds of the present invention, compounds according to the formulae of the application, over a broad content range depending on the contemplated use and the expected effect of the preparation. Generally, the content of the compounds of the present invention of the combined preparation is within the range of 0.1 to 99.9% by weight, preferably from 1 to 99% by weight, more preferably from 5 to 95% by weight.
In a particular embodiment, the compounds of the invention can be used for the treatment or prevention of infection by Candida species (e.g. C. albicans, C. glabrata, C. krusei), Aspergillus species (e.g. A. flavus, A. fumigatus, A. clavatus), Fusarium species (e.g. F. oxysporum, F. culmorum) or other fungi. More in particular, the compounds of present invention can be used as a medicament for treating or preventing fungal infections in a subject in need thereof.
The present invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
The present invention further provides agricultural compositions comprising at least one active ingredient as above defined together with a suitable carrier therefore. More generally, the invention relates to the compounds according to the formulae of the application being useful as agents having biological activity (particularly antifungal activity) or as diagnostic agents. Any of the uses mentioned with respect to the present invention may be restricted to a non-medical use, a non-therapeutic use, a nondiagnostic use, or exclusively an in vitro use, or a use related to cells remote from an animal. For example, as described herein, the compounds of present invention can be used to eradicate or reduce or prevent fungal infections on plants or materials, or can be used to eradicate or reduce or prevent biofilm formation, e.g. a biofilm wherein fungi are attached or prevail or contribute to the biofilm formation.
The compounds of the invention optionally are bonded covalently to an insoluble matrix and used for affinity chromatography (separations, depending on the nature of the groups of the compounds, for example compounds with aryl are useful in hydrophobic affinity separations.
Those of skill in the art will also recognize that the compounds of the invention may exist in many different protonation states, depending on, among other things, the pH of their environment. While the structural formulae provided herein depict the compounds in only one of several possible protonation states, it will be understood that these structures are illustrative only, and that the invention is not limited to any particular protonation state, any and all protonated forms of the compounds are intended to fall within the scope of the invention.
The term "pharmaceutically acceptable salts" as used herein means the therapeutically active non-toxic salt forms which the compounds according to the formulae of the application are able to form. Therefore, the compounds of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na+, Li+, K+, Ca+2 and Mg+2. Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid. The compounds of the invention may bear multiple positive or negative charges. The net charge of the compounds of the invention may be either positive or negative. Any associated counterions are typically dictated by the synthesis and/or isolation methods by which the compounds are obtained. Typical counterions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counter ion is not a critical feature of the invention, and that the invention encompasses the compounds in association with any type of counter ion. Moreover, as the compounds can exist in a variety of different forms, the invention is intended to encompass not only forms of the compounds that are in association with counterions (e.g., dry salts), but also forms that are not in association with counterions (e.g., aqueous or organic solutions). Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound. In addition, salts may be formed from acid addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups. Examples of such appropriate acids include, for instance, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxylacetic, 2- hydroxylpropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic (i.e. 2- hydroxylbenzoic), p-aminosalicylic and the like. Furthermore, this term also includes the solvates which the compounds according to the formulae of the application as well as their salts are able to form, such as for example hydrates, alcoholates and the like. Finally, it is to be understood that the compositions herein comprise compounds of the invention in their unionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids, especially the naturally-occurring amino acids found as protein components. The amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
The compounds of the invention also include physiologically acceptable salts thereof. Examples of physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX4 + (wherein X is C1-C4 alkyl). Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound containing a hydroxyl group include the anion of said compound in combination with a suitable cation such as Na+ and NX4 + (wherein X typically is independently selected from H or a C1-C4 alkyl group). However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
The compounds of the present invention can have different isomeric forms or can be a mixture of isomers.
As used herein and unless otherwise stated, the term "enantiomer" means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e. at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.
The term "isomers" as used herein means all possible isomeric forms, including tautomeric and sterochemical forms ("stereoisomers") and including positional isomers, which the compounds according to the formulae of the application may possess. In a particular embodiment, the term "isomers" excludes positional isomers. Typically, the structures shown herein exemplify only one tautomeric or resonance form of the compounds, but the corresponding alternative configurations are contemplated as well. Unless otherwise stated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, including stereoisomers and tautomers, said mixtures containing all diastereomers and enantiomers (since the compounds according to the formulae of the application may have at least one chiral center) of the basic molecular structure, as well as the stereochemically pure or enriched compounds. More particularly, stereogenic centers may have either the R- or S-configuration, and multiple bonds may have either cis- or trans-configuration. Pure isomeric forms of the said compounds are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure. In particular, the term "stereoisomerically pure" or "chirally pure" relates to compounds having a stereoisomers excess of at least about 80% (i.e. at least 90% of one isomer and at most 10% of the other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in a similar way, having regard to the enantiomeric excess, respectively the diastereomeric excess, of the mixture in question. Separation of stereoisomers is accomplished by standard methods known to those skilled in the art. One enantiomer of a compound of the invention can be separated substantially free of its opposing enantiomer by a method such as formation of diastereomers using optically active resolving agents ("Stereochemistry of Carbon Compounds," (1962) by E. L Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302). Separation of isomers in a mixture can be accomplished by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure enantiomers, or (3) enantiomers can be separated directly under chiral conditions. Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts. Alternatively, by method (2), the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliei, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched compounds of the invention. A method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, a-methoxy-a- (trifluoromethyl)phenyl acetate (Jacob 111. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111). Under method (3), a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase. Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives. Commercially available polysaccharide based chiral stationary phases are ChiralCelTM CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and ChiralpakTM AD, AS, OP(+) and 0T(+). Appropriate eluents or mobile phases for use in combination with said polysaccharide chiral stationary phases are hexane and the like, modified with an alcohol such as ethanol, isopropanol and the like. ("Chiral Liquid Chromatography" (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) "Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase", J. of Chromatogr. 513:375-378).
The terms cis and trans are used herein in accordance with Chemical Abstracts nomenclature and include reference to the position of the substituents on a ring moiety. The absolute stereochemical configuration of the compounds according to the formulae of the application may easily be determined by those skilled in the art while using well- known methods such as, for example, X-ray diffraction or NMR.
Tautomers are organic compounds that are interconvertible by a chemical reaction called tautomerization. As most commonly encountered, this reaction results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on everal factors, including temperature, solvent, and pH.
The compounds of the invention may be formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Formulations optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxylalkylcellulose, hydroxylalkylmethyicellulose, stearic acid and the like.
Subsequently, the term "pharmaceutically acceptable carrier" as used herein means any material or substance with which the active ingredient is formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness. The pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the compositions of this invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets or powders.
Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art, and there is no particular restriction to their selection within the present invention. They may also include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals. The pharmaceutical compositions of the present invention may be prepared in any known manner, for instance by homogeneously mixing, coating and/or grinding the active ingredients, in a one-step or multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents may also be prepared by inicronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 gm, namely for the manufacture of microcapsules for controlled or sustained release of the active ingredients.
Suitable surface-active agents, also known as emulgent or emulsifier, to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and/or anionic materials having good emulsifying, dispersing and/or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface-active agents. Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (Ci0-C22), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable form coconut oil or tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and alkylarylsulphonates. Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alky) or acyl radical having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from natural fatty acids, alkaline or alkaline- earth metal salts of sulphuric or sulphonic acid esters (such as sodium lauryf sulphate) and sulphonic acids of fatty alcohol/ethylene oxide adducts. Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulphonates are the sodium, calcium or alcanolamine salts of dodecylbenzene sulphonic acid or dibutyl-naphtalenesulphonic acid or a naphtalene-sulphonic acid/forrnaldehyde condensation product. Also suitable are the corresponding phosphates, e.g. salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and/or propylene oxide, or phospholipids. Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl-choline, dipalmitoylphoshatidyl -choline and their mixtures. Suitable non-ionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol. Further suitable non-ionic surfactants are water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups. Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit. Representative examples of non-ionic surfactants are nonylphenol -polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol and octylphenoxypolyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and pentaerythritol are also suitable non-ionic surfactants.
Suitable cationic surfactants include quaternary ammonium salts, particularly halides, having 4 hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxyl; for instance quaternary ammonium salts containing as N- substituent at least one C8-C22 alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxyl-lower alkyl radicals. A more detailed description of surface-active agents suitable for this purpose may be found for instance in "McCutcheon's Detergents and Emulsifiers Annual" (MC Publishing Crop., Ridgewood, New Jersey, 1981), "Tensid-Taschenbucw1, 2 d ed. (Hanser Verlag, Vienna, 1981) and "Encyclopaedia of Surfactants, (Chemical Publishing Co., New York, 1981). Compounds of the invention and their physiologically acceptable salts (hereafter collectively referred to as the active ingredients) and pharmaceutical compositions thereof may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural). The preferred route of administration may vary with for example the condition of the recipient.
While it is possible for the active ingredients to be administered alone it is preferable to present them as pharmaceutical formulations or compositions. The formulations, both for veterinary and for human use, of the present invention comprise at least one active ingredient, as above described, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic ingredients. The camer(s) optimally are "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. For infections of the eye or other external tissues e.g. mouth and skin, the formulations are optionally applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredients) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingredients may be employed with either a parafMnic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyll groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. [Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus the cream should optionally be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is optionally present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid earner.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc), which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit- dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Prefeσed unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
Compounds of the invention can be used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds of the invention ("controlled release formulations") in which the release of the active ingredient can be controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given invention compound. Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods.
Additional ingredients may be included in order to control the duration of action of the active ingredient in the composition. Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino acids, polyvinyl pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate and the like. The rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxylmethylcellulose, polyethyl methacryiate and the other above-described polymers. Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on. Depending on the route of administration, the pharmaceutical composition may require protective coatings. Pharmaceutical forms suitable for injectionable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol and the like and mixtures thereof.
In view of the fact that, when several active ingredients are used in combination, they do not necessarily bring out their joint therapeutic effect directly at the same time in the mammal to be treated, the corresponding composition may also be in the form of a medical kit or package containing the two ingredients in separate but adjacent repositories or compartments. In the latter context, each active ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g. one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.
Another embodiment of this invention relates to various precursor or " pro-drug " forms of the compounds of the present invention. It may be desirable to formulate the compounds of the present invention in the form of a chemical species which itself is not significantly biologically-active, but which when delivered to the animal or human will undergo a chemical reaction catalysed by the normal function of the body, inter alia, enzymes present in the stomach or in blood serum, said chemical reaction having the effect of releasing the compound of present invention as defined herein. The term "prodrug" thus relates to these species which are converted in vivo into the active pharmaceutical ingredient.
The pro-drugs of the present invention can have any form suitable to the formulator, for example, esters are non-limiting common pro-drug forms. In the present case, however, the pro-drug may necessarily exist in a form wherein a covalent bond is cleaved by the action of an enzyme present at the target locus. For example, a C-C covalent bond may be selectively cleaved by one or more enzymes at said target locus and, therefore, a pro-drug in a form other than an easily hydrolysable precursor, inter alia an ester, an amide, and the like, may be used. The counterpart of the active pharmaceutical ingredient in the pro-drug can have different structures such as an amino acid or peptide structure, alkyl chains, sugar moieties and others as known in the art. For the purposes of the present invention the term "therapeutically suitable pro-drug" is defined herein as "a compound of present invention modified in such a way as to be transformed in vivo to the therapeutically active form, whether by way of a single or by multiple biological transformations, when in contact with the tissues of the animal or human to which the pro-drug has been administered, and without undue toxicity, irritation, or allergic response, and achieving the intended therapeutic outcome ".
The compounds of the invention according to the formulae of the application can be prepared while using a series of chemical reactions known to those skilled in the art, altogether making up the process for preparing said compounds and exemplified further. The processes described further are only meant as examples and by no means are meant to limit the scope of the present invention. The compound of this invention can be prepared by the following general methods: One of the key steps in the preparation of compounds having the general formula (6) is the synthesis of the intermediate (2) as outlined in scheme 1.
Scheme 1
Figure imgf000041_0001
Figure imgf000041_0002
The synthesis of 4-N-substituted moφholin-2-one (2) has been described several times in the literature. This class of compounds can easily be obtained from N- substituted-ethanol amines (1) and a suitable 1,2-dielectrophile (glyoxal or alpha halogeno-acetate) in an apolar aprotic solvent (e.g. benzene, toluene) or in a polar aprotic sovent (e.g. DMF1 THF). When an alpha-halogeno acetate is used as electrophile, the presence of a weak base (e.g. triethylamine, potassium carbonate) might be required to obtain the intermediate (4). This intermediate can be converted into the desired compound (2) by using an strong acid (e.g. p-toluenesulfonic acid, hydrochloric acid) in various (polar, apolar, protic aprotic) solvents (e.g. dichloromethane, toluene, ethanol) at a temperature of 00C to about 11O0C1 a process known as intramolecular lactonisation. The substituted ethanolamines (1) can be obtained via commercial sources or by synthesis. Many references are available in the literature using ethanolamine or a appropriated substituted amine as starting materials. Some representative examples can be found in the following references: WO 2005123747, WO 2005080371, Tetrahedron, 61(39), 9391-9404; 2005, Organic Letters, 8(18), 3915-3918; 2006, Journal of Medicinal Chemistry, 47(15), 3823-3842; 2004, which are included herein by reference. Compound (2) can then be deprotonated on position 3 with a strong base (e.g. lithium or sodium hexamethyldisilazane, n-buthyl lithium) in a polar aprotic solvent (e.g. THF, DME) at a temperature of -78βC to about O0C (preferably -78°C). The resulting enolate can be condensed with an alpha halogen acetate ester at a temperature of - 780C to about 2O0C (preferably -78βC) to yield the desired compound (3). (Journal of Labelled Compounds & Radiopharmaceuticals, 42(7), 701-708; 1999, Synlett, (10), 1099-1101; 1998 which is included herein by reference).
Figure imgf000042_0001
3 S 6
In a certain embodiment of the invention, R1' = R1, R4' = Rz and R5' = R3.
Ester (3) can then be hydrolyzed to the carboxylic acid (5) under acidic (e.g. hydrochloric acid, trifluoroacetic acid) or basic (e.g. lithium or sodium hydroxide) conditions in various polar, apolar, protic aprotic solvents (e.g. methanol, water, dichloromethane) depending on the nature of the ester group.
Compound (5) can finally be reacted with different mono or di-substituted amines in the presence of a coupling agent such as a carbodiimide (e.g. DCC, DIC) or an uronium salts (e.g. TBTU, HATU) in polar aprotic solvents (e.g. DMF, dichloromethane) at room temperature over a period of time going from 1 to 24 hours.
All other compounds not explicitly mentioned in this general description can be prepared by using the methods as described herein and further combined with the knowledge of a person skilled in the art.
Examples
The following examples are provided for the purpose of illustrating the present invention and should in no way be interpreted as limiting the scope thereof.
Table 1 : Structures of example compounds of the invention and their respective codes.
Figure imgf000043_0001
Figure imgf000044_0001
EXAMPLE 1: ANTIFUNGAL ACTIVITY
Candida species (e.g. C. albicans, C. glabrata, C. krusei) antifungal activity:
YPD agar (1% yeast extract, 2% peptone, 2% glucose, 1,5% agar) was inoculated with 1/500 of an overnight culture in YPD of either Candida albicans or Candida glabrata, and poored in a square petridish (12 cm x 12 cm). Five μl of the compound of the invention, dissolved at 2 mg/ml DMSO, were spotted on the agar. After 24 h incubation at 37°C, compounds were assessed for their growth-inhibitory potential by measurement of the inhibitory halo of the compounds. The majority of the compounds showed a growth-inhibitory halo of > 6 mm for Candida albicans. Determination of the Minimal Fungicidal Concentration (MFC) against Candida spp. and of the Minimal Inhibitory concentration (MIC) and MFC against filamentous fungi (Aspergillus flavus, Fusarium spp.)
Two-fold dilution series of the compounds were prepared in 50% DMSO. 5 μl of these series were added to 95 μl PBS buffer inoculated with 1/500 cells of an overnight culture of either C. albicans, C. glabrata or C. knisei (final DMSO cone 2%). 2% DMSO served as negative control. After 24h incubation at 37°C of these cultures with the antifungal compounds in PBS1 the cell cultures were plated on YPD agar and colony forming units (CFUs) were determined after incubation of the plates for 2 days. MFC was determined as the minimal concentration of a compound resulting in less than 1% survival of the yeast culture relative to the DMSO control.
To determine the MIC and MFC of a compound against Aspergillus flavus, Fusarium oxysporυm or F. culmorum, a 2-fold dilution series of the compounds of the invention was incubated with the corresponding spore suspension in % PDB (potato dextrose broth, Difco) (2x104 spores/ml). After 24h incubation at 25°C, the minimal inhibitory concentration (MIC) was determined as the minimal concentration that inhibits growth of the fungus. Subsequently, the content of all the wells which showed no fungal growth was plated on PDB agar and colony forming units (CFUs) were determined after incubation of the plates for 2 days. MFC was determined as the minimal concentration of a compound resulting in less than 1% survival of the fungal culture relative to the DMSO control.
The majority of the compounds of the invention showed an antifungal activity against Candida, Aspergillus as well as against Fusarium species, while some compounds were less broad spectrum and showed activity against only one or two of Candida, Aspergillus or Fusarium species. The MICs ranged between 0.8 μg/mL and 25 μg/mL, while the MFCs ranged between 3 μg/mL and 50 μg/mL.
[EXAMPLE 2: CELLULAR CYTOTOXICITY By using MDBK cells Madin-Darbey Bovine Kidney (MDBK) cells are maintained in Dulbecco's modified Eagle medium (DMEM) supplemented with BVDV-free 5% fetal calf serum (DMEME-FCS) at 37°C in a humidified, 5% CO2 atmosphere.
The effect of the compounds on exponentially growing MDBK cells can be assessed as follows. Cells are seeded at a density of 5000 cell/well in 96 well plates in MEM medium (Gibco) supplemented with 10% fetal calf serum, 2mM L-glutamine (Life Technologies) and bicarbonate (Life Technologies). Cells are cultured for 24 hr after which serial dilutions of the test compounds are added. Cultures are then again further incubated for 3 days after which the effect on cell growth is quantified by means of the MTS method (Promega). The concentration that results in 50% inhibition of cell growth is defined as the 50 % cytostatic concentration (CC50)
By using Huh-5-2 cells
Huh-5-2 cells [a cell line with a persistent HCV replicon l389luc-ubi-neo/NS3- 375.1 ; replicon with firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein and an EMCV-IRES driven NS3-5B HCV polyprotein used here to investigate the cytostatic / cytotoxic effect of the compounds] were cultured in RPMI medium (Gibco) supplemented with 10% fetal calf serum, 2mM L-glutamine (Life Technologies), 1x nonessential amino acids (Life Technologies); 100 IU/ml penicillin and 100 μg/ml streptomycin and 250 μg/ml G418 (Geneticin, Life Technologies). Cells were seeded at a density of 7000 cells/ well of classical 96- well cell culture plates (Becton-Dickinson) in medium containing the components as described above, except for G418. Cells are allowed to adhere and proliferate for 24 hr. At that time, culture medium is removed and 5 serial dilutions (5-fold dilutions starting at 100μg/ml or 100μM) of the compounds are added in culture medium lacking G418. Plates are further incubated at 37βC and 5% CO2 for 72 hours.
The effect of the compounds on the proliferation of the cells was measured 3 days after addition of the various compounds by means of The CellTiter 968AQu60Us Non- Radioactive Cell Proliferation Assay (MTS, Promega). In this assay 3-(4,5- dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetra2θlium
(MTS) is bioreduced by cells into a formazaπ that is soluble in tissue. The number of cells correlates directly with the production of the formazan. The MTS stained cultures were quantified in a plate reader at 498nm. The 50% cytostatic concentrations (EC50) were calculated from these datasets. A selection of the compounds of the invention was tested and did not show a cytostatic activity on Huh-5-2 cells at 50 μg/mL.
EXAMPLE 3: IN VIVO EFFICACY AND TOXICITY MEASUREMENT By using a Caenorhabditis elegans model The compounds are tested in a C. elegans model for Candida infection which was developed by Breger et al., 2007 (PLoS Pathog 2007, 3: e18). Mini-host models are more and more used as simple experimental systems to study pathogenesis and immune responses of the host (Chamilos G et al., Lancet Infect. Dis. 2007, 7:42-55). Medically important fungal pathogens, like Candida sp., have been shown to infect nematodes (Mylonakis E et al. Infect Immun. 2005, 73:3833-3841). To this end, L4 larvae of a double mutant (glp-4Δ sek-1Δ) of C. elegans are used which at 250C are unable to produce eggs and die after reaching maturity. The larvae are fed for 4-8 h on either E. coli OP50 (standard feeding source) agar plates for toxicity testing of the compounds or on C. albicans agar plates for efficacy testing of the compounds. The percentage survival of the worms in the presence or absence of antifungal compounds is subsequently determined. As positive controls for efficacy testing, amphotericin B (10 μg/ml) and miconazole (10 μg/ml) in DMSO are used.
By using a rodent model
Assay for in vivo efficacy measurement using mouse model for Candidiasis Fungal burden in the kidney of infected mice are used to evaluate the prophylactic activity of the compounds in murine models of infection by C. albicans, as described in the prior art (demons KV, DA Stevens, J Antimicrob. Chemother. 2001; 47:183-186; Okawa Y et al., Biol Pharm Bull 2007, 30:1870-1873). Mice are inoculated intravenously via lateral tail vein with 2x105 C. albicans yeast cells suspended in saline. The compounds in 50 μl saline are injected intravenously 1 hour before or after the challenge with C. albicans. Four similar subsequent injections are made after 24 h intervals. Control groups are treated with 10mg/Kg doses of fluconazole or saline following the same protocol. Mice are sacrificed 5 days after fungal infection. Kidneys are excised, weighted, homogenized and the pellets are resuspended in PBS (1ml). 100μl-samples are plated onto solid brain heart infusion (BHI) plates and C. albicans CFU (colony forming units) are counted after 2 days.
EXAMPLE 4: MATERIALS AND GENERAL PREPARATION METHODS
For all reactions, analytical grade solvents were used. All moisture sensitive reactions were carried out in oven-dried glassware (135 "C) under a argon atmosphere. All standard equipment was used for the chemical preparation and analysis. For example, a Varian Unity 500 MHz spectrometer or a 200 MHz Varian Gemini apparatus can be used for 1H NMR and 13C NMR. Mass spectra can be acquired with an ion trap mass spectrometer (EsquireβOOO, Bruker, Bremen, GERMANY) equipped with a multimode probe (ESI/APCI) interface; samples can be infused in i-PrOH/H2O 1 :1 at 3 μL/min. All reactions were carried out in oven-dried glassware (110 0C) under an atmosphere of nitrogen unless as indicated otherwise. All the solvents and reagents were purchased from Sigma-Aldrich-Fluka or Acos Chemical Co and used without any further purification unless as indicated otherwise.
Analytical thin layer chromatography (TLC) was performed on precoated plates (silica gel 60 F-254), purchased from Merck Inc. Purification by column chromatography was carried out by use of pre-packed silica gel cartridges SNAP-C 18 (BIOTAGE).
Proton NMR spectra were obtained on a Varian Mercury-400 (400 MHz) spectrometer by use of chloroform-d, dimethylsulfoxide-dρ as solvents and tetramethylsilane as an internal standard. Carbon-13 NMR spectra were performed on a
Varian Mercury-400 (100 MHz) spectrometer by use of chloroform-d and dimethylsulfoxide-c/is as solvents. Carbon-13 chemical shifts are referenced to the center of the CDCI3 triplet (δ 77.0 ppm) and DMSO-dβ pentet (δ 39.54 ppm). Multiplicities are recorded by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; J, coupling constant (Hz).
EXAMPLE 5: SYNTHESIS OF 4-ETHYLMORPHOLIN-2-ONE
The synthesis of this compound has been performed according to the procedure published in US 5066804 (Wei-Yang Su). The same procedure can be used to synthesise ethanolamines with other amino substituents to obtain the reagents for the synthesis of the compounds of the invention. Alternatively, many amino-substituted ethanolamines are commercially available.
EXAMPLE 6: SYNTHESIS OF METHYL 2-(4-ETHYL-2-OXOMORPHOLIN-3- YL)ACETATE
Lithium bis(trimethylsilyl)amide (1M solution in THF/ethylbenzene; 2,5 mL; 2,5 mmol) was added dropwise to a solution of 4-ethyl-2-morpholinone (300 mg; 2,32 mmol) in dry THF (15 mL) at -7O0C. After 1h at -7O0C, methyl bromoacetate (231 μL; 2,43 mmol) was added dropwise. The mixture was stirred at -700C for 1,5h and overnight at room temperature. The reaction was quenched with saturated NH4CI and the solvents were evaporated under reduced pressure. The residue was taken up with EtOAc, dried over Na2SO4, filtered, concentrated and purified by flash column chromatography on silicagel (30-80% EtOAc/heptane) to give the desired product (203 mg; 43%) as a yellow oil. The synthesis of bigger amounts of this compound was performed as follows.
Lithium bis(trimethylsilyl)amide (1M solution in THF; 15,5 ml_; 15,500 mmol) was added dropwise to a solution of 4-ethyl-2-morpholiπone (2,000 g; 15,485 mmol) in dry THF (100 mL) at -7O0C. After 1h at -70βC, methyl bromoacetate (1,610 mL; 17,007 mmol) was added dropwise. The mixture was stirred at -700C for 3,5 h and the reaction was quenched with saturated NH4CI. After warming to room temperature, the reaction mixture was filtered and concentrated under reduced pressure. The residue was taken up with EtOAc, dried over Na2SO4, filtered, concentrated and purified by flash column chromatography on silicagel using a gradient of ethyl acetate (30 - 80%) in heptane to afford the desired product (1,641 g; 53%) as a yellow oil.
1H NMR (CDCI3) δ 1.07 (t, 3H1 J = 7.2 Hz); 2.36-2.42 (m, 1H); 2.58-2.63 (m, 1H); 2.73- 2.80 (m, 1H); 2.84-2.89 (m, 1H); 3.00-3.03 (m, 1H); 3.06-3.10 (m, 1H); 3.41-3.43 (m, 1H); 3.71 (s, 3H); 4.35-4.38 (m, 1H); 4.47-4.52 (m, 1H). MS m/z 201.9 (M+H); 224 (M+Na).
[EXAMPLE 7: SYNTHESIS OF 2-(4-ETHYL-2-OXOMORPHOLIN-3-YL)ACETIC ACID
1M LiOH (400 μL; 0,40 mmol) was added dropwise to a solution of 2-(4-ethyl-2- oxomorpholin-3-yl)acetate (0,20 mmol) in a mixture of dioxane/water (1/1; 2 mL). After 30 min to 1 hour at room temperature, the mixture was acidified/ neutralized with 1M HCI (pH = 5), concentrated and coevaporated with toluene. The crude material was used in the next step without any further purification.
EXAMPLE 8: GENERAL PROCEDURE FOR SYNTHESIS OF COMPOUNDS ACCORDING TO COMPOUND STRUCTURE (6): The crude acid (obtained in example 7) was suspended in DMF (e.g. 1 ,5 mL) and the mixture was cooled at 0βC. 0-(7-Azabenzotriazol-1-yl)-Λ/,Λ/,Λ/I,Λ/I-tetramethyluronium hexafluorophosphate (e.g. 167 mg; 0,44 mmol) and diisopropylethylamine (e.g. 103 μL; 0,59 mmol) were added. After 1 hour at OT, the amine (e.g. 0,25 mmol, 1 ,25eq) was added. The reaction mixture was stirred for an additional hour at 00C and overnight at room temperature. The solvent was evaporated. The residue was partitioned between ethyl acetate and brine. The organic phase was dried over Na2SO4, filtered, concentrated and purified by flash column chromatography on silica gel.
EXAMPLE 9: SYNTHESIS OF 2-(4-ETHYL-2-OXOMORPHOLIN-3-YL)-N-(4- ISOPROPYLPHENYL)ACETAMIDE (C1)
This compound was obtained by using the procedure of example 8 with 4- isopropylaniliπe (34μL; 0,25 mmol) to give 46 mg of desired product (76%). An example of a reaction mixture is: 2-(4-ethyl-2-oxomorpholin-3-yl)acetic acid (0,200 mmol), HATU (0,167 mg; 0,439 mmol), diisopropylethylamine (0,103 mL; 0,590 mmol) and 4- isopropylaniline (0,034 mL; 0,249 mmol) in DMF (2 mL).
1H NMR (CDCI3) δ 1.15 (t, 3H, J = 7.1 Hz); 1.22 (d, 6H, J = 7.0 Hz); 2.47-2.53 (m, 1H);
2.65-2.70 (m, 1H); 2.84-2.95 (m, 3H); 3.00-3.07 (m, 1 H); 3.12-3.16 (m, 1H); 3.52 (t, 1 H1 J = 4.5 Hz); 4.40-4.43 (m, 1H); 4.49-4.54 (m, 1H); 7.16 (d, 2H1 J = 8.4 Hz); 7.41 (d, 2H, J =
8.4 Hz); 8.68 (brs, 1H).
13C NMR (CDCI3) δ 11.51; 23.99; 33.57; 37.71; 46.49; 48.12; 61.49; 67.41; 119.97;
126.85; 135.53; 144.97; 167.71; 169.90.
MS m/z 305.0 (M+H).
EXAMPLE 10: SYNTHESIS OF 2-(4-ETHYL-2-OXOMORPHOLIN-3-YL)-N-(4-
BROMOPHENYL)ACETAMIDE (C2)
This compound was obtained by using the procedrue of example 8 with 4-bromoaniline
(43mg; 0,25 mmol) to give 49 mg of desired product (72%). An example of a reaction mixture is: 2-(4-ethyl-2-oxomorpholin-3-yl)acetic acid (0,200 mmol), HATU (0,167 mg;
0,439 mmol), diisopropylethylamine (0,103 mL; 0,590 mmol) and 4-bromoaniline (43 mg;
0,249 mmol) in DMF (2 mL).
1H NMR (CDCI3) δ 1.16 (t, 3H, J = 7.1 Hz); 2.48-2.55 (m, 1H); 2.67-2.72 (m, 1H); 2.87- 2.96 (m, 2H); 3.03-3.07 (m, 1H); 3.14-3.18 (m, 1H); 3.51-3.53 (m, 1H); 4.42-4.52 (m, 2H); 7.41 (S, 4H); 8.79 (s, 1H).
13C NMR (CDCI3) δ 11.48; 37.79; 46.53; 48.15; 61.43; 67.47; 116.76; 121.28; 131.96; 136.91; 167.82, 169.86. MS m/z 341.02 and 342.88 (M+H). EΞXAMPLE 11: SYNTHESIS OF 2-(4-ETHYL-2-OXOMORPHOLIN-3-YL)-N-(3- METHYLPHENYL)ACETAMIDE (C3)
This compound was obtained according to the procedure of example 8 from 2- (4-ethyl-2-oxomorpholin-3-yl)acetic acid (0,200 mmol), HATU (0,167 mg; 0,439 mmol), diisopropylethylamine (0,103 mL; 0,590 mmol) and 3-methylaniline (0,028 mL; 0,25 mmol) in DMF (2 mL) to give 42 mg of desired product (76%). ESI/APCI(+): 277 (M+H), 299 (M+Na).
EXAMPLE 12: SYNTHESIS OF 2-(4-ETHYL-2-OXOMORPHOLIN-3-YL)-Λ/-(THIOPHEN- 2-YLMETHYL)ACETAMIDE (C19)
This compound was obtained according to the procedure of example 8 from 2-(4- ethyl-2-oxomorpholin-3-yl)acetic acid (0,497 mmol), HATU (0,418 mg; 1,099 mmol), diisopropylethylamine (0,258 mL; 1,477 mmol) and thiophene-2-methylamine (0,067 mL; 0,653 mmol) in DMF (5 mL) to give 47 mg of desired product (33%).
1H NMR (CDCI3) δ 1.09 (t, 3H, J = 7.1 Hz); 2.5-2.9 (m, 6H); 3.57 (m, 2H); 4.05 (m, 1H);
4.84 (s, 2H); 6.93 (m, 1H); 7.10 (d, 1H1 J = 3.1 Hz); 7.21 (d, 1H, J = 5.1 Hz).
ESI/APCI(+): 283 (M+H); 305 (M+Na).
EXAMPLE 13: SYNTHESIS OF Λ/-(4-CHLOROBENZYL)-2-(4-ETHYL-2-
OXOMORPHOLIN-3-YL)ACETAMIDE (C20)
This compound was obtained according to the procedure of example 8 from 2-(4- ethyl-2-oxomorpholin-3-yl)acetic acid (0,497 mmol), HATU (0,418 mg; 1,099 mmol), diisopropylethylamine (0,258 mL; 1 ,477 mmol) and 4-chlorobenzylamine (0,079 mL;
0,649 mmol) in DMF (5 mL) to give 46 mg of desired product (30%).
1H NMR (CDCI3) δ 1.09 (t, 3H, J = 7.1 Hz); 2.5-2.9 (m, 6H); 3.57 (m, 2H); 4.05 (m, 1H); 4.63 (m, 2H); 7.2-7.3 (m, 4H). ESI/APCI(+): 311 (M+H); 333 (M+Na). ESI/APCI(-): 309 (M-H).
EXAMPLE 14: SYNTHESIS OF 2-(4-ETHYL-2-OXOMORPHOLIN-3-YL)-Λ/-(5- METHYLISOXAZOL-3-YL)ACETAMIDE (C21) This compound was obtained according to the procedure of example 8 from 2-(4- ethyi-2-oxomorpholin-3-yl)acetic acid (0,497 mmol), HATU (0,418 mg; 1,099 mmol), diisopropylethylamine (0,258 ml_; 1,477 mmol) and 3-amino-5-methylisoxazole (0,064 mg; 0,652 mmol) in DMF (5 mL) to give 14 mg of desired product (11%).
1H NMR (CDCI3) δ 1.15 (t, 3H1 J = 7.2 Hz); 2.39 (s, 3H); 2.46-2.58 (m, 1H); 2.66-2.80 (m, 1H); 2.87-2.97 (m, 2H); 3.10-3.21 (m, 2H); 3.53 (t, 1H, J = 4.3 Hz); 4.404.46 (m, 1H); 4.52-4.60 (m, 1H); 6.69 (s, 1H); 10.1 (brs, 1H). ESI/APCI(+): 268 (M+H); 290 (M+Na). ESI/APCI(-): 266 (M-H).
EXAMPLE 15: SYNTHESIS OF 2-(4-ETHYL^-OXOMORPHOLIN-S-YL)-N-(PYRIDIN-S- YL)ACETAMIDE (C22)
This compound was obtained according to the procedure of example 8 from 2-(4- ethyl-2-oxomorpholin-3-yl)acetic acid (0,497 mmol), HATU (0,418 mg; 1,099 mmol), diisopropylethylamine (0,258 mL; 1,477 mmol) and 3-aminopyridine (0,061 mg; 0,648 mmol) in DMF (5mL) to give 28 mg of desired product (21%).
ESI/APCI(+): 264 (M+H); 286 (M+Na). ESI/APCI(-): 262 (M-H).
EXAMPLE 16: SYNTHESIS OF 2-(4-ETHYL^-OXOMORPHOLIN-S-YL)-N-(I-METHYL- 1H-INDOL-5-YL)ACETAMIDE (C23)
This compound was obtained according to the procedure of example 8 from 2-(4- ethyl-2-oxomorpholin-3-yl)acetic acid (0,497 mmol), HATU (0,418 mg; 1,099 mmol), diisopropylethylamine (0,258 mL; 1,477 mmol) and 1-methyl-1H-indol-5-amine (0,095 mg; 0,650 mmol) in DMF (5 mL) to give 69 mg of desired product (44%).
1H NMR (CDCI3) δ 1.18 (t, 3H, J = 7.1 Hz); 2.7-3.0 (m, 5H); 3.03-3.12 (m, 1H); 3.66 (m, 2H); 3.81 (s, 3H); 4.25 (m, 1H); 6.50 (d, 1H, J = 3.5 Hz); 7.03 (dd, 1H, J = 1.9 Hz, J = 8.6 Hz), 7.10 (d, 1H1 J = 3.1 Hz); 7.38 (d, 1H, J = 8.7 Hz); 7.47 (d, 1H, J = 1.7 Hz). ESI/APCI(+): 316 (M+H); 338 (M+Na). ESI/APCI(-): 314 (M-H).
All other compounds of the invention can be prepared with the same procedures as described herein. Additional examples of such other compounds of present invention include:
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001

Claims

1. A compound having a structure according to the formula (I):
Figure imgf000056_0001
wherein:
- R1 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl;
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, aryl, heterocycle, arylalkyl, and heterocycle-alkyl, can each independently be substituted with one or more Rs; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S1 N=O, N=S, S=O, or S(O)2;
- each of R2 and R3 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and • wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, aryl, heterocycle, arylalkyl, and heterocycle-alkyl can each independently be substituted with one or more Rs; and • wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycioalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein R2 and R3 can be taken together in order to form a heterocycle which can be substituted with one or more Rs; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycioalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S1 N=O, N=S, S=O1 or S(O)2;
- each Rs is independently selected from halogen; hydroxyl; SR4; S(O)R5; S(O)2R5; SO2NR6R7; trifluoromethyl; nitro; NR6R7; cyano; COOR8; C(O)NR6R7; C(O)R5; alkyl; cycloalkyl; cyclalkyloxy; alkoxy; alkenyl; cycloalkenyl; cycoalkenyloxy; alkenyloxy; alkynyl; cycloalkynyl; cycloalkynyloxy; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycioalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; and heterocycle- oxy; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycioalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O1 S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycioalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O1 C=S1 N=O, N=S, S=O, or S(O)2;
- each R4 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycioalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and • wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycioalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkeπyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O1 C=S, N=O, N=S, S=O, or S(O)2;
- each R5 is independently selected from hydroxyl; alkyl; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; alkenyloxy; alkynyl; cycloalkynyl; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; and heterocycle-oxy; and
• wherein said alkyf, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O1 C=S1 N=O, N=S, S=O, or S(O)2; - each R6 and R7 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein Rβ and R7 can be taken together in order to form a (5-, 6-, or 7- membered) heterocycle which can be substituted or unsubstituted; and • wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S1 S=O, or S(O)2; - each R8 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2; and isomers, solvates, pharmaceutically acceptable salts or prodrugs thereof, and wherein said compound is NOT a compound having a structure according to the formula (I) wherein
- R1 is C6H5 and R2 is hydrogen and R3 is C6H5;
- R1 is ethyl and R2 is hydrogen and R3 is (i-methylethyl)phenyl;
- R1 is ethyl and R2 is hydrogen and R3 is 4-methylpheπyl;
- R1 is ethyl and R2 is hydrogen and R3 is 4-fluorophenyl; - R1 is phenylmethyl and R2 is hydrogen and R3 is 4-bromophenyl; or
- R1 is phenylmethyl and R2 is hydrogen and R3 is (i-methylethyl)phenyl.
2. The compound according to claim 1 wherein R1 is alkyl.
3. The compound according to claims 1 and 2 wherein R2 is hydrogen and R3 is selected from aryl; arylalkyl; heterocycle and heterocycle-alkyl; wherein said aryl, arylalkyl, heterocycle, and heterocycle-alkyl can be unsubstituted or substituted with one or more R8.
4. The compound according to claim 3 wherein Rs is independently selected from the list of halogen, hydroxyl, thiol, CF3, nitro, cyano, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy.
5. The compound according to claims 1 to 3 selected from the list of - N-(4-bromophenyl)-2-(4-ethyl-2-oxomoφholin-3-yl)acetamide; - 2-(4-ethyl-2-oxomoφholiπ-3-yl)-N-m-tolylacetamide; - N-(3-chlorophenyl)-2-(4-ethyi-2-oxomoφholin-3-yl)acetamide; - 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(4-nnethoxyphenyl)acetamide; - 2-(4-benzyl-2-oxomoφholin-3-yl)-N-(2,4-dibromophenyl)acetamide; - 2-(4-benzyl-3-oxomoφholin-2-yl)-N-(3-chlorophenyl)acetamide;
- 2-(4-ethyl-2-oxomθφholi n-3-yl)-N-(3-methoxyphenyl)acetamide; - 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(3-(trifIuoromethyl)phenyl)acetamide; - 2-(4-ethyl-2-oxomoφholin-3-yl)-N-o-tolylacetamide; - 2-(4-benzyl-2-oxomoφholin-3-yl)-N-(4-fluorophenyl)acetamide;
- 2-(4-benzyl-2-oxomoφholin-3-yl)-N-m-tolylacetamide;
- 2-(4-benzyl-2-oxomoφholin-3-yl)-N-(3-methoxyphenyI)acetamide;
- 2-(4-methyl-2-oxomoφholin-3-yl)-N-(4-(6-methyIbenzo[d]thiazol-2-yl)phenyi)acetamide;
- 2-(2-oxo-4-propylmoφholin-3-yl)-N-phenylac»tamide; - 2-(4-ethyl-2-oxomoφholin-3-y!)-N-(3,415-trimethoxyphenyl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(thiophen-2-ylmethyl)acetamide;
- N-(4-chlorobenzyl)-2-(4-ethyl-2-oxomoφholin-3-yl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(5-methylisoxazol-3-yl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(pyridin-3-yl)acetamide; and - 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(1 -methyl-1 H-indol-5-yl)acetamide.
6. A compound having a structure according to the formula (I):
Figure imgf000060_0001
wherein: - R1 is independently selected from hydrogen; alky]; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkyπyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl;
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, aryl, heterocycle, arylalkyl, and heterocycle-alkyl, can each independently be substituted with one or more Rs; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2;
- each of R2 and R3 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and • wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, aryl, heterocycle, arylalkyl, and heterocycle-alkyl can each independently be substituted with one or more Rs; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein R2 and R3 can be taken together in order to form a heterocycle which can be substituted with one or more Rs; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S1 S=O, or S(O)2; - each Rs is independently selected from halogen; hydroxyl; SR4; S(O)R5; S(O)2R5; SO2NR6R7; trifluoromethyl; nitro; NR6R7; cyano; COOR8; C(O)NR6R7; C(O)R5; alkyl; cycloalkyl; cyclalkyloxy; alkoxy; alkenyl; cycloalkenyl; cycoalkenyloxy; alkenyloxy; alkynyl; cycloalkynyl; cycloalkynyloxy; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; and heterocycle- oxy; and
• wherein said alkyl, alkenyi, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyi, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O1 S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyi, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2;
- each R4 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyi; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and • wherein said alkyl, alkenyi, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyi, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and • wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyi, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S1 N=O, N=S, S=O, or S(O)2;
- each R5 is independently selected from hydroxyl; alkyl; cycloalkyl; alkoxy; alkenyi; cycloalkenyl; alkenyloxy; alkynyl; cycloalkynyl; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; and heterocycle-oxy; and
• wherein said alkyl, alkenyi, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyi, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and • wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S1 N=O, N=S1 S=O, or S(O)2; - each R6 and R7 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein R6 and R7 can be taken together in order to form a (5-, 6-, or 7- membered) heterocycle which can be substituted or unsubstituted; and • wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O1 C=S, N=O, N=S, S=O1 or S(O)2;
- each R8 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O,
S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O1 C=S, N=O, N=S, S=O, or S(O)2; and isomers, solvates, pharmaceutically acceptable salts or prodrugs thereof, for use as a medicament.
7. The compound according to claim 6 wherein R1 is alkyl.
8. The compound according to claims 6 and 7 wherein R2 is hydrogen and R3 is selected from aryl; arylalkyl; heterocycle and heterocycle-alkyl; wherein said aryl, arylalkyl, heterocycle, and heterocycle-alkyl can be unsubstituted or substituted with one or more Rs.
9. The compound according to daim 8 wherein Rs is independently selected from the list of halogen, hydroxyl, thiol, CF3, nitro, cyano, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy.
10. The compound according to claims 6 to 8 selected from the list of - 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(4-isopropylphenyl)acetamide; - N-(4-bromophenyl)-2-(4-ethyl-2-oxomoφholin-3-yl)acetamide; - 2-(4-ethyl-2-oxomorpholin-3-yl)-N-m-tolylacetamide;
- 2-(4-ethyI-2-oxomorpholin-3-yl)-N-p-tolylacetamide;
- N-(3-chlorophenyl)-2-(4-ethyl-2-oxomorpholin-3-yl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(4-methoxyphenyl)acetamide;
- 2-(4-benzyl-2-oxomoφholin-3-yl)-N-(2,4-dibromophenyI)acetamide; - 2-(4-ethyl-2-oxomoφholiπ-3-yl)-N-(4-fluorophenyl)acetamide;
- 2-(4-ben2yl-3-oxomoφhoIin-2-yl)-N-(3-chlorophenyl)acetamide;
- 2-(4-ethyl-2-oxomorpholin-3-yl)-N-(3-methoxyphenyl)acetamide;
- 2-(4-ethyl-2-oxomθφhoIin-3-yl)-N-(3-(trifluoromethyl)phenyl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-o-tolylacetamide; - 2-(4-benzyl-2-oxomoφholin-3-yl)-N-(4-fluorophenyl)acetamide;
- 2-(4-benzyl-2-oxomoφholin-3-yl)-N-m-tolylacetamide;
- 2-(4-benzyl-2-oxomoφholin-3-yl)-N-(3-methoxyphenyl)acetamide;
- 2-(4-methyl-2-oxomoφholiπ-3-yl)-N-(4-(6-methylben2θ[d]thiazol-2-yl)phenyl)acetamide;
- 2-(2-oxo-4-propylmoφholin-3-yl)-N-phenylacetamide; - 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(thiophen-2-ylmethyl)acetamide;
- N-(4-chlorobenzyl)-2-(4-ethyl-2-oxomoφholin-3-yl)acetamide;
- 2-(4-ethyl-2-oxomoφholin-3-yl)-N-(5-methylisoxazol-3-yl)acetamide;
- 2-(4-ethyl-2-oxomorpholin-3-yl)-N-(pyridin-3-yl)acetamide; and - 2-(4-ethyl-2-oxomorpholin-3-yl)-N-(1-methyl-1H-indol-5-yl)acetamide.
11. The compound according to the claims 6 to 10 for use as a medicament for the prevention or treatment of a fungal infection in an animal or human.
12. The compound according to claim 11, wherein said fungal infection is caused by Candida species, Aspergillus species or Fusarium species.
13. The compound according to claim 12, wherein said fungal infection is a systemic infection.
14. The compound according to claim 12, wherein said fungal infection is a topical infection.
15. The use of a compound according to formula (I)
Figure imgf000065_0001
wherein:
- R1 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl;
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, aryl, heterocycle, arylalkyl, and heterocycle-alkyl, can each independently be substituted with one or more Rs; and • wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and • wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2; - each of R2 and R3 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, aryl, heterocycle, arylalkyl, and heterocycle-alkyl can each independently be substituted with one or more Rs; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O,
S and N; and
• wherein R2 and R3 can be taken together in order to form a heterocycle which can be substituted with one or more Rs; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2;
- each Rs is independently selected from halogen; hydroxyl; SR4; S(O)R5; S(O)2R5; SO2NR6R7; trifluoromethyl; nitro; NR6R7; cyano; COOR8; C(O)NR6R7; C(O)R5; alkyl; cycloalkyl; cyclalkyloxy; alkoxy; alkenyl; cycloalkenyl; cycoalkenyloxy; alkenyloxy; alkynyl; cycloalkynyl; cycloalkynyloxy; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; and heterocycle- oxy; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and • wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycfoalkynyl, cycloalkylaikyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S1 N=O, N=S1 S=O, or S(O)2; - each R4 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylaikyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylaikyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylaikyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S1 N=O, N=S, S=O, or S(O)2;
- each R5 is independently selected from hydroxy!; alkyl; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; alkeπyloxy; alkynyl; cycloalkynyl; alkynyloxy; cycloalkylaikyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; and heterocycle-oxy; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylaikyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl. alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylaikyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2; - each R6 and R7 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylaikyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and • wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein R6 and R7 can be taken together in order to form a (5-, 6-, or 7- membered) heterocycle which can be substituted or unsubstituted; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, aikenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2;
- each R8 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and • wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and • wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2; and isomers, solvates, pharmaceutically acceptable salts or prodrugs thereof, for the manufacture of a medicament.
16. The use of a compound according to claim 15 wherein said medicament is for the prevention or treatment of a fungal infection in an animal or mammal.
17. The use according to claim 16 wherein said fungal infection is caused by Candida species or Aspergillus species.
18. A pharmaceutical composition comprising a compound according to formula (I)
Figure imgf000069_0001
wherein:
- R1 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocyde; arylalkyl; and heterocycle-alkyl;
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, aryl, heterocyde, arylalkyl, and heterocycle-alkyl, can each independently be substituted with one or more Rs; and • wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cydoalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and • wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2;
- each of R2 and R3 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocyde; arylalkyl; and heterocycle-alkyl; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, aryl, heterocyde, arylalkyl, and heterocycle-alkyl can each independently be substituted with one or more Rs; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cydoalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein R2 and R3 can be taken together in order to form a heterocycle which can be substituted with one or more Rs; and • wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, Or S(O)2;
- each Rs is independently selected from halogen; hydroxyl; SR4; S(O)R5; S(O)2R5; SO2NR6R7; trifluoromethyl; πitro; NR6R7; cyano; COOR8; C(O)NR6R7; C(O)R5; alkyl; cycloalkyl; cyclalkyloxy; alkoxy; alkenyl; cycloalkenyl; cycoalkenyloxy; alkenyloxy; alkynyl; cycloalkynyl; cycloalkynyloxy; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; and heterocycle- oxy; and • wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and • wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2;
- each R4 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O,
S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2;
- each R5 is independently selected from hydroxyl; alkyl; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; alkenyloxy; alkynyl; cycloalkynyl; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; and heterocycle-oxy; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O,
S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O1 N=S, S=O, or S(O)2;
- each R6 and R7 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein Rβ and R7 can be taken together in order to form a (5-, 6-, or 7- membered) heterocycle which can be substituted or uπsubstituted; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2; - each R8 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and • wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkeπyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O,
S S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, Or S(O)2; 0 and isomers, solvates, pharmaceutically acceptable salts or prodrugs thereof, as an active ingredient in admixture with at least a pharmaceutically acceptable carrier.
19. A pharmaceutical composition according to claim 18 having antifungal activity.
20. A method to treat or to prevent a fungal infection in an animal or mammal, comprising administering to the animal or mammal in need of such treatment a therapeutically effective amount of a compound according to formula (I)
Figure imgf000072_0001
wherein: - R1 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl;
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, aryl, heterocycle, arylalkyl,5 and heterocycle-alkyl, can each independently be substituted with one or more
Rs; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyf, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S1 N=O, N=S, S=O1 or S(O)2;
- each of R2 and R3 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and • wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, aryl, heterocycle, arylalkyl, and heterocycle-alkyl can each independently be substituted with one or more Rs; and
• wherein said alkyl,' alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein R2 and R3 can be taken together in order to form a heterocycle which can be substituted with one or more Rs; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2; - each Rs is independently selected from halogen; hydroxyl; SR4; S(O)R5; S(O)2R5;
SO2NR6R7; trifluoromethyl; nitro; NR6R7; cyano; COOR8; C(O)NR6R7; C(O)R5; alkyl; cycloalkyl; cyclalkyloxy; alkoxy; alkenyl; cycloalkenyl; cycoalkenyloxy; alkenyloxy; alkynyl; cycloalkynyl; cycloalkynyloxy; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; and heterocycle- oxy; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O1 S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2;
- each R4 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and • wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and • wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, Or S(O)2;
- each R5 is independently selected from hydroxyl; alkyl; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; alkenyloxy; alkynyl; cycloalkynyl; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; and heterocycle-oxy; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O1 S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl. cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S1 N=O, N=S, S=O, or S(O)2;
- each R6 and R7 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and • wherein said alky!, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- aikyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein R6 and R7 can be taken together in order to form a (5-, 6-, or 7- membered) heterocycle which can be substituted or unsubstituted; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S1 S=O, or S(O)2;
- each R8 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and • wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and • wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O1 N=S, S=O, or S(O)2; and isomers, solvates, pharmaceutically acceptable salts or prodrugs thereof.
21. A method for the preparation of the compound according to formula (I)
Figure imgf000075_0001
wherein: - R1 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl;
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, aryl, heterocycle, arylalkyl, and heterocycle-alkyl, can each independently be substituted with one or more Rs; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2;
- each of R2 and R3 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and • wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, aryl, heterocycle, arylalkyl, and heterocycle-alkyl can each independently be substituted with one or more Rs; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein R2 and R3 can be taken together in order to form a heterocycle which can be substituted with one or more Rs; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O1 C=S1 N=O, N=S, S=O, or S(O)2;
- each Rs is independently selected from halogen; hydroxyl; SR4; S(O)R5; S(O)2R5; SO2NR6R7; trifluoromethyl; nitro; NR6R7; cyano; COOR8; C(O)NR6R7; C(O)R5; alkyl; cycloalkyl; cyclalkyloxy; alkoxy; alkenyl; cycloalkenyl; cycoalkenyloxy; alkenyloxy; alkynyl; cycloalkynyl; cycloalkynyloxy; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; and heterocycle- oxy; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycfoalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, Or S(O)2;
- each R4 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, OrS(O)2; - each R5 is independently selected from hydroxyl; alkyl; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; alkenyloxy; alkynyl; cycloalkynyl; alkynyloxy; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; heterocycle-alkyl; aryloxy; and heterocycle-oxy; and • wherein said alky), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkeπylalkyl, cycloalkynylalkyl, aryfalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, or S(O)2; - each R6 and R7 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O, S and N; and
• wherein R6 and R7 can be taken together in order to form a (5-, 6-, or 7- membered) heterocycle which can be substituted or unsubstituted; and • wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S, N=O, N=S, S=O, Or S(O)2;
- each R8 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; aryl; heterocycle; arylalkyl; and heterocycle-alkyl; and
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle- alkyl can contain a heteroatom in or at the end of their alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety, said heteroatom selected from O,
S and N; and
• wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, arylalkyl, and heterocycle-alkyl can be taken together to form a C=O, C=S1 N=O, N=S, S=O, OrS(O)2; and isomers, solvates, pharmaceutically acceptable salts or prodrugs thereof, comprising the steps of: 1) Hydrolysing of an N-substituted or unsubstituted morpholin-2-one-3-acetate ester under acidic or basic conditions leading to the free carboxylic acid; and 2) Coupling said free carboxylic acid with an appropriated amine in the presence of a coupling agent.
22. The method according to claim 21 comprising, prior to step 1 , the following steps: i) Condensating an N-substituted-ethanolamine with an alpha halogen acetate ester in the presence of a base to obtain an N-substituted-2-(2-hydroxyethylamino)acetate ester; ii) Obtaining an N-substituted-morpholin-2-one by intramolecular lactonisation of said N- substituted-2-(2-hydroxyethylamino)acetate ester in acidic medium; and iii) Condensating said N-substituted-morpholin-2-one with an alpha halogen acetate ester in the presence of a base.
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