EP1620413A2 - Composes, compositions et procedes - Google Patents

Composes, compositions et procedes

Info

Publication number
EP1620413A2
EP1620413A2 EP04750041A EP04750041A EP1620413A2 EP 1620413 A2 EP1620413 A2 EP 1620413A2 EP 04750041 A EP04750041 A EP 04750041A EP 04750041 A EP04750041 A EP 04750041A EP 1620413 A2 EP1620413 A2 EP 1620413A2
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
ylamine
phenyl
trifluoromethyl
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04750041A
Other languages
German (de)
English (en)
Inventor
Adam Tomasi
Bradley P. Morgan
Jr. David J. Morgans
Andrew Mcdonald
David Roof
Mary Maxon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cytokinetics Inc
Original Assignee
Cytokinetics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cytokinetics Inc filed Critical Cytokinetics Inc
Publication of EP1620413A2 publication Critical patent/EP1620413A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms

Definitions

  • This invention relates to compounds which are inhibitors of the fungal kinesin Kipl and are useful in the treatment of fungal disorders.
  • Candida albicans represent important new targets for antifungal drugs.
  • fungi like mammalian cells, are eukaryotes, there is relatively low homology between the fungal kinesin Kipl and human Kipl. See, e.g., PCT Application No. PCT/US03/35669, which is incorporated herein by reference. As such, it is possible to specifically inhibit the fungal protein and not the human Kipl, thus, decreasing or even eliminating toxic side effects.
  • the present invention provides compositions and methods that can be used to treat fungal infections.
  • the compositions inhibit the fungal kinesin Kipl .
  • the invention relates to methods for the treatment of a fungal infection and more particularly, a fungal infection caused by a Candida species, such as Candida albicans, Candida tropicalis, Candida (Torulopsis) glabrata, Candida parapsilosis, Candida lusitaneae, Candida rugosa, and Candida pseudotropicalis.
  • Fungal infections which can be inhibited or treated with compositions provided herein include candidiasis including but not limited to onchomycosis, chronic mucocutaneous candidiasis, oral candidiasis, epiglottistis, esophagitis, gastrointestinal infections, and genitourinary infections.
  • the invention relates to compounds of Formula I
  • R is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
  • R , R , R , and R are independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted alkoxy, optionally substituted aralkoxy, optionally substituted heteroaralkoxy, halogen, hydroxyl, nitro, cyano, optionally substituted amino, sulfonyl, sulfanyl, carboxy, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aryl or optionally substituted heteroaryl; or R and R , together with the carbons to which they are attached, form an optionally substituted 5- or 6-membered alicyclic ring; and
  • R is hydrogen, cyano, halogen, optionally substituted acyl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, sulfonyl, or optionally substituted amino; provided that
  • R is not trifluoromethyl when X is NR 1 ; R , R , R , and R are hydrogen; and R is optionally substituted lower alkyl;
  • R is not trifluoromethoxy, optionally substituted lower alkyl or halo
  • X is not S, when R and R , together with the carbons to which they are o 5 2 attached form a cyclohexyl ring; R is amino; and R and R are hydrogen; and
  • R is not lower alkyl or halo, when X is NR ; R , R , R , and R 1 are hydrogen; and R is amino; including single stereoisomers, mixtures of stereoisomers, and pharmaceutically acceptable salts thereof.
  • the compounds of Formula I are useful as active agents in practice of the methods of treatment and in manufacture of the pharmaceutical formulations of the invention, and as intermediates in the synthesis of such active agents.
  • the invention relates to a pharmaceutical formulation including a pharmaceutically acceptable excipient, and to a method of treatment for fungal infection, each entailing a therapeutically effective amount of a compound represented by Formula I.
  • Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof.
  • Lower alkyl refers to alkyl groups of from 1 to 5 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl and the like. Preferred alkyl groups are those of C 0 or below.
  • alkyl groups are those of C 13 or below. Yet more preferred are alkyl groups of C 6 and below.
  • Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 13 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c- pentyl, norbornyl, adamantyl and the like.
  • alkyl refers to alkanyl, alkenyl and alkynyl residues; it is intended to include cyclohexylmethyl, vinyl, allyl, isoprenyl and the like.
  • Alkylene is another subset of alkyl, referring to the same residues as alkyl, but having two points of attachment.
  • alkylene include ethylene ( - CH2CH2-), propylene (-CH2CH2CH2-), dimethylpropylene ( -CH 2 C(CH 3 ) 2 CH 2 -) and cyclohexylpropylene (-CH 2 CH 2 CH(C 6 H ⁇ 3 )- ).
  • alkyl residue having a specific number of carbons When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, "butyl” is meant to include n-butyl, sec- butyl, isobutyl and t-butyl; “propyl” includes n-propyl and isopropyl.
  • Alkoxy or alkoxyl refers to the group -O-alkyl, preferably including from
  • Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
  • Lower alkoxy refers to groups containing one to four carbons.
  • Acyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated, aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality.
  • One or more carbons in the acyl residue can be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Lower-acyl refers to groups containing one to four carbons.
  • Alicyclic refers to an aliphatic, cyclic residue.
  • Examples of alicyclic groups include cyclopentyl, cyclohexyl, and the like.
  • Amino refers to the group -NH .
  • Substituted amino refers to the group
  • each R is independently chosen from the group: optionally substituted alkyl-, optionally substituted alkoxy, optionally substituted aminocarbonyl-, optionally substituted aryl-, optionally substituted heteroaryl-, optionally substituted heterocyclyl-, acyl-, alkoxycarbonyl-, sulfanyl-, sulfinyl and sulfonyl-, e.g., diethylamino, methylsulfonylamino, furanyl-oxy-sulfonamino.
  • Substituted amino includes the groups - NR c COR b , -NR c CO 2 R a , and -NR°CONR b R c , where
  • R a is an optionally substituted d-C ⁇ alkyl-, aryl-, heteroaryl-, aryl-Ci-O alkyl-, or heteroaryl-C ⁇ -C alkyl- group;
  • R is H or optionally substituted d-C ⁇ alkyl-, aryl-, heteroaryl-, aryl-C ⁇ -C alkyl-, or heteroaryl-C 1 -C 4 alkyl- group;
  • R c is hydrogen or C1-C4 alkyl-; and where each optionally substituted R group is independently unsubstituted or substituted with one or more substituents independently chosen from C1-C4 alkyl-, aryl-, heteroaryl-, aryl-C ⁇ -C 4 alkyl-, heteroaryl-C 1 -C 4 alkyl-, C1-C4 haloalkyl-, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halogen, -OH, -NH 2 , -C1-C4 alkyl-NH 2 , -N(d-C 4 alkyl)(C 1 -C 4 alkyl), -NH(Ci-C 4 alkyl), -N(C ⁇ -C 4 alkyl)(C 1 -C 4 alkylphenyl), -
  • Aminocarbonyl refers to the group -CONR b R c , where
  • R is H or optionally substituted C ⁇ -C 6 alkyl-, aryl-, heteroaryl-, aryl-d-C 4 alkyl-, or heteroaryl-C ⁇ -C4 alkyl- group;
  • R c is hydrogen or d-C alkyl-; and where each optionally substituted R group is independently unsubstituted or substituted with one or more substituents independently chosen from C1-C4 alkyl-, aryl-, heteroaryl-, aryl-C 1 -C4 alkyl-, heteroaryl-d-C 4 alkyl-, C1-C4 haloalkyl-, -OCi-C4 alkyl-, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halogen, -OH, -NH 2 , -C1-C4 alkyl-NH 2 , -N(C ⁇ -C4 alkyl)(C 1 -C 4 alkyl), -NH(d-C 4 alkyl), -N(C ⁇ -C4 alkyl)(C ⁇ -C4 alkylphenyl), -NH(
  • Aminocarbonyl is meant to include carbamoyl-; lower-alkyl carbamoyl-; benzylcarbamoyl-; phenylcarbamoyl-; methoxymethyl-carbamoyl-; and the like.
  • Aralkyl refers to a residue in which an aryl moiety is attached to the parent structure via an alkyl residue. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like. Heteroaralkyl refers to a residue in which a heteroaryl moiety is attached to the parent structure via an alkyl residue. Examples include furanylmethyl, pyridinylmethyl, pyrimidinylethyl and the like.
  • Aralkoxy refers to the group -O-aralkyl.
  • heteroaralkoxy refers to the group -O-heteroaralkyl;
  • aryloxy refers to the group -O-aryl;
  • acyloxy refers to the group -O — acyl.
  • Aryl and heteroaryl refer to a 5- or 6-membered aromatic or heteroaromatic ring containing 0 to 4 heteroatoms selected from O, N, and S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0 to 4 (or more) heteroatoms selected from O, N, and S; or a tricyclic 12- to 14-membered aromatic or heteroaromatic ring system containing 0 to 4 (or more) heteroatoms selected from O, N, and S.
  • the aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • Aryloxy and heteroaryloxy refer to aryl and heteroaryl groups, respectively, attached to the parent structure through an oxygen.
  • ATPase refers to an enzyme that hydrolyzes ATP.
  • ATPases include proteins comprising molecular motors such as the myosins.
  • Halogen or halo refers to fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are preferred.
  • Dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with a plurality of halogens, but not necessarily a plurality of the same halogen; thus 4-chloro-3 -fluorophenyl is within the scope of dihaloaryl.
  • Heterocyclyl means a cycloalkyl or aryl residue in which one to four of the carbons is replaced by a heteroatom such as oxygen, nitrogen or sulfur.
  • heterocycles that fall within the scope of the invention include imidazoline, pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, piperidine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like.
  • N-Heterocyclyl refers to a nitrogen-containing heterocycle as a substituent residue.
  • the term heterocyclyl encompasses heteroaryl, which is a subset of heterocyclyl.
  • Examples of N-heterocyclyl residues include 4-morpholinyl,
  • substituted heterocyclyl examples include
  • Isolated, purified, or biologically pure refer to material that is substantially or essentially free from components that normally accompany it as found in its native state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography.
  • Stepoisomers are isomers that differ only in the way the atoms are arranged in space.
  • Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(. ⁇ .)” is used to designate a racemic mixture where appropriate.
  • Diastereoisomers are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold- Prelog R-S system.
  • stereochemistry at each chiral carbon can be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
  • the R- and S-isomers can be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which can be separated, for example, by crystallisation; via formation of diastereoisomeric derivatives which can be separated, for example, by crystallisation, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • Optional or optionally means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted alkyl means either "alkyl” or "substituted alkyl” as defined herein. It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and/or synthetically non-feasible and/or inherently unstable.
  • Pharmaceutically acceptable carrier or pharmaceutically acceptable excipient includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Substituted- alkyl, aryl, heteroaryl and heterocyclyl refer respectively to alkyl, aryl, heteroaryl and heterocyclyl wherein one or more (up to about 5, preferably up to about 3) hydrogen atoms are replaced by a substituent independently selected from the group: optionally substituted alkyl (e.g., fluoroalkyl), optionally substituted alkoxy, alkylenedioxy (e.g.
  • optionally substituted amino e.g., alkylamino and dialkylamino
  • optionally substituted amidino optionally substituted aryl (e.g., phenyl), optionally substituted aralkyl (e.g., benzyl), optionally substituted aryloxy (e.g., phenoxy), optionally substituted aralkoxy (e.g., benzyloxy), carboxy (-COOH), carboalkoxy (i.e., acyloxy or -OOCR), carboxyalkyl (i.e., esters or -COOR), carboxamido, aminocarbonyl, benzyloxycarbonylamino (CBZ-amino), cyano, carbonyl, halogen, hydroxy, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaryloxy, optionally substituted heteroaralkoxy, nitro, sulfanyl, s
  • Substituted alkoxy refers to the group -O-(substituted alkyl).
  • One preferred substituted alkoxy group is "polyalkoxy" or -O-(optionally substituted alkylene)-(optionally substituted alkoxy), and includes groups such as -OCH 2 CH 2 OCH 3 , and glycol ethers such as polyethyleneglycol and -O(CH 2 CH2 ⁇ ) x CH 3 , where x is an integer of about 2-20, preferably about 2-10, and more preferably about 2-5.
  • Another preferred substituted alkoxy group is hydroxyalkoxy or -OCH2(CH 2 ) y OH, where y is an integer of about 1-10, preferably about 1-4.
  • Pharmaceutically acceptable acid addition salt refers to those salts that retain the biological effectiveness of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,'maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic
  • Pharmaceutically acceptable base addition salts include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • esters refers to esters of compounds of the present invention which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • examples of pharmaceutically acceptable, non-toxic esters of the present invention include d to C 6 alkyl esters and C 5 to C cycloalkyl esters, although Ci - to C alkyl esters are preferred.
  • Esters of the compounds of Formula I can be prepared according to conventional methods.
  • Pharmaceutically acceptable, non-toxic esters of the present invention also include prodrug ester groups, i.e., any of several ester-forming groups that are hydrolyzed under physiological conditions.
  • prodrug ester groups examples include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art.
  • Other examples of prodrug ester groups can be found in the book “Pro-drugs as Novel Delivery Systems,” by Higuchi and Stella., V. 14 of the
  • Pharmaceutically acceptable amide refers to non-toxic amides of the present invention derived from ammonia, primary Ci to C 6 alkyl amines and secondary d to C 6 dialkyl amines. In the case of secondary amines, the amine can also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, Ci to C 3 alkyl primary amides and O to C 3 dialkyl secondary amides are preferred. Amides of the compounds of Formula I can be prepared according to conventional methods.
  • Subject or patient refers to an animal, preferably a mammal, that has been the object of treatment, observation or experiment, and most preferably refers to a human who is or has been the object of treatment and/or observation.
  • Sulfanyl refers to the groups: -S-(optionally substituted alkyl),
  • Sulfinyl refers to the groups: -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-optionally substituted aryl), -S(O)-(optionally substituted heteroaryl), and
  • Sulfonyl refers to the groups: -S(O 2 )-H, -S(O 2 )-(optionally substituted alkyl), -S(O2)-optionally substituted aryl), -S(O2)-optionally substituted aralkyl),
  • Therapeutically effective amount refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a research, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • Treatment or treating refers to any treatment of a disease in a subject, including: a) preventing the disease, that is, causing the clinical symptoms of the disease not to develop; b) inhibiting the disease, that is, slowing or arresting the development of clinical symptoms; and/or c) relieving the disease, that is, causing the regression of clinical symptoms.
  • compounds of the invention can exist in various equilibrium forms, depending on conditions including choice of solvent, pH, and others known to the practitioner skilled in the art. All such forms of these compounds are expressly included in the present invention.
  • Some of the crystalline forms for the compounds can exist as polymorphs and as such are included in the present invention.
  • some of the compounds can form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also encompassed within the scope of this invention.
  • the present invention includes within its scope prodrugs of the compounds shown herein. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound.
  • the term "administering” shall encompass the treatment of the various disorders described with the compounds specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to a subject in need thereof.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", H. Bundgaard ed., Elsevier, 1985. Protected forms of the inventive compounds are included within the scope of the present invention.
  • Implicit hydrogen atoms are omitted from the formulae for clarity, but should be understood to be present.
  • Certain embodiments of the invention are directed to a class of novel compounds that are inhibitors of the fungal kinesin, Candida albicans Kipl. Certain embodiments of the invention also provide methods for treating fungal infection by inhibiting the fungal kinesin Kipl. The methods employ compounds represented by Formula I
  • R is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
  • R 2 , R , R 4 , and R are independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted alkoxy, optionally substituted aralkoxy, optionally substituted heteroaralkoxy, halogen, hydroxyl, nitro, cyano, optionally substituted amino, sulfonyl, sulfanyl, carboxy, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aryl or optionally substituted heteroaryl; or R and R , together with the carbons to which they are attached, form an optionally substituted 5- or 6-membered alicyclic ring; and
  • R 8 is hydrogen, cyano, halogen, optionally substituted acyl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, sulfonyl, or optionally substituted amino; provided that
  • R 4 is not trifluoromethyl when X is NR 1 ;
  • R 5 , R 3 , R 2 , and R 1 are hydrogen; and
  • R is optionally substituted lower alkyl;
  • R is not trifluoromethoxy, optionally substituted lower alkyl or halo when X is S; R 5 , R 4 , and R 2 are hydrogen; and R 8 is amino;
  • X is not S, when R and R , together with the carbons to which they are attached form a cyclohexyl ring; R is amino; and R and R are hydrogen; and
  • R 4 is not lower alkyl or halo, when X is NR 1 ; R 5 , R 3 , R 2 , and R 1 are hydrogen; and R is amino; including single stereoisomers, mixtures of stereoisomers, and the pharmaceutically acceptable salts thereof.
  • the compound of Formula I wherein X is NR ; R is 2-dimethylamino-ethyl; R is hydrogen; R is hydrogen; R is cyclohexyl; R is hydrogen; and R is acetyl can be named 1 - [5 -cyclohexyl- 1 -(2-dimethylamino-ethyl)- 1 H-benzoimidazol-2-yl] -ethanone . [0053] Likewise, the compound:
  • R is hydrogen; R is hydrogen; and R is amino can be named 6-trifluoromethyl- benzothiazol-2-ylamine.
  • the compounds of Formula I can be readily prepared by those skilled in the art using commonly employed synthetic methodology from substituted indole carboxylic acids that are commercially available, e.g., from Aldrich Chemical Company, Milwaukee, WI.
  • a compound of Formula R COC1 wherein R is not optionally substituted amino is added to a solution of a compound of Formula 101 and a base such as pyridine in an inert solvent such as dichloromethane. The solution is stirred at room temperature overnight and then the volatiles are removed in vacuo to give a solid. An acid such as toluenesulfonic acid monohydrate in an inert solvent such as xylenes is added to the crude residue and the resulting mixture is stirred at about 140°C for about 6 hours. The product, a compound of Formula 105, is isolated and optionally purified.
  • Compounds of Formula I, wherein X is S and R is optionally substituted amino can be prepared by treatment of a phenylamine of Formula 201 with an excess of bromine and either NaSCN or KSCN in acetic acid.
  • Compounds of Formula 203 are isolated and purified.
  • a solution of a compound of Formula 301 wherein X is S or NH and an excess of cyanogen bromide in a polar, protic solvent such as aqueous methanol is maintained at room temperature for about 8 hours.
  • the product, a compound of Formula 303 is isolated and optionally purified.
  • compounds of Formula 303 can be further derivatized using techniques known in the art.
  • R 2 , R 3 , R 4 , or R 5 is a halogen
  • the corresponding compound wherein the halogen is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl can be prepared via a palladium- catalyzed coupling reaction.
  • R HNCS (wherein R is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl) in an inert solvent such as ethyl acetate are heated at about 75 °C with stirring for about 2 hours. The solvent is removed and the residue is dissolved in a polar protic solvent such as ethanol. Mercury(II) oxide and sulfur are added and the mixture is heated at about 75°C for about 2 hours. The product, a compound of Formula 405, is isolated and optionally purified.
  • a racemic mixture of isomers of a compound of Formula I is placed on a chromatography column and separated into (R)- and (S)- enantiomers. [0064] A compound of Formula I is contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salt.
  • a pharmaceutically acceptable acid addition salt of Formula I is contacted with a base to form the corresponding free base of Formula I.
  • X is -S-.
  • X is -NR - and R is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl. In a more particular embodiment, R is hydrogen.
  • X is -NR 1 - and R 1 is -(C R 10 R ⁇ ) felicit-NR 12 R 13 wherein R and R are independently hydrogen or optionally substituted lower alkyl; n is 1, 2, or 3; and R and R together with the nitrogen to which they are attached form an optionally substituted heterocyclyl group.
  • X is -NR - and R together with R , and the atoms to which they are attached, form an optionally substituted 5- to 7-membered heterocyclic ring.
  • R is a substituted amino group and the
  • R , R , R , and R are independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted alkoxy, optionally substituted aralkoxy, optionally substituted heteroaralkoxy, halogen, hydroxyl, nitro, cyano, optionally substituted amino, sulfonyl, sulfanyl, carboxy, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aryl or optionally substituted heteroaryl.
  • R 2 , R 3 , R 4 , and R 5 are independently hydrogen; hydroxyl; halogen (particularly chloro, bromo, or fluoro); optionally substituted alkyl (particularly cyclohexyl, methyl, or trifluoromethyl); optionally substituted lower alkoxy (particularly methoxy or trifluoromethoxy); phenyl; phenyl substituted with one or more of the following substituents: halo, optionally substituted lower alkyl (particularly methyl or trifluoromethyl), and optionally substituted lower alkoxy (particularly methoxy or trifluoromethoxy); acetyl; optionally substituted aralkoxy (particularly benzyloxy); nitro; or cyano.
  • only one of R , R , R , and R 5 is not hydrogen,
  • R is trifluoromethyl- and R , R , and R are hydrogen. In another certain embodiment, only two of R 2 , R 3 , R 4 , and R 5 are not hydrogen. In one embodiment, R and R 4 are not hydrogen.
  • R 3 and R together with the carbons to which they are attached, form an optionally substituted 5- or 6-membered alicyclic ring and R and R are as defined above.
  • R is hydrogen, cyano, halogen, optionally substituted acyl; optionally substituted lower alkyl; optionally substituted aryl; optionally substituted heteroaryl; sulfonyl, or optionally substituted amino.
  • R is hydrogen; amino; amino substituted with optionally substituted lower alkyl; amino substituted with sulfonyl; acyl (especially, formyl or acetyl); phenyl; phenyl substituted with lower alkyl, halo, or lower alkoxy; halogen (especially, chloro); optionally substituted lower alkyl (especially, methyl, cyclopropyl, trifluoromethyl, hydroxymethyl-, 1-hydroxyethyl-, 2-hydroxyethyl-, or 3- hydroxyprop-lyl); furan-2-yl; furan-3-yl; pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; sulfonyl;
  • X is -NR 1 -;
  • R 1 is hydrogen
  • R , R , R , and R are independently hydrogen; hydroxyl; halogen; optionally substituted alkyl; acetyl; optionally substituted lower alkoxy; phenyl; phenyl substituted with one or more of the following substituents: halo, optionally substituted lower alkyl, and optionally substituted lower alkoxy; optionally substituted aralkoxy; nitro; or cyano; and
  • R is hydrogen; amino; amino substituted with optionally substituted lower alkyl; amino substituted with sulfonyl; acyl (especially, formyl or acetyl); phenyl; phenyl substituted with lower alkyl, halo, or lower alkoxy; halogen (especially, chloro); optionally substituted lower alkyl (especially, methyl, cyclopropyl, trifluoromethyl, hydroxymethyl-, 1-hydroxyethyl-, 2-hydroxyethyl-, or 3-hydroxyprop-lyl); furan-2-yl; furan-3-yl; pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; sulfonyl; or cyano. More particularly, R is trifluoromethyl-; and R , R , and R are hydrogen.
  • X is S
  • R , R , R , and R are independently hydrogen; hydroxyl; halogen; optionally substituted alkyl; acetyl; optionally substituted lower alkoxy; phenyl; phenyl substituted with one or more of the following substituents: halo, optionally substituted lower alkyl, and optionally substituted lower alkoxy; optionally substituted aralkoxy; nitro; or cyano; and
  • R is hydrogen; amino; amino substituted with optionally substituted lower alkyl; amino substituted with sulfonyl; acyl (especially, formyl or acetyl); phenyl; phenyl substituted with lower alkyl, halo, or lower alkoxy; halogen (especially, chloro); optionally substituted lower alkyl (especially, methyl, cyclopropyl, trifluoromethyl, hydroxymethyl-, 1-hydroxyethyl-, 2-hydroxyethyl-, or 3-hydroxyprop-lyl); furan-2-yl; furan-3-yl; pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; sulfonyl; or cyano. More particularly, R is trifluoromethyl-; and R , R , and R are hydrogen.
  • compounds of the invention include
  • Test compounds can be assayed in a highly parallel fashion by using multiwell plates and placing the compounds either individually in wells or testing the compounds in mixtures. Assay components including the target protein complex, coupling enzymes and substrates, and ATP can then be added to the wells and the absorbance or fluorescence of each well of the plate can be measured with a plate reader.
  • the method uses a 384 well plate format and a 25 ⁇ L reaction volume. A pyruvate kinase/lactate dehydrogenase coupled enzyme system (Huang et al.
  • Compounds of Formula I exhibit antifungal activity.
  • the compounds of Formula I inhibit the growth of various infectious fungi including Candida spp. such as Candida albicans, Candida tropicalis, Candida (Torulopsis) glabrata, Candida parapsilosis, Candida lusitaneae, Candida rugosa and Candida pseudotropicalis.
  • Fungal infections which can be inhibited or treated with compositions identified using the methods provided herein include but are not limited to: candidiasis including but not limited to onchomycosis, chronic mucocutaneous candidiasis, oral candidiasis, epiglottistis, esophagitis, gastrointestinal infections, and genitourinary infections, for example, caused by any Candida species, including those listed above.
  • candidiasis including but not limited to onchomycosis, chronic mucocutaneous candidiasis, oral candidiasis, epiglottistis, esophagitis, gastrointestinal infections, and genitourinary infections, for example, caused by any Candida species, including those listed above.
  • a variety of cell-based assays can be used to determine activity. Among these are microtiter plate, disc plate diffusion, and inhibition of fungal hyphae length. These assays utilize standard techniques that are well-known in the art ((R.N. Jones et al, th)
  • Antifungal activity of a test compound can be determined in vitro by obtaining the minimum inhibitory concentration (MIC) of the compound using a standard agar dilution test or a disc-diffusion test. The compound is then tested in vivo (in mice) to determine the effective dose of the test compound for controlling a systemic fungal infection.
  • MIC minimum inhibitory concentration
  • representative compounds of the present invention are tested for, and display, antifungal activity against at least one of the following fungi: C. albicans, C parapsilosis, C. neoformans, Histoplasma spp, and A. fumigatus.
  • the invention herein includes application to cells or individuals afflicted or impending affliction with any one of these disorders or states.
  • compositions of the invention can be administered to cells.
  • administered herein is meant administration of a therapeutically effective amount or dose of at least one compound of the invention to a cell either in cell culture or in a subject.
  • the exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by those skilled in the art.
  • Compounds having the desired pharmacological activity can be administered in a physiologically acceptable carrier to a subject, as described herein. Depending upon the manner of introduction, the compounds can be formulated in a variety of ways as discussed herein.
  • the concentration of therapeutically active compound in the formulation can vary from about 0.1-100 wt.%.
  • the agents can be administered alone or in combination with other treatments, i.e., other agents for the treatment of fungal infection.
  • the pharmaceutical compositions are in a water soluble form, such as pharmaceutically acceptable salts, which is meant to include both acid and base addition salts.
  • the pharmaceutical compositions can be prepared in various forms, such as granules, tablets, pills, suppositories, capsules, suspensions, salves, lotions and the like.
  • Pharmaceutical grade organic or inorganic carriers and/or diluents suitable for oral and topical use can be used to make up compositions containing the therapeutically-active compounds. Diluents known to the art include aqueous media, vegetable and animal oils and fats.
  • Stabilizing agents wetting and emulsifying agents, salts for varying the osmotic pressure or buffers for securing an adequate pH value, and skin penetration enhancers can be used as auxiliary agents.
  • the pharmaceutical compositions can also include one or more of the following: carrier proteins such as serum albumin; buffers; fillers such as microcrystalline cellulose, lactose, corn and other starches; binding agents; sweeteners and other flavoring agents; coloring agents; and polyethylene glycol. Additives are well known in the art, and can be used in a variety of formulations. /
  • the administration of the compounds of the present invention can be done in a variety of ways as discussed herein, including, but not limited to, orally, subcutaneously, intravenously, intranasally, transdermally, intraperitoneally, intramuscularly, intrapulmonary, vaginally, rectally, or intraocularly.
  • the compounds can be directly applied as a solution or spray.
  • Solution 1 consists of 3 mM phosphoenolpyruvate potassium salt (Sigma P-7127), 2 mM ATP (Sigma A-3377), 1 mM IDTT (Sigma D-9779), 5 ⁇ M paclitaxel (Sigma T-7402), 10 ppm antifoam 289 (Sigma A-8436), 25 mM Pipes/KOH pH 6.8 (Sigma P6757), 2 mM MgCl 2 (VWR JT400301), and 1 mM EGTA (Sigma E3889).
  • Solution 2 consists of 1 mM NADH (Sigma N8129), 0.2 mg/n L BSA (Sigma A7906), pyruvate kinase 7U/mL, L-lactate dehydrogenase 10 U/mL (Sigma P0294), 100 nM Kipl motor domain, 50 ⁇ g/mL microtubules, 1 mM DTT (Sigma D9779), 5 ⁇ M paclitaxel (Sigma T-7402), 10 ppm antifoam 289 (Sigma A-8436), 25 mM Pipes/KOH pH 6.8 (Sigma P6757), 2 mM MgCl 2 (VWR JT4003-01), and 1 mM EGTA (Sigma E3889).
  • Serial dilutions (8-12 two-fold dilutions) of the compound are made in a 96-well microtiter plate (Corning Costar 3695) using Solution 1. Following serial dilution each well has 50 ⁇ l of Solution 1.
  • the reaction is started by adding 50 ⁇ l of solution 2 to each well. This may be done with a multichannel pipettor either manually or with automated liquid handling devices.
  • the microtiter plate is then transferred to a microplate absorbance reader and multiple absorbance readings at 340 nm are taken for each well in a kinetic mode.
  • the observed rate of change which is proportional to the ATPase rate, is then plotted as a function of the compound concentration.
  • the data acquired is fit by the following four parameter equation using a nonlinear fitting program (e.g., Grafit

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Abstract

L'invention concerne des indoles substitués utiles pour traiter des infections fongiques par modulation de l'activité de la kinésines fongiques Kip1.
EP04750041A 2003-04-30 2004-04-29 Composes, compositions et procedes Withdrawn EP1620413A2 (fr)

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