WO2012084804A1 - NOVEL ANTIFUNGAL 5,6-DIHYDRO-4H-PYRROLO[1,2-a][1,4]- BENZODIAZEPINES AND 6H-PYRROLO[1,2-a][1,4]BENZODIAZEPINES SUBSTITUTED WITH BICYCLIC BENZENE DERIVATIVES - Google Patents

NOVEL ANTIFUNGAL 5,6-DIHYDRO-4H-PYRROLO[1,2-a][1,4]- BENZODIAZEPINES AND 6H-PYRROLO[1,2-a][1,4]BENZODIAZEPINES SUBSTITUTED WITH BICYCLIC BENZENE DERIVATIVES Download PDF

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Publication number
WO2012084804A1
WO2012084804A1 PCT/EP2011/073215 EP2011073215W WO2012084804A1 WO 2012084804 A1 WO2012084804 A1 WO 2012084804A1 EP 2011073215 W EP2011073215 W EP 2011073215W WO 2012084804 A1 WO2012084804 A1 WO 2012084804A1
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Prior art keywords
pyrrolo
dihydro
formula
spp
compound
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PCT/EP2011/073215
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French (fr)
Inventor
Lieven Meerpoel
Louis Jules Roger Marie Maes
Kelly De Wit
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Janssen Pharmaceutica Nv
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Priority to CA2818623A priority Critical patent/CA2818623C/en
Priority to KR1020137019234A priority patent/KR101839365B1/en
Priority to EP11802072.6A priority patent/EP2668187B1/en
Priority to ES11802072.6T priority patent/ES2527032T3/en
Priority to MX2013007166A priority patent/MX2013007166A/en
Priority to US13/995,526 priority patent/US9040524B2/en
Priority to EA201390921A priority patent/EA022407B1/en
Application filed by Janssen Pharmaceutica Nv filed Critical Janssen Pharmaceutica Nv
Priority to JP2013545254A priority patent/JP5918258B2/en
Priority to AU2011347577A priority patent/AU2011347577B2/en
Priority to SG2013042643A priority patent/SG190971A1/en
Priority to AP2013006886A priority patent/AP4012A/en
Priority to UAA201306467A priority patent/UA109796C2/en
Priority to CN201180061514.2A priority patent/CN103282367B/en
Priority to NZ610939A priority patent/NZ610939A/en
Priority to BR112013016007A priority patent/BR112013016007A2/en
Publication of WO2012084804A1 publication Critical patent/WO2012084804A1/en
Priority to IL227053A priority patent/IL227053A/en
Priority to ZA2013/04577A priority patent/ZA201304577B/en
Priority to HK14102027.7A priority patent/HK1188792A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention is concerned with novel antifungal 5,6-dihydro-4H-pyrrolo- [l,2-a][l,4]benzodiazepines and 6H-pyrrolo[l,2-a][l,4]benzodiazepines, both substituted with bicyclic benzene derivatives, active mainly against dermatophytes and systemic fungal infections.
  • the invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
  • Dermatophyte is a common label for a group of 3 types of fungi that commonly causes skin disease in animals and humans. These anamorphic (asexual or imperfect fungi) genera are: Microsporum, Epidermophyton and Trichophyton. There are about 40 species in these 3 genera.
  • Dermatophytes cause infections of the skin, hair and nails due to their ability to obtain nutrients from keratinized material.
  • the organisms colonize the keratin tissues and inflammation is caused by host response to metabolic by-products. They are usually restricted to the cornified layer of the epidermis because of their inability to penetrate viable tissue of an immunocompetent host. However, occasionally the organisms do invade subcutaneous tissues, resulting in kerion development. Invasion does elicit a host response ranging from mild to severe. Acid proteinases, elastase, keratinases, and other proteinases reportedly act as virulence factors.
  • SFI Systemic fungal infections
  • posaconazole shows much improvement of treatment towards life threatening invasive SFI such as candidiasis, aspergillosis, and infections due to Fusarium species at clinical relevant dosages.
  • posaconazole shows efficacy against infections caused by the emerging Zygomycetes spp.
  • Echinocandins such as anidulafungin, caspofungin, and micafungin, which are non-competitive inhibitors of l,3- -glucan synthesis in fungal cell walls, display high efficacy against Candida spp. and Aspergillus spp., but no activity against Cryptococcus, Fusarium, or Zygomycetes spp..
  • azoles still represent a unique class of compounds displaying the broadest antifungal spectrum via inhibition of 14-a- demethylase, an enzyme being essential for ergosterol biosynthesis in fungi.
  • Onychomycosis is the most common disease of the nails and constitutes about a half of all nail abnormalities. The prevalence of onychomycosis is about 6-8 % in the adult population. The causative pathogens of onychomycosis include dermatophytes,
  • Candida and non-dermatophytic moulds. Dermatophytes are the fungi most commonly responsible for onychomycosis in the temperate western countries; meanwhile, Candida and non-dermatophytic moulds are more frequently involved in the tropics and subtropics. Trichophyton rubrum is the most common dermatophyte involved in onychomycosis. Other dermatophytes that may be involved are Trichophyton interdigitale, Epidermophyton floccosum, Trichophyton violaceum, Microsporum gypseum, Trichophyton tonsurans, Trichophyton soudanense and Trichophyton verrucosum. Other causative pathogens include Candida and non-dermatophytic moulds, in particular members of the mould generation Scytalidium (also
  • Neoscytalidium the Neoscytalidium
  • Scopulariopsis Scopulariopsis
  • Aspergillus the Neoscytalidium
  • WO02/34752 describes 4-substituted 5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepines as a new class of antifungal compounds. However, WO02/34752 does not disclose the present substitution pattern on the phenyl moiety in the 4-position.
  • antifungal compounds of the present invention or part of the compounds of the present invention are structurally different and may have improved potency, improved metabolic stability properties, improved solubility, improved plasma binding, reduced hERG channel inhibition, reduced cytochrome P450 liabilities, or improved
  • bioavailability compared with compounds disclosed in the prior art.
  • said compounds Preferably have a broad antifungal spectrum, and maintain adequately high
  • the present invention concerns novel compounds of Formula (I):
  • R 1 is hydrogen, halo, Ci- 4 alkyl or Ci- 4 alkyloxy
  • R 2 is hydrogen or halo
  • R 3 and R 4 are hydrogen; or R 3 and R 4 taken together form a bond;
  • R 5 is hydrogen or Ci- 4 alkyloxy
  • R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula:
  • bivalent radical -R 6 -R 7 - may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl, hydroxyl,
  • Y 1 represents O, R 8a or S
  • Y 2a and Y 2b each independently represent O, R 8b or S;
  • R 8a represents hydrogen or Ci- 4 alkyl
  • R represents hydrogen or Ci- 4 alkyl
  • n 0, 1 or 2;
  • n 2, 3 or 4;
  • s 3, 4 or 5;
  • t 1, 2 or 3;
  • r represents 0 or 1 ;
  • q 0 or 1 ;
  • the compound is not 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[l,2-a][l,4]benzodiazepine or 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine .HQ .
  • the present invention also concerns methods for the preparation of compounds of Formula (I) and pharmaceutical compositions comprising them.
  • the present compounds are useful agents for combating fungi in vivo.
  • novel compounds described in the present invention may be useful in the treatment or prevention of infections caused by dermatophytes, systemic fungal infections and onychomycosis.
  • novel compounds described in the present invention may be active against a wide variety of fungi, such as Candida spp., e.g. Candida albicans, Candida glabrata, Candida krucei ' , Candida parapsilosis, Candida kefyr, Candida tropicalis; Aspergillus spp., e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum spp., e.g.
  • Microsporum canis Microsporum gypseum
  • Trichophyton spp. e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum, Trichophyton tonsurans, Trichophyton verrucosum, Trichophyton violaceum, Trichophyton inter digitale, Trichophyton soudanense
  • Fusarium spp. e.g. Fusarium solani
  • Rhizomucor spp. e.g. Rhizomucor miehei, Rhizomucor pusillus; Mucor circinelloides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Malassezia furfur; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.; Scytalidium; Scedosporium spp., e.g. Scedosporium apiospermum, Scedosporium prolificans; Trichoderma spp.; Penici Ilium spp. ; Penici Ilium marneffei; Blastoschizomyces.
  • the invention also relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable addition salts and the solvates thereof, for use in the treatment or prevention of fungal infections.
  • One advantage of the compounds or a part of the compounds of the present invention may lie in their enhanced bioavailability, improved metabolic stability properties, improved PK properties, reduced hERG channel inhibition, or reduced cytochrome P450 liabilities compared with the compounds disclosed in the prior art.
  • substituted is used in the present invention, it is meant, unless otherwise is indicated or is clear from the context, to indicate that one or more hydrogens, in particular from 1 to 4 hydrogens, preferably from 1 to 3 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using
  • substituted are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
  • halo or halogen as a group or part of a group is generic for fluoro, chloro, bromo, iodo unless otherwise is indicated or is clear from the context.
  • Ci- 4 alkyl refers to a hydrocarbyl radical of Formula C n H 2n+ i wherein n is a number ranging from 1 to 4.
  • Ci- 4 alkyl groups comprise from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, still more preferably 1 to 2 carbon atoms.
  • Alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain.
  • Ci- 4 alkyl includes all linear, or branched alkyl groups with between 1 and 4 carbon atoms, and thus includes such as for example methyl, ethyl, ⁇ -propyl, i- propyl, 2-methyl-ethyl, butyl and its isomers (e.g. «-butyl, zsobutyl and tert-butyl), and the like.
  • Ci- 4 alkyloxy refers to a radical having the Formula -OR a wherein R a is Ci- 4 alkyl.
  • suitable radicals having the Formula -OR a wherein R a is Ci- 4 alkyl.
  • Ci- 4 alkyloxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy and tert-butyloxy.
  • pharmaceutically acceptable addition salts and solvates may contain one or more centers of chirality and exist as stereoisomeric forms.
  • stereoisomeric forms as used hereinbefore defines all the possible isomeric forms that the compounds of Formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms.
  • compound of formula (I) inherently includes all stereoisomers of the compound of formula (I) either as a pure stereoisomer or as a mixture of two or more stereoisomers.
  • Enantiomers are stereoisomers that are non-superimposable mirror images of each other.
  • a 1 : 1 mixture of a pair of enantiomers is a racemate or racemic mixture.
  • Diastereomers or diastereoisomers
  • stereoisomers are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration.
  • the absolute configuration is specified according to the Cahn-Ingold-Prelog system.
  • the configuration at an asymmetric atom is specified by either R or S.
  • Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • a compound of the present invention is for instance specified as (R)
  • E when a compound of the present invention is for instance specified as E, this means that the compound is substantially free of the Z isomer
  • a compound of the present invention is for instance specified as cis, this means that the compound is substantially free of the trans isomer.
  • salts of the compounds of Formula (I) are those wherein the counterion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether
  • the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of Formula (I) are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • salt forms can be converted by treatment with an appropriate base into the free base form.
  • the compounds of Formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g.
  • the salt form can be converted by treatment with acid into the free acid form.
  • solvate comprises the hydrates and solvent addition forms which the compounds of Formula (I) are able to form, as well as the salts thereof. Examples of such forms are e.g. hydrates, alcoholates and the like.
  • the compounds of Formula (I) as prepared in the processes described below may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers that can be separated from one another following art-known resolution procedures.
  • a manner of separating the enantiomeric forms of the compounds of Formula (I) involves liquid chromatography using a chiral stationary phase.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • a compound according to the invention is inherently intended to comprise all isotopic combinations of its chemical elements.
  • a chemical element in particular when mentioned in relation to a compound according to Formula (I), comprises all isotopes and isotopic mixtures of this element.
  • hydrogen when hydrogen is mentioned, it is understood to refer to 1H, 2 H, 3 H and mixtures thereof.
  • a compound according to the invention therefore inherently comprises a compound with one or more isotopes of one or more element, and mixtures thereof, including a radioactive compound, also called radiolabelled compound, wherein one or more nonradioactive atoms has been replaced by one of its radioactive isotopes.
  • radiolabelled compound is meant any compound according to Formula (I), or a pharmaceutically acceptable salt thereof, which contains at least one radioactive atom.
  • a compound can be labelled with positron or with gamma emitting radioactive isotopes.
  • the 3 H-atom or the 125 I-atom is the atom of choice to be replaced.
  • radioactive isotopes are C, F, O and N, all of which are accelerator produced and have half-lives of 20, 100, 2 and 10 minutes respectively. Since the half-lives of these radioactive isotopes are so short, it is only feasible to use them at institutions which have an accelerator on site for their production, thus limiting their use. The most widely used of these are 18 F, 99m Tc, 201 T1 and 123 I. The handling of these radioactive isotopes, their production, isolation and incorporation in a molecule are known to the skilled person.
  • the radioactive atom is selected from the group of hydrogen, carbon, nitrogen, sulfur, oxygen and halogen.
  • the radioactive isotope is selected from the group of 3 ⁇ 4 U C, 18 F, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and
  • a compound means one compound or more than one compound.
  • the present invention concerns novel compounds of Formula (I):
  • R 1 is hydrogen, halo, Ci- 4 alkyl or Ci- 4 alkyloxy
  • R 2 is hydrogen or halo
  • R 3 and R 4 are hydrogen
  • substituents selected from the group consisting of halo, Ci- 4 alkyl, hydroxyl, Ci- 4 alkyloxy and oxo;
  • Y 1 represents O, R 8a or S
  • Y 2a and Y 2b each independently represent O, R 8b or S;
  • R a represents hydrogen or Ci- 4 alkyl;
  • R represents hydrogen or Ci- 4 alkyl
  • n 0, 1 or 2;
  • n 2, 3 or 4;
  • s 3, 4 or 5;
  • t 1, 2 or 3;
  • r represents 0 or 1 ;
  • q 0 or 1 ;
  • the compound is not 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[l,2-a][l,4]benzodiazepine or 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine .HC1.
  • the invention relates to compounds of Formula (I) and
  • R 1 is halo, Ci- 4 alkyl or Ci- 4 alkyloxy; in particular wherein R 1 is halo;
  • R 2 is hydrogen or halo
  • R 3 and R 4 are hydrogen
  • R 5 is hydrogen or Ci- 4 alkyloxy
  • R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula:
  • bivalent radical -R 6 -R 7 - may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl, hydroxyl,
  • Y 1 represents O, R 8a or S
  • Y 2a and Y 2b each independently represent O, R 8b or S;
  • R 8a represents hydrogen or Ci- 4 alkyl
  • R represents hydrogen or Ci- 4 alkyl
  • n 0, 1 or 2;
  • n 2, 3 or 4;
  • s 3, 4 or 5;
  • t 1, 2 or 3;
  • the invention relates to compounds of Formula (I) and
  • R 1 is halo, Ci- 4 alkyl or Ci- 4 alkyloxy; in particular wherein R 1 is halo;
  • R 2 is hydrogen or halo
  • R 3 and R 4 are hydrogen
  • R 5 is hydrogen or Ci- 4 alkyloxy
  • R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula:
  • bivalent radical -R 6 -R 7 - having formula (a), (b), (c) or (e) may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl, hydroxyl, Ci- 4 alkyloxy and oxo;
  • bivalent radical -R 6 -R 7 - having formula (d) is substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl, hydroxyl,
  • Y 1 represents O, R 8a or S
  • Y 2a and Y 2b each independently represent O, R 8b or S;
  • R 8a represents hydrogen or Ci- 4 alkyl
  • R represents hydrogen or Ci- 4 alkyl
  • n 0, 1 or 2;
  • n 2, 3 or 4;
  • s 3, 4 or 5;
  • t 1, 2 or 3;
  • r represents 0 or 1 ;
  • q 0 or 1 ;
  • the invention relates to compounds of Formula (I) and stereoisomeric forms thereof, wherein
  • R 1 is hydrogen, halo, Ci- 4 alkyl or Ci- 4 alkyloxy
  • R 2 is hydrogen or halo;
  • R 3 and R 4 are hydrogen;
  • R 5 is hydrogen or Ci- 4 alkyloxy
  • R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula:
  • bivalent radical -R 6 -R 7 - may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl and oxo;
  • Y 1 represents O or R 8a ;
  • Y 2a and Y 2b each independently represent O or R 8b ;
  • R 8a represents hydrogen or Ci- 4 alkyl; in particular R 8a represents hydrogen;
  • R 8b represents hydrogen or Ci- 4 alkyl; in particular R 8b represents hydrogen;
  • n 0, 1 or 2;
  • n 2 or 3;
  • s 3 or 4;
  • t 1 ;
  • the compound is not 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[l,2-a][l,4]benzodiazepine or 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine .HQ .
  • the invention relates to compounds of Formula (I) and stereoisomeric forms thereof, wherein
  • R 1 is hydrogen, halo, Ci- 4 alkyl or Ci- 4 alkyloxy
  • R 2 is hydrogen or halo
  • R 3 and R 4 are hydrogen
  • R 5 is hydrogen or Ci- 4 alkyloxy
  • R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula:
  • bivalent radical -R 6 -R 7 - having formula (a), (b) or (c) may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl and oxo;
  • bivalent radical -R 6 -R 7 - having formula (d) is substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl and oxo;
  • Y 1 represents O or R 8a ;
  • Y a and Y each independently represent O or R ;
  • R 8a represents hydrogen or Ci- 4 alkyl; in particular R 8a represents hydrogen;
  • R 8b represents hydrogen or Ci- 4 alkyl; in particular R 8b represents hydrogen;
  • n 0, 1 or 2;
  • n 2 or 3;
  • s 3 or 4;
  • t 1 ;
  • the invention relates to compounds of Formula (I) and
  • R 1 is hydrogen, halo, Ci- 4 alkyl or Ci- 4 alkyloxy
  • R 2 is hydrogen or halo
  • R 3 and R 4 are hydrogen
  • R 5 is hydrogen or Ci- 4 alkyloxy
  • R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula:
  • bivalent radical -R 6 -R 7 - having formula (a), (b), (c) or (e) may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl, hydroxyl, Ci- 4 alkyloxy and oxo;
  • bivalent radical -R 6 -R 7 - having formula (d) is substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl, hydroxyl, Ci- 4 alkyloxy and oxo;
  • Y 1 represents O, R 8a or S
  • Y 2a and Y 2b each independently represent O, R 8b or S;
  • R 8a represents hydrogen or Ci- 4 alkyl
  • R represents hydrogen or Ci- 4 alkyl
  • n 0, 1 or 2;
  • n 2, 3 or 4;
  • s 3, 4 or 5;
  • t 1, 2 or 3;
  • r represents 0 or 1 ;
  • q represents 0 or 1 ; provided that at least one of r and q is 1;
  • the invention relates to compounds of Formula (I) and
  • R 1 is hydrogen, halo or Ci- 4 alkyloxy; in particular hydrogen, chloro, fluoro or methoxy;
  • R 2 is hydrogen or halo; in particular hydrogen, chloro or fluoro;
  • R 3 and R 4 are hydrogen
  • R 5 is hydrogen or Ci- 4 alkyloxy; in particular hydrogen, methoxy or ethoxy;
  • R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula:
  • bivalent radical -R 6 -R 7 - may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl and oxo; in particular fluoro, methyl and oxo;
  • Y 1 represents O or H
  • Y 2a represents O
  • Y 2b represent O or NH
  • n 0, 1 or 2;
  • n 2 or 3;
  • s 3 or 4;
  • t 1 ;
  • the compound is not 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[l,2-a][l,4]benzodiazepine or 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine .HQ .
  • the invention relates to compounds of Formula (I) and
  • R 1 is hydrogen, halo or Ci- 4 alkyloxy; in particular hydrogen, chloro, fluoro or methoxy;
  • R 2 is hydrogen or halo; in particular hydrogen, chloro or fluoro;
  • R 3 and R 4 are hydrogen
  • R 5 is hydrogen or Ci- 4 alkyloxy; in particular hydrogen, methoxy or ethoxy;
  • R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula:
  • bivalent radical -R 6 -R 7 - having formula (a) or (c) may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl and oxo; in particular fluoro, methyl and oxo;
  • bivalent radical -R 6 -R 7 - having formula (d) is substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl and oxo; in particular halo; more in particular fluoro;
  • Y 1 represents O or H
  • Y 2a represents O
  • Y 2b represent O or NH
  • n 0, 1 or 2;
  • n 2 or 3;
  • s 3 or 4;
  • t 1 ;
  • the invention relates to compounds of Formula (I) and
  • R 1 is halo; in particular chloro or fluoro
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen; or R 3 and R 4 taken together form a bond; in particular R 3 and R 4 are taken together to form a bond;
  • R 5 is hydrogen
  • R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula:
  • bivalent radical -R 6 -R 7 - may, where possible, be substituted with one or more substituents selected from the group consisting of halo and oxo; in particular halo; m represents 0 or 1;
  • n 3;
  • s 3 or 4;
  • the invention relates to compounds of Formula (I) and
  • R 1 is halo; in particular chloro or fluoro
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen; or R 3 and R 4 taken together form a bond; in particular R 3 and R 4 are taken together to form a bond;
  • R 5 is hydrogen
  • R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula:
  • bivalent radical -(CH 2 ) m -0-(CH 2 ) n-m - or -(CH 2 ) S - may, where possible, be substituted with one or more substituents selected from the group consisting of halo and oxo; in particular halo;
  • bivalent radical -0-CH 2 -0- is substituted with one or more substituents selected from the group consisting of halo and oxo; in particular halo; more in particular fluoro;
  • n 0 or 1
  • n 3;
  • s 3 or 4;
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein the bivalent radical -R 6 -R 7 - when having formula (d) is always substituted with one or more substituents selected from the group consisting of halo, C ⁇ alkyl and oxo; in particular halo; more in particular fluoro.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 3 and R 4 are hydrogen.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 3 and R 4 are taken together to form a bond.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 5 is hydrogen.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 1 is halo.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 1 is halo, Ci- 4 alkyl or Ci- 4 alkyloxy.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 2 is halo.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 1 is halo, and R 3 and R 4 are taken together to form a bond.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 1 is halo and is in the 7-position, and R 3 and R 4 are taken together to form a bond.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 2 is hydrogen.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 1 is halo and R 2 is hydrogen.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 1 is halo and is in the 9-position; in particular wherein R 1 is chloro or fluoro and is in the 9- position; more in particular wherein R 1 is chloro and is in the 9-position.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 1 is halo and is in the 7-position; in particular wherein R 1 is chloro or fluoro and is in the 7- position; more in particular wherein R 1 is chloro and is in the 7-position.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments
  • R 1 is halo and is in the 7-position, and R 2 is hydrogen;
  • R 1 is chloro or fluoro and is in the 7-position, and R 2 is hydrogen; more in particular wherein R 1 is chloro and is in the 7-position, and R 2 is hydrogen.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments
  • R 1 is halo and is in the 7-position, and R 2 is hydrogen or halo and is in the 9- position; in particular wherein R 1 is chloro or fluoro and is in the 7-position, and R 2 is hydrogen, chloro or fluoro and is in the 9-position;
  • R 1 is chloro and is in the 7-position
  • R 2 is hydrogen or chloro and is in the 9-position
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments
  • R 1 is halo and is in the 7-position
  • R 2 is hydrogen
  • R 3 and R 4 are taken together to form a bond
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments
  • R 1 is chloro and is in the 7-position
  • R 2 is hydrogen
  • R 3 and R 4 are taken together to form a bond
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula (a), (b), (c) or (d), in particular having formula (a), (c) or (d), wherein said bivalent radical -R 6 -R 7 - may, where possible, be substituted according to any of the other embodiments.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula (a), (b), (c) or (e), in particular having formula (a), (b) or (c), wherein said bivalent radical -R 6 -R 7 - may, where possible, be substituted according to any of the other embodiments.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula (a) or (b), wherein said bivalent radical -R 6 -R 7 - may, where possible, be substituted according to any of the other embodiments.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula (c), wherein said bivalent radical -R 6 -R 7 - may, where possible, be substituted according to any of the other embodiments.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula (d) or (e), in particular having formula (d), wherein said bivalent radical -R 6 -R 7 - may, where possible, be substituted according to any of the other embodiments.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 6 and R taken together form a bivalent radical -R 6 -R 7 -, having formula (d); wherein said bivalent radical -R 6 -R 7 - may, where possible, be substituted according to any of the other embodiments;
  • t represents 1 ; and wherein Y 2a and Y 2b each independently represents O or R 8b , in particular wherein Y 2a and Y 2b represent O.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 6 and R taken together form a bivalent radical -R 6 -R 7 -, having formula
  • bivalent radical -(CH 2 ) m -Y 1 -(CH 2 ) n-m -, -(CH 2 ) n-m -Y 1 -(CH 2 ) m -, or -(CH 2 ) S - may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl, hydroxyl, Ci- 4 alkyloxy and oxo;
  • Y 1 represents O, R 8a or S
  • R 8a represents hydrogen or Ci- 4 alkyl
  • n 0, 1 or 2;
  • n 2, 3 or 4;
  • s 3, 4 or 5.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 6 and R taken together form a bivalent radical -R 6 -R 7 -, having formula
  • bivalent radical -(CH 2 ) m -Y 1 -(CH 2 ) n-m -, -(CH 2 ) n-m -Y 1 -(CH 2 ) m -, or -(CH 2 ) S - may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl, hydroxyl, Ci- 4 alkyloxy and oxo;
  • Y 1 represents O, R 8a or S
  • R 8a represents hydrogen or Ci- 4 alkyl
  • n 0, 1 or 2;
  • n 2, 3 or 4;
  • s represents 3, 4 or 5.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula:
  • bivalent radical -R 6 -R 7 - may, where possible, be substituted with one or more substituents selected from the group consisting of halo and oxo.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula:
  • bivalent radical -(CH 2 ) m -0-(CH 2 ) n-m - or -(CH 2 ) S - may, where possible, be substituted with one or more substituents selected from the group consisting of halo and oxo; and wherein the bivalent radical -0-CH 2 -0- is substituted with one or more substituents selected from the group consisting of halo and oxo.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein m represents 0, 1 or 2; n represents 2 or 3; s represents 3 or 4; t represents 1; r represents 0 or 1; q represents 0 or 1; provided that exactly one of q and r represents 0 and the other one represents 1.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula:
  • bivalent radical -R 6 -R 7 - may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl, hydroxyl, Ci- 4 alkyloxy and oxo;
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, having formula:
  • bivalent radical -R 6 -R 7 - having formula (a), (b) or (c) may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl, hydroxyl, Ci- 4 alkyloxy and oxo;
  • bivalent radical -R 6 -R 7 - having formula (d) is substituted with one or more substituents selected from the group consisting of halo, Ci- 4 alkyl, hydroxyl, Ci- 4 alkyloxy and oxo;
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 -, wherein -R 6 -R 7 - is selected from the group consisting of -0-CH 2 -0- and -0-CF 2 -0-; in particular wherein -R 6 -R 7 - is -0-CF 2 -0-
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 6 and R 7 taken together form a bivalent radical -R 6 -R 7 - having the formula -0-CH 2 -0-, wherein -0-CH 2 -0- may be substituted with one or two substituents selected from the group consisting of halo, Ci- 4 alkyl, hydroxyl, Ci- 4 alkyloxy and oxo; in particular halo and Ci- 4 alkyl.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 6 and R taken together form a bivalent radical -R 6 -R 7 - having the formula -0-CH 2 -0-, wherein -0-CH 2 -0- is substituted with one or two substituents selected from the group consisting of halo, Ci- 4 alkyl, hydroxyl, Ci- 4 alkyloxy and oxo; in particular halo and Ci- 4 alkyl; more in particular halo; even more in particular fluoro.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 6 and R when representing a bivalent radical of formula (d), is always substituted with a substituent as defined in any of the other embodiments.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R 8a and R represent hydrogen.
  • An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein Y 2a and Y 2b represent O.
  • the compound of Formula (I) is selected from the group consisting of:
  • the compound of Formula (I) is selected from the group consisting of:
  • the compound of Formula (I) is selected from the group consisting of:
  • the present invention also encompasses processes for the preparation of compounds of Formula (I) and subgroups thereof.
  • the compounds of Formula (I) and the subgroups thereof can be prepared by a succession of steps as described hereunder. They are generally prepared from starting materials which are either commercially available or prepared by standard means obvious to those skilled in the art.
  • the compounds of the present invention can be also prepared using standard synthetic processes commonly used by those skilled in the art of organic chemistry.
  • dichloromethane DCM
  • trichloromethane trichloromethane
  • a compound of formula (I-b) can be prepared by an intramolecular cyclization of an intermediate of formula (II).
  • an acid such as, for example, POCl 3
  • the amide in the intermediate of formula (II) can function as a C- electrophile, resulting in a ring closure.
  • the reaction may be performed in a suitable solvents such as, for example, DCM (CH 2 CI 2 ). Stirring and heating may enhance the rate of the reaction.
  • a compound of formula (I-a) can be prepared from an intermediate of formula (IV) by converting it in a salt (III) by reaction with an acid H + X " of formula (XI), and reacting said salt of formula (III) with an aldehyde of formula (XII) in an appropriate solvent such as an alcohol, e.g. methanol (MeOH), ethanol (EtOH), isopropanol, at an elevated temperature, preferably at reflux temperature.
  • an alcohol e.g. methanol (MeOH), ethanol (EtOH), isopropanol
  • the intermediate of formula (IV) may be reacted first with the aldehyde of formula (XII) and the thus formed imine may be cyclized in the presence of an acid H + X " of formula (XI) to a compound of formula (I-a).
  • a compound of formula (I-a) may be obtained by the reduction of a compound of formula (I-b) by using methods well-known to those skilled in the art.
  • An intermediate of formula (II) may be prepared by a coupling reaction between an intermediate of formula (III) and (XIII). Said reaction may be performed in the presence of coupling agents such as typically 1 -hydroxy- lH-benzotriazole (HOBT) and N , -(ethylcarbonimidoyl)-N,N-dimethyl-l,3-propanediamine monohydrochloride (EDCI). The reaction may be performed in the presence of a base such as trietylamine (Et 3 N) and a suitable solvent such as, for example, DCM.
  • an acid chloride derivative of (XIII) or a reactive ester derivative of (XIII) can also be used in this type of reaction to prepare an intermediate of formula (II).
  • An intermediate of formula (V) in turn is commercially available or alternatively can be easily prepared by, for example, treating a 2-aminobenzonitrile derivative of formula (VI) with tetrahydro-2,5-dimethoxyfuran in an inert solvent such as dioxane or tetrahydrofuran (THF) in the presence of an acid such as 4-chloropyridine
  • an intermediate of formula (V) can also be prepared from an intermediate of formula (X).
  • an acidic solvent such as glacial acetic acid
  • an intermediate of formula (IV) may be prepared by treating an intermediate of formula (VII) with borane-dimethyl sulfide (1 : 1) in a suitable solvent such as, for example, THF.
  • the reaction typically can be performed in the presence of an acid such as HC1.
  • the reaction mixture can be basified with a suitable base such as NaOH.
  • the reaction can be performed at an elevated temperature, preferably at reflux temperature.
  • An intermediate of formula (VII) can be prepared from an intermediate of formula (VIII).
  • An intermediate of formula (VIII) can be reacted with a nitrogen source such as, NH 3 .H 2 0 in the presence of HOBT and EDCI. This type of reaction typically can be performed in a suitable solvent like DMF. Stirring of the reaction mixture may enhance the rate of reaction.
  • An intermediate of formula (VIII) can be easily prepared by treating an intermediate of formula (IX) with tetrahydro-2,5-dimethoxyfuran in an inert solvent such as dioxane in the presence of an acid such as pyridine hydrochloride (1 : 1) at an elevated temperature, preferably at reflux temperature.
  • a reactive ester derivative of (IX) can also be used in this type of reaction to prepare an intermediate of formula (VIII).
  • reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and
  • stereoisomers can be isolated chromatographically using a chiral stationary phase such as, for example, Chiralpak® AD (amylose 3,5 dimethylphenyl carbamate) or Chiralpak® AS, both purchased from Daicel Chemical Industries, Ltd, in Japan.
  • a chiral stationary phase such as, for example, Chiralpak® AD (amylose 3,5 dimethylphenyl carbamate) or Chiralpak® AS, both purchased from Daicel Chemical Industries, Ltd, in Japan.
  • the chirally pure forms of the compounds of Formula (I) form a preferred group of compounds. It is therefore that the chirally pure forms of the intermediates and their salt forms are particularly useful in the preparation of chirally pure compounds of Formula (I). Also enantiomeric mixtures of the intermediates are useful in the preparation of compounds of Formula (I) with the corresponding configuration.
  • pharmaceutically acceptable addition salts, and the solvates thereof may be active against dematiaceous hyphomycetes, dimorphic pathogens, dermatophytes,
  • pharmaceutically acceptable addition salts, and the solvates thereof may be active against dimorphic pathogens, yeasts and yeastlike organisms.
  • compositions may be active against moulds.
  • Candida spp. e.g. Candida albicans, Candida glabrata, Candida krucei ' , Candida parapsilosis, Candida kefyr, Candida tropicalis
  • Aspergillus spp. e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus
  • Cryptococcus neoformans e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus
  • Cryptococcus neoformans Sporothrix schenckii
  • Epidermophyton floccosum fungi
  • Microsporum spp. e.g. Microsporum canis, Microsporum gypseum; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum, Trichophyton tonsurans, Trichophyton verrucosum, Trichophyton violaceum, Trichophyton inter digitale, Trichophyton soudanense; Fusarium spp., e.g. Fusarium solani, Fusarium oxysporum, Fusarium proliferatum, Fusarium
  • Rhizomucor spp. e.g. Rhizomucor miehei, Rhizomucor pusillus; Mucor circinelloides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Malassezia furfur; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.;
  • compositions may be active against a wide variety of fungi, such as Candida parapsilosis; Aspergillus spp., e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus
  • Microsporum spp. e.g. Microsporum canis, Microsporum gypseum; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum, Trichophyton tonsurans, Trichophyton verrucosum, Trichophyton violaceum, Trichophyton inter digitale, Trichophyton soudanense; Fusarium spp., e.g. Fusarium solani,
  • Rhizomucor spp. e.g. Rhizomucor miehei, Rhizomucor pusillus; Mucor circinelloides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.; Scytalidium; Scedosporium spp., e.g.
  • compositions may be active against a wide variety of fungi, such as Candida parapsilosis; Aspergillus spp., e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus
  • Microsporum spp. e.g. Microsporum canis, Microsporum gypseum
  • Trichophyton spp. e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum, Trichophyton tonsurans
  • Fusarium spp. e.g. Fusarium solani, Fusarium oxysporum, Fusarium proliferatum, Fusarium verticillioides
  • Rhizomucor spp. e.g. Rhizomucor miehei, Rhizomucor pusillus
  • Mucor circinelloides Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.; Scytalidium; Scedosporium spp., e.g.
  • Microsporum spp. e.g. Microsporum canis, Microsporum gypseum
  • Trichophyton spp. e.g. Trichophyton mentagrophytes, Trichophyton rubrum
  • Trichophyton quinckeanum Trichophyton tonsurans, Trichophyton verrucosum, Trichophyton violaceum, Trichophyton inter digitale, Trichophyton soudanense;
  • Fusarium spp. e.g. Fusarium solani, Fusarium oxysporum, Fusarium proliferatum, Fusarium verticillioides; Rhizomucor spp., e.g. Rhizomucor miehei, Rhizomucor pusillus; Mucor circinelloides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.; Scytalidium; Scedosporium spp., e.g. Scedosporium apiospermum, Scedosporium prolificans; Trichoderma spp.; Penicillium spp. ; Penicillium marneffei;
  • compositions may be active against a wide variety of fungi, such as Candida parapsilosis; Aspergillus spp.
  • Cryptococcus neoformans Cryptococcus neoformans; Sporothrix schenckii; Microsporum spp.; Fusarium spp.; Scedosporium spp.;
  • Candida parapsilosis in particular Candida parapsilosis; Aspergillus spp.; Cryptococcus neoformans;
  • Microsporum spp. Fusarium spp.; Scedosporium spp.;
  • Aspergillus spp. Cryptococcus neoformans
  • Microsporum spp. Fusarium spp.
  • compositions may be active against a wide variety of fungi, such as Candida parapsilosis; Aspergillus spp.;
  • Cryptococcus neoformans Trichophyton spp.; Sporothrix schenckii; Microsporum spp.; Fusarium spp.; Scedosporium spp.;
  • compositions may be active against fungi such as Candida parapsilosis, Aspergillus spp., Cryptococcus neoformans, Microsporum spp., and Trichophyton spp.
  • compositions may be active against fungi such as Candida parapsilosis; Aspergillus spp., e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum canis; Trichophyton spp., e.g.
  • Trichophyton mentagrophytes Trichophyton rubrum, Trichophyton quinckeanum; in particular Candida parapsilosis; Aspergillus spp., e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Epidermophyton floccosum; Microsporum canis; Trichophyton spp., e.g. Trichophyton mentagrophytes,
  • Aspergillus spp. e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Epidermophyton floccosum;
  • Microsporum canis Trichophyton spp., e.g. Trichophyton mentagrophytes,
  • compositions may be active against Candida parapsilosis, Aspergillus fumigatus, Cryptococcus neoformans, Sporothrix schenckii, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, Scedosporium apiospermum and Scedosporium prolificans; in particular Aspergillus fumigatus, Microsporum canis, Trichophyton mentagrophytes,
  • compositions may be active against fungi such as Candida parapsilosis; Aspergillus spp.; Cryptococcus neoformans; Microsporum spp.; Trichophyton spp.; Scedosporium spp..
  • compositions may be active against Candida parapsilosis, Aspergillus fumigatus, Cryptococcus neoformans,
  • Candida parapsilosis Aspergillus fumigatus, Cryptococcus neoformans, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum,
  • compositions may be active against Candida parapsilosis, Aspergillus fumigatus, Cryptococcus neoformans, Sporothrix schenckii, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, Scedosporium apiospermum, Scedosporium prolifwans, Rhizopus oryzae, Rhizomucor miehei.
  • Candida parapsilosis B66126 Aspergillus fumigatus B42928, Cryptococcus neoformans B66663, Sporothrix schenckii B62482, Microsporum canis B68128, Trichophyton mentagrophytes B 70554, Trichophyton rubrum B 68183, Scedosporium apiospermum IHEM3817, Scedosporium prolifwans IHEM21157.
  • Candida parapsilosis B66126 Aspergillus fumigatus B42928, Cryptococcus neoformans B66663, Sporothrix schenckii B62482, Microsporum canis B68128, Trichophyton mentagrophytes B 70554, Trichophyton rubrum B68183, Scedosporium apiospermum IHEM3817, Scedosporium prolificans IHEM21157, Rhizopus oryzae IHEM5223 and Rhizomucor miehei IHEM13391.
  • compositions may be active against Candida parapsilosis, Aspergillus fumigatus, Cryptococcus neoformans, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum.
  • compositions may be active against Microsporum canis, Trichophyton rubrum, Aspergillus fumigatus,
  • compositions may be active against Candida parapsilosis B66126, Aspergillus fumigatus B42928, Cryptococcus neoformans B66663, Microsporum canis B68128, Trichophyton mentagrophytes B 70554, Trichophyton rubrum B 68183, Rhizopus oryzae IHEM5223, Rhizomucor miehei IHEM 13391.
  • compositions may be active against Candida parapsilosis B66126, Aspergillus fumigatus B42928, Cryptococcus neoformans B66663, Microsporum canis B68128, Trichophyton mentagrophytes B 70554, Trichophyton rubrum B 68183.
  • pharmaceutically acceptable addition salts, and the solvates thereof may be active against a variety of fungi that infect the skin, hair and nails, as well as subcutaneous and systemic fungal pathogens.
  • compositions may be active against the 3 dermatophyte genera: Trichophyton, Microsporum and Epidermophyton; in particular against Trichophyton and Microsporum.
  • compositions may be active against dermatophytes and Aspergillus spp.; in particular dermatophytes and Aspergillus fumigatus; more in particular Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum and Aspergillus fumigatus; even more in particular Microsporum canis, Trichophyton mentagrophytes and Trichophyton rubrum.
  • the compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Trichophyton mentagrophytes, Trichophyton rubrum and Aspergillus spp.; in particular Trichophyton mentagrophytes, Trichophyton rubrum and Aspergillus fumigatus.
  • the compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Trichophyton mentagrophytes; Trichophyton rubrum; Aspergillus spp., e.g. Aspergillus fumigatus; Fusarium spp.; Mucor Spp.; Zygomycetes spp.; Scedosporium spp.; Microsporum canis; Sporothrix schenckii; Cryptococcus neoformans and Candida parapsilosis.
  • the compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against dermatophytes.
  • the compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Aspergillus fumigatus.
  • the compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Microsporum canis, in particular Microsporum canis B68128.
  • the compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Trichophyton rubrum, in particular Trichophyton rubrum B68183.
  • the compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against a wide variety of fungi, such as one or more of the fungi mentioned hereinbefore.
  • the compounds of the present invention may be useful as ergosterol synthesis inhibitors.
  • treatment is intended to refer to all processes, wherein there may be a slowing, interrupting, arresting, or stopping of the progression of an infection, but does not necessarily indicate a total elimination of all symptoms.
  • the invention relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use as a medicament.
  • the invention also relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for the treatment or prevention of fungal infections; in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.
  • the invention also relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for the treatment of fungal infections; in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.
  • the invention also relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use in the treatment or prevention of fungal infections; in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.
  • the invention also relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use in the treatment of fungal infections; in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.
  • the invention also relates to compounds according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use in the treatment or prevention, in particular treatment, of fungal infections; in particular fungal infections caused by one or more of the fungi selected from a group consisting of fungi mentioned hereinbefore.
  • the invention also relates to compounds according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use in the treatment or prevention of a fungal infection, in particular a fungal infection caused by one or more of the fungi mentioned hereinbefore.
  • the invention also relates to compounds according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use in the treatment or prevention of a fungal infection, wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Candida spp.; Aspergillus spp. Cryptococcus
  • Arthrographis spp. Scytalidium; Scedosporium spp.; Trichoderma spp.; Penicillium spp. ; Penicillium marneffei; and Blastoschizomyces;
  • the fungal infection is caused by one or more of the fungi selected from the group consisting of Candida parapsilosis; Aspergillus spp.; Cryptococcus neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum spp.; Trichophyton spp.; Fusarium spp.; Rhizomucor spp.; Mucor circinelloides; Rhizopus spp.; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.;
  • the fungal infection is caused by one or more of the fungi selected from the group consisting of Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum and Aspergillus fumigatus.
  • novel compounds described in the present invention may be useful in the treatment or prevention of diseases or conditions selected from the group consisting of infections caused by dermatophytes, systemic fungal infections and onychomycosis.
  • the novel compounds described in the present invention may be useful in the treatment or prevention of diseases or conditions such as for example infections caused by dermatophytes, systemic fungal infections or onychomycosis.
  • the invention also relates to the use of a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for the manufacture of a medicament.
  • the invention also relates to the use of a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for the manufacture of a medicament for the treatment or prevention, in particular treatment, of fungal infections, in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.
  • the compounds of the present invention can be administered to mammals, preferably humans, for the treatment or prevention, in particular treatment, of fungal infections, in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.
  • mammals preferably humans
  • treatment or prevention, in particular treatment, of fungal infections, in particular fungal infections caused by one or more of the fungi mentioned hereinbefore are provided.
  • Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of an effective amount of a compound of Formula (I), a stereoisomeric form thereof or a pharmaceutically acceptable addition salt or solvate thereof, to warm-blooded animals, including humans.
  • Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of an effective amount of a compound of Formula (I), to warm-blooded animals, including humans.
  • An effective therapeutic daily amount would be from about 0.005 mg/kg to 50 mg/kg, in particular 0.01 mg/kg to 50 mg/kg body weight, more in particular from 0.01 mg/kg to 25 mg/kg body weight, preferably from about 0.01 mg/kg to about 15 mg/kg, more preferably from about 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.01 mg/kg to about 1 mg/kg, most preferably from about 0.05 mg/kg to about 1 mg/kg body weight.
  • the amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutically effect will of course, vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.
  • a method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day.
  • the compounds according to the invention are preferably formulated prior to
  • suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition.
  • compositions for treating or preventing fungal infections comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.
  • the carrier or diluent must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • the compounds of the present invention may be administered alone or in combination with one or more additional therapeutic agents.
  • Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of Formula (I) and one or more additional therapeutic agents, as well as administration of the compound of Formula (I) and each additional therapeutic agents in its own separate pharmaceutical dosage formulation.
  • a compound of Formula (I) and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.
  • the subject compounds may be formulated into various pharmaceutical forms for administration purposes.
  • the compounds according to the invention in particular the compounds according to Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • compositions are desirable in unitary dosage form suitable, in particular, for administration orally, rectally, percutaneously, by parenteral injection or by inhalation.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid
  • compositions such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • Injectable solutions containing compounds of Formula (I) may be formulated in an oil for prolonged action.
  • Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils.
  • Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • Transungual compositions are in the form of a solution and the carrier optionally comprises a penetration enhancing agent which favours the penetration of the antifungal into and through the keratinized ungual layer of the nail.
  • the solvent medium comprises water mixed with a co-solvent such as an alcohol having from 2 to 6 carbon atoms, e.g. ethanol.
  • ⁇ -, ⁇ - or ⁇ - cyclodextrins or their derivatives in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl-P-cyclodextrin or sulfobutyl-P-cyclodextrin.
  • co-solvents such as alcohols may improve the solubility and/or the stability of the compounds according to the invention in pharmaceutical compositions.
  • the ratio of active ingredient over cyclodextrin may vary widely. For example ratios of 1/100 to 100/1 may be applied. Interesting ratios of active ingredient over cyclodextrin range from about 1/10 to 10/1. More interesting ratios of active ingredient over cyclodextrin range from about 1/5 to 5/1.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0.1 to 70 % by weight, even more preferably from 0.1 to 50 % by weight of the compound of Formula (I), and, from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
  • cyclodextrins are ⁇ -, ⁇ -, ⁇ -cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C ⁇ .galkyl, particularly methyl, ethyl or isopropyl, e.g.
  • hydroxyCi .galkyl particularly hydroxy ethyl, hydroxy-propyl or hydroxybutyl
  • carboxyCi .galkyl particularly carboxymethyl or carboxy-ethyl
  • Ci-6alkylcarbonyl particularly acetyl.
  • complexants and/or solubilizers are ⁇ -CD, randomly methylated ⁇ -CD, 2,6-dimethyl ⁇ -CD, 2-hydroxyethyl ⁇ -CD, 2-hydroxyethyl-y-CD,
  • mixed ether denotes cyclodextrin derivatives wherein at least two
  • cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxy-propyl and hydroxy ethyl.
  • the average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose.
  • the average substitution degree (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit.
  • the M.S. and D.S value can be determined by various analytical techniques such as nuclear magnetic resonance (MR), mass spectrometry (MS) and infrared
  • IR spectroscopy
  • compositions for oral or rectal administration comprise particles consisting of a solid dispersion comprising a compound of Formula (I) and one or more appropriate pharmaceutically acceptable water-soluble polymers.
  • a solid dispersion defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, in casu the compound of Formula (I) and the water-soluble polymer, wherein one component is dispersed more or less evenly throughout the other component or components ( in case additional
  • compositions such as plasticizers, preservatives and the like.
  • plasticizers such as plasticizers, preservatives and the like.
  • Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered. This advantage can probably be explained by the ease with which said solid solutions can form liquid solutions when contacted with a liquid medium such as the gastro-intestinal juices.
  • the ease of dissolution may be attributed at least in part to the fact that the energy required for dissolution of the components from a solid solution is less than that required for the dissolution of components from a crystalline or microcrystalline solid phase.
  • a solid dispersion also comprises dispersions which are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase.
  • a solid dispersion also relates to a system having domains or small regions wherein amorphous, microcrystalline or crystalline compound of Formula (I), or amorphous, microcrystalline or crystalline water-soluble polymer, or both, are dispersed more or less evenly in another phase comprising water-soluble polymer, or compound of Formula (I), or a solid solution comprising compound of Formula (I) and water-soluble polymer. Said domains are regions within the solid dispersion distinctively marked by some physical feature, small in size, and evenly and randomly distributed throughout the solid dispersion.
  • the present antifungal compounds may further be convenient to formulate the present antifungal compounds in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm.
  • Useful surface modifiers are believed to include those which physically adhere to the surface of the antifungal agent but do not chemically bond to the antifungal agent.
  • Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.
  • Yet another interesting way of formulating the present compounds involves a pharmaceutical composition whereby the present antifungals are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration.
  • Said beads comprise a central, rounded or spherical core, a coating film of a
  • hydrophilic polymer and an antifungal agent and a seal-coating layer.
  • Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness.
  • examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.
  • Unit dosage form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
  • compositions comprising said compounds for
  • Triethylamine trihydrofluoride (8.05 g, 50 mmol, (C 2 H 5 ) 3 N ⁇ 3HF) was added to a mixture of intermediate 8 (3.0 g, 10 mmol) in DCM (50 ml) at -78 °C. Then 1,3- dibromo-5,5-dimethyl-2,4-imidazolidinedione (14.3 g, 50 mmol) in DCM (30 ml) was added in 30 min. The mixture was stirred for 2 h at r.t. Subsequently, the solution was quenched with NaOH (IN, q.s.) and extracted with DCM (200 ml).
  • 1,2-Ethanedithiol (4.7 g, 50 mmol) in DCM (100 ml) was added to trimethylaluminium (50 ml of a 2 M solution in toluene; 100 mmol) at -78 °C. After addition, the mixture was warmed to r.t. for 30 min. The mixture was cooled to -20 °C, and then 6-Bromo- 3,4-dihydro-2H-l-Benzopyran-2-one (11.35 g, 50 mmol) in DCM (200 ml) was added dropwise to the mixture. The mixture was stirred overnight. The mixture was poured out into ice-water, acidified by concentrated HC1, and extracted with DCM.
  • Triethylamine tri(hydrogen fluoride) (5.36 g, 33.24 mmol) was added to the mixture of intermediate 21 (2 g, 6.59 mmol) in DCM (100 ml) at -78 °C. Then l,3-dibromo-5,5- dimethyl-2,4-imidazolidinedione (9.54 g, 33.24 mmol) in DCM (100 ml) was added slowly, and the resulting mixture was stirred for 2 h at r.t. Subsequently, the mixture was quenched with NaOH (I N) and extracted with DCM. The separated organic layer was dried (Na 2 S0 4 ), filtered and the solvent was evaporated.
  • 'Co. No.' means compound number.
  • 'Pr.' refers to the Example number according to which protocol the compound was synthesized. In case no salt form is indicated, the compound was obtained as a free base.
  • HBr salt forms were obtained by using procedures known to those skilled in the art. A typical procedure is described in WO02/34752.
  • the FIPLC measurement was performed using an Agilent 1100 module comprising a pump, a diode-array detector (DAD) (wavelength used 220 nm), a column heater and a column as specified in the respective methods below. Flow from the column was split to a Agilent MSD Series G1946C and G1956A. MS detector was configured with API- ES (atmospheric pressure electrospray ionization). Mass spectra were acquired by scanning from 100 to 1000. The capillary needle voltage was 2500 V for positive and 3000 V for negative ionization mode. Fragmentation voltage was 50 V. Drying gas temperature was maintained at 350 °C at a flow of 10 1/min.
  • DAD diode-array detector
  • Reversed phase HPLC was carried out on a YMC- Pack ODS-AQ, 50x2.0 mm 5 ⁇ column with a flow rate of 0.8 ml/min.
  • Two mobile phases (mobile phase A: water with 0.1 % TFA; mobile phase B: acetonitrile with 0.05 % TFA) were used.
  • 100 % A was hold for 1 minute.
  • a gradient was applied to 40 % A and 60 % B in 4 minutes and hold for 2.5 minutes. Typical injection volumes of 2 ⁇ were used.
  • Oven temperature was 50 °C. (MS polarity: positive)
  • Reversed phase HPLC was carried out on a YMC- Pack ODS-AQ, 50x2.0 mm 5 ⁇ column with a flow rate of 0.8 ml/min.
  • 2 mobile phases (mobile phase A: water with 0.1 % TFA; mobile phase B: CH 3 CN with 0.05 % TFA) were used.
  • 90 % A and 10 % B was hold for 0.8 min.
  • a gradient was applied to 20 % A and 80 % B in 3.7 min and hold for 3 min. Typical injection volumes of 2 ⁇ were used.
  • Oven temperature was 50 °C. (MS polarity: positive)
  • Reversed phase HPLC was carried out on an Ultimate XB-C18, 50x2.1 mm 5 ⁇ column with a flow rate of 0.8 ml/min.
  • Two mobile phases (mobile phase C: 10 mmol/1 H 4 HC0 3 ; mobile phase D: CH 3 CN) were used.
  • 100 % C was hold for 1 minute.
  • a gradient was applied to 40 % C and 60 % D in 4 minutes and hold for 2.5 min.
  • Typical injection volumes of 2 ⁇ were used.
  • Oven temperature was 50 °C. (MS polarity: positive)
  • melting points (m.p.) were determined with a WRS-2A melting point apparatus purchased from Shanghai Precision and Scientific Instrument Co. Ltd. Melting points were measured with a linear heating up rate of 0.2-5.0 °C/min The reported values are melt ranges. The maximum temperature was 300 °C.
  • 1H NMR spectra were recorded on a Bruker DPX-300, a Bruker DPX-400, or on a Bruker Avance 600 spectrometer spectrometer with standard pulse sequences, operating at 300 MHz, 400 MHz and 600 MHz respectively, using CHLOROFORM- ⁇ (deuterated chloroform, CDC1 3 ) or DMS0 (deuterated DMSO, dimethyl-d6 sulfoxide) as solvents. Chemical shifts ( ⁇ ) are reported in parts per million (ppm) relative to tetramethylsilane (TMS), which was used as internal standard.
  • CHLOROFORM- ⁇ deuterated chloroform, CDC1 3
  • DMS0 deuterated DMSO, dimethyl-d6 sulfoxide
  • Example D. l Measurement of antifungal activity in vitro
  • the standard susceptibility screen was performed in 96-well plates (U-bottom, Greiner Bio-One). Serial dilutions (2-fold or 4-fold) of 20 mM compound stock solutions were made in 100 % DMSO, followed by an intermediate dilution step in water. These serial dilutions (10 ⁇ ) were then spotted onto test-plates that could be stored in the dark at 4 °C for a maximum period of 2 weeks. An adequate broad dose-range was included with 64 ⁇ as the highest in-test concentration.
  • the culture medium RPMI-1640 was supplemented with L-glutamine, 2% glucose and buffered with 3-(N-morpholino)- propanesulfonic acid (MOPS) at pH 7.0 ⁇ 0.1.
  • Table 3a Incubation conditions for the different fungal species. 'Resa time' represents the additional incubation time after the addition of resazurin to the test system.

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Abstract

The present invention is concerned with novel antifungal 5,6-dihydro-4H-pyrrolo- [1,2-a][1,4]benzodiazepines and 6H-pyrrolo[1,2-a][1,4]benzodiazepines substituted with bicyclic benzene derivatives of Formula (I) wherein R1, R2, R3, R4, R5, R6 and R7 have the meaning defined in the claims. The compounds according to the present invention are active mainly against dermatophytes and systemic fungal infections. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

Description

NOVEL ANTIFUNGAL 5,6-DIHYDRO-4H-PYRROLO[l,2-a][l,4]- BENZ ODI AZEPINE S AND 6H-PYRROLO[l,2-a][l,4]BENZODIAZEPINES SUBSTITUTED WITH BICYCLIC BENZENE DERIVATIVES Field of the Invention
The present invention is concerned with novel antifungal 5,6-dihydro-4H-pyrrolo- [l,2-a][l,4]benzodiazepines and 6H-pyrrolo[l,2-a][l,4]benzodiazepines, both substituted with bicyclic benzene derivatives, active mainly against dermatophytes and systemic fungal infections. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
Background of the invention
Dermatophyte is a common label for a group of 3 types of fungi that commonly causes skin disease in animals and humans. These anamorphic (asexual or imperfect fungi) genera are: Microsporum, Epidermophyton and Trichophyton. There are about 40 species in these 3 genera.
Dermatophytes cause infections of the skin, hair and nails due to their ability to obtain nutrients from keratinized material. The organisms colonize the keratin tissues and inflammation is caused by host response to metabolic by-products. They are usually restricted to the cornified layer of the epidermis because of their inability to penetrate viable tissue of an immunocompetent host. However, occasionally the organisms do invade subcutaneous tissues, resulting in kerion development. Invasion does elicit a host response ranging from mild to severe. Acid proteinases, elastase, keratinases, and other proteinases reportedly act as virulence factors.
Systemic fungal infections (SFI) are life-threatening conditions that most commonly affect patients with reduced immunity often resulting from therapeutic interventions to treat malignant diseases. The number of SFFs in modern hospitals keeps increasing, and the number of different fungi that have been involved in SFI is large and still growing. Despite many cases of invasive candidiasis and aspergillosis there has been an increased incidence of infections due to other molds like Scedosporium apiospermum, Fusarium spp. , and Zygomycetes, Rhizopus and Mucor spp.. Effective therapeutic agents treating all these infections very well therefore need to have very broad spectrum of activity. In the past few decades itraconazole, fluconazole, ketoconazole, and intravenous or liposomal amphotericin B have been used in SFI, and all of these agents have their limitations with regard to spectrum, safety or ease of administration. More recently a third generation of azoles have been investigated and introduced to the market, improving the treatment options in intensive care units. Voriconazole
(Vfend™) and posaconazole (Noxafil™) show much improvement of treatment towards life threatening invasive SFI such as candidiasis, aspergillosis, and infections due to Fusarium species at clinical relevant dosages. Moreover posaconazole shows efficacy against infections caused by the emerging Zygomycetes spp. Echinocandins, such as anidulafungin, caspofungin, and micafungin, which are non-competitive inhibitors of l,3- -glucan synthesis in fungal cell walls, display high efficacy against Candida spp. and Aspergillus spp., but no activity against Cryptococcus, Fusarium, or Zygomycetes spp.. Of all antimycotic agents, azoles still represent a unique class of compounds displaying the broadest antifungal spectrum via inhibition of 14-a- demethylase, an enzyme being essential for ergosterol biosynthesis in fungi.
Onychomycosis is the most common disease of the nails and constitutes about a half of all nail abnormalities. The prevalence of onychomycosis is about 6-8 % in the adult population. The causative pathogens of onychomycosis include dermatophytes,
Candida, and non-dermatophytic moulds. Dermatophytes are the fungi most commonly responsible for onychomycosis in the temperate western countries; meanwhile, Candida and non-dermatophytic moulds are more frequently involved in the tropics and subtropics. Trichophyton rubrum is the most common dermatophyte involved in onychomycosis. Other dermatophytes that may be involved are Trichophyton interdigitale, Epidermophyton floccosum, Trichophyton violaceum, Microsporum gypseum, Trichophyton tonsurans, Trichophyton soudanense and Trichophyton verrucosum. Other causative pathogens include Candida and non-dermatophytic moulds, in particular members of the mould generation Scytalidium (also
Neoscytalidium), Scopulariopsis, and Aspergillus.
5,6-Dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepines have been described in J. Chem. Soc.(C), 2732-2734 (1971); J. Heterocyclic Chem., 13, 711-716 (1976); and J.
Heterocyclic Chem., 16, 241-244 (1979). The compounds disclosed in these references all have a different substitution on the phenyl moiety in the 4-position and moreover no biological activities were reported in any of these references.
A new synthetic route to aryl(heteroaryl)-annulated pyrrolo[l,2-a][l,4]diazepines has been described in Org. Biomol. Chem., 8, 3316-3327 (2010).
Compounds 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine (CAS Registry Number [845288-06-4]) and 4-(l,3-benzodioxol-5-yl)-5,6- dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine .HC1 (CAS Registry Number [1215546- 57-8]) are commercially available, but no use is known for these compounds.
WO02/34752 describes 4-substituted 5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepines as a new class of antifungal compounds. However, WO02/34752 does not disclose the present substitution pattern on the phenyl moiety in the 4-position.
The PhD thesis of De Wit K. describes the implementation of an in vitro and in vivo mycological evaluation platform and activity profiling of antifungal
pyrrolobenzodiazepines (PhD Thesis; University of Antwerp, Belgium; Faculty of Pharmaceutical, Biomedical and Veterinary Sciences; Department of Biomedical Sciences; 2011; 220 p.).
The antifungal compounds of the present invention or part of the compounds of the present invention are structurally different and may have improved potency, improved metabolic stability properties, improved solubility, improved plasma binding, reduced hERG channel inhibition, reduced cytochrome P450 liabilities, or improved
bioavailability compared with compounds disclosed in the prior art. Preferably said compounds have a broad antifungal spectrum, and maintain adequately high
thereapeutic efficacy and adequately low toxicity or other side effects.
It is accordingly an object of the present invention to provide novel compounds with antifungal activity to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide useful alternative compounds.
Summary of the invention
It has been found that the compounds of the present invention are useful as antifungal compounds.
The present invention concerns novel compounds of Formula (I):
Figure imgf000004_0001
and stereoisomeric forms thereof, wherein
R1 is hydrogen, halo, Ci-4alkyl or Ci-4alkyloxy;
R2 is hydrogen or halo;
R3 and R4 are hydrogen; or R3 and R4 taken together form a bond;
R5 is hydrogen or Ci-4alkyloxy;
R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
-(CH2)m-Y1-(CH2)n-m- (a), -Y2a-(CH2)t-Y2b- (d), or
-(CH2)n-m-Y1-(CH2)m- (b), -(CH2)r-Y2a-CH2-Y2b-(CH2)q- (e);
-(CH2)S- (c),
wherein the bivalent radical -R6-R7- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl, hydroxyl,
Ci-4alkyloxy and oxo;
Y1 represents O, R8a or S;
Y2a and Y2b each independently represent O, R8b or S;
R8a represents hydrogen or Ci-4alkyl;
R represents hydrogen or Ci-4alkyl;
m represents 0, 1 or 2;
n represents 2, 3 or 4;
s represents 3, 4 or 5;
t represents 1, 2 or 3;
r represents 0 or 1 ;
q represents 0 or 1 ;
provided that at least one of r and q is 1;
and the pharmaceutically acceptable addition salts, and the solvates thereof;
provided that the compound is not 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[l,2-a][l,4]benzodiazepine or 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine .HQ .
The present invention also concerns methods for the preparation of compounds of Formula (I) and pharmaceutical compositions comprising them.
The present compounds are useful agents for combating fungi in vivo.
The novel compounds described in the present invention may be useful in the treatment or prevention of infections caused by dermatophytes, systemic fungal infections and onychomycosis.
The novel compounds described in the present invention may be active against a wide variety of fungi, such as Candida spp., e.g. Candida albicans, Candida glabrata, Candida krucei ', Candida parapsilosis, Candida kefyr, Candida tropicalis; Aspergillus spp., e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum spp., e.g. Microsporum canis, Microsporum gypseum; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum, Trichophyton tonsurans, Trichophyton verrucosum, Trichophyton violaceum, Trichophyton inter digitale, Trichophyton soudanense; Fusarium spp., e.g. Fusarium solani,
Fusarium oxysporum, Fusarium proliferatum, Fusarium verticillioides; Rhizomucor spp., e.g. Rhizomucor miehei, Rhizomucor pusillus; Mucor circinelloides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Malassezia furfur; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.; Scytalidium; Scedosporium spp., e.g. Scedosporium apiospermum, Scedosporium prolificans; Trichoderma spp.; Penici Ilium spp. ; Penici Ilium marneffei; Blastoschizomyces.
In view of the aforementioned pharmacology of the present compounds, it follows that they are suitable for use as a medicament.
The invention also relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable addition salts and the solvates thereof, for use in the treatment or prevention of fungal infections.
One advantage of the compounds or a part of the compounds of the present invention may lie in their enhanced bioavailability, improved metabolic stability properties, improved PK properties, reduced hERG channel inhibition, or reduced cytochrome P450 liabilities compared with the compounds disclosed in the prior art.
The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or
advantageous.
Detailed description
When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise.
Whenever the term "substituted" is used in the present invention, it is meant, unless otherwise is indicated or is clear from the context, to indicate that one or more hydrogens, in particular from 1 to 4 hydrogens, preferably from 1 to 3 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using
"substituted" are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
Whenever the bivalent radical -R6-R7- is substituted with one or more substituents, those substituents may replace any hydrogen atom bound to a carbon atom.
The term "halo" or "halogen" as a group or part of a group is generic for fluoro, chloro, bromo, iodo unless otherwise is indicated or is clear from the context.
The term "Ci-4alkyl" as a group or part of a group refers to a hydrocarbyl radical of Formula CnH2n+i wherein n is a number ranging from 1 to 4. Ci-4alkyl groups comprise from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, still more preferably 1 to 2 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Thus, for example, Ci-4alkyl includes all linear, or branched alkyl groups with between 1 and 4 carbon atoms, and thus includes such as for example methyl, ethyl, ^-propyl, i- propyl, 2-methyl-ethyl, butyl and its isomers (e.g. «-butyl, zsobutyl and tert-butyl), and the like.
The term "Ci-4alkyloxy" as a group or part of a group refers to a radical having the Formula -ORa wherein Ra is Ci-4alkyl. Non-limiting examples of suitable
Ci-4alkyloxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy and tert-butyloxy.
The chemical names of the compounds of the present invention were generated according to the nomenclature rules agreed upon by the Chemical Abstracts Service, using Advanced Chemical Development, Inc., nomenclature software (ACD/Name product version 10.01 ; Build 15494, 1 Dec 2006).
In case of tautomeric forms, it should be clear that the other non-depicted tautomeric form is also included within the scope of the present invention.
The atoms in the tricyclic system are numbered as shown in the following formula (Q):
Figure imgf000007_0001
It will be appreciated that some of the compounds of Formula (I) and their
pharmaceutically acceptable addition salts and solvates may contain one or more centers of chirality and exist as stereoisomeric forms.
As used in the description, whenever the term "compound(s) of formula (I)" is used, it is meant to include the stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof.
The terms "stereoisomers", "stereoisomeric forms" or "stereochemically isomeric forms" hereinbefore or hereinafter are used interchangeably.
The term "stereoisomeric forms" as used hereinbefore defines all the possible isomeric forms that the compounds of Formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms.
The definition of "compound of formula (I)" inherently includes all stereoisomers of the compound of formula (I) either as a pure stereoisomer or as a mixture of two or more stereoisomers. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a racemate or racemic mixture. Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E or Z-stereochemistry at said double bond. Stereoisomeric forms of the compounds of Formula (I) are embraced within the scope of this invention. Therefore, the invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.
The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
When a specific stereoisomeric form is indicated, this means that said form is substantially free, i.e. associated with less than 50 %, preferably less than 20 %, more preferably less than 10 %, even more preferably less than 5 %, further preferably less than 2 % and most preferably less than 1 % of the other isomer(s). Thus, when a compound of the present invention is for instance specified as (R), this means that the compound is substantially free of the (S) isomer; when a compound of the present invention is for instance specified as E, this means that the compound is substantially free of the Z isomer; when a compound of the present invention is for instance specified as cis, this means that the compound is substantially free of the trans isomer.
Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
The compounds of formula (I) have been drawn herein in a single tautomeric form, the different tautomers are equivalent to each other and all possible tautomeric forms are included within the scope of the invention.
For therapeutic use, salts of the compounds of Formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether
pharmaceutically acceptable or not, are included within the ambit of the present invention.
The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of Formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.
The compounds of Formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g.
primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers,
dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n- butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, tri ethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N- methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.
The term solvate comprises the hydrates and solvent addition forms which the compounds of Formula (I) are able to form, as well as the salts thereof. Examples of such forms are e.g. hydrates, alcoholates and the like.
The compounds of Formula (I) as prepared in the processes described below may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers that can be separated from one another following art-known resolution procedures. A manner of separating the enantiomeric forms of the compounds of Formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
In the framework of this application, a compound according to the invention is inherently intended to comprise all isotopic combinations of its chemical elements. In the framework of this application, a chemical element, in particular when mentioned in relation to a compound according to Formula (I), comprises all isotopes and isotopic mixtures of this element. For example, when hydrogen is mentioned, it is understood to refer to 1H, 2H, 3H and mixtures thereof.
A compound according to the invention therefore inherently comprises a compound with one or more isotopes of one or more element, and mixtures thereof, including a radioactive compound, also called radiolabelled compound, wherein one or more nonradioactive atoms has been replaced by one of its radioactive isotopes. By the term "radiolabelled compound" is meant any compound according to Formula (I), or a pharmaceutically acceptable salt thereof, which contains at least one radioactive atom. For example, a compound can be labelled with positron or with gamma emitting radioactive isotopes. For radioligand-binding techniques, the 3H-atom or the 125I-atom is the atom of choice to be replaced. For imaging, the most commonly used positron
11 18 15 13
emitting (PET) radioactive isotopes are C, F, O and N, all of which are accelerator produced and have half-lives of 20, 100, 2 and 10 minutes respectively. Since the half-lives of these radioactive isotopes are so short, it is only feasible to use them at institutions which have an accelerator on site for their production, thus limiting their use. The most widely used of these are 18F, 99mTc, 201T1 and 123I. The handling of these radioactive isotopes, their production, isolation and incorporation in a molecule are known to the skilled person.
In particular, the radioactive atom is selected from the group of hydrogen, carbon, nitrogen, sulfur, oxygen and halogen. In particular, the radioactive isotope is selected from the group of ¾ UC, 18F, 122I, 123I, 125I, 131I, 75Br, 76Br, 77Br and
As used in the specification and the appended claims, the singular forms "a", "an," and "the" also include plural referents unless the context clearly dictates otherwise. By way of example, "a compound" means one compound or more than one compound.
The terms described above and others used in the specification are well understood to those in the art.
Preferred features of the compounds of this invention are now set forth.
The present invention concerns novel compounds of Formula (I):
Figure imgf000011_0001
and stereoisomeric forms thereof, wherein
R1 is hydrogen, halo, Ci-4alkyl or Ci-4alkyloxy;
R2 is hydrogen or halo;
3 and R4 are hydrogen;
Figure imgf000011_0002
more substituents selected from the group consisting of halo, Ci-4alkyl, hydroxyl, Ci-4alkyloxy and oxo;
Y1 represents O, R8a or S;
Y2a and Y2b each independently represent O, R8b or S; R a represents hydrogen or Ci-4alkyl;
R represents hydrogen or Ci-4alkyl;
m represents 0, 1 or 2;
n represents 2, 3 or 4;
s represents 3, 4 or 5;
t represents 1, 2 or 3;
r represents 0 or 1 ;
q represents 0 or 1 ;
provided that at least one of r and q is 1;
and the pharmaceutically acceptable addition salts, and the solvates thereof;
provided that the compound is not 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[l,2-a][l,4]benzodiazepine or 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine .HC1.
In an embodiment, the invention relates to compounds of Formula (I) and
stereoisomeric forms thereof, wherein
R1 is halo, Ci-4alkyl or Ci-4alkyloxy; in particular wherein R1 is halo;
R2 is hydrogen or halo;
R3 and R4 are hydrogen;
or R3 and R4 taken together form a bond;
R5 is hydrogen or Ci-4alkyloxy;
R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
-(CH2)m-Y1-(CH2)n-m- (a), -Y2a-(CH2)t-Y2b- (d), or
-(CH2)n-m-Y1-(CH2)m- (b), -(CH2)r-Y2a-CH2-Y2b-(CH2)q- (e);
-(CH2)S- (c),
wherein the bivalent radical -R6-R7- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl, hydroxyl,
Ci-4alkyloxy and oxo;
Y1 represents O, R8a or S;
Y2a and Y2b each independently represent O, R8b or S;
R8a represents hydrogen or Ci-4alkyl;
R represents hydrogen or Ci-4alkyl;
m represents 0, 1 or 2;
n represents 2, 3 or 4;
s represents 3, 4 or 5;
t represents 1, 2 or 3;
r represents 0 or 1 ; q represents 0 or 1 ;
provided that at least one of r and q is 1;
and the pharmaceutically acceptable addition salts, and the solvates thereof.
In an embodiment, the invention relates to compounds of Formula (I) and
stereoisomeric forms thereof, wherein
R1 is halo, Ci-4alkyl or Ci-4alkyloxy; in particular wherein R1 is halo;
R2 is hydrogen or halo;
R3 and R4 are hydrogen;
or R3 and R4 taken together form a bond;
R5 is hydrogen or Ci-4alkyloxy;
R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
-(CH2)m-Y1-(CH2)n-m- (a), -Y2a-(CH2)t-Y2b- (d), or
-(CH2)n-m-Y1-(CH2)m- (b), -(CH2)r-Y2a-CH2-Y2b-(CH2)q- (e);
-(CH2)S- (c),
wherein the bivalent radical -R6-R7- having formula (a), (b), (c) or (e) may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl, hydroxyl, Ci-4alkyloxy and oxo;
and wherein the bivalent radical -R6-R7- having formula (d) is substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl, hydroxyl,
Ci-4alkyloxy and oxo;
Y1 represents O, R8a or S;
Y2a and Y2b each independently represent O, R8b or S;
R8a represents hydrogen or Ci-4alkyl;
R represents hydrogen or Ci-4alkyl;
m represents 0, 1 or 2;
n represents 2, 3 or 4;
s represents 3, 4 or 5;
t represents 1, 2 or 3;
r represents 0 or 1 ;
q represents 0 or 1 ;
provided that at least one of r and q is 1;
and the pharmaceutically acceptable addition salts, and the solvates thereof. In an embodiment, the invention relates to compounds of Formula (I) and stereoisomeric forms thereof, wherein
R1 is hydrogen, halo, Ci-4alkyl or Ci-4alkyloxy;
R2 is hydrogen or halo; R3 and R4 are hydrogen;
or R3 and R4 taken together form a bond;
R5 is hydrogen or Ci-4alkyloxy;
R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
-(CH2)m-Y1-(CH2)n-m- (a), -(CH2)S- (c), or
-(CH2)n-m-Y1-(CH2)m- (b), -Y2a-(CH2)t-Y2b- (d);
wherein the bivalent radical -R6-R7- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl and oxo;
Y1 represents O or R8a;
Y2a and Y2b each independently represent O or R8b;
R8a represents hydrogen or Ci-4alkyl; in particular R8a represents hydrogen;
R8b represents hydrogen or Ci-4alkyl; in particular R8b represents hydrogen;
m represents 0, 1 or 2;
n represents 2 or 3;
s represents 3 or 4;
t represents 1 ;
and the pharmaceutically acceptable addition salts, and the solvates thereof;
provided that the compound is not 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[l,2-a][l,4]benzodiazepine or 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine .HQ .
In an embodiment, the invention relates to compounds of Formula (I) and stereoisomeric forms thereof, wherein
R1 is hydrogen, halo, Ci-4alkyl or Ci-4alkyloxy;
R2 is hydrogen or halo;
R3 and R4 are hydrogen;
or R3 and R4 taken together form a bond;
R5 is hydrogen or Ci-4alkyloxy;
R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
-(CH2)m-Y1-(CH2)n-m- (a), -(CH2)S- (c), or
-(CH2)n-m-Y1-(CH2)m- (b), -Y2a-(CH2)t-Y2b- (d);
wherein the bivalent radical -R6-R7- having formula (a), (b) or (c) may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl and oxo;
wherein the bivalent radical -R6-R7- having formula (d) is substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl and oxo;
Y1 represents O or R8a; Y a and Y each independently represent O or R ;
R8a represents hydrogen or Ci-4alkyl; in particular R8a represents hydrogen;
R8b represents hydrogen or Ci-4alkyl; in particular R8b represents hydrogen;
m represents 0, 1 or 2;
n represents 2 or 3;
s represents 3 or 4;
t represents 1 ;
and the pharmaceutically acceptable addition salts, and the solvates thereof.
In an embodiment, the invention relates to compounds of Formula (I) and
stereoisomeric forms thereof, wherein
R1 is hydrogen, halo, Ci-4alkyl or Ci-4alkyloxy;
R2 is hydrogen or halo;
R3 and R4 are hydrogen;
or R3 and R4 taken together form a bond;
R5 is hydrogen or Ci-4alkyloxy;
R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
(CH2)m-Y1-(CH2) 'nn--m" (a) , Y2a-(CH2)t-Y2B- (d), or (CH2)n-m-Y1-(CH2) 'in (b) , (CH2)r-Y2a-CH2-Y2b-(CH2)q- (e);
(CH2)S- (c) ,
wherein the bivalent radical -R6-R7- having formula (a), (b), (c) or (e) may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl, hydroxyl, Ci-4alkyloxy and oxo;
and wherein the bivalent radical -R6-R7- having formula (d) is substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl, hydroxyl, Ci-4alkyloxy and oxo;
Y1 represents O, R8a or S;
Y2a and Y2b each independently represent O, R8b or S;
R8a represents hydrogen or Ci-4alkyl;
R represents hydrogen or Ci-4alkyl;
m represents 0, 1 or 2;
n represents 2, 3 or 4;
s represents 3, 4 or 5;
t represents 1, 2 or 3;
r represents 0 or 1 ;
q represents 0 or 1 ; provided that at least one of r and q is 1;
and the pharmaceutically acceptable addition salts, and the solvates thereof.
In an embodiment, the invention relates to compounds of Formula (I) and
stereoisomeric forms thereof, wherein
R1 is hydrogen, halo or Ci-4alkyloxy; in particular hydrogen, chloro, fluoro or methoxy; R2 is hydrogen or halo; in particular hydrogen, chloro or fluoro;
R3 and R4 are hydrogen;
or R3 and R4 taken together form a bond;
R5 is hydrogen or Ci-4alkyloxy; in particular hydrogen, methoxy or ethoxy;
R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
-(CH2)m-Y1-(CH2)n-m- (a), -(CH2)S- (c), or
-Y2a-(CH2)t-Y2b- (d);
wherein the bivalent radical -R6-R7- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl and oxo; in particular fluoro, methyl and oxo;
Y1 represents O or H;
Y2a represents O;
Y2b represent O or NH;
m represents 0, 1 or 2;
n represents 2 or 3;
s represents 3 or 4;
t represents 1 ;
and the pharmaceutically acceptable addition salts, and the solvates thereof;
provided that the compound is not 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[l,2-a][l,4]benzodiazepine or 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine .HQ .
In an embodiment, the invention relates to compounds of Formula (I) and
stereoisomeric forms thereof, wherein
R1 is hydrogen, halo or Ci-4alkyloxy; in particular hydrogen, chloro, fluoro or methoxy; R2 is hydrogen or halo; in particular hydrogen, chloro or fluoro;
R3 and R4 are hydrogen;
or R3 and R4 taken together form a bond;
R5 is hydrogen or Ci-4alkyloxy; in particular hydrogen, methoxy or ethoxy;
R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
-(CH2)m-Y1-(CH2)n-m- (a), -(CH2)S- (c), or
-Y2a-(CH2)t-Y2b- (d); wherein the bivalent radical -R6-R7- having formula (a) or (c) may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl and oxo; in particular fluoro, methyl and oxo;
wherein the bivalent radical -R6-R7- having formula (d) is substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl and oxo; in particular halo; more in particular fluoro;
Y1 represents O or H;
Y2a represents O;
Y2b represent O or NH;
m represents 0, 1 or 2;
n represents 2 or 3;
s represents 3 or 4;
t represents 1 ;
and the pharmaceutically acceptable addition salts, and the solvates thereof.
In an embodiment, the invention relates to compounds of Formula (I) and
stereoisomeric forms thereof, wherein
R1 is halo; in particular chloro or fluoro;
R2 is hydrogen;
R 3 and R 4 are hydrogen; or R 3 and R 4 taken together form a bond; in particular R 3 and R4 are taken together to form a bond;
R5 is hydrogen;
R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
_(CH2)m-0-(CH2)n-m- ,
-(CH2)S- , or
Figure imgf000017_0001
wherein the bivalent radical -R6-R7- may, where possible, be substituted with one or more substituents selected from the group consisting of halo and oxo; in particular halo; m represents 0 or 1;
n represents 3;
s represents 3 or 4;
and the pharmaceutically acceptable addition salts, and the solvates thereof.
In an embodiment, the invention relates to compounds of Formula (I) and
stereoisomeric forms thereof, wherein
R1 is halo; in particular chloro or fluoro;
R2 is hydrogen;
R 3 and R 4 are hydrogen; or R 3 and R 4 taken together form a bond; in particular R 3 and R4 are taken together to form a bond;
R5 is hydrogen;
R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
_(CH2)m-0-(CH2)n-m- ,
-(CH2)S- , or
Figure imgf000018_0001
wherein the bivalent radical -(CH2)m-0-(CH2)n-m- or -(CH2)S- may, where possible, be substituted with one or more substituents selected from the group consisting of halo and oxo; in particular halo;
wherein the bivalent radical -0-CH2-0- is substituted with one or more substituents selected from the group consisting of halo and oxo; in particular halo; more in particular fluoro;
m represents 0 or 1;
n represents 3;
s represents 3 or 4;
and the pharmaceutically acceptable addition salts, and the solvates thereof.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein the bivalent radical -R6-R7- when having formula (d) is always substituted with one or more substituents selected from the group consisting of halo, C^alkyl and oxo; in particular halo; more in particular fluoro.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R3 and R4 are hydrogen.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R3 and R4 are taken together to form a bond.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R5 is hydrogen.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R1 is halo. An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R1 is halo, Ci-4alkyl or Ci-4alkyloxy.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R2 is halo.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R1 is halo, and R3 and R4 are taken together to form a bond.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R1 is halo and is in the 7-position, and R3 and R4 are taken together to form a bond.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R2 is hydrogen.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R1 is halo and R2 is hydrogen.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R1 is halo and is in the 9-position; in particular wherein R1 is chloro or fluoro and is in the 9- position; more in particular wherein R1 is chloro and is in the 9-position.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R1 is halo and is in the 7-position; in particular wherein R1 is chloro or fluoro and is in the 7- position; more in particular wherein R1 is chloro and is in the 7-position.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments
wherein R1 is halo and is in the 7-position, and R2 is hydrogen;
in particular wherein R1 is chloro or fluoro and is in the 7-position, and R2 is hydrogen; more in particular wherein R1 is chloro and is in the 7-position, and R2 is hydrogen.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments
wherein R1 is halo and is in the 7-position, and R2 is hydrogen or halo and is in the 9- position; in particular wherein R1 is chloro or fluoro and is in the 7-position, and R2 is hydrogen, chloro or fluoro and is in the 9-position;
more in particular wherein R1 is chloro and is in the 7-position, and R2 is hydrogen or chloro and is in the 9-position.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments
wherein R1 is halo and is in the 7-position, R2 is hydrogen, and R3 and R4 are taken together to form a bond.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments
wherein R1 is chloro and is in the 7-position, R2 is hydrogen, and R3 and R4 are taken together to form a bond.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R7 taken together form a bivalent radical -R6-R7-, having formula (a), (b), (c) or (d), in particular having formula (a), (c) or (d), wherein said bivalent radical -R6-R7- may, where possible, be substituted according to any of the other embodiments.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R7 taken together form a bivalent radical -R6-R7-, having formula (a), (b), (c) or (e), in particular having formula (a), (b) or (c), wherein said bivalent radical -R6-R7- may, where possible, be substituted according to any of the other embodiments.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R7 taken together form a bivalent radical -R6-R7-, having formula (a) or (b), wherein said bivalent radical -R6-R7- may, where possible, be substituted according to any of the other embodiments.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R7 taken together form a bivalent radical -R6-R7-, having formula (c), wherein said bivalent radical -R6-R7- may, where possible, be substituted according to any of the other embodiments.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R7 taken together form a bivalent radical -R6-R7-, having formula (d) or (e), in particular having formula (d), wherein said bivalent radical -R6-R7- may, where possible, be substituted according to any of the other embodiments.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R taken together form a bivalent radical -R6-R7-, having formula (d); wherein said bivalent radical -R6-R7- may, where possible, be substituted according to any of the other embodiments;
wherein t represents 1 ; and wherein Y2a and Y2b each independently represents O or R8b, in particular wherein Y2a and Y2b represent O.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R taken together form a bivalent radical -R6-R7-, having formula
-(CH2)m-Y1-(CH2)n-m-, -(CH2)n-m-Y1-(CH2)m-, -(CH2)S- -0-CH2-0- -0-CF2-0- or -0-C(=0)-N(CH3)-;
wherein the bivalent radical -(CH2)m-Y1-(CH2)n-m-, -(CH2)n-m-Y1-(CH2)m-, or -(CH2)S-, may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl, hydroxyl, Ci-4alkyloxy and oxo;
Y1 represents O, R8a or S;
R8a represents hydrogen or Ci-4alkyl;
m represents 0, 1 or 2;
n represents 2, 3 or 4;
s represents 3, 4 or 5.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R taken together form a bivalent radical -R6-R7-, having formula
-(CH2)m-Y1-(CH2)n-m-, -(CH2)n-m-Y1-(CH2)m-, -(CH2)S- -0-CF2-0- or -0-C(=0)-N(CH3)-;
wherein the bivalent radical -(CH2)m-Y1-(CH2)n-m-, -(CH2)n-m-Y1-(CH2)m-, or -(CH2)S-, may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl, hydroxyl, Ci-4alkyloxy and oxo;
Y1 represents O, R8a or S;
R8a represents hydrogen or Ci-4alkyl;
m represents 0, 1 or 2;
n represents 2, 3 or 4;
s represents 3, 4 or 5. An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
_(CH2)m-0-(CH2)n-m- ,
-(CH2)S- , or
Figure imgf000022_0001
wherein the bivalent radical -R6-R7- may, where possible, be substituted with one or more substituents selected from the group consisting of halo and oxo.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
_(CH2)m-0-(CH2)n-m- ,
-(CH2)S- , or
Figure imgf000022_0002
wherein the bivalent radical -(CH2)m-0-(CH2)n-m- or -(CH2)S- may, where possible, be substituted with one or more substituents selected from the group consisting of halo and oxo; and wherein the bivalent radical -0-CH2-0- is substituted with one or more substituents selected from the group consisting of halo and oxo.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein m represents 0, 1 or 2; n represents 2 or 3; s represents 3 or 4; t represents 1; r represents 0 or 1; q represents 0 or 1; provided that exactly one of q and r represents 0 and the other one represents 1.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
-(CH2)m-Y1-(CH2)n-m- (a), -Y2a-(CH2)t-Y2b- (d);
-(CH2)n-m-Y1-(CH2)m- (b),
-(CH2)S- (c),
wherein the bivalent radical -R6-R7- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl, hydroxyl, Ci-4alkyloxy and oxo;
wherein m represents 0, 1 or 2; n represents 2 or 3; s represents 3 or 4; t represents 1. An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
-(CH2)m-Y1-(CH2)n-m- (a), -Y2a-(CH2)t-Y2b- (d);
-(CH2)n-m-Y1-(CH2)m- (b),
-(CH2)S- (c),
wherein the bivalent radical -R6-R7- having formula (a), (b) or (c) may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl, hydroxyl, Ci-4alkyloxy and oxo;
wherein the bivalent radical -R6-R7- having formula (d) is substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl, hydroxyl, Ci-4alkyloxy and oxo;
wherein m represents 0, 1 or 2; n represents 2 or 3; s represents 3 or 4; t represents 1.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R7 taken together form a bivalent radical -R6-R7-, wherein -R6-R7- is selected from the group consisting of -0-CH2-0- -(CH2)3- -(CH2)4- -(CH2)2-0- -CH2-CH(CH3)-0-, -C(=0)-(CH2)2- -C(=0)-(CH2)3- -0-(CH2)2- -0-(CH2)3- -CH2-0-(CH2)2- -(CH2)2-C(=0)-, -0-CF2-(CH2)2- -(CH2)2-C(=0)-,
-CF2-(CH2)2- -C(=0)-0-CH2- -CH2-0-C(=0)-, -0-CF2-0- -0-C(=0)-N(CH3)-, -N(CH3)-(CH2)2- and -N(CH3)-C(=0)-C(CH3)2-;
in particular wherein -R6-R7- is selected from the group consisting of -(CH2)3-, -(CH2)4- -(CH2)2-0- -CH2-CH(CH3)-0-, -C(=0)-(CH2)2-, -C(=0)-(CH2)3-, -0-(CH2)2- -0-(CH2)3- -CH2-0-(CH2)2- -(CH2)2-C(=0)-, -0-CF2-(CH2)2-, -(CH2)2-C(=0)-, -CF2-(CH2)2- -C(=0)-0-CH2- -CH2-0-C(=0)-, -0-CF2-0- -0-C(=0)-N(CH3)-, -N(CH3)-(CH2)2- and -N(CH3)-C(=0)-C(CH3)2- .
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R7 taken together form a bivalent radical -R6-R7-, wherein -R6-R7- is selected from the group consisting of -0-CH2-0- and -0-CF2-0-; in particular wherein -R6-R7- is -0-CF2-0-
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R7 taken together form a bivalent radical -R6-R7- having the formula -0-CH2-0-, wherein -0-CH2-0- may be substituted with one or two substituents selected from the group consisting of halo, Ci-4alkyl, hydroxyl, Ci-4alkyloxy and oxo; in particular halo and Ci-4alkyl.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R taken together form a bivalent radical -R6-R7- having the formula -0-CH2-0-, wherein -0-CH2-0- is substituted with one or two substituents selected from the group consisting of halo, Ci-4alkyl, hydroxyl, Ci-4alkyloxy and oxo; in particular halo and Ci-4alkyl; more in particular halo; even more in particular fluoro.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R6 and R when representing a bivalent radical of formula (d), is always substituted with a substituent as defined in any of the other embodiments.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R8a and R represent hydrogen.
An embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein Y2a and Y2b represent O.
In a next embodiment the compound of Formula (I) is selected from the group consisting of:
4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine .HBr,
4-(l,3-benzodioxol-5-yl)-7-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine,
4-(l,3-benzodioxol-5-yl)-7-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine .HBr,
4-(l,3-benzodioxol-5-yl)-8-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine .HBr,
4-(l,3-benzodioxol-5-yl)-8-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine,
4-(l,3-benzodioxol-5-yl)-9-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine .HBr,
4-(l,3-benzodioxol-5-yl)-9-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine,
4-(l,3-benzodioxol-5-yl)-10-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine .HBr,
4-(l,3-benzodioxol-5-yl)-10-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine,
4-(l,3-benzodioxol-5-yl)-5,6-dihydro-7-methoxy-4H-pyrrolo[l,2-a][l,4]benzo- diazepine .HBr,
4-(l,3-benzodioxol-5-yl)-5,6-dihydro-7-methoxy-4H-pyrrolo[l,2-a][l,4]benzo- diazepine,
4-(l,3-benzodioxol-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine,
4-( 1 ,3-benzodioxol-5-yl)-7-chloro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine,
4-( 1 ,3-benzodioxol-5-yl)-8-chloro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine,
7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine .HC1,
7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine .HBr,
7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine,
7-chloro-4-(6-ethoxy-2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a]- [l,4]benzodiazepine .HBr,
7-chloro-4-(6-ethoxy-2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a]- [ 1 ,4]benzodiazepine,
7-chloro-5,6-dihydro-4-(5,6,7,8-tetrahydro-3-methoxy-2-naphthalenyl)-4H-pyrrolo- [l,2-a][l,4]benzodiazepine .HBr,
7-chloro-5,6-dihydro-4-(5,6,7,8-tetrahydro-3-methoxy-2-naphthalenyl)-4H-pyrrolo- [ 1 ,2-a] [ 1 ,4]benzodiazepine,
7, 10-dichloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine .HC1,
7, 10-dichloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine,
8, 10-dichloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine .HC1,
8, 10-dichloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine,
7,8-dichloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine .HC1,
7.8- dichloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine,
7.9- dichloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine .HC1,
7,9-dichloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine,
7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine,
7-chloro-4-(5,6,7,8-tetrahydro-2-naphthalenyl)-6H-pyrrolo[l,2-a][l,4]benzo- diazepine,
7.8- dichloro-4-(2,3-dihydro-lH-inden-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine,
7.9- dichloro-4-(2,3-dihydro-lH-inden-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine,
7.10- dichloro-4-(2,3 -dihydro- lH-inden-5-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine, 8, 10-dichloro-4-(2,3 -dihydro- lH-inden-5-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine, 7-chloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine .HC1,
7-chloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine,
7-chloro-4-(2,3-dihydro-6-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine .HC1,
7-chloro-4-(2,3-dihydro-6-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine,
7-chloro-4-(3,4-dihydro-lH-2-benzopyran-6-yl)-5,6-dihydro-4H-pyrrolo[l,2-a]- [l,4]benzodiazepine .HC1,
7-chloro-4-(3,4-dihydro-lH-2-benzopyran-6-yl)-5,6-dihydro-4H-pyrrolo[l,2-a]- [ 1 ,4]benzodiazepine,
4-(3,4-dihydro-lH-2-benzopyran-6-yl)-7-fluoro-5,6-dihydro-4H-pyrrolo[l,2-a]- [l,4]benzodiazepine .HC1,
4-(3,4-dihydro-lH-2-benzopyran-6-yl)-7-fluoro-5,6-dihydro-4H-pyrrolo[l,2-a]- [ 1 ,4]benzodiazepine,
7,8-dichloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine .HC1,
7.8- dichloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine,
7.9- dichloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine .HC1,
7.9- dichloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine,
7.10- dichloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine .HC1,
7, 10-dichloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine,
7, 10-dichloro-4-(2,3 -dihydro-6-benzofuranyl)-5,6-dihydro-4H-pyrrolo[ 1 ,2-a] [1,4]- benzodiazepine .HC1,
7, 10-dichloro-4-(2,3 -dihydro-6-benzofuranyl)-5,6-dihydro-4H-pyrrolo[ 1 ,2-a] [1,4]- benzodiazepine,
8, 10-dichloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine .HC1,
8, 10-dichloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine,
7-chloro-4-(2,3-dihydro-5-benzofuranyl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-(2,3-dihydro-6-benzofuranyl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-(3 ,4-dihydro- lH-2-benzopyran-6-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
7-chloro-4-(3 ,4-dihydro-2H- 1 -benzopyran-6-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
4-(3 ,4-dihydro- lH-2-benzopyran-6-yl)-7-fluoro-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
4-(3 ,4-dihydro-2H- 1 -benzopyran-6-yl)-7-fluoro-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine ,
9-chloro-4-(3 ,4-dihydro- lH-2-benzopyran-6-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
9- chloro-4-(3 ,4-dihydro-2H- 1 -benzopyran-6-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
10- chloro-4-(3 ,4-dihydro-2H- 1 -benzopyran-6-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
7.8- dichloro-4-(2,3-dihydro-5-benzofuranyl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine,
7.9- dichloro-4-(2,3-dihydro-5-benzofuranyl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 4-(3 ,4-dihydro-2H- 1 -benzopyran-6-yl)-7,9-difluoro-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
7.10- dichloro-4-(2,3 -dihydro-6-benzofuranyl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
8, 10-dichloro-4-(2,3 -dihydro-5-benzofuranyl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
7-chloro-4-(2,3-dihydro-5-methoxy-2-methyl-6-benzofuranyl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine .HBr,
7-chloro-4-(2,3-dihydro-5-methoxy-2-methyl-6-benzofuranyl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine, 7-chloro-4-(5-ethoxy-2,3-dihydro-2-methyl-6-benzofuranyl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine .HBr,
7-chloro-4-(5-ethoxy-2,3-dihydro-2-methyl-6-benzofuranyl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine,
5-(7-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-2,3-dihydro- lH-inden-l-one .HC1,
5- (7-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-2,3-dihydro- lH-inden-l-one,
6- (7-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-2,3-dihydro- lH-inden-l-one,
6-(7-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-2,3-dihydro- lH-inden-l-one .HC1,
4-(2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-7-fluoro-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine .HC1,
4-(2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-7-fluoro-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine,
4-(2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-7,9-difluoro-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine .HC1,
4- (2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-7,9-difluoro-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine,
6-(7-chloro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepin-4-yl)-2,3 -dihydro- IH-inden- 1 - one,
5- (7-chloro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepin-4-yl)-2,3 -dihydro- IH-inden- 1 - one,
5- ( 10-chloro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepin-4-yl)-2,3 -dihydro- IH-inden- 1 - one,
6- (7-chloro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepin-4-yl)-3 ,4-dihydro- 1 (2H)- naphthalenone,
6-(7-fluoro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepin-4-yl)-3 ,4-dihydro- 1 (2H)- naphthalenone,
6-(9-chloro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepin-4-yl)-3 ,4-dihydro- 1 (2H)- naphthalenone,
6-( 10-chloro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepin-4-yl)-3 ,4-dihydro- 1 (2H)- naphthalenone,
6-(7-chloro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepin-4-yl)- 1 (3H)-isobenzofuranone, 6-(7-fluoro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepin-4-yl)- 1 (3H)-isobenzofuranone, 6-(7,9-dichloro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepin-4-yl)- 1 (3H)- i sob enzofuranone,
5-(7-chloro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepin-4-yl)- 1 (3H)-isobenzofuranone,
7-chloro-4-(l, l-difluoro-2,3-dihydro-lH-inden-5-yl)-6H-pyrrolo[l,2-a][l,4]benzo- diazepine,
9- chloro-4-(l, l-difluoro-2,3-dihydro-lH-inden-5-yl)-6H-pyrrolo[l,2-a][l,4]benzo- diazepine,
10- chloro-4-( 1 , 1 -difluoro-2,3-dihydro- lH-inden-5 -yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
7-chloro-4-(2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-6H-pyrrolo[l,2-a]- [ 1 ,4]benzodiazepine,
4-(2,2-difluoro-3 ,4-dihydro-2H- 1 -benzopyran-6-yl)-7-fluoro-6H-pyrrolo[ 1 ,2-a]- [ 1 ,4]benzodiazepine,
9- chloro-4-(2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-6H-pyrrolo[l,2-a]- [ 1 ,4]benzodiazepine,
10- chloro-4-(2,2-difluoro-3 ,4-dihydro-2H- 1 -benzopyran-6-yl)-6H-pyrrolo[ 1 ,2-a]- [ 1 ,4]benzodiazepine,
4-(2,2-difluoro-3 ,4-dihydro-2H- 1 -benzopyran-6-yl)-7,9-difluoro-6H-pyrrolo[ 1 ,2-a]- [ 1 ,4]benzodiazepine,
7-chloro-4-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
9- chloro-4-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
10- chloro-4-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
4-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-7-fluoro-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
4- (2,2-difluoro-l,3-benzodioxol-5-yl)-7,9-difluoro-6H-pyrrolo[l,2-a][l,4]benzo- diazepine,
7,9-dichloro-4-(2,2-difluoro- 1 ,3 -benzodioxol-5-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
5- (7-chloro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepin-4-yl)-3 -methyl-2(3H)- benzoxazolone,
4-(2,3-dihydro- 1 -methyl- lH-indol-5-yl)-7-fluoro-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
7-chloro-4-(2,3-dihydro- 1 -methyl- lH-indol-5-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
10-chloro-4-(3 ,4-dihydro- lH-2-benzopyran-6-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzo- diazepine,
9-chloro-4-(2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine,
5-(10-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-2,3-dihydro- lH-inden-l-one,
5-(10-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-2,3-dihydro- lH-inden-l-one .HC1,
9- chloro-4-(3,4-dihydro-lH-2-benzopyran-6-yl)-5,6-dihydro-4H-pyrrolo[l,2-a]- [ 1 ,4]benzodiazepine,
10- chloro-4-(2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine,
7-chloro-4-( 1 , 1 -difluoro-2, 3 -dihydro- lH-inden-5 -yl)-9-fluoro-6H-pyrrolo [ 1 ,2-a] - [ 1 ,4]benzodiazepine,
5-(7-chloro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepin-4-yl)- 1 ,3 -dihydro- 1 ,3 ,3 -trimethyl- 2H-indol-2-one,
including stereoisomeric forms thereof,
and the pharmaceutically acceptable addition salts and the solvates thereof.
In a next embodiment the compound of Formula (I) is selected from the group consisting of:
7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine,
7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-(5,6,7,8-tetrahydro-2-naphthalenyl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzo- diazepine,
4-(2,2-difluoro-l,3-benzodioxol-5-yl)-7,9-difluoro-6H-pyrrolo[l,2-a][l,4]benzo- diazepine,
4-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-7-fluoro-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
6-(7-fluoro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepin-4-yl)-3 ,4-dihydro- 1 (2H)- naphthalenone,
7-chloro-4-(2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-6H-pyrrolo[l,2-a]- [ 1 ,4]benzodiazepine,
4-(3 ,4-dihydro- lH-2-benzopyran-6-yl)-7-fluoro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzo- diazepine, 7-chloro-4-(3 ,4-dihydro- lH-2-benzopyran-6-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
9-chloro-4-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine, and 10-chloro-4-(3,4-dihydro-2H-l-benzopyran-6-yl)-6H-pyrrolo[l,2-a]- [l,4]benzodiazepine.
In a next embodiment the compound of Formula (I) is selected from the group consisting of:
7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine,
7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine .HC1,
7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine .HBr,
7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-(5,6,7,8-tetrahydro-2-naphthalenyl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine, 4-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-7,9-difluoro-6H-pyrrolo[ 1 ,2-a][ 1 ^benzodiazepine,
4-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-7-fluoro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine, 6-(7-fluoro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepin-4-yl)-3 ,4-dihydro- 1 (2H)- naphthalenone,
7-chloro-4-(2,2-difluoro-3 ,4-dihydro-2H- 1 -benzopyran-6-yl)-6H-pyrrolo[ 1 ,2-a] [1,4]- benzodiazepine,
4-(3,4-dihydro-lH-2-benzopyran-6-yl)-7-fluoro-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-(3,4-dihydro-lH-2-benzopyran-6-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 9-chloro-4-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine, and 10-chloro-4-(3 ,4-dihydro-2H- 1 -benzopyran-6-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
including stereoisomeric forms thereof,
and the pharmaceutically acceptable addition salts and the solvates thereof.
All possible combinations of the above-indicated interesting embodiments are considered to be embraced within the scope of this invention.
The present invention also encompasses processes for the preparation of compounds of Formula (I) and subgroups thereof. The compounds of Formula (I) and the subgroups thereof can be prepared by a succession of steps as described hereunder. They are generally prepared from starting materials which are either commercially available or prepared by standard means obvious to those skilled in the art. The compounds of the present invention can be also prepared using standard synthetic processes commonly used by those skilled in the art of organic chemistry.
The compounds of the present invention, can be prepared according to Scheme 1 :
Scheme 1
Figure imgf000033_0001
Figure imgf000033_0002
The compounds of Formula (I) wherein R3 and R4 together form an extra bond, said compounds being represented by formula (I-b), can be prepared from the compounds represented by the formula (I-a), following art-known amine to imine oxidation reactions. These oxidation reactions may be conducted by reacting a compound of formula (I-a) with an oxidant such as, for example, lead tetra-acetate or manganese dioxide, in a reaction inert solvent such as a halogenated hydrocarbon e.g.
dichloromethane (DCM) or trichloromethane. The reaction rate can be enhanced by stirring and optionally heating the reaction mixture.
Alternatively, a compound of formula (I-b) can be prepared by an intramolecular cyclization of an intermediate of formula (II). In the presence of an acid such as, for example, POCl3, the amide in the intermediate of formula (II) can function as a C- electrophile, resulting in a ring closure. The reaction may be performed in a suitable solvents such as, for example, DCM (CH2CI2). Stirring and heating may enhance the rate of the reaction.
A compound of formula (I-a) can be prepared from an intermediate of formula (IV) by converting it in a salt (III) by reaction with an acid H+X" of formula (XI), and reacting said salt of formula (III) with an aldehyde of formula (XII) in an appropriate solvent such as an alcohol, e.g. methanol (MeOH), ethanol (EtOH), isopropanol, at an elevated temperature, preferably at reflux temperature.
Alternatively, the intermediate of formula (IV) may be reacted first with the aldehyde of formula (XII) and the thus formed imine may be cyclized in the presence of an acid H+X" of formula (XI) to a compound of formula (I-a).
Alternatively, a compound of formula (I-a) may be obtained by the reduction of a compound of formula (I-b) by using methods well-known to those skilled in the art. An intermediate of formula (II) may be prepared by a coupling reaction between an intermediate of formula (III) and (XIII). Said reaction may be performed in the presence of coupling agents such as typically 1 -hydroxy- lH-benzotriazole (HOBT) and N,-(ethylcarbonimidoyl)-N,N-dimethyl-l,3-propanediamine monohydrochloride (EDCI). The reaction may be performed in the presence of a base such as trietylamine (Et3N) and a suitable solvent such as, for example, DCM. Alternatively, an acid chloride derivative of (XIII) or a reactive ester derivative of (XIII) can also be used in this type of reaction to prepare an intermediate of formula (II).
An intermediate of formula (XIII) or its acid chloride or ester derivative, can be easily prepared by those skilled in the art. Intermediates of formula (III) and (IV) are prepared by reducing a l-(2-cyano- phenyl)pyrrole derivative of formula (V). Several procedures well-known to those skilled in the art may be used to reduce the nitrile function such as, for example:
1. LiAlH4/THF [S. Raines, S.Y. Chai and F.P. Palopoli; J. Heterocyclic Chem., 13, 711-716 (1976)]
2. i. sodium bis(2-methoxyethoxy)aluminate (Red-Al®) 70% w/w Toluene, RT : ii. NaOH 10%, RT [G.W.H. Cheeseman and S.G. Greenberg; J. Heterocyclic
Chem., 16, 241-244(1979)]
3a. i. KBH4/CF3COOH, THF; ii. H20; iii. HC1 [P. Trinka, P. Slegel and J. Reiter;
J. Prakt. Chem., 338, 675-678(1996)]
3b. Borane-dimethyl sulfide (1 : 1), THF
4a. RaNi (Raney Nickel) / H2
4b. RaNi / thiophene solution / (MeOH/NHs)
Even other well-known methods for reducing the nitrile function may also be used. An intermediate of formula (V) in turn is commercially available or alternatively can be easily prepared by, for example, treating a 2-aminobenzonitrile derivative of formula (VI) with tetrahydro-2,5-dimethoxyfuran in an inert solvent such as dioxane or tetrahydrofuran (THF) in the presence of an acid such as 4-chloropyridine
hydrochloride, or in an acidic solvent such as glacial acetic acid, at an elevated temperature, preferably at reflux temperature. Alternatively, an intermediate of formula (V) can also be prepared from an intermediate of formula (X). Typically, an
intermediate of formula (X) wherein Halo is defined as Br, I, CI or F, is reacted with pyrrole in the presence of a base such as, for example, Cs2C03 or NaH, in a suitable solvent such as typically DMF.
Alternatively, an intermediate of formula (IV) may be prepared by treating an intermediate of formula (VII) with borane-dimethyl sulfide (1 : 1) in a suitable solvent such as, for example, THF. The reaction typically can be performed in the presence of an acid such as HC1. After the reaction has proceeded, the reaction mixture can be basified with a suitable base such as NaOH. The reaction can be performed at an elevated temperature, preferably at reflux temperature.
An intermediate of formula (VII) can be prepared from an intermediate of formula (VIII). An intermediate of formula (VIII) can be reacted with a nitrogen source such as, NH3.H20 in the presence of HOBT and EDCI. This type of reaction typically can be performed in a suitable solvent like DMF. Stirring of the reaction mixture may enhance the rate of reaction. An intermediate of formula (VIII) can be easily prepared by treating an intermediate of formula (IX) with tetrahydro-2,5-dimethoxyfuran in an inert solvent such as dioxane in the presence of an acid such as pyridine hydrochloride (1 : 1) at an elevated temperature, preferably at reflux temperature. Alternatively, a reactive ester derivative of (IX) can also be used in this type of reaction to prepare an intermediate of formula (VIII).
All other intermediates and starting materials are commercially available or can be easily prepared by those skilled in the art. The synthesis of some intermediates and some of the starting materials is exemplified in the experimental part.
The person skilled in the art will realize that for some of the above mentioned reactions anhydrous conditions need to be applied and/or an inert protecting atmosphere such as, for example, N2 or argon, must be used.
In all these preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and
chromatography. In particular, stereoisomers can be isolated chromatographically using a chiral stationary phase such as, for example, Chiralpak® AD (amylose 3,5 dimethylphenyl carbamate) or Chiralpak® AS, both purchased from Daicel Chemical Industries, Ltd, in Japan.
Pure stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of art-known procedures. Enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by
chromatographic techniques using chiral stationary phases. Said pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms of the appropriate starting materials, provided that the reaction occurs stereoselectively or stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereoselective or stereospecific methods of preparation. These methods will advantageously employ chirally pure starting materials. Stereoisomeric forms of the compounds of Formula (I) are obviously intended to be included within the scope of the invention.
The chirally pure forms of the compounds of Formula (I) form a preferred group of compounds. It is therefore that the chirally pure forms of the intermediates and their salt forms are particularly useful in the preparation of chirally pure compounds of Formula (I). Also enantiomeric mixtures of the intermediates are useful in the preparation of compounds of Formula (I) with the corresponding configuration. The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against dematiaceous hyphomycetes, dimorphic pathogens, dermatophytes,
zygomycetes, hyaline hyphomycetes, yeasts and yeastlike organisms.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against dimorphic pathogens, yeasts and yeastlike organisms.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against moulds.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against a wide variety of fungi, such as Candida spp., e.g. Candida albicans, Candida glabrata, Candida krucei', Candida parapsilosis, Candida kefyr, Candida tropicalis; Aspergillus spp., e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Sporothrix schenckii; Epidermophyton floccosum;
Microsporum spp., e.g. Microsporum canis, Microsporum gypseum; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum, Trichophyton tonsurans, Trichophyton verrucosum, Trichophyton violaceum, Trichophyton inter digitale, Trichophyton soudanense; Fusarium spp., e.g. Fusarium solani, Fusarium oxysporum, Fusarium proliferatum, Fusarium
verticillioides; Rhizomucor spp., e.g. Rhizomucor miehei, Rhizomucor pusillus; Mucor circinelloides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Malassezia furfur; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.;
Scytalidium; Scedosporium spp., e.g. Scedosporium apiospermum, Scedosporium proliflcans; Trichoderma spp.; Penicillium spp.; Penicillium marneffei;
Blastoschizomyces.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against a wide variety of fungi, such as Candida parapsilosis; Aspergillus spp., e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus
neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum spp., e.g. Microsporum canis, Microsporum gypseum; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum, Trichophyton tonsurans, Trichophyton verrucosum, Trichophyton violaceum, Trichophyton inter digitale, Trichophyton soudanense; Fusarium spp., e.g. Fusarium solani,
Fusarium oxysporum, Fusarium proliferatum, Fusarium verticillioides; Rhizomucor spp., e.g. Rhizomucor miehei, Rhizomucor pusillus; Mucor circinelloides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.; Scytalidium; Scedosporium spp., e.g.
Scedosporium apiospermum, Scedosporium prolificans; Trichoderma spp.; Penicillium spp. ; Penicillium marneffei; Blastoschizomyces.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against a wide variety of fungi, such as Candida parapsilosis; Aspergillus spp., e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus
neoformans; Epidermophyton floccosum; Microsporum spp., e.g. Microsporum canis, Microsporum gypseum; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum, Trichophyton tonsurans,
Trichophyton verrucosum, Trichophyton violaceum, Trichophyton inter digitale,
Trichophyton soudanense; Fusarium spp., e.g. Fusarium solani, Fusarium oxysporum, Fusarium proliferatum, Fusarium verticillioides; Rhizomucor spp., e.g. Rhizomucor miehei, Rhizomucor pusillus; Mucor circinelloides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.; Scytalidium; Scedosporium spp., e.g. Scedosporium apiospermum, Scedosporium prolificans; Trichoderma spp.; Penicillium spp. ; Penicillium marneffei; Blastoschizomyces; in particular Aspergillus spp., e.g. Aspergillus fumigatus,
Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Epidermophyton floccosum; Microsporum spp., e.g. Microsporum canis, Microsporum gypseum;
Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum,
Trichophyton quinckeanum, Trichophyton tonsurans, Trichophyton verrucosum, Trichophyton violaceum, Trichophyton inter digitale, Trichophyton soudanense;
Fusarium spp., e.g. Fusarium solani, Fusarium oxysporum, Fusarium proliferatum, Fusarium verticillioides; Rhizomucor spp., e.g. Rhizomucor miehei, Rhizomucor pusillus; Mucor circinelloides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.; Scytalidium; Scedosporium spp., e.g. Scedosporium apiospermum, Scedosporium prolificans; Trichoderma spp.; Penicillium spp. ; Penicillium marneffei;
Blastoschizomyces.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against a wide variety of fungi, such as Candida parapsilosis; Aspergillus spp.
Cryptococcus neoformans; Sporothrix schenckii; Microsporum spp.; Fusarium spp.; Scedosporium spp.;
in particular Candida parapsilosis; Aspergillus spp.; Cryptococcus neoformans;
Microsporum spp.; Fusarium spp.; Scedosporium spp.;
more in particular Aspergillus spp.; Cryptococcus neoformans; Microsporum spp.; Fusarium spp.; Scedosporium spp.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against a wide variety of fungi, such as Candida parapsilosis; Aspergillus spp.;
Cryptococcus neoformans; Trichophyton spp.; Sporothrix schenckii; Microsporum spp.; Fusarium spp.; Scedosporium spp.;
in particular Aspergillus spp.; Microsporum spp.; Trichophyton spp.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against fungi such as Candida parapsilosis, Aspergillus spp., Cryptococcus neoformans, Microsporum spp., and Trichophyton spp.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against fungi such as Candida parapsilosis; Aspergillus spp., e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum canis; Trichophyton spp., e.g.
Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum; in particular Candida parapsilosis; Aspergillus spp., e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Epidermophyton floccosum; Microsporum canis; Trichophyton spp., e.g. Trichophyton mentagrophytes,
Trichophyton rubrum, Trichophyton quinckeanum;
more in particular Aspergillus spp., e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Epidermophyton floccosum;
Microsporum canis; Trichophyton spp., e.g. Trichophyton mentagrophytes,
Trichophyton rubrum, Trichophyton quinckeanum.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Candida parapsilosis, Aspergillus fumigatus, Cryptococcus neoformans, Sporothrix schenckii, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, Scedosporium apiospermum and Scedosporium prolificans; in particular Aspergillus fumigatus, Microsporum canis, Trichophyton mentagrophytes,
Trichophyton rubrum, Scedosporium apiospermum and Scedosporium prolifwans.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against fungi such as Candida parapsilosis; Aspergillus spp.; Cryptococcus neoformans; Microsporum spp.; Trichophyton spp.; Scedosporium spp..
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Candida parapsilosis, Aspergillus fumigatus, Cryptococcus neoformans,
Sporothrix schenckii, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, Scedosporium apiospermum, Scedosporium prolifwans;
in particular Candida parapsilosis, Aspergillus fumigatus, Cryptococcus neoformans, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum,
Scedosporium apiospermum and Scedosporium prolifwans;
more in particular Aspergillus fumigatus, Cryptococcus neoformans, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, Scedosporium
apiospermum and Scedosporium prolifwans.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Candida parapsilosis, Aspergillus fumigatus, Cryptococcus neoformans, Sporothrix schenckii, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, Scedosporium apiospermum, Scedosporium prolifwans, Rhizopus oryzae, Rhizomucor miehei.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Candida parapsilosis B66126, Aspergillus fumigatus B42928, Cryptococcus neoformans B66663, Sporothrix schenckii B62482, Microsporum canis B68128, Trichophyton mentagrophytes B 70554, Trichophyton rubrum B 68183, Scedosporium apiospermum IHEM3817, Scedosporium prolifwans IHEM21157.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Candida parapsilosis B66126, Aspergillus fumigatus B42928, Cryptococcus neoformans B66663, Sporothrix schenckii B62482, Microsporum canis B68128, Trichophyton mentagrophytes B 70554, Trichophyton rubrum B68183, Scedosporium apiospermum IHEM3817, Scedosporium prolificans IHEM21157, Rhizopus oryzae IHEM5223 and Rhizomucor miehei IHEM13391.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Candida parapsilosis, Aspergillus fumigatus, Cryptococcus neoformans, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Microsporum canis, Trichophyton rubrum, Aspergillus fumigatus,
Cryptococcus neoformans and Trichophyton mentagrophytes;
in particular Microsporum canis B68128, Trichophyton rubrum B68183, Aspergillus fumigatus B42928, Cryptococcus neoformans B66663 and Trichophyton
mentagrophytes B 70554.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Candida parapsilosis B66126, Aspergillus fumigatus B42928, Cryptococcus neoformans B66663, Microsporum canis B68128, Trichophyton mentagrophytes B 70554, Trichophyton rubrum B 68183, Rhizopus oryzae IHEM5223, Rhizomucor miehei IHEM 13391.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Candida parapsilosis B66126, Aspergillus fumigatus B42928, Cryptococcus neoformans B66663, Microsporum canis B68128, Trichophyton mentagrophytes B 70554, Trichophyton rubrum B 68183.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against a variety of fungi that infect the skin, hair and nails, as well as subcutaneous and systemic fungal pathogens.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against the 3 dermatophyte genera: Trichophyton, Microsporum and Epidermophyton; in particular against Trichophyton and Microsporum.
The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, may be active against dermatophytes and Aspergillus spp.; in particular dermatophytes and Aspergillus fumigatus; more in particular Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum and Aspergillus fumigatus; even more in particular Microsporum canis, Trichophyton mentagrophytes and Trichophyton rubrum.
The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Trichophyton mentagrophytes, Trichophyton rubrum and Aspergillus spp.; in particular Trichophyton mentagrophytes, Trichophyton rubrum and Aspergillus fumigatus.
The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Trichophyton mentagrophytes; Trichophyton rubrum; Aspergillus spp., e.g. Aspergillus fumigatus; Fusarium spp.; Mucor Spp.; Zygomycetes spp.; Scedosporium spp.; Microsporum canis; Sporothrix schenckii; Cryptococcus neoformans and Candida parapsilosis.
The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against dermatophytes.
The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Aspergillus fumigatus.
The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Microsporum canis, in particular Microsporum canis B68128.
The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Trichophyton rubrum, in particular Trichophyton rubrum B68183.
The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against a wide variety of fungi, such as one or more of the fungi mentioned hereinbefore. The compounds of Formula (I) and stereoisomeric forms thereof, and the
pharmaceutically acceptable addition salts, and the solvates thereof, are potent antifungals when administered orally or topically.
The compounds of the present invention may be useful as ergosterol synthesis inhibitors.
In view of the utility of the compound of Formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from, or a method of preventing warm-blooded animals, including humans, to suffer from any one of the diseases mentioned hereinbefore. Hence, compounds of Formula (I) are provided for use as a medicine. Also the use of a compound of Formula (I) in the manufacture of a medicament useful in treating fungal infections is provided. Further compounds of Formula (I) are provided for use in the treatment of fungal infections
As used herein, the term "treatment" is intended to refer to all processes, wherein there may be a slowing, interrupting, arresting, or stopping of the progression of an infection, but does not necessarily indicate a total elimination of all symptoms.
The invention relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use as a medicament.
The invention also relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for the treatment or prevention of fungal infections; in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.
The invention also relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for the treatment of fungal infections; in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.
The invention also relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use in the treatment or prevention of fungal infections; in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.
The invention also relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use in the treatment of fungal infections; in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.
The invention also relates to compounds according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use in the treatment or prevention, in particular treatment, of fungal infections; in particular fungal infections caused by one or more of the fungi selected from a group consisting of fungi mentioned hereinbefore.
The invention also relates to compounds according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use in the treatment or prevention of a fungal infection, in particular a fungal infection caused by one or more of the fungi mentioned hereinbefore.
The invention also relates to compounds according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use in the treatment or prevention of a fungal infection, wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Candida spp.; Aspergillus spp. Cryptococcus
neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum spp.; Trichophyton spp; Fusarium spp.; Rhizomucor spp.; Mucor circinelloides; Rhizopus spp.; Malassezia furfur; Acremonium spp.; Paecilomyces; Scopulariopsis;
Arthrographis spp.; Scytalidium; Scedosporium spp.; Trichoderma spp.; Penicillium spp. ; Penicillium marneffei; and Blastoschizomyces;
in particular wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Candida parapsilosis; Aspergillus spp.; Cryptococcus neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum spp.; Trichophyton spp.; Fusarium spp.; Rhizomucor spp.; Mucor circinelloides; Rhizopus spp.; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.;
Scytalidium; Scedosporium spp.; Trichoderma spp.; Penicillium spp. ; Penicillium marneffei; and Blastoschizomyces;
even more in particular wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum and Aspergillus fumigatus.
The novel compounds described in the present invention may be useful in the treatment or prevention of diseases or conditions selected from the group consisting of infections caused by dermatophytes, systemic fungal infections and onychomycosis. The novel compounds described in the present invention may be useful in the treatment or prevention of diseases or conditions such as for example infections caused by dermatophytes, systemic fungal infections or onychomycosis.
The invention also relates to the use of a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for the manufacture of a medicament.
The invention also relates to the use of a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for the manufacture of a medicament for the treatment or prevention, in particular treatment, of fungal infections, in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.
The compounds of the present invention can be administered to mammals, preferably humans, for the treatment or prevention, in particular treatment, of fungal infections, in particular fungal infections caused by one or more of the fungi mentioned hereinbefore. In view of the utility of the compound of Formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from or a method of preventing warm-blooded animals, including humans, to suffer from fungal infections, in particular fungal infections caused by one or more of the fungi mentioned
hereinbefore.
Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of an effective amount of a compound of Formula (I), a stereoisomeric form thereof or a pharmaceutically acceptable addition salt or solvate thereof, to warm-blooded animals, including humans.
Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of an effective amount of a compound of Formula (I), to warm-blooded animals, including humans.
Those of skill in the treatment of such diseases could determine the effective therapeutic daily amount from the test results presented hereinafter. An effective therapeutic daily amount would be from about 0.005 mg/kg to 50 mg/kg, in particular 0.01 mg/kg to 50 mg/kg body weight, more in particular from 0.01 mg/kg to 25 mg/kg body weight, preferably from about 0.01 mg/kg to about 15 mg/kg, more preferably from about 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.01 mg/kg to about 1 mg/kg, most preferably from about 0.05 mg/kg to about 1 mg/kg body weight. The amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutically effect will of course, vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.
A method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day. In these methods of treatment the compounds according to the invention are preferably formulated prior to
administration. As described herein below, suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition.
The present invention also provides compositions for treating or preventing fungal infections comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.
The carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
The compounds of the present invention,that are suitable to treat or prevent fungal infections, may be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of Formula (I) and one or more additional therapeutic agents, as well as administration of the compound of Formula (I) and each additional therapeutic agents in its own separate pharmaceutical dosage formulation. For example, a compound of Formula (I) and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.
In view of their useful pharmacological properties, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. The compounds according to the invention, in particular the compounds according to Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally, rectally, percutaneously, by parenteral injection or by inhalation. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid
preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of Formula (I) may be formulated in an oil for prolonged action. Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be
administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. Acid or base addition salts of compounds of Formula (I) due to their increased water solubility over the corresponding base or acid form, are more suitable in the preparation of aqueous compositions. Transungual compositions are in the form of a solution and the carrier optionally comprises a penetration enhancing agent which favours the penetration of the antifungal into and through the keratinized ungual layer of the nail. The solvent medium comprises water mixed with a co-solvent such as an alcohol having from 2 to 6 carbon atoms, e.g. ethanol.
In order to enhance the solubility and/or the stability of the compounds of Formula (I) in pharmaceutical compositions, it can be advantageous to employ α-, β- or γ- cyclodextrins or their derivatives, in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl-P-cyclodextrin or sulfobutyl-P-cyclodextrin. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds according to the invention in pharmaceutical compositions.
The ratio of active ingredient over cyclodextrin may vary widely. For example ratios of 1/100 to 100/1 may be applied. Interesting ratios of active ingredient over cyclodextrin range from about 1/10 to 10/1. More interesting ratios of active ingredient over cyclodextrin range from about 1/5 to 5/1.
Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0.1 to 70 % by weight, even more preferably from 0.1 to 50 % by weight of the compound of Formula (I), and, from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
For parenteral compositions, also other ingredients, to aid solubility for example, e.g. cyclodextrins, may be included. Appropriate cyclodextrins are α-, β-, γ-cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C\ .galkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD; hydroxyCi .galkyl, particularly hydroxy ethyl, hydroxy-propyl or hydroxybutyl; carboxyCi .galkyl, particularly carboxymethyl or carboxy-ethyl; Ci-6alkylcarbonyl, particularly acetyl.
Especially noteworthy as complexants and/or solubilizers are β-CD, randomly methylated β-CD, 2,6-dimethyl^-CD, 2-hydroxyethyl^-CD, 2-hydroxyethyl-y-CD,
2-hydroxypropyl-y-CD and (2-carboxymethoxy)propyl^-CD, and in particular
2-hydroxypropyl^-CD (2-ΗΡ-β ϋ).
The term mixed ether denotes cyclodextrin derivatives wherein at least two
cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxy-propyl and hydroxy ethyl. The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The average substitution degree (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit. The M.S. and D.S value can be determined by various analytical techniques such as nuclear magnetic resonance ( MR), mass spectrometry (MS) and infrared
spectroscopy (IR). Depending on the technique used, slightly different values may be obtained for one given cyclodextrin derivative. Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125 to 10 and the D.S. ranges from 0.125 to 3.
Other suitable compositions for oral or rectal administration comprise particles consisting of a solid dispersion comprising a compound of Formula (I) and one or more appropriate pharmaceutically acceptable water-soluble polymers.
The term "a solid dispersion" defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, in casu the compound of Formula (I) and the water-soluble polymer, wherein one component is dispersed more or less evenly throughout the other component or components ( in case additional
pharmaceutically acceptable formulating agents, generally known in the art, are included, such as plasticizers, preservatives and the like). When said dispersion of the components is such that the system is chemically and physically uniform or
homogenous throughout or consists of one phase as defined in thermo-dynamics, such a solid dispersion will be called "a solid solution". Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered. This advantage can probably be explained by the ease with which said solid solutions can form liquid solutions when contacted with a liquid medium such as the gastro-intestinal juices. The ease of dissolution may be attributed at least in part to the fact that the energy required for dissolution of the components from a solid solution is less than that required for the dissolution of components from a crystalline or microcrystalline solid phase.
The term "a solid dispersion" also comprises dispersions which are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase. For example, the term "a solid dispersion" also relates to a system having domains or small regions wherein amorphous, microcrystalline or crystalline compound of Formula (I), or amorphous, microcrystalline or crystalline water-soluble polymer, or both, are dispersed more or less evenly in another phase comprising water-soluble polymer, or compound of Formula (I), or a solid solution comprising compound of Formula (I) and water-soluble polymer. Said domains are regions within the solid dispersion distinctively marked by some physical feature, small in size, and evenly and randomly distributed throughout the solid dispersion.
It may further be convenient to formulate the present antifungal compounds in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Useful surface modifiers are believed to include those which physically adhere to the surface of the antifungal agent but do not chemically bond to the antifungal agent.
Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.
Yet another interesting way of formulating the present compounds involves a pharmaceutical composition whereby the present antifungals are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration.
Said beads comprise a central, rounded or spherical core, a coating film of a
hydrophilic polymer and an antifungal agent and a seal-coating layer.
Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Since the compounds according to the invention are potent orally administrable compounds, pharmaceutical compositions comprising said compounds for
administration orally are especially advantageous. The following examples illustrate the present invention.
Experimental part
Hereinafter, the term "DCM" means dichloromethane; "LCMS" means Liquid
Chromatography/Mass spectrometry; "Pd(OAc)2 means palladium(II) acetate; "Et3 " means trietylamine; "DMF" means N,N-dimethylformamide; "TLC" means thin layer chromatography; "PE" means petroleum ether; "TFA" means trifluoroacetic acid; "psi" means pound-force per square inch; "FIPLC" means high-performance liquid chromatography; "r.t." means room temperature; "m.p." means melting point; "min" means minute(s); "h" means hour(s); "EtOAc" means ethyl acetate; "EtOH" means ethanol; "MeOH" means methanol; "r.m." means reaction mixture(s); "q.s." quantum sufficit; "TFIF" means tetrahydrofuran; "HO Ac" means acetic acid; "DPPP" means l, l'-(l,3-propanediyl)bis[l,l-diphenylphosphine]; "HOBT" means 1-hydroxy-lH- benzotriazole; "Me2S" means dimethyl sulfide; and "EDCI" means
N,-(ethylcarbonimidoyl)-N,N-dimethyl-l,3-propanediamine monohydrochloride.
The person skilled in the art will realize that for some reactions in the examples anhydrous conditions need to be applied and/or an inert protecting atmosphere such as, for example, N2 or argon, must be used.
A. Preparation of the intermediates
Example Al
a) Preparation of intermediate 1
Figure imgf000051_0001
A mixture of 2-amino-6-chlorobenzonitrile (17.72 g, 0.116 mol) and tetrahydro-2,5- dimethoxyfuran (0.116 mol) in HO Ac (100 ml) was stirred and refluxed for 30 min. Subsequently, the mixture was cooled and evaporated. The residue was purified over silica gel on a glass filter (eluent: DCM). The product fractions were collected and the solvent was evaporated. The residue was crystallized from EtOH. Yield: 18.83 g of intermediate 1 (80 % yield).
b) Preparation of intermediate 2
Figure imgf000051_0002
Borane-dimethyl sulphide (1 : 1) (2.5 ml of a 10 N solution of BH3 in Me2S, 0.0247 mol) was added at r.t. under N2 atmosphere to a solution of intermediate 1 (5.0 g, 0.0247 mol) in THF (20 ml). The mixture was heated to reflux for 10 h. After cooling to r. , HC1 (6 N aqueous solution; 15 ml) was added dropwise. Subsequently the mixture was heated under reflux for 30 min. The solution was cooled to 0 °C and then NaOH (6 N; q.s.) was added. The mixture was extracted with DCM (50 ml x 3) and the separated organic layer was dried (Na2S04), filtered, and the solvent was evaporated to yield an oil. HCl/dioxane (6 N; 5 ml) and dioxane (20 ml) were added and the precipitate was collected by filtration and dried. Yield: 5.14 g of intermediate 2 (86 % yield; .HQ).
Example A2
a) Preparation of intermediat
Figure imgf000052_0001
NaH (60 % in mineral oil; 5.66 g, 141.48 mmol) was added portionwise to a mixture of 5-bromo-l,3-dihydro-2H-Indol-2-one (10.0 g, 47.16 mmol) in THF (100 ml) at 0 °C.
The mixture was stirred for 30 min, and then CH3I (21.42 g, 150.91 mmol) was added.
The r.m. was stirred at 0 °C for 30 min. Subsequently, H20 (2 ml) was added dropwise.
The solvent was removed in vacuo. The residue was dissolved in H20 (q.s.) and extracted with EtOAc. The separated organic layer was washed with brine, dried (Na2S04), filtered and evaporated in vacuo. The residue was purified by column chromatography (eluent: PE/EtOAc 20/1). The desired fractions were collected and the solvent was evaporated. Yield: 9.5 g of intermediate 3 (79 % yield).
b) Preparation of intermediat
Figure imgf000052_0002
Pd(OAc)2 (0.31 g, 1.38 mmol) was added to a mixture of intermediate 3 (5.0 g, 19.7 mmol), DPPP (0.568 g, 1.38 mmol) and Et3N (27 ml) in MeOH (200 ml) and DMF (200 ml). The solution was stirred and pressurized to 40 psi with CO at 70 °C for 4 h. Subsequently, the mixture was cooled to r.t. and diluted with H20. The mixture was extracted with EtOAc. The separated organic layer was washed with H20 and brine, was dried (Na2S04), filtered, and concentrated in vacuo. The crude was purified by column chromatography (eluent: PE/EtOAc 10/1). The desired fractions were collected and the solvent was evaporated. Yield: 2.4 g of intermediate 4 (52 % yield). c) Preparation of intermedia
Figure imgf000053_0001
A mixture of intermediate 4 (2.4 g, 10.3 mmol) in NaOH (2N; 20 ml) and EtOH (30 ml) was stirred at r.t. for 4 h. Subsequently, HCl was added to pH 1-2. The mixture was extracted with EtOAc. The separated organic layer was dried (Na2S04), filtered, and the solvent was evaporated in vacuo to yield 2.1 g of intermediate 5 as a white solid
(100 % yield).
d) Preparation of intermediate
Figure imgf000053_0002
Intermediate 5 (1.35 g, 6.17 mmol) was dissolved in DCM (30 ml). Et3N (4.5 ml, 30.86 mmol), HOBT (0.83 g, 6.17 mmol), EDCI (1.18 g, 6.17 mmol) and intermediate 2 (1.5 g, 6.17 mmol) were added to the solution. The r.m. was stirred overnight at r.t. The mixture was concentrated, and H20 was added to the residue. This aqueous mixture was extracted with DCM. The separated organic layer was dried (Na2S04), filtered and the solvent was evaporated. The crude product was purified by HPLC (YMC column 25 x 150 mm; mobile phase: 35%-45% CH3CN (0.1 % TFA)/H20 (0.1 % TFA); flow rate 20 ml/min; 20 min). The product fractions were collected and the solvent was evaporated. Yield: 0.77 g of intermediate 6 (34 % yield).
Example A3
Preparation of intermedia
Figure imgf000053_0003
The mixture of intermediate 2 (1.0 g, 4.2 mmol), 5,6,7,8-tetrahydro-2- naphthalenecarboxylic acid (0.88 g, 5.0 mmol), Et3N (5.0 ml, 36.2 mmol), HOBT (0.62 g, 4.6 mmol) and EDCI (0.96 g, 5.0 mmol) in DCM (50 ml) was stirred overnight at r.t. Subsequently, the mixture was washed with H20 (3 x 100 ml), dried (MgS04), filtered and the solvent was evaporated. The residue was washed with MeOH. The solid was collected and dried in vacuo. Yield: 0.9 g of intermediate 7 (59 % yield).
Example A4
a) Preparation of intermedia
Figure imgf000054_0001
A mixture of 1,2-ethanedithiol (1.88 g, 20 mmol) in DCM (20 ml) was added to trimethylaluminum (20 ml) at -78 °C. After addition, the mixture was warmed to r.t. for 30 min. Subsequently, the mixture was cooled again to -20 °C, and a mixture of 6- bromo-3,4-dihydro-2H-l-benzopyran-2-one (4.54 g, 20 mmol) in DCM (80 ml) was added dropwise. The r.m. was stirred overnight at r.t., poured into ice-water, acidified (concentrated HC1), and extracted with DCM. The separated organic layer was dried (MgS04), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: PE/EtOAc 100/1). The desired fractions were collected and the solvent was evaporated to yield 3.5 g of intermediate 8 (58 % yield; white solid).
b) Preparation of intermediate 9
Figure imgf000054_0002
Triethylamine trihydrofluoride (8.05 g, 50 mmol, (C2H5)3N■ 3HF) was added to a mixture of intermediate 8 (3.0 g, 10 mmol) in DCM (50 ml) at -78 °C. Then 1,3- dibromo-5,5-dimethyl-2,4-imidazolidinedione (14.3 g, 50 mmol) in DCM (30 ml) was added in 30 min. The mixture was stirred for 2 h at r.t. Subsequently, the solution was quenched with NaOH (IN, q.s.) and extracted with DCM (200 ml). The separated organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluent: PE) The desired fractions were collected and the solvent was evaporated. Yield: 2 g of intermediate 9 (80 % yield; oil).
c) Preparation of intermediate 10
Figure imgf000054_0003
Et3N (13 ml, 92.4 mmol) was added to a mixture of intermediate 9 (2.0 g, 8.03 mmol), DPPP (0.267 g, 0.646 mol) and Pd(OAc)2 (0.145 g, 0.646 mol) in H20 (40 ml) and CH3CN (100 ml). The r.m. was stirred and pressurized to 4 MPa with CO at 100 °C for 24 h. Then, the mixture was cooled to r.t. and diluted with H20. The precipitate was filtered off, and the filtrate was adjusted with HCl. The precipitate was filtered off, washed with H20, and dried in vacuo to yield 0.3 g of intermediate 10 (17 % yield). d) Preparation of intermediate 11
Figure imgf000055_0001
Et3N (2 ml, 12.18 mmol), HOBT (0.1 g, 0.77 mmol), EDCI (0.15 g, 0.77 mmol) and intermediate 2 (0.17 g, 0.7 mmol) were added to a solution of intermediate 10 (0.17 g, 0.77 mmol) in DCM (15 ml). The r.m. was stirred at r.t. overnight. H20 was added and the aqueous mixture was extracted with DCM. The separated organic layer was dried (Na2S04), filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: PE/EtOAc from 15/1 to 10/1). The product fractions were collected and the solvent was evaporated in vacuo to yield 0.180 g of intermediate 11 (64 % yield).
Example A5
a) Preparation of intermediate 12
Figure imgf000055_0002
A mixture of 2,6-difluorobenzonitrile (27.8 g, 200 mmol), pyrrole (13.4 g, 400 mmol) and Cs2C03 (97 g, 600 mmol) in DMF (500 ml) was stirred and heated overnight to 80 °C. The mixture was cooled to r.t., the solid was filtered off, and the solvent was removed. The residue was purified by column chromatography over silica gel (eluent: PE/EtOAc 5/1). The desired fractions were collected and the solvent was evaporated to yield 19 g of intermediate 12 (51 % yield; white solid).
b) Preparation of intermediate 13
.HCl
Figure imgf000055_0003
Borane-dimethyl sulphide (1 : 1) (12 ml of a 10 M solution of BH3 in Me2S, 0.120 mol) was added at r.t. under N2 atmosphere to a solution of intermediate 12 (19 g, 0.102 mol) in THF (250 ml). The mixture was heated to reflux overnight under N2. Then, HCl (6 N; 10 ml) was added to the mixture while the mixture was cooled on an ice-water bath. The mixture was refluxed again for 30 min, and then solid NaOH was added until pH>9 while the mixture was cooled on an ice-water bath. The mixture was extracted with DCM (2 x 300 ml). The organic layer was separated, dried (MgS04), filtered and the solvent was evaporated. The brown residue was converted to the HCl salt (1 : 1) with HCl/2-propanol. Yield: 17 g of intermediate 13 (75 % yield; .HCl).
c) Preparation of intermediate 14
Figure imgf000056_0001
A mixture of intermediate 13 (0.95 g, 4.2 mmol), 2,2-difluoro-l,3-benzodioxole-5- carboxylic acid (1.0 g, 5.0 mmol), Et3N (5.0 ml, 36 mmol), HOBT (0.62 g) and EDCI (0.95 g) in DCM (50 ml) was stirred overnight at r.t. The mixture was washed with H20 (3 x 100 ml), dried (MgS04), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (eluent: PE/EtOAc from 20/1 to 10/1). The desired fractions were collected and the solvent was evaporated in vacuo. Yield: 0.8 g of intermediate 14 (51 % yield).
Example A6
a) Preparation of intermediate
Figure imgf000056_0002
A mixture of 2-amino-3-chlorobenzoic acid (25 g, 145.7 mmol), tetrahydro-2,5- dimethoxyfuran (145.7 mmol), and 4-chloropyridine hydrochloride (1 : 1) in dioxane (300 ml) was heated to reflux overnight. The reaction mixture was washed with H20 (3 x 300 ml) and extracted with DCM (3 x 200 ml). The separated organic layer was dried and evaporated in vacuo. Yield: 32 g of crude intermediate 15 (99 % yield), used as such in the next reaction step. b) Preparation of intermediate
Figure imgf000057_0001
A mixture of intermediate 15 (32 g crude, approximately 145 mmol), HOBT (22.3 g, 165 mmol), EDCI (31.6 g, 165 mmol) and NH3.H20 (35 ml) in DMF (300 ml) was stirred overnight at r.t. The mixture was quenched with H20 (300 ml), and the product was filtered off. Yield: 23 g of intermediate 16 (72 % yield).
c) Preparation of intermediate
Figure imgf000057_0002
Reaction under N2 atmosphere: Intermediate 16 (2.0 g, 9.1 mmol) was dissolved in THF (50 ml). LiAlH4 (1.7 g, 45.5 mmol) was added while the solution was cooled on an ice-water bath. Subsequently, the mixture was heated to reflux for 3 h, and then the solution was cooled to r.t. H20 (5 ml) was added while the r.m. was cooled on an ice- water bath. EtOAc (50 ml) was added and the mixture was filtered. The filtrate was extracted with EtOAc (3 x 25 ml). The separated organic layer was dried (Na2S04), filtered, and evaporated in vacuo. Yield: 1.2 g of intermediate 17 (64 % yield).
d) Preparation of intermediate 18
Figure imgf000057_0003
A mixture of intermediate 17 (1.1 g, 5.3 mmol), 3,4-dihydro-2H-l-Benzopyran-6- carboxylic acid (1.1 g, 6.4 mmol) Et3N (7.5 ml, 47.7 mmol), HOBT (0.77 g, 5.7 mmol) and EDCI (1.1 g, 5.8 mmol) in DCM (40 ml) was heated to reflux for 5 h, and was then cooled to r.t. The solution was poured into ice-water. A 2 M NaOH solution was added to pH 8. This mixture was extracted with DCM (3 x 50 ml). The organic layers were combined, washed with H20 (3 x 20 ml), washed with brine (3 x 20 ml), dried
(Na2S04), filtered, and the solvent was evaporated in vacuo. The residue was purified by HPLC (Luna column 50 x 300 mm; mobile phase: 0%-30% CH3CN (0.1 %
TFA)/H20 (0.1 % TFA); flow rate 80 ml/min; 25 min). The product fractions were collected and neutralized with a saturated NaHC03 solution. The mixture was extracted with DCM. The separated organic layer was dried (Na2SC>4), filtered and the solvent was evaporated. Yield: 0.8 g of intermediate 18 (41 % yield).
Example A7
a) Preparation of intermediate
Figure imgf000058_0001
Reaction under N2 atmosphere. Tetrahydro-2,5-dimethoxyfuran (11.1 g, 83.6 mmol) was added to a mixture of 2-amino-4-chlorobenzonitrile (10 g, 65.5 mmol) in acetic acid (45 ml). The mixture was heated to reflux and stirred for 1 h. Subsequently, the solvent was evaporated in vacuum. The residue was purified by column
chromatography over silica gel (eluent: PE/EtOAc 4/1). The desired fractions were collected and the solvent was evaporated in vacuum. Yield: 13.0 g of intermediate 19 (98 % yield). b) Preparation of intermediate 20
Figure imgf000058_0002
Intermediate 19 (13 g, 64.2 mmol) was dissolved in THF (80 ml). Borane-dimethyl sulphide (1 : 1) (6.9 ml of a 10 M solution of BH3 in Me2S, 69.3 mmol) was added slowly inot the solution under N2. The r.m. was stirred and refluxed overnight.
Subsequently, the mixture was cooled off. MeOH (15 ml) was added to the mixture (cooled on an ice-water bath). The mixture was stirred for 30 min. HCl/MeOH (15 ml of a 4 N solution) was added slowly. The solvent of the mixture was evaporated in vacuo and an additional amount of HCl/MeOH (20 ml of a 4 N solution) was added to the residue. The solvent of the mixture was evaporated in vacuo. The crude
intermediate 20 (15 g) was used as such in the next reaction step. Example A8
a) Preparation of intermedia
Figure imgf000059_0001
1,2-Ethanedithiol (4.7 g, 50 mmol) in DCM (100 ml) was added to trimethylaluminium (50 ml of a 2 M solution in toluene; 100 mmol) at -78 °C. After addition, the mixture was warmed to r.t. for 30 min. The mixture was cooled to -20 °C, and then 6-Bromo- 3,4-dihydro-2H-l-Benzopyran-2-one (11.35 g, 50 mmol) in DCM (200 ml) was added dropwise to the mixture. The mixture was stirred overnight. The mixture was poured out into ice-water, acidified by concentrated HC1, and extracted with DCM. The separated organic layer was dried (Na2SC>4), filtered and the solvent was evaporated. The residue was purified by column chromatography (gradient eluent: PE/EtOAc from 80/1 to 50/1). The product fractions were collected and the solvent was evaporated in vacuo to yield 2 g of intermediate 21 (15 % yield).
b) Preparation of intermediate 22
Figure imgf000059_0002
Triethylamine tri(hydrogen fluoride) (5.36 g, 33.24 mmol) was added to the mixture of intermediate 21 (2 g, 6.59 mmol) in DCM (100 ml) at -78 °C. Then l,3-dibromo-5,5- dimethyl-2,4-imidazolidinedione (9.54 g, 33.24 mmol) in DCM (100 ml) was added slowly, and the resulting mixture was stirred for 2 h at r.t. Subsequently, the mixture was quenched with NaOH (I N) and extracted with DCM. The separated organic layer was dried (Na2S04), filtered and the solvent was evaporated. The residue was purified by column chromatography (gradient eluent: PE/EtOAc from 50/1 to 30/1). The product fractions were collected and the solvent was evaporated in vacuo to yield 1.1 g of intermediate 22 (69 % yield; oil).
c) Preparation of intermediate 23
Figure imgf000059_0003
Reaction under anhydrous conditions.
A 2.5 M solution of n-butyllithium in n-hexane (4.02 ml, 10 mmol)) was added dropwise to a solution of intermediate 22 (1.25 g, 5.02 mmol) in THF (30 ml) under N2. The mixture was stirred for 2 h at -78 °C. DMF (0.78 ml, 10 mmol) was added and the mixture was stirred for 2 h at -78 °C. Subsequently the mixture was quenched with ^
H4CI, and was then extracted with DCM. The separated organic layer was dried (Na2S04), filtered and the solvent was evaporated in vacuo. Yield: 1.0 g of intermediate 23 (100 % yield).
B. Preparation of the compounds
Example Bl
Preparation of compou
Figure imgf000060_0001
Intermediate 6 (0.77 g, 1.88 mmol) was dissolved in POCI3 (5 ml). The mixture was stirred and refluxed overnight. Subsequently, the mixture was cooled and poured into H20 (q.s.). The aqueous mixture was neutralized with NaOH to pH 7, and was then extracted with DCM. The separated organic layer was dried (MgS04), filtered, and the solvent was evaporated. The residue was washed with isopropyl ether. The solid was filtered off and dried in vacuo. Yield: 0.587 g of compound 82 (80 % yield).
Example B2
Preparation of compound
Figure imgf000060_0002
Intermediate 7 (0.9 g, 2.5 mmol) was dissolved in POCI3 (12.0 ml). The mixture was stirred overnight at 100 °C, and was then poured into ice water. The aqueous mixture was extracted with DCM. The separated organic layer was dried (Na2S04), filtered and the filtrate was evaporated in vacuo. The residue was purified by column
chromatography over silica gel (eluent: PE/EtOAc from 10/1 to 5/1). The desired fractions were collected and the solvent was evaporated in vacuo. Yield: 0.450 g of compound 21 (52 % yield). Example B3
a) Preparation of compou
Figure imgf000061_0001
A mixture of intermediate 2 (1.00 g, 0.004 mol) and 2,3-dihydro-lH-Indene-5- carboxaldehyde ( 0.004 mol) in EtOH (20 ml) was stirred and refluxed for 3 h. The mixture was crystallized overnight. The product was filtered off, washed 3 x with EtOH, and dried. Yield: 1.02 g of compound 12 (69 % yield; .HC1).
b) Preparation of compound
Figure imgf000061_0002
A mixture of H20 (20 ml) and H3.H2O (5 ml) was added to a solution of compound 12 (0.185 g, 0.0005 mol) in DCM (10 ml). The layers were separated and dried, filtered and Mn02 (1.2 g) was added. The r.m. was reacted for 96 h at 25 °C. The precipitate was filtered off over diatomaceous earth and the filtrate was evaporated. The residue was purified by preparative TLC (eluent: PE/EtOAc 5/1). The desired fractions were collected and the solvent was evaporated. Yield: 0.04 g of compound 20 (25 % yield).
Example B4
Preparation of compound 69
Figure imgf000061_0003
Intermediate 1 1 (0.18 g, 0.45 mmol) was dissolved in POCI3 (4 ml). The mixture was stirred and refluxed overnight. Subsequently, the mixture was cooled and poured into H20. The aqueous mixture was neutralized with NaOH to pH 7, and was then extracted with DCM. The separated organic layer was dried (Na2S04), filtered and the solvent was evaporated. The residue was purified by preparative HPLC (Synergy column 30 x 150 mm; mobile phase: 33%-63% CH3CN (0.1 % TFA)/H20 (0.1 % TFA); flow rate 25 ml/min; 19 min). The product fractions were collected and the solvent was evaporated. The residue was neutralized with a saturated NaHC03 solution. The organic layer was dried (Na2S04), filtered and the solvent was evaporated. Yield:
0.050 g of compound 69 (29 % yield).
Example B5
Preparation of compound
Figure imgf000062_0001
Intermediate 14 (0.80 g, 2.1 mmol) was dissolved in POCl3 (3 ml). The mixture was stirred overnight at 100 °C, and was then poured into ice-water. NaOH was added to pH 8-9. The mixture was extracted with DCM. The separated organic layer was dried (Na2S04), filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography over silica gel (eluent: PE/EtOAc from 10/1 to 5/1). The desired fractions were collected and the solvent was evaporated in vacuo. Yield: 0.5 g of compound 77 (67 % yield).
Example B6
Preparation of compoun
Figure imgf000062_0002
Intermediate 18 (0.8 g, 2.18 mmol) was dissolved in POCl3 (5 ml). The solution was heated to reflux for 5 h, and was then cooled to r.t. The solution was poured into ice. A 2 M NaOH solution was added to pH 8. Subsequently, the mixture was extracted with DCM (3 x 50 ml). The combined organic layers were washed with H20 (3 x 20 ml), brine (3 x 20 ml), dried (Na2S04), filtered, and the solvent was evaporated in vacuo. The residue was purified by HPLC (Luna column 50 x 300 mm; mobile phase: 35%- 50% CH3CN (0.1 % TFA)/H20 (0.1 % TFA); flow rate 80 ml/min; 25 min). The product fractions were collected and neutralized with a saturated NaHC03 solution. The mixture was extracted with DCM. The separated organic layer was dried (Na2S04), filtered, and the solvent was evaporated. Yield: 0.560 g of compound 43 (74 % yield). Example B7
a) Preparation of compound 84
Figure imgf000063_0001
Intermediate 23 (0.3 g, 1.5 mmol) was added to a solution of intermediate 20 (0.36 g, 1.5 mmol) in EtOH (1 ml). The r.m. was heated to reflux temperature and stirred overnight. The solution was filtered through diatomaceous earth and the filtrate was collected. The solvent of the filtrate was evaporated in vacuum. The residue was purified by HPLC (Synergy column 25 x 150 mm; mobile phase: 35%-50% CH3CN (0.1 % TFA)/H20 (0.1 % TFA); flow rate 25 ml/min; 14.4 min). The product fractions were collected and neutralized with a saturated NaHC03 solution. The mixture was extracted with DCM. The separated organic layers were dried (Na2S04), filtered and the solvent was evaporated. Yield: 0.120 g of compound 84 (21 % yield).
b) Preparation of compound 71
Figure imgf000063_0002
Compound 84 (0.120 g, 0.31 mmol) was dissolved in DCM (10 ml). Mn02 (0.27 g, 3.1 mmol) was added to the solution. The r.m. was stirred overnight, and was then filtrated through diatomaceous earth. The filtrate was collected and the solvent was evaporated in vacuum. The residue was purified by column chromatography over silica gel (eluent: PE/EtOAC from 10/1 to 5/1). The desired fractions were collected and the solvent was evaporated in vacuo. Yield: 0.040 g of compound 71 (34 % yield).
By using analogous reaction protocols as described in the foregoing examples, the following compounds have been prepared. 'Co. No.' means compound number. 'Pr.' refers to the Example number according to which protocol the compound was synthesized. In case no salt form is indicated, the compound was obtained as a free base.
HBr salt forms were obtained by using procedures known to those skilled in the art. A typical procedure is described in WO02/34752.
Compounds for which no specific stereochemistry is indicated for a stereocenter in Tables la, lb, lc or Id were obtained as racemic mixtures of R and S enantiomers. Table la:
Figure imgf000064_0001
Figure imgf000064_0003
Table lb:
Figure imgf000064_0002
Co. No. Pr. R1 R2 R3 R4 R5 s Salt Form
12 B3.a 7-Cl H H H H 3 HC1
13 B3.a 7-Cl H H H H 3 HBr
14 B3.a 7-Cl H H H OCH2CH3 3 HBr
15 B3.a 7-Cl H H H OCH3 4 HBr
16 B3.a 7-Cl 10-Cl H H H 3 HC1
17 B3.a 8-Cl 10-Cl H H H 3 HC1
18 B3.a 7-Cl 8-Cl H H H 3 HC1
19 B3.a 7-Cl 9-Cl H H H 3 HC1
20 B3.b 7-Cl H bond H 3
21 B2 7-Cl H bond H 4
22 B3.b 7-Cl 8-Cl bond H 3
23 B3.b 7-Cl 9-Cl bond H 3
24 B3.b 7-Cl 10-Cl bond H 3
25 B3.b 8-Cl 10-Cl bond H 3 Table lc:
Figure imgf000065_0001
Table Id:
Figure imgf000066_0001
Figure imgf000067_0001
C. Analytical results
LCMS - General procedure
The FIPLC measurement was performed using an Agilent 1100 module comprising a pump, a diode-array detector (DAD) (wavelength used 220 nm), a column heater and a column as specified in the respective methods below. Flow from the column was split to a Agilent MSD Series G1946C and G1956A. MS detector was configured with API- ES (atmospheric pressure electrospray ionization). Mass spectra were acquired by scanning from 100 to 1000. The capillary needle voltage was 2500 V for positive and 3000 V for negative ionization mode. Fragmentation voltage was 50 V. Drying gas temperature was maintained at 350 °C at a flow of 10 1/min.
LCMS Method 1
In addition to the general procedure: Reversed phase HPLC was carried out on a YMC- Pack ODS-AQ, 50x2.0 mm 5μπι column with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: water with 0.1 % TFA; mobile phase B: acetonitrile with 0.05 % TFA) were used. First, 100 % A was hold for 1 minute. Then a gradient was applied to 40 % A and 60 % B in 4 minutes and hold for 2.5 minutes. Typical injection volumes of 2 μΐ were used. Oven temperature was 50 °C. (MS polarity: positive)
LCMS Method 2
In addition to the general procedure: Reversed phase HPLC was carried out on a YMC- Pack ODS-AQ, 50x2.0 mm 5 μπι column with a flow rate of 0.8 ml/min. 2 mobile phases (mobile phase A: water with 0.1 % TFA; mobile phase B: CH3CN with 0.05 % TFA) were used. First, 90 % A and 10 % B was hold for 0.8 min. Then a gradient was applied to 20 % A and 80 % B in 3.7 min and hold for 3 min. Typical injection volumes of 2 μΐ were used. Oven temperature was 50 °C. (MS polarity: positive)
LCMS Method 3
In addition to the general procedure: Reversed phase HPLC was carried out on an Ultimate XB-C18, 50x2.1 mm 5μπι column with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase C: 10 mmol/1 H4HC03; mobile phase D: CH3CN) were used. First, 100 % C was hold for 1 minute. Then a gradient was applied to 40 % C and 60 % D in 4 minutes and hold for 2.5 min. Typical injection volumes of 2 μΐ were used. Oven temperature was 50 °C. (MS polarity: positive)
Melting Points
For a number of compounds, melting points (m.p.) were determined with a WRS-2A melting point apparatus purchased from Shanghai Precision and Scientific Instrument Co. Ltd. Melting points were measured with a linear heating up rate of 0.2-5.0 °C/min The reported values are melt ranges. The maximum temperature was 300 °C.
The results of the analytical measurements are shown in table 2.
Table 2: Retention time (Rt) in min., [M+H]+ peak (protonated molecule), and m.p. (melting point in °C). ("n.d." means not determined; "dec" means decomposed).
Co. LCMS Co. LCMS
Rt [M+H]+ m.p. (°C) Rt [M+H]+ m.p. (°C) No. Method No. Method
2 n.d. n.d. - n.d. 32 3.69 371 2 n.d.
3 n.d. n.d. - n.d. 33 3.62 371 2 262.9-264.4
4 n.d. n.d. - n.d. 34 3.75 371 2 261.7-263.6
5 n.d. n.d. - n.d. 35 3.17 335 2 206.4-208.9
6 n.d. n.d. - n.d. 36 3.42 335 2 180.5-181.2
7 n.d. n.d. - n.d. 37 2.78 349 2 190.5-193.4
8 n.d. n.d. - n.d. 38 3.23 349 2 >280
9 n.d. n.d. - n.d. 39 3.96 333 1 168.6-169.0
10 n.d. n.d. - n.d. 40 3.75 333 2 >280
1 1 n.d. n.d. - n.d. 41 3.63 349 2 n.d.
12 3.81 335 2 242.7-243.5 42 3.86 349 2 >280
13 n.d. n.d. - n.d. 43 3.79 349 2 103.7-103.7
14 n.d. n.d. - n.d. 44 3.39 369 2 n.d.
15 n.d. n.d. - n.d. 45 3.80 369 2 190.0-191.8
16 4.10 369 2 172.5-176.6 46 3.70 351 2 n.d.
17 4.04 369 2 n.d. 47 7.06 369 3 203.5-205.2
18 3.99 369 2 238.8-240.2 48 3.65 369 2 102.7-105.6
19 4.16 369 2 205.7-207.3 49 n.d. n.d. - n.d.
20 3.74 333 2 181.3-182.7 50 n.d. n.d. - n.d.
21 3.92 347 2 180.0-181.5 51 2.95 349 2 >280
22 3.87 367 2 199.3-201.6 52 3.04 349 2 n.d.
23 4.12 367 2 n.d. 53 3.21 371 2 n.d.
24 3.89 367 2 194.0-194.2 54 3.29 389 2 n.d.
25 2.62 367 2 178.5-180.2 55 5.86 347 3 214.0-217.0
26 3.22 337 2 237.9-239.7 56 5.89 347 3 226.7-227.6
27 3.47 337 2 165.1-167.2 57 3.41 347 2 n.d.
28 2.79 351 2 n.d. 58 3.04 361 2 209.8-210.7
29 3.90 335 1 n.d. 59 2.93 345 2 n.d.
30 3.44 371 2 224.9-226.0 60 3.70 361 2 >280°C
31 3.83 371 2 257.7-260.6 61 3.65 361 2 n.d. Co. LCMS Co. LCMS
t [M+H]+ m.p. (°C) Rt [M+H]+ m.p. (°C) No. Method No. Method
62 3.76 349 1 107.9 (dec) 74 3.66 373 2 184.9-186.0
63 3.60 333 1 224.6-246.0 75 4.39 373 1 151.3-152.7
64 3.33 383 2 210.5-212.0 76 4.34 373 1 139.3-141.1
65 3.84 349 1 251.2-253.0 77 3.39 357 2 n.d.
66 3.90 369 2 193.4-193.8 78 3.46 375 2 n.d.
67 3.95 369 2 >280°C 79 3.61 407 2 85.3-87.3
68 3.95 369 2 n.d. 80 4.15 364 1 218.6-221.0
69 4.38 385 1 199.7-201.2 81 3.36 332 2 164.0-165.4
70 3.16 369 2 158.9-159.3 82 6.00 349 3 n.d.
71 3.99 385 2 n.d. 83 4.63 348 2 n.d.
72 3.88 385 2 n.d. 88 3.84 387 2 170.2-171.8
73 3.88 387 2 n.d. 1 3.49 390 2 233.7-235.1
HNMR
For a number of compounds, 1H NMR spectra were recorded on a Bruker DPX-300, a Bruker DPX-400, or on a Bruker Avance 600 spectrometer spectrometer with standard pulse sequences, operating at 300 MHz, 400 MHz and 600 MHz respectively, using CHLOROFORM-^ (deuterated chloroform, CDC13) or DMS0 (deuterated DMSO, dimethyl-d6 sulfoxide) as solvents. Chemical shifts (δ) are reported in parts per million (ppm) relative to tetramethylsilane (TMS), which was used as internal standard.
Compound 17: 1H NMR (300 MHz, DMSO- ,) δ ppm 2.04 (quin, J=7.4 Hz, 2 H), 2.79 - 2.97 (m, 4 H), 3.59 (d, J=13.2 Hz, 1 H), 4.34 (d, J=13.4 Hz, 1 H), 5.22 (s, 1 H), 5.92 (d, J=3.7 Hz, 1 H), 6.27 (t, J=3.3 Hz, 1 H), 7.32 (d, J=7.7 Hz, 1 H), 7.37 (dd, J=3.0, 1.5 Hz, 1 H), 7.51 (d, J=7.8 Hz, 1 H), 7.63 (s, 1 H), 7.78 (d, J=2.4 Hz, 1 H), 8.05 (d, J=2.3 Hz, 1 H), 10.01 (br. s, 1 H), 10.62 (br. s, 1 H).
Compound 20: 1H NMR (400 MHz, CHLOROF ORM-<f) δ ppm 1.99 - 2.13 (m, 2 H)
2.79 - 2.97 (m, 4 H) 4.15 (br. s., 1 H) 5.47 (br. s., 1 H) 6.43 (br. s., 1 H) 6.51 (br. s., 1 H) 7.18 (d, J=7.8 Hz, 1 H) 7.26 - 7.33 (m, 3 H) 7.36 (d, J=7.0 Hz, 1 H) 7.43 (d, J=7.8
Hz, 1 H) 7.60 (s, 1 H).
Compound 22: 1H NMR (400 MHz, CHLOROF ORM-i ) δ ppm 2.01 - 2.14 (m, 2 H)
2.80 - 2.98 (m, 4 H) 4.19 (br. s., 1 H) 5.52 (br. s., 1 H) 6.45 (br. s., 1 H) 6.53 (br. s., 1 H) 7.21 (m, J=9.2, 9.2 Hz, 2 H) 7.29 (br. s., 1 H) 7.43 (d, J=7.5 Hz, 1 H) 7.47 (d, J=8.8 Hz, 1 H) 7.60 (s, 1 H).
Compound 23 : 1H NMR (300 MHz, CHLOROF ORM-i ) δ ppm 2.08 (quin, J=7.4 Hz, 2 H) 2.80 - 3.02 (m, 4 H) 4.1 1 (br. s., 1 H) 5.44 (br. s., 1 H) 6.46 (br. s., 1 H) 6.54 (br. s., 1 H) 7.19 (d, J=7.9 Hz, 1 H) 7.27 (d, J=1.9 Hz, 1 H) 7.31 (br. s., 1 H) 7.36 - 7.40 (m, 1 H) 7.42 (d, J=7.9 Hz, 1 H) 7.59 (s, 1 H). Compound 24: 1H NMR (300 MHz, DMSO- ,) δ ppm 2.02 (quin, J=7.4 Hz, 2 H) 2.78 - 2.99 (m, 4 H) 3.94 (d, J=11.3 Hz, 1 H) 5.20 (d, J=11.3 Hz, 1 H) 6.43 - 6.48 (m, 1 H) 6.48 - 6.52 (m, 1 H) 7.25 (d, J=7.7 Hz, 1 H) 7.47 (d, J=7.9 Hz, 1 H) 7.53 - 7.60 (m, 2 H) 7.64 (d, J=8.8 Hz, 1 H) 7.66 - 7.69 (m, 1 H).
Compound 25 : 1H NMR (400 MHz, CHLOROF ORM-<f) δ ppm 2.08 (quin, J=7.4 Hz, 2 H) 2.91 (m, J=8.0, 8.0, 8.0 Hz, 4 H) 4.23 (d, J=11.3 Hz, 1 H) 4.73 (d, J=11.0 Hz, 1 H) 6.39 (t, J=3.0 Hz, 1 H) 6.50 (d, J=2.3 Hz, 1 H) 7.20 (d, J=7.8 Hz, 1 H) 7.36 - 7.42 (m, 1 H) 7.43 - 7.46 (m, 1 H) 7.48 (br. s., 1 H) 7.51 (d, J=8.0 Hz, 1 H) 7.64 (s, 1 H).
Compound 27: 1H NMR (300 MHz, DMSO- ,) δ ppm 3.22 (t, J=8.7 Hz, 2 H), 3.83 (d, J=13.8 Hz, 1 H), 4.53 (d, J=13.9 Hz, 1 H), 4.57 (t, J=8.7 Hz, 2 H), 5.15 (br. s., 1 H), 5.88 (d, J=3.8 Hz, 1 H), 6.29 (t, J=3.3 Hz, 1 H), 7.19 (d, J=7.6 Hz, 1 H), 7.23 (s, 1 H), 7.31 (d, J=7.6 Hz, 1 H), 7.37 - 7.43 (m, 1 H), 7.58 - 7.74 (m, 3 H), 10.21 (br. s, 1 H), 10.56 (br. s, 1 H).
Compound 28: 1H NMR (400 MHz, DMSO- ,) δ ppm 2.71 - 2.86 (m, 2 H), 3.83 (br. s, 1 H), 3.88 (t, J=5.7 Hz, 2 H), 4.53 (d, J=13.8 Hz, 1 H), 4.70 (s, 2 H), 5.16 (br. s, 1 H), 5.90 (d, J=3.0 Hz, 1 H), 6.28 (t, J=3.3 Hz, 1 H), 7.13 (d, J=7.8 Hz, 1 H), 7.40 (s, 1 H), 7.48 - 7.55 (m, 2 H), 7.57 - 7.64 (m, 2 H), 7.67 (t, J=7.9 Hz, 1 H), 10.05 (br. s, 1 H),
10.40 (br. s, 1 H).
Compound 31 : 1H NMR (300 MHz, DMSO- ,) δ ppm 3.14 - 3.30 (m, 2 H), 3.74 - 3.86 (m, 1 H), 4.49 (d, J=13.9 Hz, 1 H), 4.59 (t, J=8.7 Hz, 2 H), 5.17 - 5.25 (m, 1 H), 5.93 (d, J=3.6 Hz, 1 H), 6.30 (t, J=3.2 Hz, 1 H), 6.85 (d, J=8.2 Hz, 1 H), 7.42 - 7.51 (m, 2 H), 7.65 (s, 1 H), 7.78 (d, J=2.3 Hz, 1 H), 7.84 (d, J=2.3 Hz, 1 H), 10.08 (br. s, 1 H),
10.41 (br. s, 1 H).
Compound 36: 1H NMR (400 MHz, CHLOROF ORM-i ) δ ppm 3.21 (t, J=8.7 Hz, 2 H), 4.14 (br. s, 1 H), 4.57 (t, J=8.6 Hz, 2 H), 5.47 (br. s, 1 H), 6.37 - 6.47 (m, 1 H), 6.47 - 6.59 (m, 1 H), 7.12 (s, 1 H), 7.15 (d, J=7.7 Hz, 1 H), 7.21 (d, J=8.0 Hz, 1 H), 7.23 - 7.34 (m, 3 H), 7.36 (d, J=7.0 Hz, 1 H).
Compound 37: 1H NMR (400 MHz, CHLOROFORM-<f) δ ppm 2.88 (br. s, 2 H), 3.97 (t, J=5.7 Hz, 2 H), 4.16 (br. s, 1 H), 4.80 (s, 2 H), 5.49 (br. s, 1 H), 6.42 - 6.48 (m, 1 H), 6.48 - 6.55 (m, 1 H), 6.97 (d, J=8.0 Hz, 1 H), 7.23 - 7.32 (m, 2 H), 7.34 (s, 1 H), 7.38 (dd, J=7.2, 1.8 Hz, 1 H), 7.46 (d, J=8.0 Hz, 1 H), 7.53 (s, 1 H).
Compound 39: 1H NMR (300 MHz, CHLOROF ORM-i ) δ ppm 2.87 (t, J=5.7 Hz, 2 H), 3.96 (t, J=5.7 Hz, 2 H), 4.61 (br. s, 2 H), 4.79 (s, 2 H), 6.44 (dd, J=3.8, 2.8 Hz, 1 H), 6.51 (dd, J=3.8, 1.5 Hz, 1 H), 6.96 (d, J=8.0 Hz, 1 H), 7.06 (t, J=8.5 Hz, 1 H), 7.16 (d, J=8.0 Hz, 1 H), 7.27 - 7.38 (m, 2 H), 7.45 (dd, J=8.1, 1.3 Hz, 1 H), 7.51 (s, 1 H).
Compound 42: 1H NMR (400 MHz, CHLOROF ORM-<f) δ ppm 2.01 (quin, J=6.4 Hz, 2 H) 2.80 (t, J=6.5 Hz, 2 H) 4.21 (t, J=5.0 Hz, 2 H) 4.34 (br. s., 1 H) 4.80 (br. s., 1 H) 6.45 (t, J=3.3 Hz, 1 H) 6.54 (dd, J=305.0, 1.3 Hz, 1 H) 6.75 (d, J=8.5 Hz, 1 H) 7.23 - 7.27 (m, 1 H) 7.30 - 7.34 (m, 1 H) 7.35 - 7.43 (m, 3 H) 7.47 (s, 1 H).
Compound 43 : 1H NMR (400 MHz, CHLOROF ORM-<f) δ ppm 1.95 - 2.06 (m, 2 H) 2.70 - 2.91 (m, 2 H) 4.17 - 4.22 (m, 2 H) 4.24 (d, J=11.3 Hz, 1 H) 4.76 (d, J=11.3 Hz, 1 H) 6.40 (dd, J=3.8, 3.0 Hz, 1 H) 6.51 (dd, J=3.8, 1.8 Hz, 1 H) 6.76 (d, J=8.5 Hz, 1 H) 7.22 (t, J=7.9 Hz, 1 H) 7.41 (dd, J=7.5, 1.3 Hz, 1 H) 7.44 (dd, J=8.0, 1.3 Hz, 1 H) 7.50 (dd, J=8.5, 2.3 Hz, 1 H) 7.53 (ddd, J=3.3, 2.1, 1.8 Hz, 2 H).
Compound 44: 1H NMR (400 MHz, CHLOROF ORM-i ) δ ppm 3.20 - 3.38 (m, 2 H) 4.38 (br. s., 1 H) 4.66 - 4.80 (m, 2 H) 5.68 (br. s., 1 H) 6.69 - 6.80 (m, 1 H) 6.88 (d, J=8.3 Hz, 1 H) 7.10 (d, J=3.3 Hz, 1 H) 7.28 (d, J=7.0 Hz, 1 H) 7.53 (d, J=8.3 Hz, 1 H) 7.64 (d, J=8.5 Hz, 1 H) 7.75 (br. s., 1 H) 7.84 (br. s., 1 H).
Compound 45: 1H NMR (400 MHz, CHLOROF ORM-i ) δ ppm 3.22 (t, J=9.5 Hz, 2 H) 4.12 (br. s., 1 H) 4.62 (t, J=8.8 Hz, 2 H) 5.41 (br. s., 1 H) 6.47 (t, J=2.8 Hz, 1 H) 6.56 (br. s., 1 H) 6.74 (d, J=8.5 Hz, 1 H) 7.28 (d, J=2.0 Hz, 1 H) 7.29 - 7.35 (m, 1 H) 7.40 (d, J=1.8 Hz, 1 H) 7.44 (d, J=8.0 Hz, 1 H) 7.66 (br. s., 1 H).
Compound 46: 1H NMR (400 MHz, CHLOROF ORM-i ) δ ppm 2.00 (qd, J=6.2, 4.5 Hz, 2 H), 2.79 (t, J=6.5 Hz, 2 H), 4.03 (br. s, 1 H), 4.20 (dd, J=5.8, 4.5 Hz, 2 H), 5.19 (br. s, 1 H), 6.45 (dd, J=3.8, 2.9 Hz, 1 H), 6.53 (dd, J=3.8, 1.6 Hz, 1 H), 6.74 (d, J=8.5 Hz, 1 H), 6.81 (td, J=9.0, 2.5 Hz, 1 H), 6.92 (dt, J=9.1, 2.0 Hz, 1 H), 7.28 (dd, J=2.9, 1.7 Hz, 1 H), 7.36 (dd, J=8.5, 2.3 Hz, 1 H), 7.47 (d, J=2.3 Hz, 1 H).
Compound 47: 1H NMR (300 MHz, CHLOROF ORM-i ) δ ppm 3.21 (t, J=8.6 Hz, 2 H), 4.03 (d, J=11.3 Hz, 1 H), 4.57 (t, J=8.7 Hz, 2 H), 5.39 (d, J=11.3 Hz, 1 H), 6.34 - 6.45 (m, 1 H), 6.51 (dd, J=3.8, 1.5 Hz, 1 H), 7.17 (d, J=7.6 Hz, 1 H), 7.19 - 7.23 (m, 1 H), 7.23 - 7.39 (m, 3 H), 7.48 (dd, J=2.7, 1.4 Hz, 1 H).
Compound 53 : 1H NMR (400 MHz, DMSO- ,) δ ppm 2.42 - 2.48 (m, 2 H), 2.86 - 3.06 (m, 2 H), 3.72 (d, J=13.7 Hz, 1 H), 4.43 (d, J=13.8 Hz, 1 H), 5.22 (s, 1 H), 5.90 (d, J=2.9 Hz, 1 H), 6.29 (t, J=3.3 Hz, 1 H), 7.12 (d, J=8.5 Hz, 1 H), 7.35 - 7.44 (m, 2 H), 7.49 (d, J=8.0 Hz, 1 H), 7.65 - 7.75 (m, 3 H), 10.30 (br. s., 1 H), 10.62 (br. s., 1 H).
Compound 55: 1H NMR (400 MHz, CHLOROF ORM-i ) δ ppm 2.71 - 2.76 (m, 2 H), 3.15 - 3.26 (m, 2 H), 5.39 (br. s, 2 H), 6.49 - 6.54 (m, 1 H), 6.56 - 6.62 (m, 1 H), 7.27 - 7.31 (m, 1 H), 7.34 (t, J=8.0 Hz, 1 H), 7.42 (d, J=7.5 Hz, 1 H), 7.46 (s, 1 H), 7.59 (d, J=8.0 Hz, 1 H), 7.99 (s, 1 H), 8.19 (d, J=8.0 Hz, 1 H).
Compound 56: 1H NMR (300 MHz, CHLOROF ORM-<f) δ ppm 2.61 - 2.83 (m, 2 H)
3.02 - 3.27 (m, 2 H) 4.24 (br. s., 1 H) 5.51 (br. s., 1 H) 6.37 - 6.60 (m, 2 H) 7.27 - 7.44 (m, 4 H) 7.63 - 7.78 (m, 2 H) 7.87 (s, 1 H).
Compound 57: 1H NMR (300 MHz, CHLOROF ORM-<f) δ ppm 2.61 - 2.81 (m, 2 H)
3.03 - 3.28 (m, 2 H) 4.31 (d, J=10.9 Hz, 1 H) 4.89 (d, J=11.3 Hz, 1 H) 6.40 - 6.46 (m, 1 H) 6.46 - 6.51 (m, 1 H) 7.20 - 7.26 (m, 1 H) 7.49 (d, J=7.9 Hz, 1 H) 7.44 (d, J=7.2 Hz, 1 H) 7.60 (br. s., 1 H) 7.69 - 7.84 (m, 2 H) 7.91 (s, 1 H).
Compound 58: 1H NMR (400 MHz, CHLOROF ORM-i ) δ ppm 2.15 (quin, J=6.3 Hz, 2 H), 2.68 (t, J=6.5 Hz, 2 H), 2.99 (t, J=5.8 Hz, 2 H), 4.20 (br. s, 1 H), 5.54 (br. s, 1 H), 6.44 - 6.50 (m, 2 H), 7.28 - 7.29 (m, 1 H), 7.32 (t, J=7.8 Hz, 1 H), 7.37 (dd, J=2.7, 1.7 Hz, 1 H), 7.40 (dd, J=7.5, 1.8 Hz, 1 H), 7.57 (dd, J=8.1, 1.8 Hz, 1 H), 7.68 (s, 1 H), 8.01 (d, J=8.1 Hz, 1 H).
Compound 59: 1H NMR (600 MHz, CHLOROF ORM-i ) δ ppm 2.14 (m, 2 H), 2.67 (dd, J=7.3, 5.8 Hz, 2 H), 2.98 (t, J=6.0 Hz, 2 H), 4.72 (br. s., 2 H), 6.45 (dd, J=3.8, 2.8 Hz, 1 H), 6.48 (dd, J=3.8, 1.7 Hz, 1 H), 7.07 (t, J=8.5 Hz, 1 H), 7.17 (d, J=8.1 Hz, 1 H), 7.33 (td, J=8.2, 5.8 Hz, 1 H), 7.37 (dd, J=2.8, 1.6 Hz, 1 H), 7.56 (dd, J=8.2, 1.7 Hz, 1 H), 7.66 (d, J=1.7 Hz, 1 H), 8.00 (d, J=8.2 Hz, 1 H).
Compound 60: 1H NMR (400 MHz, CHLOROF ORM-i ) δ ppm 2.14 (quin, J=6.5 Hz, 2 H) 2.63 - 2.73 (m, 2 H) 2.99 (t, J=5.9 Hz, 2 H) 4.63 (br. s., 2 H) 6.43 - 6.52 (m, 2 H) 7.29 (dd, J=8.0, 2.3 Hz, 1 H) 7.36 (dd, J=2.8, 1.8 Hz, 1 H) 7.40 (d, J=2.0 Hz, 1 H) 7.42 (d, J=8.3 Hz, 1 H) 7.57 (dd, J=8.0, 1.8 Hz, 1 H) 7.64 (d, J=1.0 Hz, 1 H) 8.01 (d, J=8.0 Hz, 1 H)
Compound 61 : 1H NMR (400 MHz, CHLOROFORM-<f) δ ppm 2.13 (quin, J=6.3 Hz, 2 H), 2.63 - 2.70 (m, 2 H), 2.91 - 3.05 (m, 2 H), 4.28 (d, J=l l . l Hz, 1 H), 4.86 (d, J=l l . l Hz, 1 H), 6.41 (dd, J=3.9, 3.0 Hz, 1 H), 6.47 (dd, J=3.8, 1.5 Hz, 1 H), 7.23 (t, J=7.8 Hz, 1 H), 7.42 (dd, J=7.6, 1.5 Hz, 1 H), 7.47 (dd, J=8.1, 1.4 Hz, 1 H), 7.57 (dd, J=2.9, 1.5 Hz, 1 H), 7.67 (dd, J=8.3, 1.8 Hz, 1 H), 7.70 (d, J=1.8 Hz, 1 H), 8.01 (d, J=8.1 Hz, 1 H).
Compound 63 : 1H NMR (400 MHz, CHLOROF ORM-i ) δ ppm 4.62 (br. s, 2 H), 5.35 (s, 2 H), 6.44 - 6.50 (m, 2 H), 7.08 (t, J=8.5 Hz, 1 H), 7.19 (d, J=8.1 Hz, 1 H), 7.35 (td, J=8.2, 5.8 Hz, 1 H), 7.38 (t, J=2.3 Hz, 1 H), 7.51 (d, J=8.1 Hz, 1 H), 8.15 - 8.21 (m, 2 H). Compound 64: 1H NMR (400 MHz, DMSO- ,) δ ppm 4.12 (br. s., 1 H) 5.27 (br. s., 1 H) 5.48 (s, 2 H) 6.47 - 6.61 (m, 2 H) 7.65 - 7.78 (m, 3 H) 7.86 (s, 1 H) 7.96 (s, 1 H) 8.09 (d, J=9.0 Hz, 1 H).
Compound 65: 1H NMR (300 MHz, CHLOROF ORM-<f) δ ppm 4.26 (br. s, 1 H), 5.32 (s, 2 H), 5.50 (br. s, 1 H), 6.37 - 6.62 (m, 2 H), 7.27 - 7.47 (m, 4 H), 7.79 - 7.98 (m, 3 H).
Compound 66: 1H NMR (400 MHz, CHLOROF ORM-<f) δ ppm 2.60 (tt, J=13.9, 6.9 Hz, 2 H), 3.04 (br. s, 2 H), 4.18 (br. s, 1 H), 5.52 (br. s, 1 H), 6.39 - 6.54 (m, 2 H), 7.23 - 7.28 (m, 1 H), 7.31 (t, J=8.0 Hz, 1 H), 7.36 (s, 1 H), 7.39 (d, J=7.6 Hz, 1 H), 7.51 (d, J=8.0 Hz, 1 H), 7.63 (d, J=8.1 Hz, 1 H), 7.68 (s, 1 H).
Compound 67: 1H NMR (400 MHz, CHLOROF ORM-i ) δ ppm 2.50 - 2.73 (m, 2 H)
2.97 - 3.17 (m, 2 H) 4.64 (br. s., 2 H) 6.43 - 6.51 (m, 2 H) 7.29 (dd, J=8.0, 2.0 Hz, 1 H) 7.36 (dd, J=2.8, 1.8 Hz, 1 H) 7.40 (d, J=2.0 Hz, 1 H) 7.42 (d, J=8.0 Hz, 1 H) 7.53 (d, J=7.8 Hz, 1 H) 7.63 (d, J=8.5 Hz, 1 H) 7.65 (br. s., 1 H).
Compound 68: 1H NMR (400 MHz, CHLOROF ORM-i ) δ ppm 2.54 - 2.68 (m, 2 H) 2.99 - 3.13 (m, 2 H) 4.30 (d, J=l 1.0 Hz, 1 H) 4.89 (d, J=11.5 Hz, 1 H) 6.45 (t, J=2.9 Hz, 1 H) 6.53 (br. s., 1 H) 7.27 - 7.29 (m, 1 H) 7.49 (d, J=8.3 Hz, 1 H) 7.45 (d, J=7.5 Hz, 1 H) 7.55 (d, J=7.5 Hz, 1 H) 7.62 (br. s., 1 H) 7.76 (m, J=7.8 Hz, 2 H).
Compound 69: 1H NMR (300 MHz, CHLOROF ORM-i ) δ ppm 2.34 (tdd, J=7.8, 7.8, 7.7, 7.4 Hz, 2 H) 2.99 (t, J=5.6 Hz, 2 H) 4.17 (br. s., 1 H) 5.47 (br. s., 1 H) 6.42 - 6.47 (m, 1 H) 6.48 - 6.53 (m, 1 H) 6.93 (d, J=8.3 Hz, 1 H) 7.20 - 7.42 (m, 4 H) 7.52 (d, J=9.0 Hz, 1 H) 7.61 (s, 1 H).
Compound 70: 1H NMR (400 MHz, CHLOROF ORM-i ) δ ppm 2.28 - 2.39 (m, 2 H),
2.98 (t, J=7.0 Hz, 2 H), 4.15 (br. s, 1 H), 5.20 (br. s, 1 H), 6.44 (dd, J=3.9, 2.9 Hz, 1 H), 6.50 (dd, J=3.8, 1.6 Hz, 1 H), 6.92 (d, J=8.5 Hz, 1 H), 7.06 (t, J=8.5 Hz, 1 H), 7.16 (d,
J=8.0 Hz, 1 H), 7.35 (dd, J=2.8, 1.8 Hz, 1 H), 7.32 (td, J=8.2, 5.8 Hz, 1 H), 7.50 (dd, J=8.5, 2.2 Hz, 1 H), 7.60 (d, J=2.3 Hz, 1 H).
Compound 71 : 1H NMR (400 MHz, CHLOROF ORM-i ) δ ppm 2.34 (quin, J=7.7 Hz, 2 H), 2.98 (t, J=6.9 Hz, 2 H), 4.38 (br. s, 1 H), 4.75 (br. s, 1 H), 6.44 - 6.48 (m, 1 H), 6.48 - 6.52 (m, 1 H), 6.93 (d, J=8.6 Hz, 1 H), 7.27 - 7.29 (m, 1 H), 7.33 (s, 1 H), 7.37 - 7.42 (m, 2 H), 7.48 - 7.52 (m, 1 H), 7.57 (s, 1 H).
Compound 72: 1H NMR (300 MHz, CHLOROF ORM-i ) δ ppm 2.34 (quin, J=7.8 Hz, 2 H), 2.89 - 3.08 (m, 2 H), 4.25 (d, J=11.2 Hz, 1 H), 4.80 (d, J=11.2 Hz, 1 H), 6.41 (t, J=3.2 Hz, 1 H), 6.49 (d, J=3.8 Hz, 1 H), 6.94 (d, J=8.3 Hz, 1 H), 7.23 (t, J=7.8 Hz, 1 H), 7.42 (d, J=7.4 Hz, 1 H), 7.46 (d, J=8.1 Hz, 1 H), 7.56 (s, 1 H), 7.58 - 7.69 (m, 2 H).
Compound 79: 1H NMR (400 MHz, CHLOROF ORM-<f) δ ppm 4.11 (br. s, 1 H), 5.43 (br. s, 1 H), 6.45 - 6.49 (m, 1 H), 6.49 - 6.54 (m, 1 H), 7.03 (d, J=8.3 Hz, 1 H), 7.28 (d, J=1.9 Hz, 1 H), 7.33 (s, 1 H), 7.40 (d, J=2.0 Hz, 1 H), 7.45 (dd, J=8.3, 1.3 Hz, 1 H), 7.49 (d, J=1.2 Hz, 1 H).
Compound 80: 1H NMR (300 MHz, CHLOROF ORM-i ) δ ppm 3.47 (s, 3 H), 4.21 (br. s, 1 H), 5.58 (br. s, 1 H), 6.50 - 6.58 (m, 1 H), 6.65 (br. s, 1 H), 7.17 (d, J=8.3 Hz, 1 H), 7.27 - 7.31 (m, 1 H), 7.35 (t, J=7.9 Hz, 1 H), 7.40 - 7.50 (m, 3 H), 7.73 (br. s, 1 H). Compound 81 : 1H NMR (300 MHz, CHLOROF ORM-i ) δ ppm 2.78 (s, 3 H), 2.95 (t, J=8.2 Hz, 2 H), 3.37 (t, J=8.3 Hz, 2 H), 4.06 (br. s, 1 H), 5.23 (br. s, 1 H), 6.35 (d, J=8.2 Hz, 1 H), 6.42 (dd, J=3.8, 2.8 Hz, 1 H), 6.56 (dd, J=3.8, 1.7 Hz, 1 H), 7.03 (t, J=8.5 Hz, 1 H), 7.15 (d, J=7.9 Hz, 1 H), 7.27 - 7.34 (m, 2 H), 7.41 (dd, J=8.1, 1.8 Hz, 1 H), 7.52 (d, J=1.9 Hz, 1 H).
Compound 82: 1H NMR (400 MHz, CHLOROF ORM-i ) δ ppm 2.77 - 3.00 (m, 2 H) 3.97 (t, J=5.6 Hz, 2 H) 4.27 (d, J=11.0 Hz, 1 H) 4.80 (s, 2 H) 4.83 (d, J=11.5 Hz, 1 H) 6.38 - 6.46 (m, 1 H) 6.52 (br. s., 1 H) 6.99 (d, J=8.0 Hz, 1 H) 7.21 - 7.26 (m, 1 H) 7.47 (d, J=8.0 Hz, 1 H) 7.43 (d, J=7.3 Hz, 1 H) 7.54 - 7.63 (m, 3 H).
D. Pharmacological examples
Example D. l : Measurement of antifungal activity in vitro
The standard susceptibility screen was performed in 96-well plates (U-bottom, Greiner Bio-One). Serial dilutions (2-fold or 4-fold) of 20 mM compound stock solutions were made in 100 % DMSO, followed by an intermediate dilution step in water. These serial dilutions (10 μΐ) were then spotted onto test-plates that could be stored in the dark at 4 °C for a maximum period of 2 weeks. An adequate broad dose-range was included with 64 μΜ as the highest in-test concentration. The culture medium RPMI-1640 was supplemented with L-glutamine, 2% glucose and buffered with 3-(N-morpholino)- propanesulfonic acid (MOPS) at pH 7.0 ± 0.1.
The different fungal species/isolates (Table 3a) were cryopreserved and 1/1000 diluted in medium just prior to use. A standard inoculum of 200 μΐ containing 103 colony- forming unit (cfu) was then added to each well. A positive control (100 % growth = fungal culture without antifungal) and a negative control (0 % growth = RPMI-MOPS medium) were included on each plate. Optimal incubation time and temperature were dependent on the fungal species and varied from 24 h for yeasts (37 °C) to one week or more for dermatophytes (27 °C). Inhibition of fungal growth was measured after adding 10 μΐ of 0.005% (w/v) resazurin (Sigma Aldrich) to each well, based on the principle that living cells convert the non-fluorescent blue resazurin into the pink and fluorescent resorufin, allowing fluorimetric reading
Figure imgf000075_0001
590 nm) after an additional incubation period ('resa' time mentioned in Table 3a). Results are shown in Table 3b as pIC5o values.
Table 3a: Incubation conditions for the different fungal species. 'Resa time' represents the additional incubation time after the addition of resazurin to the test system.
Figure imgf000075_0002
Table 3b: Activities of the test compounds in vitro
('n.d.' means not determined; 'Inf.' means infection; values are pIC5o values)
Inf. G : Trichophyton mentagrophytes B70554
Inf. Ά ': Sporothrix schenkii B62482
Inf. 'B ': Microsporum canis B68128 Inf. Ή': Scedosporium apiospermum IHEM3817 Inf. 'C: Trichophyton rubrum B68183 Inf. T: Scedosporium prolifi cans IHEM21157 Inf. 'D': Candida parapsilosis B66126 Inf. 'J': Rhizopus oryzae IHEM5223
Inf. Έ': Aspergillus fumigatus B42928 Inf. 'K': Rhizomucor miehei IHEM13391
Inf. 'F': Cryptococcus neoformans
B66663
Co. Inf. Inf. Inf. Inf. Inf. Inf. Inf. Inf. Inf. Inf. Inf. No. A B C D E F G H I J K
3 <4A9 4.91 4.47 <4.19 <4.19 4.30 4.71 n.d. n.d. n.d. n.d.
4 <4.19 5.09 5.70 <4.19 <4.19 4.38 n.d. n.d. n.d. n.d. n.d.
2 <4A9 4.42 4.96 <4.19 <4.19 <4.19 n.d. n.d. n.d. n.d. n.d.
17 <4.19 <4.19 5.70 <4.19 5.46 <4.19 4.71 n.d. n.d. n.d. n.d.
25 5.70 6.08 6.10 <4.19 6.81 6.00 6.42 <4.19 n.d. <4.19 4.40
12 4.19 6.42 6.86 6.24 6.82 5.52 7.23 <4.19 <4.19 <4.19 <4.19
13 5.15 6.36 6.47 5.52 5.70 5.30 6.95 4.52 5.72 <4.19 <4.19
18 <4.19 4.62 5.70 <4.19 4.67 <4.19 5.26 n.d. n.d. n.d. n.d.
22 <4.49 5.52 6.00 <4.49 4.85 5.60 n.d. n.d. n.d. n.d. n.d.
20 5.70 6.89 7.15 6.47 6.57 6.42 n.d. 5.05 6.07 <4.95 4.86
34 <4.19 5.70 5.70 <4.19 <4.19 5.52 4.96 n.d. n.d. n.d. n.d.
48 5.40 6.30 6.78 <4.19 5.00 5.70 6.29 4.94 5.79 <4.19 <4.19 Inf. Inf. Inf. Inf. Inf. Inf. Inf. Inf. Inf. Inf. Inf.
A B C D E F G H I J K
<4.19 6.00 6.25 4.25 4.85 <4.19 5.70 n.d. n.d. n.d. n.d.
<4.19 6.00 5.22 <4.19 <4.19 5.22 5.00 n.d. n.d. n.d. n.d.
<4.19 5.30 5.40 <4.19 <4.19 4.64 4.47 n.d. n.d. n.d. n.d.
4.21 5.00 5.15 <4.19 <4.19 5.10 4.50 n.d. n.d. n.d. n.d.
<4.19 4.66 5.22 <4.19 <4.19 <4.19 <4.19 n.d. n.d. n.d. n.d.
<4.19 5.11 5.05 <4.19 <4.19 4.42 n.d. n.d. n.d. n.d. n.d.
<4.19 5.05 5.10 <4.19 <4.19 4.34 n.d. n.d. n.d. n.d. n.d.
<4.19 4.92 5.52 <4.19 <4.19 4.74 <4.19 n.d. n.d. n.d. n.d.
<4.19 5.10 5.52 <4.19 <4.19 4.82 n.d. n.d. n.d. n.d. n.d.
<4.19 <4.19 5.40 <4.19 <4.19 <4.19 <4.19 n.d. n.d. n.d. n.d.
<4.19 5.52 6.00 <4.19 <4.19 <4.19 5.80 n.d. n.d. n.d. n.d.
<4.19 5.00 5.40 <4.19 <4.19 <4.19 4.52 n.d. n.d. n.d. n.d.
<4.19 5.40 6.00 <4.19 4.96 5.70 5.63 n.d. n.d. n.d. n.d.
5.52 6.59 6.48 5.10 6.00 6.00 6.48 4.49 5.21 <4.19 <4.19
<4.49 5.05 5.40 <4.49 <4.49 <4.49 5.22 n.d. n.d. n.d. n.d.
4.47 6.00 6.17 5.70 6.04 6.34 6.10 4.62 6.22 <4.19 <4.19
5.30 5.30 5.30 4.92 <4.19 5.15 5.10 n.d. n.d. n.d. n.d.
4.85 6.00 6.36 5.70 5.70 5.30 6.10 4.41 5.89 <4.19 4.27
<4.19 5.52 5.22 <4.19 <4.19 4.64 4.92 n.d. n.d. n.d. n.d.
<4.19 5.00 5.70 <4.19 <4.19 4.48 5.30 n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d.
<4.19 5.15 6.32 <4.19 <4.19 <4.19 4.96 n.d. n.d. n.d. n.d.
<4.19 5.52 5.15 <4.19 <4.19 <4.19 <4.19 n.d. n.d. n.d. n.d.
4.89 6.17 6.88 4.68 5.70 4.30 6.62 5.55 5.92 <4.19 <4.19
<4.19 5.40 5.92 <4.19 <4.19 <4.19 <4.19 n.d. n.d. n.d. n.d.
<4.19 <4.19 <4.19 <4.19 <4.19 <4.19 <4.19 n.d. n.d. n.d. n.d.
<4.19 5.03 5.10 <4.19 5.65 5.37 4.58 n.d. n.d. n.d. n.d.
5.86 6.31 6.77 5.85 7.33 6.47 6.22 6.92 7.40 5.70 6.03
5.11 5.69 5.74 5.29 6.43 4.99 5.72 6.12 6.23 <4.19 <4.19
<4.19 <4.19 <4.19 <4.19 <4.19 <4.19 <4.19 n.d. n.d. n.d. n.d.
<4.19 6.87 7.39 <4.19 7.08 <4.19 6.58 5.5 7.05 <4.19 <4.19
5.28 6.26 6.85 5.64 6.44 <4.19 6.24 4.19 5.98 <4.19 <4.19
5.45 6.87 7.71 5.47 7.25 5.27 6.94 4.65 5.76 4.92 <4.19
5.04 5.80 5.94 4.65 6.25 <4.19 5.27 4.25 4.65 <4.19 <4.19
<4.19 <4.80 4.55 <4.19 <4.19 <4.19 4.31 n.d. n.d. n.d. n.d.
<4.19 5.41 5.71 <4.19 <4.19 <4.19 4.60 n.d. n.d. n.d. n.d.
4.46 5.59 5.84 4.91 5.24 4.74 5.32 4.67 5.32 <4.19 4.29
4.90 6.28 6.29 5.62 5.71 5.60 5.79 5.72 5.98 <4.19 <4.19
<4.19 4.26 5.13 <4.19 <4.19 <4.19 <4.19 6.03 5.8 <4.19 <4.19
5.65 6.77 6.74 5.54 6.44 5.88 6.25 6.35 6.96 <4.19 5.32
5.67 6.78 6.69 <4.19 6.87 6.38 6.49 5.23 5.03 4.31 5.16
5.37 6.43 6.89 5.56 6.40 5.95 6.47 6.13 5.83 <4.89 5.83
4.49 5.28 5.65 4.60 4.39 5.29 4.90 n.d. n.d. n.d. n.d. Co. Inf. Inf. Inf. Inf. Inf. Inf. Inf. Inf. Inf. Inf. Inf.
No. A B C D E F G H I J K
69 5.98 6.89 6.91 6.15 6.89 7.02 6.42 6.64 6.15 5.92 6.33
28 <4.19 6.24 6.66 5.53 5.99 4.71 6.29 4.97 4.63 <4.19 4.39
29 <4.19 <4.19 4.44 <4.19 <4.19 <4.19 <4.19 n.d. n.d. n.d. n.d.
39 4.95 6.36 6.89 5.83 6.77 5.21 6.54 5.40 5.76 <4.19 4.38
37 5.26 6.62 6.89 5.79 6.77 5.88 6.47 4.48 5.85 <4.19 <4.19
75 4.85 5.74 6.85 5.09 6.24 5.84 6.42 <4.19 <4.19 <4.19 <4.19
76 5.69 6.70 6.82 5.18 5.94 5.82 6.38 5.13 5.04 4.57 4.98
68 <4.19 <4.19 <4.19 <4.19 4.19 <4.19 <4.19 n.d. n.d. n.d. n.d.
61 4.50 <4.19 4.31 5.36 4.49 5.09 <4.19 n.d. n.d. n.d. n.d.
60 4.52 <4.19 <4.19 5.44 <4.19 5.15 <4.19 n.d. n.d. n.d. n.d.
41 <4.19 4.48 <4.19 5.60 <4.19 4.52 4.49 n.d. n.d. n.d. n.d.
67 5.10 5.09 <4.19 5.90 5.10 5.36 5.09 n.d. n.d. n.d. n.d.
66 4.46 4.49 <4.19 5.55 5.09 6.11 <4.19 n.d. n.d. n.d. n.d.
40 <4.19 4.49 <4.19 5.56 <4.19 5.87 <4.19 n.d. n.d. n.d. n.d.
46 4.49 4.48 4.44 5.79 4.49 5.49 <4.19 n.d. n.d. n.d. n.d.
38 n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d.
54 <4.19 5.09 5.10 <4.19 <4.19 5.11 4.49 n.d. n.d. n.d. n.d.
53 <4.19 4.49 4.50 <4.19 4.97 4.87 4.49 n.d. n.d. n.d. n.d.
42 5.10 4.49 <4.19 5.63 <4.19 6.82 <4.19 n.d. n.d. n.d. n.d.
73 4.50 5.03 4.49 5.67 <4.19 5.33 4.49 n.d. n.d. n.d. n.d.
70 <4.19 4.19 <4.19 6.12 <4.19 6.02 <4.19 n.d. n.d. n.d. n.d.
43 6.04 6.80 6.89 5.36 6.85 6.68 6.66 n.d. n.d. n.d. n.d.
71 5.71 6.21 6.57 5.09 6.66 7.00 6.51 n.d. n.d. n.d. n.d.
72 5.58 6.39 6.39 4.96 6.21 6.42 5.79 n.d. n.d. n.d. n.d.
57 5.65 5.70 5.80 <4.19 5.62 5.23 5.40 n.d. n.d. n.d. n.d.
82 5.06 5.69 5.95 4.77 5.56 5.26 5.56 n.d. n.d. n.d. n.d.
83 5.14 5.66 5.71 5.28 5.89 5.57 5.06 4.76 5.85 <4.19 <4.19
88 4.27 6.27 6.35 <4.19 6.38 6.39 6.06 6.77 5.59 <4.19 <4.19
E. Composition example
"Active ingredient" as used throughout these examples, relates to a compound of Formula (I), including any stereochemically isomeric form thereof, a pharmaceutically acceptable salt thereof or a solvate thereof; in particular to any one of the exemplified compounds.
Example El : Injectable solution.
1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams sodium hydroxide are dissolved in about 0.5 1 of boiling water for injection. After cooling to about 50°C there are added while stirring 0.05 grams propylene glycol and 4 grams of the active ingredient. The solution is cooled to room temperature and supplemented with water for injection q.s. ad 1 1, giving a solution comprising 4 mg/ml of active ingredient. The solution is sterilized by filtration and filled in sterile containers. Example E2 : Transungual composition.
0.144 g KH2P04, 9 g NaCl, 0.528 g Na2HP04.2H20 is added to 800 ml H20 and the mixture is stirred. The pH is adjusted to 7.4 with NaOH and 500 mg NaN3 is added. Ethanol (42 v/v %) is added and the pH is adjusted to 2.3 with HC1.
15 mg active ingredient is added to 2.25 ml PBS (Phosphate Buffer Saline)/Ethanol (42 %; pH 2.3) and the mixture is stirred and treated with ultrasound. 0.25 ml PBS/Ethanol (42 %; pH 2.3) is added and the mixture is further stirred and treated with ultrasound until all active ingredient is dissolved, yielding the desired transungual composition.
Example E3 : Oral drops
500 Grams of the A.I. is dissolved in 0.5 1 of a sodium hydroxide solution and 1.5 1 of the polyethylene glycol at 60-80 °C. After cooling to 30~40°C there are added
35 1 of polyethylene glycol and the mixture is stirred well. Then there is added a solution of 1750 grams of sodium saccharin in 2.5 1 of purified water and while stirring there are added 2.5 1 of cocoa flavor and polyethylene glycol q.s. to a volume of 50 1, providing an oral drop solution comprising 10 mg/ml of A.I.. The resulting solution is filled into suitable containers.
Example E4 : Capsules
20 Grams of the A.I., 6 grams sodium lauryl sulfate, 56 grams starch, 56 grams lactose, 0.8 grams colloidal silicon dioxide, and 1.2 grams magnesium stearate are vigorously stirred together. The resulting mixture is subsequently filled into 1000 suitable hardened gelatin capsules, comprising each 20 mg of the active ingredient.
Example E5 : Film-coated tablets
Preparation . of tablet core
A mixture of 100 grams of the A.I., 570 grams lactose and 200 grams starch is mixed well and thereafter humidified with a solution of 5 grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture is sieved, dried and sieved again. Then there is added 100 grams microcrystalline cellulose and 15 grams hydrogenated vegetable oil. The whole is mixed well and compressed into tablets, giving 10.000 tablets, each containing 10 mg of the active ingredient.
Coating
To a solution of 10 grams methyl cellulose in 75 ml of denaturated ethanol there is added a solution of 5 grams of ethyl cellulose in 150 ml of dichloromethane. Then there are added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol is molten and dissolved in 75 ml of dichloromethane. The latter solution is added to the former and then there are added 2.5 grams of magnesium octadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentrated colour suspension and the whole is homogenated. The tablet cores are coated with the thus obtained mixture in a coating apparatus.
Example E6 : 2 % Cream
Stearyl alcohol (75 mg), cetyl alcohol (20 mg), sorbitan monostearate (20 mg) and isopropyl myristate (10 mg) are introduced in a doublewall jacketed vessel and heated until the mixture has completely molten. This mixture is added to a seperately prepared mixture of purified water, propylene glycol (200 mg) and polysorbate 60 (15 mg) having a temperature of 70 to 75 °C while using a homogenizer for liquids. The resulting mixture is allowed to cool to below 25°C while continuously mixing. A solution of A. I. (20 mg), polysorbate 80 (1 mg) and purified water q.s. ad lg and a solution of sodium sulfite anhydrous (2 mg) in purified water are next added to the emulsion while continuously mixing. The cream is homogenized and filled into suitable tubes.
Example E7 : 2 % Cream
A mixture of A.I. (2 g), phosphatidyl choline (20 g), cholesterol (5 g) and ethyl alcohol (10 g) is stirred and heated at 55-60 °C until complete solution and is added to a solution of methyl paraben(0.2 g), propyl paraben (0.02 g), disodium edetate
(0.15 g) and sodium chloride (0.3 g) in purified water (ad 100 g) while homogenizing. Hydroxypropylmethylcellulose (1.5 g) in purified water is added and the mixing is continued until swelling is complete.

Claims

Claims
1. A compound of formula (I)
Figure imgf000080_0001
or a stereoisomeric form thereof, wherein
R1 is hydrogen, halo, Ci-4alkyl or Ci-4alkyloxy;
R2 is hydrogen or halo;
R3 and R4 are hydrogen;
or R3 and R4 taken together form a bond;
R5 is hydrogen or Ci-4alkyloxy;
R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
-(CH2)m-Y1-(CH2)n-m- (a), -Y2a-(CH2)t-Y2b- (d), or
-(CH2)n-m-Y1-(CH2)m- (b), -(CH2)r-Y2a-CH2-Y2b-(CH2)q- (e);
-(CH2)S- (c),
wherein the bivalent radical -R6-R7- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl, hydroxyl, Ci-4alkyloxy and oxo;
Y1 represents O, R8a or S;
Y2a and Y2b each independently represent O, R8b or S;
R8a represents hydrogen or Ci-4alkyl;
R represents hydrogen or Ci-4alkyl;
m represents 0, 1 or 2;
n represents 2, 3 or 4;
s represents 3, 4 or 5;
t represents 1, 2 or 3;
r represents 0 or 1 ;
q represents 0 or 1 ;
provided that at least one of r and q is 1;
or a pharmaceutically acceptable addition salt or a solvate thereof;
provided that the compound is not 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[l,2-a][l,4]benzodiazepine or 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H- pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine .HC1.
2. The compound according to claim 1 wherein
R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
-(CH2)m-Y1-(CH2)n-m- (a), -(CH2)S- (c), or
-(CH2)n-m-Y1-(CH2)m- (b), -Y2a-(CH2)t-Y2b- (d);
wherein the bivalent radical -R6-R7- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl and oxo; Y1 represents O or R8a;
Y2a and Y2b each independently represent O or R8b;
R8a represents hydrogen or Ci-4alkyl;
R represents hydrogen or Ci-4alkyl;
m represents 0, 1 or 2;
n represents 2 or 3;
s represents 3 or 4;
t represents 1.
3. The compound according to claim 1 wherein
R1 is hydrogen, halo or Ci-4alkyloxy;
R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
-(CH2)m-Y1-(CH2)n-m- (a), -(CH2)S- (c), or
-Y2a-(CH2)t-Y2b- (d);
wherein the bivalent radical -R6-R7- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci-4alkyl and oxo;
Y1 represents O or H;
Y2a represents O;
Y2b represent O or NH;
m represents 0, 1 or 2;
n represents 2 or 3;
s represents 3 or 4;
t represents 1.
4. The compound according to claim 1 wherein
R1 is halo;
R2 is hydrogen; R5 is hydrogen;
R6 and R7 taken together form a bivalent radical -R6-R7-, having formula:
_(CH2)m-0-(CH2)n-m- ,
-(CH2)S- , or
Figure imgf000082_0001
wherein the bivalent radical -(CH2)m-0-(CH2)n-m- or -(CH2)S- may, where possible, be substituted with one or more substituents selected from the group consisting of halo and oxo;
wherein the bivalent radical -0-CH2-0- is substituted with one or more substituents selected from the group consisting of halo and oxo;
m represents 0 or 1 ;
n represents 3;
s represents 3 or 4.
5. The compound according to claim 1 wherein R1 is halo.
6. The compound according to claim 1 wherein R6 and R7 taken together form a bivalent radical -R6-R7-, wherein -R6-R7- is selected from the group consisting of -(CH2)3- -(CH2)4- -(CH2)2-0- -CH2-CH(CH3)-0-, -C(=0)-(CH2)2- -C(=0)-(CH2)3- -0-(CH2)2- -0-(CH2)3- -CH2-0-(CH2)2- -(CH2)2-C(=0)-, -0-CF2-(CH2)2- -(CH2)2-C(=0)-, -CF2-(CH2)2- -C(=0)-0-CH2- -CH2-0-C(=0)-, -0-CF2-0- -0-C(=0)-N(CH3)-, -N(CH3)-(CH2)2-, and -N(CH3)-C(=0)-C(CH3)2-.
7. The compound according to claim 1 wherein R6 and R7 taken together form a bivalent radical -R6-R7- having the formula -0-CH2-0-,
wherein -0-CH2-0- is substituted with one or two substituents selected from the group consisting of halo, Ci-4alkyl, hydroxyl, Ci-4alkyloxy and oxo.
8. The compound according to any one of claims 1 to 7 wherein
R3 and R4 are taken together to form a bond. 9. The compound according to claim 1 wherein the compound is
7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine, 7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine .HC1,
7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzo- diazepine .HBr,
7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine,
7-chloro-4-(5,6,7,8-tetrahydro-2-naphthalenyl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine, 4-(2,2-difluoro-l,3-benzodioxol-5-yl)-7,9-difluoro-6H-pyrrolo[l,2-a][l,4]benzo- diazepine,
4-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-7-fluoro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine,
6- (7-fluoro-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepin-4-yl)-3 ,4-dihydro- 1 (2H)- naphthalenone,
7- chloro-4-(2,2-difluoro-3 ,4-dihydro-2H- 1 -benzopyran-6-yl)-6H-pyrrolo[ 1 ,2-a] [1,4]- benzodiazepine,
4-(3,4-dihydro-lH-2-benzopyran-6-yl)-7-fluoro-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-(3,4-dihydro-lH-2-benzopyran-6-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine,
9-chloro-4-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine, or 10-chloro-4-(3 ,4-dihydro-2H- 1 -benzopyran-6-yl)-6H-pyrrolo[ 1 ,2-a] [ 1 ^benzodiazepine,
a stereoisomeric form thereof,
or a pharmaceutically acceptable addition salt or a solvate thereof.
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined in any one of claims 1 to 9.
11. A compound as defined in any one of claims 1 to 9 for use as a medicament.
12. A compound as defined in any one of claims 1 to 9 for use in the treatment or prevention of a fungal infection.
13. The compound for use according to claim 12 wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Candida spp.;
Aspergillus spp.; Cryptococcus neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum spp.; Trichophyton spp; Fusarium spp.; Rhizomucor spp.; Mucor circinelloides; Rhizopus spp.; Malassezia furfur; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrogr aphis spp.; Scytalidium; Scedosporium spp.; Trichoderma spp.; Penicillium spp. ; Penicillium marneffei; Blastoschizomyces.
14. The compound for use according to claim 12 wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Candida parapsilosis,
Aspergillus spp., Cryptococcus neoformans, Microsporum spp., and Trichophyton spp.
15. The compound for use according to claim 12 wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum and Aspergillus fumigates.
PCT/EP2011/073215 2010-12-21 2011-12-19 NOVEL ANTIFUNGAL 5,6-DIHYDRO-4H-PYRROLO[1,2-a][1,4]- BENZODIAZEPINES AND 6H-PYRROLO[1,2-a][1,4]BENZODIAZEPINES SUBSTITUTED WITH BICYCLIC BENZENE DERIVATIVES WO2012084804A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
CN201180061514.2A CN103282367B (en) 2010-12-21 2011-12-19 5,6-dihydro-4H-pyrrolo-[1,2-A] [Isosorbide-5-Nitrae] the benzodiazepine * that two ring benzene derivatives replace and the new anti-mycotic agent of 6H-pyrrolo-[1,2-A] [Isosorbide-5-Nitrae] benzodiazepine *
EP11802072.6A EP2668187B1 (en) 2010-12-21 2011-12-19 NOVEL ANTIFUNGAL 5,6-DIHYDRO-4H-PYRROLO[1,2-a][1,4]- BENZODIAZEPINES AND 6H-PYRROLO[1,2-a][1,4]BENZODIAZEPINES SUBSTITUTED WITH BICYCLIC BENZENE DERIVATIVES
ES11802072.6T ES2527032T3 (en) 2010-12-21 2011-12-19 5,6-dihydro-4H-pyrrolo [1,2-a] [1,4] -benzodiazepines and 6H-pyrrolo [1,2-a] [1,4] novel antifungal substituted benzodiazepines with bicyclic benzene derivatives
MX2013007166A MX2013007166A (en) 2010-12-21 2011-12-19 NOVEL ANTIFUNGAL 5,6-DIHYDRO-4H-PYRROLO[1,2-a][1,4]- BENZODIAZEPINES AND 6H-PYRROLO[1,2-a][1,4]BENZODIA ZEPINES SUBSTITUTED WITH BICYCLIC BENZENE DERIVATIVES.
US13/995,526 US9040524B2 (en) 2010-12-21 2011-12-19 Antifungal 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]-benzodiazepines and 6H-pyrrolo[1,2-a][1,4]benzodiazepines substituted with bicycle benzene derivatives
EA201390921A EA022407B1 (en) 2010-12-21 2011-12-19 ANTIFUNGAL 5,6-DIHYDRO-4H-PYRROLO[1,2-a][1,4]BENZODIAZEPINES AND 6H-PYRROLO[1,2-a][1,4]BENZODIAZEPINES SUBSTITUTED WITH BICYCLIC BENZENE DERIVATIVES
SG2013042643A SG190971A1 (en) 2010-12-21 2011-12-19 NOVEL ANTIFUNGAL 5,6-DIHYDRO-4H-PYRROLO[1,2-a][1,4]- BENZODIAZEPINES AND 6H-PYRROLO[1,2-a][1,4]BENZODIAZEPINES SUBSTITUTED WITH BICYCLIC BENZENE DERIVATIVES
JP2013545254A JP5918258B2 (en) 2010-12-21 2011-12-19 Novel antifungal 5,6-dihydro-4H-pyrrolo- [1,2-a] [1,4] benzodiazepines and 6H-pyrrolo- [1,2-a] [1 substituted with bicyclic benzene derivatives , 4] Benzodiazepine
AU2011347577A AU2011347577B2 (en) 2010-12-21 2011-12-19 Novel antifungal 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]-benzodiazepines and 6H-pyrrolo[1,2-a][1,4]benzodiazepines substituted with bicyclic benzene derivatives
CA2818623A CA2818623C (en) 2010-12-21 2011-12-19 Antifungal 5,6-dihydro-4h-pyrrolo[1,2-a][1,4]-benzodiazepines and 6h-pyrrolo[1,2-a][1,4]benzodiazepines substituted with bicyclic benzene derivatives
AP2013006886A AP4012A (en) 2010-12-21 2011-12-19 NOVEL ANTIFUNGAL 5,6-DIHYDRO-4H-PYRROLO[1,2-a][1,4]- BENZODIAZEPINES AND 6H-PYRROLO[1,2-a][1,4]BENZODIAZEPINES SUBSTITUTED WITH BICYCLIC BENZENE DERIVATIVES
UAA201306467A UA109796C2 (en) 2010-12-21 2011-12-19 ANTIFUNGAL 5,6-DIHYDRO-4H-PYROLO 1,2,2-a] $ 1,4] BENZODIAZEPINES AND 6H-PYROL $ 1,2-a] $ 1,4] BENZODIAZEPINES SUBSTITUTED BY BICYCLIC BICYCLIC
KR1020137019234A KR101839365B1 (en) 2010-12-21 2011-12-19 NOVEL ANTIFUNGAL 5,6-DIHYDRO-4H-PYRROLO[1,2-a][1,4]-BENZODIAZEPINES AND 6H-PYRROLO[1,2-a][1,4]BENZODIAZEPINES SUBSTITUTED WITH BICYCLIC BENZENE DERIVATIVES
NZ610939A NZ610939A (en) 2010-12-21 2011-12-19 Novel antifungal 5,6-dihydro-4h-pyrrolo[1,2-a][1,4]- benzodiazepines and 6h-pyrrolo[1,2-a][1,4]benzodiazepines substituted with bicyclic benzene derivatives
BR112013016007A BR112013016007A2 (en) 2010-12-21 2011-12-19 5,6-dihydro-4h-pyrrolo [1,2-a] [1,4] benzodiazepines and 6h-pyrrolo [1,2-a] [1,4] antifungal benzodiazepines substituted by bicyclic benzene derivatives
IL227053A IL227053A (en) 2010-12-21 2013-06-19 Antifungal 5,6-dihydro-4h-pyrrolo [1,2-a][1,4]-benzodiazepines and 6h-pyrrolo[1,2-a][1,4]benzodiazepines substituted with bicyclic benzene derivatives, pharmaceutical compositions comprising them and uses thereof
ZA2013/04577A ZA201304577B (en) 2010-12-21 2013-06-20 Novel antifungal 5,6-dihydro-4h-pyrrolo{,2-@}[1,4]-benzodiazepines and 6h-pyrrolo[1,2@[1,4]benzodiazepines susbstituted with bicyclic benzene derivatives
HK14102027.7A HK1188792A1 (en) 2010-12-21 2014-02-28 Novel antifungal 5,6-dihydro-4h-pyrrolo[1,2-a][1,4]- benzodiazepines and 6h-pyrrolo[1,2-a][1,4]benzodiazepines substituted with bicyclic benzene derivatives 56--4h-[12-a][14] 6h- [12-a][14]

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CN103282367A (en) 2013-09-04
JP5918258B2 (en) 2016-05-18
HK1188792A1 (en) 2014-05-16
CA2818623C (en) 2019-03-12
BR112013016007A2 (en) 2018-07-10
SG190971A1 (en) 2013-07-31
JP2014500288A (en) 2014-01-09
UA109796C2 (en) 2015-10-12
CA2818623A1 (en) 2012-06-28
ZA201304577B (en) 2014-12-23
AP2013006886A0 (en) 2013-05-31
ES2527032T3 (en) 2015-01-19
MX2013007166A (en) 2013-08-01
AU2011347577B2 (en) 2016-04-28
US9040524B2 (en) 2015-05-26
IL227053A (en) 2015-10-29
AP4012A (en) 2017-01-22
MY161360A (en) 2017-04-14
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AU2011347577A1 (en) 2013-06-13
NZ610939A (en) 2014-07-25
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