WO2015020553A1 - Composés carbazole et leurs méthodes d'utilisation - Google Patents

Composés carbazole et leurs méthodes d'utilisation Download PDF

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WO2015020553A1
WO2015020553A1 PCT/RU2013/000683 RU2013000683W WO2015020553A1 WO 2015020553 A1 WO2015020553 A1 WO 2015020553A1 RU 2013000683 W RU2013000683 W RU 2013000683W WO 2015020553 A1 WO2015020553 A1 WO 2015020553A1
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group
compound
mmol
substituted
atom
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PCT/RU2013/000683
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Katerina Gurova
Elena RYDKINA
Varren WADE
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Obschestvo S Ogranichennoy Otvetstvennost'yu "Panacela Labs"
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Priority to PCT/RU2013/000683 priority Critical patent/WO2015020553A1/fr
Publication of WO2015020553A1 publication Critical patent/WO2015020553A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • 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
    • 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
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present disclosure provides carbazole compounds and carbazole-like compounds.
  • the compounds can be used to treat microbial infections (e.g., fungal infections) and selectively kill cancer cells.
  • heterocyclic compounds having the following structure:
  • alkyl group refers to branched or unbranched hydrocarbons.
  • alkyl groups include methyl groups, ethyl groups, propyl groups, butyl groups, isopropyl groups, tert-butyl groups, and the like.
  • the alkyl group can be a C ⁇ to C 6 alkyl group including all integer numbers of carbons and ranges of numbers of carbons therebetween.
  • Alkyl groups can be substituted with various other functional groups.
  • the alkyl groups can be substituted with groups such as, for example, amines (acyclic and cyclic), alcohol groups, ether groups, and halogen atoms.
  • halogen atom refers to a fluorine, chlorine, bromine, or iodine atom.
  • alkoxy group refers to the following structure: ⁇ 0 , where R is a C ⁇ to C 3 alkyl group, unless otherwise stated, including all integer numbers of carbons and ranges of numbers of carbons therebetween.
  • the alkoxy groups can be substituted with various other functional groups.
  • the alkyl groups can be unsubstituted or substituted with groups such as, for example, halogen atoms.
  • cycloalkyl group refers to a to a saturated or partially unsaturated carbocyclic group (not aromatic) of from 3 carbons to 11 carbons having a single cyclic ring or multiple condensed rings.
  • the cycloalkyl groups can be cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclohexene, cycloheptane, cycloheptene, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.3.0]octane, bicyclo[4.4.0]octane, and the like.
  • Cycloalkyl also includes carbocyclic groups to which is fused an aryl or heteroaryl ring, for example indane and tetrahydronaphthalene.
  • cycloalkyl groups can be unsubstituted or substituted with groups such as, for example, alkyl groups, carbonyl groups, ether groups, or halogen groups.
  • groups such as, for example, alkyl groups, carbonyl groups, ether groups, or halogen groups.
  • heterocycloalkyl group refers to a saturated or partially unsaturated group having a single cyclic ring or multiple condensed having from 2 to 1 1 carbon atoms and 1 to 5 heteroatoms, selected from nitrogen, oxygen, sulfur, and combinations thereof.
  • the heterocycloalkyl groups can be, for example, dihydrofuran, tetrahydrofuran, pyrrolidine, dihydropyran, tetrahydropyran, 1,3 dioxane, 1,4-dioxane, dihydropyridinone, piperidine, piperazine, morpholine, thiomorpholine, urazole, 2-aza-bicyclo[2.2.2]oct-5-ane-3-one, and the like.
  • Heteroccycloalkyl also includes heterocyclic groups to which is fused an aryl or heteroaryl ring, for example tetrahydroisoquinoline or indoline.
  • the heterocycloalkyl groups can be unsubstituted or substituted with groups such as, for example, alkyl groups, carbonyl groups, or halogen atoms.
  • heterocycle refers to a cyclic compound having a ring where at least one or more of the atoms forming the ring is a heteroatom (e.g., oxygen, nitrogen, sulfur, etc.).
  • the heterocyclic ring can be aromatic or nonaromatic, and include compounds that are saturated, partially unsaturated, and fully unsaturated.
  • the heterocyclic ring can be a 4, 5, 6, 7, or 8 membered ring containing a number of carbon atoms ranging between 1 and 7 and a number of heteroatoms ranging between 1 and 7.
  • the heterocyclic ring can be unsubstituted or substituted with groups such as, for example, alkyl groups, carbonyl groups, or halogen atoms.
  • the carbocyclic ring can be aromatic or nonaromatic, and include compounds that are saturated and partially unsaturated, and fully unsaturated. Examples of such groups include cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentanol, indane, indanone, phenyl, naphthyl and the like.
  • the carbocyclic ring is a C 5 to C 7 carbocyclic ring, including all integer numbers of carbons and ranges of numbers of carbons therebetween.
  • the carbocyclic ring can be unsubstituted or substituted with groups such as, for example, alkyl groups, carbonyl groups, or halogen atoms.
  • heterocyclic compounds having the following structure (II):
  • F and G are replaced by the atoms of the following structures , or to form a ring, where R 6 is hydrogen atom or a substituted or unsubstituted Ci-C 3 alkyl group.
  • R 1 is selected from one of the following structures:
  • R 1 is selected from one of the following structures:
  • R 6 and R 7 are as defined herein.
  • R is -CH(CH 3 ) 2 , -CH 2 CH 3 , cyclopropyl, or cyclobutyl;
  • R 4 is -a hydrogen atom, -CH 3 , -CH 2 CH 3 or taken together with R 3 and the nitrogen to which
  • the compound of the disclosure has the following structure (III):
  • the compound of the disclosure has the following structure (IV):
  • the compound of the present disclosure has the following
  • R 1 , R 2 , R 3 , R 4 , R 6 , C, D, and E are as defined herein.
  • the compound of the present disclosure has the following structure (VI):
  • R 4 is a hydrogen atom, -CH 3 , -CH 2 CH 3 or together with R 3 and the nitrogen to which
  • R 1 , R 2 , R 3 and R 5 is as defined herein.
  • the compound of the present disclosure has the following structure (VII):
  • R , R , R and R is as defined herein.
  • the compound of the present disclosure has the following construct (VIII):
  • R is a five membered heterocycle containing at least one nitrogen atom; R is a hydrogen atom or a fluorine atom; and Z is CH 2 or NCH 3 , where R 3 and R 4 are as defined herein.
  • the compound of the present disclosure has the following structure (IX):
  • R is a five membered heterocycle containing at least one oxygen atom; R is a hydrogen atom or a fluorine atom; and Z is CH 2 or NCH 3 , where R 3 and R 4 are as defined herein.
  • the R is a cyano group, where R 1 , R 2 , R 3 , R 4 , X, Y, C,
  • the compound of the present disclosure has the following structure (X) or (XI):
  • the compound of the present disclosure has the following structure (XII):
  • R is a ketone group, an ester group or an amide group; R at each occurrence is independently a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a cyano group, a methyl group, or a methoxy group; R 3 is selected from the group consisting of a hydrogen atom, a substituted or unsubstituted C !
  • R 4 is selected from the group consisting of a hydrogen atom, a substituted or unsubstituted Ci-C 6 alkyl group, cycloalkyl group, and heterocycloalkyl group;
  • X and Y are a carbon or nitrogen atom;
  • D is absent or CH 2 ;
  • E is absent, CH 2 , or CH Q-Cs alkyl); optionally, E and R 4 taken together with the nitrogen to which they are attached form a four to seven membered heterocyclic ring substituted with one to twelve R 5 's;
  • R 5 at each occurrence is independently selected from the group consisting of a hydrogen atom, a fluorine atom, a hydroxyl group, a
  • W is N(R 6 ) and not absent and R 6 is as defined herein. In an embodiment, W is N(R 6 ) and T and V are not absent. In an embodiment, W is absent, V is absent, T is NH, S is CH or N, U is CH or N, and a double bond is between S and U. In an embodiment, W is absent, V is absent, T is N(R 6 ), where R 6 is not H and otherwise is as defined herein, S is CH or N, U is CH or N, and a double bond is between S and U. In an embodiment, W is absent, V is absent, T is CH, S is O or N(R 6 ) where R 6 is as defined herein, U is CH, and a double bond is between S and T.
  • the compound of the present disclosure is selected from the following structures:
  • the compound of the present disclosure is sleeted from the following structures:
  • the disclosure provides a method of treating in an individual diagnosed with or suspected of having a microbial, protozoan, or viral infection comprising administering to the individual a therapeutically effective amount of a compound as described herein.
  • each Z' independently is a halogen, a trifluoromethanesulfonate, a trialkyltin, a boronic acid, or boronic ester as long as one coupling partner Z' is a halogen and the other coupling partner Z' is not a halogen.
  • Ring A, R l , R 2 , R 3 , R 4 , X, Y, C, D, and E are as defined herein.
  • suitable reaction conditions for cross coupling, the Cadogan reaction, alkylation, and other functional group transformations are within the purview of one having skill in the art.
  • heterocycles of the present invention it may be necessary to form the heterocycles of the present invention by well-established condensation reactions.
  • To assemble the coupling partners or further functionalize the aromatic components of the present invention it may be necessary to use of electrophilic aromatic substitution reactions, nucleophilic aromatic substitution reactions, anion chemistry, and the like.
  • electrophilic aromatic substitution reactions nucleophilic aromatic substitution reactions, anion chemistry, and the like.
  • Other oxidation state and functional groups manipulations are within the purview of one having skill in the art.
  • the present disclosure provides a composition comprising at least one compound of the disclosure.
  • Compositions comprising at least one compound of the disclosure include, for example, pharmaceutical preparations.
  • the present disclosure includes all possible stereoisomers and geometric isomers of a compound having the structure (I) to (XII).
  • the present disclosure includes both racemic compounds and optically active isomers.
  • a compound having the structure (I) to (XII) is desired as a single enantiomer, it can be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or use of a chiral auxiliary reagent, for example, see Z.
  • Prodrugs of a compound having the structure (I) to (XII) also can be used as the compound in a method of the present disclosure. It is well established that a prodrug approach, wherein a compound is derivatized into a form suitable for formulation and/or administration, then released as a drug in vivo, has been successfully employed to transiently (e.g., bioreversibly) alter the physicochemical properties of the compound (see, H. Bundgaard, Ed., “Design of Prodrugs,” Elsevier, Amsterdam, (1985); R.B. Silverman, "The Organic Chemistry of Drug Design and Drug Action,” Academic Press, San Diego, chapter 8, (1992); K.M. Hillgren et al., Med. Res. Rev., 15, 83 (1995)).
  • Compounds of the present disclosure can contain one or more functional groups.
  • the functional groups if desired or necessary, can be modified to provide a prodrug.
  • Suitable prodrugs include, for example, acid derivatives, such as amides and esters. It also is appreciated by those skilled in the art that N-oxides can be used as a prodrug.
  • compositions of the disclosure can exist as salts.
  • Pharmaceutically acceptable salts of the compounds of the disclosure generally are preferred in the methods of the disclosure.
  • the term "pharmaceutically acceptable salts” refers to salts or zwitterionic forms of a compound having the structure (I) to (XII). Salts of compounds having the structure (I) to (XII) can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with an acid having a suitable cation.
  • the pharmaceutically acceptable salts of a compound having the structure (I) to (XII) are acid addition salts formed with pharmaceutically acceptable acids.
  • acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • Nonlimiting examples of salts of compounds of the disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3- phenylproprionate, picrate
  • any reference to compounds of the present disclosure appearing herein is intended to include a compound having the structure (I) to (XII) as well as pharmaceutically acceptable salts, hydrates, or prodrugs thereof.
  • a compound having the structure (I) to (XII) also can be conjugated or linked to auxiliary moieties that promote a beneficial property of the compound in a method of therapeutic use.
  • Such conjugates can enhance delivery of the compounds to a particular anatomical site or region of interest (e.g., a tumor), enable sustained therapeutic concentrations of the compounds in target cells, alter pharmacokinetic and pharmacodynamics properties of the compounds, and/or improve the therapeutic index or safety profile of the compounds.
  • Suitable auxiliary moieties include, for example, amino acids, oligopeptides, or polypeptides, e.g., antibodies such as monoclonal antibodies and other engineered antibodies; and natural or synthetic ligands to receptors in target cells or tissues.
  • Other suitable auxiliaries include fatty acid or lipid moieties that promote biodistribution and/or uptake of the compound by target cells (see, e.g., Bradley et al., Clin. Cancer Res. (2001) 7:3229).
  • compositions comprising at least one compound of the disclosure.
  • compositions comprising at least one compound of the disclosure include, for example, pharmaceutical preparations.
  • terapéuticaally effective amount of a compound of the disclosure refers to an amount of an agent which is effective, upon single or multiple dose administration to the patient, in inhibiting cell proliferation and/or symptoms of a cell proliferative disorder, or in prolonging the survivability of the patient with such a cell proliferative disorder beyond that expected in the absence of such treatment.
  • the exact amount desired or required will vary depending on the particular compound or composition used, its mode of administration, and the like. Appropriate effective amount can be determined by one of ordinary skill in the art informed by the instant disclosure using only routine experimentation.
  • treatment also includes relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions.
  • the treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.
  • compositions comprising a compound of the disclosure and a pharmaceutical agent can be prepared at a patient's bedside, or by a pharmaceutical manufacture.
  • the compositions can be provided in any suitable container, such as a sealed sterile vial or ampoule, and may be further packaged to include instruction documents for use by a pharmacist, physician or other health care provider.
  • the compositions can be provided as a liquid, or as a lyophilized or powder form that can be reconstituted if necessary when ready for use.
  • the compositions can be provided in combination with any suitable delivery form or vehicle, examples of which include, for example, liquids, caplets, capsules, tablets, inhalants or aerosol, etc.
  • the delivery devices may comprise components that facilitate release of the pharmaceutical agents over certain time periods and/or intervals, and can include compositions that enhance delivery of the pharmaceuticals, such as nanoparticle, microsphere or liposome formulations, a variety of which are known in the art and are commercially available. Further, each composition described herein can comprise one or more pharmaceutical agents.
  • the compositions described herein can include one or more standard pharmaceutically acceptable carriers. Some examples of pharmaceutically acceptable carriers can be found in: Remington: The Science and Practice of Pharmacy (2005) 21st Edition, Philadelphia, PA. Lippincott Williams & Wilkins.
  • compositions of the disclosure can be administered in any manner including, but not limited to, orally, parenterally, sublingually, transdermally, rectally, transmucosally, topically, via inhalation, via buccal administration, or combinations thereof.
  • Parenteral administration includes, but is not limited to, intravenous, intraarterial, intracranial, intradermal, subcutaneous, intraperitoneal, subcutaneous, intramuscular, intrathecal, and intraarticular.
  • the carbazole compound also can be administered in the form of an implant, which allows a slow release of the compound, as well as a slow controlled i.v. infusion.
  • the dose of the composition comprising a compound of the disclosure and a pharmaceutical agent generally depends upon the needs of the individual to whom the composition of the disclosure is to be administered. These factors include, for example, the weight, age, sex, medical history, and nature and stage of the disease for which a therapeutic or prophylactic effect is desired.
  • the compositions can be used in conjunction with any other conventional treatment modality designed to improve the disorder for which a desired therapeutic or prophylactic effect is intended, non-limiting examples of which include surgical interventions and radiation therapies.
  • the compositions can be administered once, or over a series of administrations at various intervals determined using ordinary skill in the art, and given the benefit of the present disclosure.
  • compositions of the disclosure can comprise more than one pharmaceutical agent.
  • a first composition comprising a compound of the disclosure and a first pharmaceutical agent can be separately prepared from a composition which comprises the same compound of the disclosure and a second pharmaceutical agent, and such preparations can be mixed to provide a two-pronged (or more) approach to achieving the desired prophylaxis or therapy in an individual.
  • compositions of the disclosure can be prepared using mixed preparations of any of the compounds disclosed herein.
  • a compound having the structure (I) to (XII) are useful in the treatment of a variety of conditions and diseases.
  • the present disclosure concerns the use of a compound having the structure (I) to (XII), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the treatment of such conditions and diseases.
  • the compounds of the present disclosure can be therapeutically administered as the neat chemical, but it is preferred to administer a compound having the structure (I) to (XII) as a pharmaceutical composition or formulation.
  • a pharmaceutical composition comprising a compound having the structure (I) to (XII) together with a pharmaceutically acceptable diluent or carrier therefor.
  • a process of preparing a pharmaceutical composition comprising admixing a compound having the structure (I) to (XII) with a pharmaceutically acceptable diluent or carrier therefor.
  • the present disclosure further provides pharmaceutical formulations comprising a compound having the structure (I) to (XII), or a pharmaceutically acceptable salt, prodrug, or hydrate thereof, together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carriers are "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Examples of pharmaceutically-acceptable carrier include pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.
  • pharmaceutically-acceptable carrier include pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • the pharmaceutically-acceptable formulation is such that it provides sustained delivery of a compound having the structure (I) to (XII) to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically-acceptable formulation is administered to the subject.
  • these pharmaceutical compositions are suitable for topical or oral administration to a subject.
  • the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles.
  • compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of a compound having the structure (I) to (XII) which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, more preferably from about 10 per cent to about 30 per cent.
  • Methods of preparing these compositions include the step of bringing into association a compound having the structure (I) to (XII) with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound having the structure (I) to (XII) with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions of the disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound having the structure (I) to (XII) as an active ingredient.
  • lozenges using a flavored basis, usually sucrose and acacia or tragacanth
  • a compound having the structure (I) to (XII) may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents,
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present disclosure may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of a compound having the structure (I) to (XII) include pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • the composition may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • compositions of the disclosure for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a compound having the structure (I) to (XII) with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
  • compositions of the present disclosure which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound having the structure (I) to (XII) include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • a compound having a structure (I) to (XII) may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to a compound having the structure (I) to (XII), excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound having a structure (I) to (XII), excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically-acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular a compound having the structure (I) to (XII), but typically include nonionic surfactants (T weens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound having the structure (I) to (XII) to the body.
  • dosage forms can be made by dissolving or dispersing the agent in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the active ingredient across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active ingredient in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of the disclosure.
  • compositions of the disclosure suitable for parenteral administration comprise a compound having the structure (I) to (XII) in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of a compound having the structure (I) to (XII) in biodegradable polymers such as polylactide- polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • a compounds having a structure (I) to (XII) are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically-acceptable carrier.
  • a compound having the structure (I) to (XII), which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present disclosure, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • the pharmaceutical preparations may be given by forms suitable for each administration route.
  • these preparations are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories.
  • Oral administration is preferred.
  • the injection can be bolus or can be continuous infusion.
  • a compound having the structure (I) to (XII) of the present disclosure can be coated with or disposed in a selected material to protect it from natural conditions which may detrimentally affect its ability to perform its intended function.
  • a compound having the structure (I) to (XII) may be administered alone, or in conjunction with either another agent as described above or with a pharmaceutically- acceptable carrier, or both.
  • a compound having the structure (I) to (XII) may be administered prior to the administration of the other agent, simultaneously with the agent, or after the administration of the agent.
  • a compound having the structure (I) to (XII) can also be administered in a pro-drug form which is converted into its active metabolite, or more active metabolite in vivo.
  • the methods of the disclosure include administering to a subject a therapeutically effective amount of a compound having the structure (I) to (XII) in combination with another pharmaceutically active ingredient.
  • pharmaceutically active ingredients known to treat cell proliferative disorders, e.g., anticancer agent, antiproliferative agent, chemotherapeutic.
  • Other pharmaceutically active ingredients that may be used can be found in Harrison's Principles of Internal Medicine, Thirteenth Edition, Eds. T.R. Harrison et al. McGraw-Hill N.Y., NY; and the Physicians Desk Reference 50th Edition 1997, Oradell New Jersey, Medical Economics Co., the complete contents of which are expressly incorporated herein by reference.
  • a compound having the structure (I) to (XII) and the pharmaceutically active ingredient may be administered to the subject in the same pharmaceutical composition or in different pharmaceutical compositions (at the same time or at different times).
  • Methods delineated herein include those wherein the subject is identified as in need of a particular stated treatment. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method). In other methods, the subject is prescreened or identified as in need of such treatment by assessment for a relevant marker or indicator of suitability for such treatment.
  • a compound having the structure (I) to (XII) determined to be effective for the prevention or treatment of cell proliferative disorders in animals may also be useful in treatment of tumors in humans.
  • animals e.g., dogs, chickens, and rodents
  • Those skilled in the art of treating tumors in humans will know, based upon the data obtained in animal studies, the dosage and route of administration of a compound having the structure (I) to (XII) to humans. In general, the dosage and route of administration in humans is expected to be similar to that in animals.
  • the identification of those patients who are in need of prophylactic treatment for cell proliferative disorders is well within the ability and knowledge of one skilled in the art.
  • the subject may have a cell proliferative disorder, may be at risk of developing a cell proliferative disorder, or may need prophylactic treatment prior to anticipated or unanticipated exposure to a condition(s) capable of increasing susceptibility to a cell proliferative disorder, e.g., exposure to carcinogens or to ionizing radiation.
  • a method of monitoring the progress of a subject being treated with a compound having the structure (I) to (XII) includes determining the pre-treatment status (e.g., size, growth rate, or invasiveness of a tumor) of the cell proliferative disorder, administering a therapeutically effective amount of a compound having the structure (I) to (XII) to the subject, and determining the status (e.g., size, growth rate, or invasiveness of a tumor) of the cell proliferative disorder after an initial period of treatment with a compound having the structure (I) to (XII), wherein the modulation of the status indicates efficacy of the treatment.
  • the pre-treatment status e.g., size, growth rate, or invasiveness of a tumor
  • the disclosure provides a packaged composition including a therapeutically effective amount of a compound having the structure (I) to (XII) and a pharmaceutically acceptable carrier or diluent.
  • the composition may be formulated for treating a subject suffering from or susceptible to a cell proliferative disorder, and packaged with instructions to treat a subject suffering from or susceptible to a cell proliferative disorder.
  • the disclosure provides a kit for treating a cell proliferative disorder, microbial disease, e.g., fungal disease; protozoan disease; or viral disease in a subject is provided and includes a compound having the structure (I) to (XII), pharmaceutically acceptable esters, salts, and prodrugs thereof, and instructions for use.
  • the disclosure provides kits for inhibiting cell proliferation, assessing the efficacy of an anti-cell proliferative treatment in a subject, monitoring the progress of a subject being treated with a cell proliferation inhibitor, selecting a subject with a cell proliferative disorder for treatment with cell proliferation inhibitor, and/or treating a subject suffering from or susceptible to cancer.
  • the disclosure provides: a kit for treating a cell proliferative disorder, microbial disease, e.g., fungal disease; protozoan disease; or viral disease in a subject, the kit comprising a compound having the structure (I) to (XII).
  • microbial disease e.g., fungal disease; protozoan disease; or viral disease
  • kit comprising a compound having the structure (I) to (XII).
  • a compound having the structure (I) to (XII), or a pharmaceutically acceptable salt or prodrug is administered as a suitably acceptable formulation in accordance with normal veterinary practice.
  • the veterinarian can readily determine the dosing regimen and route of administration that is most appropriate for a particular animal.
  • Animals treatable by the present compounds and methods include, but are not limited to, pets, livestock, show animals, and zoo specimens.
  • a present carbazole compound When administered in combination with other therapeutics, a present carbazole compound may be administered at relatively lower dosages. In addition, the use of targeting agents may allow the necessary dosage to be relatively low. Certain compounds may be administered at relatively high dosages due to factors including, but not limited to, low toxicity and high clearance.
  • a compound having the structure (I) to (XII) can be administered alone, but generally is administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • Pharmaceutical compositions for use in accordance with the present disclosure can be formulated in a conventional manner using one or more physiologically acceptable carrier comprising excipients and auxiliaries that facilitate processing of a compound having the structure (I) to (XII) into pharmaceutical preparations.
  • the present carbazole compounds can be administered simultaneously or metronomically with other anti-cancer treatments, such as chemotherapy and/or radiation therapy.
  • anti-cancer treatments such as chemotherapy and/or radiation therapy.
  • sustaneous or “simultaneously” means that the other anti-cancer treatment and the carbazole compound are administered within 6 hours, 3 hours or less, of each other.
  • minomically means the administration of the other anti-cancer treatments at times different from the anti-cancer treatments and at a certain frequency relative to repeat administration and/or the anti-cancer treatment regimen.
  • the carbazole compounds of the present disclosure can be used to treat a variety of diseases and conditions.
  • compounds of the present disclosure can be used in combination with radiation and/or a chemotherapeutic agent in the treatment of cancers.
  • the carbazole compounds can be used to enhance treatment of tumors that are customarily treated with an antimetabolite, e.g., methotrexate or 5-fluorouracil (5- FU).
  • an antimetabolite e.g., methotrexate or 5-fluorouracil (5- FU).
  • carbazole compounds of the present disclosure can result in partial or complete regression of cancer cells, i.e., the partial or complete disappearance of such cells from the cell population.
  • a method of the disclosure can be used to slow the rate of tumor growth, decrease the size or number of tumors, or to induce partial or complete tumor regression.
  • a compound having the structure (I) to (XII) can be used for treating a disease or condition in vivo by administration to an individual in need thereof.
  • the disease or condition can be a cancer.
  • a variety of cancers can be treated including, but not limited to: carcinomas, including bladder (including accelerated and metastic bladder cancer), breast, colon (including colorectal cancer), kidney, liver, lung (including small and non- small cell lung cancer and lung adenocarcinoma), ovary, prostate, testes, genitourinary tract, lymphatic system, rectum, larynx, pancreas (including exocrine pancreatic carcinoma), esophagus, stomach, gall bladder, cervix, thyroid, renal, and skin (including squamous cell carcinoma); hematopoietic tumors oflymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, 8-celllymphoma, T-cell lymphoma
  • One method of the present disclosure comprises administration of a therapeutically effective amount of a present carbazole compound in combination with a chemotherapeutic agent that can effect single- or double-strand DNA breaks or that can block DNA replication or cell proliferation.
  • a method of the present disclosure comprises administration of a therapeutically effective amount of at least one present carbazole compound in combination with therapies that include use of an antibody, e.g., herceptin, that has activity in inhibiting the proliferation of cancer cells.
  • cancers for example, colorectal cancers, head and neck cancers, pancreatic cancers, breast cancers, gastric cancers, bladder cancers, vulvar cancers, leukemias, lymphomas, melanomas, renal cell carcinomas, ovarian cancers, brain tumors, osteosarcomas, and lung carcinomas, are susceptible to enhanced treatment by administration of a present carbazole in combination with a chemotherapeutic agent or an antibody.
  • Cancers treatable by the present disclosure also include solid tumors, i.e., carcinomas and sarcomas.
  • Carcinomas include malignant neoplasms derived from epithelial cells which infiltrate (i.e., invade) surrounding tissues and give rise to metastases.
  • Adenocarcinomas are carcinomas derived from glandular tissue, or from tissues that form recognizable glandular structures.
  • Another broad category of cancers includes sarcomas, which are tumors whose cells are embedded in a fibrillar or homogeneous substance, like embryonic connective tissue.
  • the present disclosure also enables treatment of cancers of the myeloid or lymphoid systems, including leukemias, lymphomas, and other cancers that typically are not present as a tumor mass, but are distributed in the vascular or lymphoreticular systems.
  • Additional forms of cancer treatable by the present carbazole compounds include, for example, adult and pediatric oncology, growth of solid tumors/malignancies, myxoid and round cell carcinoma, locally advanced tumors, metastatic cancer, human soft tissue sarcomas, including Ewing's sarcoma, cancer metastases, including lymphatic metastases, squamous cell carcinoma, particularly of the head and neck, esophageal squamous cell carcinoma, oral carcinoma, blood cell malignancies, including multiple myeloma, leukemias, including acute lymphocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, and hairy cell leukemia, effusion lymphomas (body cavity based lymphomas), thymic lymphoma lung cancer (including small cell carcinoma, cutaneous T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma
  • a compound having the structure (I) to (XII) exhibit antimicrobial activity, e.g., fungal infection; antiprotozoan activity; and antiviral activity.
  • the fungal infection is from the pathogenic fungi from C. albicans, C. glabrata, A. fumigatus, or a combination thereof.
  • the compounds of the invention are those in which show ⁇ 40% growth inhibition at 20 ⁇ , >10 ⁇ , 5-10 ⁇ , or ⁇ 5 ⁇ MIC for 95% inhibition of growth towards three different fungal species (i.e., C. albicans, C. glabrata, and A. fumigatus).
  • additional active or ancillary agents can be used in the methods described herein. Reference herein to treatment also extends to prophylaxis, as well as to treatment of established diseases or symptoms.
  • the present disclosure can be applied to cell populations ex vivo.
  • the present carbazole compounds can be used ex vivo to determine the optimal schedule and/or dosing of administration of the present carbazole compound for a given indication, cell type, patient, and other parameter. Information gleaned from such use can be used for experimental purposes or in the clinic to set protocol for in vivo treatment. Other ex vivo uses for which the disclosure is suited are apparent to those skilled in the art.
  • a present carbazole compound also can be administered in combination with radiation.
  • Diseases that are treatable with electromagnetic radiation include neoplastic diseases, benign and malignant tumors, and cancerous cells.
  • Electromagnetic radiation treatment of other diseases not listed herein also is contemplated by the present disclosure.
  • Preferred embodiments of the present disclosure employ the electromagnetic radiation of: gamma-radiation (10-20 to 10- 13 m), X-ray radiation (10-12 to 10-9 m), ultraviolet light (10 nm to 400 nm), visible light (400 nm to 700 nm), infrared radiation (700 nm to 1 mm), and microwave radiation (1 mm to 30 em).
  • radiosensitizers activated by electromagnetic radiation, e.g., X-rays.
  • X-ray-activated radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FUdR), hydroxyurea, cis-platin, and therapeutically effective analogs and derivatives of the same.
  • metronidazole misonidazole
  • desmethylmisonidazole pimonidazole
  • etanidazole nimorazole
  • mitomycin C RSU 1069
  • Photodynamic therapy (PDT) of cancers employs visible light as the radiation activator of the sensitizing agent.
  • photodynamic radiosensitizers include the following, but are not limited to: hematoporphyrin derivatives, PHOTOFRTNriD, benzoporphyrin derivatives, NPe6, tin etioporphyrin (SnET2), pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives of the same.
  • Radiosensitizers can be administered in conjunction with a therapeutically effective amount of one or more compounds in addition to a present carbazole compound, such compounds including, but not limited to, compounds that promote the incorporation of radiosensitizers to the target cells, compounds that control the flow of therapeutics, nutrients, and/or oxygen to the target cells, chemotherapeutic agents that act on the tumor with or without additional radiation, or other therapeutically effective compounds for treating cancer or other disease.
  • radiosensitizers examples include, but are not limited to, 5-fluorouracil (5-FU), leucovorin, oxygen, carbogen, red cell transfusions, perfluorocarbons (e.g., FLUOSOLW®- DA), 2,3-DPG, BW12C, calcium channel blockers, pentoxifylline, antiangiogenesis compounds, hydralazine, and L-BSO.
  • 5-fluorouracil 5-FU
  • leucovorin oxygen
  • carbogen red cell transfusions
  • perfluorocarbons e.g., FLUOSOLW®- DA
  • 2,3-DPG 2,3-DPG
  • BW12C calcium channel blockers
  • pentoxifylline e.g., antiangiogenesis compounds
  • hydralazine hydralazine
  • L-BSO L-BSO
  • the chemotherapeutic agent can be any pharmacological agent or compound that induces apoptosis.
  • the pharmacological agent or compound can be, for example, a small organic molecule, peptide, polypeptide, nucleic acid, or antibody.
  • Chemotherapeutic agents that can be used include, but are not limited to, alkylating agents, antimetabolites, hormones and antagonists thereof, natural products and their derivatives, radioisotopes, antibodies, as well as natural products, and combinations thereof.
  • a carbazole compound of the present disclosure can be administered with antibiotics, such as doxorubicin and other anthracycline analogs, nitrogen mustards, such as cyclophosphamide, pyrimidine analogs such as 5-fluorouracil, cis-platin, hydroxyurea, taxol and its natural and synthetic derivatives, and the like.
  • antibiotics such as doxorubicin and other anthracycline analogs
  • nitrogen mustards such as cyclophosphamide
  • pyrimidine analogs such as 5-fluorouracil, cis-platin, hydroxyurea, taxol and its natural and synthetic derivatives, and the like.
  • the compound in the case of mixed tumors, such as adenocarcinoma of the breast, where the tumors include gonadotropin-dependent and gonadotropin-independent cells, the compound can be administered in conjunction with leuprolide or goserelin (synthetic peptide analogs of LH-R
  • antineoplastic protocols include the use of an inhibitor compound with another treatment modality, e.g., surgery or radiation, also referred to herein as "adjunct anti-neoplastic modalities.”
  • Additional chemotherapeutic agents useful in the disclosure include hormones and antagonists thereof, radioisotopes, antibodies, natural products, and combinations thereof.
  • a compound having the structure (I) to (XII) of this disclosure can be provided in pharmaceutical compositions.
  • the pharmaceutical composition comprises one or more compounds having the structure (I) to (XII) of the present disclosure and a pharmaceutically acceptable carrier.
  • the kits of the disclosure can comprise one or more compounds of the structure (I) to (XII), alone, as pharmaceutical preparations, or separate pharmaceutical preparations with each pharmaceutical preparation comprising a separate compound having the structure (I) to (XII).
  • HPLC column Kinetex, 2.6 ⁇ , CI 8, 50 x 2.1 mm, maintained at 40 °C.
  • HPLC Gradient 1.0 mL/min, 95:5:0.1 water:acetonitrile:formic acid to 5:95:0.1 water :acetonitrile: formic acid in 2.0 min, maintaining for 0.5 min. Reported retention times are for method A unless indicated otherwise.
  • Analytical LC MS method B was performed on a Shimadzu system with an attached API 165 single quadrupole mass spectrometer. Retention times were determined from the 220 nm chromatogram.
  • HPLC column Phenomenex, CI 8, 2.5 ⁇ , 20 x 2 mm, maintained at 25 °C.
  • HPLC Gradient 0.5 mL/min, 95:5:0.02 water:acetonitrile:CF 3 COOH to 5:95:0.02 water:acetonitrile:CF 3 COOH in 2.9 min, maintaining for 0.9 min.
  • Step 1 To a stirred solution of w-butyllithium (1.6 M in hexane, 8.78 mL, 14.05 mmol) under argon at -20°C was added 2,2,6,6-tetramethylpiperidine (2.37 mL, 14.05 mmol) in anhydrous tetrahydrofuran (15 mL). The mixture was cooled to -50 °C and a solution of 3-chlorobenzoic acid (1.0 g, 6.39 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise. The mixture was stirred for 3 h.
  • Step 2 To a solution of 3-chloro-2-formylbenzoic acid (Preparation 2a-l, 1.35 g, 7.31 mmol) in water (13.5 mL) was added hydrazine hydrate (1.78 mL, 36.65 mmol), and the mixture was stirred at 95 °C for 4 h. The resulting precipitate was collected, washed with water (5 mL) and dried in air to give the title compound (545 mg, 3.01 mmol, 41%) as a white powder.
  • Step 1 A solution of 3-bromo-2-methoxybenzoic acid (3.0 g, 12.98 mmol) in thionyl chloride (15 mL) was stirred at 50 °C for 2 h and then evaporated. The residue was taken up in dichloromethane (50 mL) and to this solution was added methoxymethylamine hydrochloride (1.27 g, 13.0 mmol) and N,N-diisopropylethylamine (4.53 mL, 26.0 mmol). The mixture stirred at room temperature for 16 h. The reaction mixture was washed with water (2 x 20 mL) and the organic layer was dried over sodium sulfate and evaporated.
  • Step 2 3-Bromo-2,N-dimethoxy-N-methyl-benzamide (Preparation 6a- 1 , 1.92 g, 7.0 mmol) was dissolved in tetrahydrofuran (6 mL). To this solution was added methylmagnesium bromide (3M in diethyl ether, 4.67 mL, 14.0 mmol) at 0 °C and the mixture stirred for 3 h. The reaction was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (2 x 15 mL).
  • Step 1 To a suspension of 4-hydroxyindan-l-one (25.0 g, 169 mrnol) in concentrated sulfuric acid (250 mL) at -25 °C was added slowly a mixture of fuming nitric acid (8.46 mL) and concentrated sulfuric acid (8.46 mL), maintaining the temperature between -25 °C and -10 °C during the addition. The reaction was monitored by TLC ( «- hexane: ethyl acetate, 4: 1) until complete conversion was achieved (25 min). The reaction mixture was poured onto crushed ice (ca. 1.5 kg) and the yellow precipitate collected by filtration.
  • Step 2 To a solution of 4-hydroxy-5-nitroindan-l-one (Preparation 8a-l, 5.0 g, 25.8 mmol) and triethylamine (3.97 mL, 28.5 mmol) in dichloromethane (50 mL) was added trifluoromethanesulfonic acid anhydride (4.57 mL, 27.2 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 1 h and washed with water (50 mL), 10% aqueous sodium carbonate (2 x 50 mL) and brine (25 mL). The organic layer was dried over sodium sulfate and evaporated.
  • Step 1 To a suspension of 1 -(4-aminophenyl)-ethanone (14.7 g, 109 mmol) in toluene (150 mL) at 40 °C was added N-bromosuccinimide (19.4 g, 109 mmol) in several portions over 30 min. After the addition was complete, the mixture was stirred at 40 °C for 15 min. Water (30 mL) was added and the organic layer was separated, washed with water (3 x 30 mL), dried over magnesium sulfate and evaporated to give the title compound (16.5 g, 77 mmol, 71%) as a brown crystalline solid. The crude product was used without further purification. LCMS: 97%, Rt 1.188 min, ESMS m/z 214 (M+H) + .
  • Step 2 To a stirred mixture of l-(4-amino-3-bromophenyl)-ethanone (Preparation 9a- 1, 33 g, 154 mmol) in 20% aqueous tetrafluoroboric acid (143 mL) at 0 °C was added sodium nitrite (4M aqueous solution, 60 mL, 240 mmol) over 15 min. The mixture was stirred at 0 °C for 30 min. The resulting yellow foamy suspension was added to a vigorously stirring mixture of copper powder (53 g, 0.83 mol) and sodium nitrite (143 g, 2.07 mol) in water (286 mL) at room temperature.
  • copper powder 53 g, 0.83 mol
  • sodium nitrite 143 g, 2.07 mol
  • Step 1 To a solution of 2-bromo-3-nitrobenzoic acid (4.85 g, 19.7 mmol) in ethanol (40 mL) was added concentrated sulfuric acid (2 mL) and the mixture was heated to reflux for 4 h. The reaction mixture was evaporated and the residue taken up in chloroform (40 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (20 mL) and water (15 mL), dried over sodium sulfate and evaporated to give the title compound (5.26 g, 19.2 mmol, 97%) as a light brown powder. LCMS: 93%, Rt 1.750 min, ESMS m/z 274 (M+H) + .
  • Step 2 To a solution of 2-bromo-3-nitrobenzoic acid ethyl ester (Preparation lOa-1, 1 g, 3.65 mmol) in ethanol (20 mL) was added hydrazine hydrate (2.76 mL, 36.5 mmol) as a solution in water (4.6 mL) and the mixture stirred at room temperature for 4 h. The reaction mixture was concentrated and the precipitate collected by filtration. The solid was washed with water (5 mL) and diethyl ether (5 mL) to afford the title compound (643 mg, 2.47 mmol, 68%) as a gray powder.
  • Step 3 A mixture of 3-bromo-4-nitrobenzoic acid hydrazide (Preparation lOb-1 , 623 mg, 2.39 mmol), triethyl orthoformate (10.0 mL, 60.0 mmol) and p- toluenesulfonic acid (5 mg, cat. amount) in ethanol (16 mL) was stirred at 85 °C for 3 h. The mixture was evaporated and the residue partitioned between water (20 mL) and chloroform (15 mL). The aqueous layer was extracted with chloroform (2 x 15 mL).
  • Stepl A solution of 3-bromo-4-nitrobenzoic acid ethyl ester (1.30 g, 4.75 mmol) in tetrahydrofuran (50 mL) was cooled to 0 °C. To this solution was added dropwise diisobutylaluminum hydride solution (20% in toluene, 11.2 mL, 13.44 mmol). The mixture was stirred at 0 °C for 1 h, quenched with saturated aqueous ammonium chloride (10 mL) and allowed to warm to room temperature. The mixture was diluted with ethyl acetate (50 mL) and acidified to pH 4 by addition of 2 N hydrochloric acid (5 mL).
  • Step 2 To a solution of (Preparation l la-1, 3-bromo-4-nitrophenyl)- methanol (978 mg, 4.21 mmol) in dichloromethane (50 mL) was added manganese(IV) oxide (1.83 g, 21.05 mmol) and the mixture stirred at room temperature. After 16 h three additional portions of manganese(IV) oxide (3 x 366 mg, 12.63 mmol) were added and the mixture stirred for 8 h with monitoring by TLC. The suspension was filtered and washed with dichloromethane (2 x 10 mL). The filtrate was concentrated to afford the title compound (802 mg, 3.92 mmol, 93%) as a light brown powder.
  • Step 3 A mixture of 3-bromo-4-nitrobenzaldehyde (Preparation l lb-1, 760 mg, 3.30 mmol), potassium carbonate (913 mg, 6.60 mmol), 7-toluenesulfonylmethyl isocyanide (709 mg, 3.63 mmol) and methanol (20 mL) was stirred at 60 °C for 2 h. The reaction mixture was evaporated and the residue taken up in water (20 mL). The aqueous layer was extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over sodium sulfate and evaporated. The crude product was dissolved in dichloromethane (20 mL) and silica gel (5 g) was added. The mixture was stirred for 10 min, then filtered and concentrated to afford the title compound (830 mg, 3.08 mmol, 93%) as a yellow powder. LCMS: 90%, Rt 1.504 min, ESMS m/z 269.
  • Step 1 A biphasic mixture of 4-bromo-l-indanone (1.0 g, 4.74 mmol), 2- nitrophenylboronic acid (1.60 g, 9.48 mmol), l,r-6w(diphenylphosphino)ferrocene palladium(II) dichloride (173 mg, 0.24 mmol) and potassium carbonate (1.31 g, 9.48 mmol) in 1,4-dioxane: water (4: 1, 32 mL) was heated at 120 °C for 80 min under microwave irradiation. The mixture was poured into concentrated sodium bicarbonate (50 mL), extracted with ethyl acetate (3 x 30 mL).
  • Step 2 A mixture of 4-(2-nitrophenyl)-indan-l -one (Preparation 12a-l, 870 mg, 3.44 mmol) and triphenylphosphine (2.25 g, 8.60 mmol) in chlorobenzene (14 mL) was heated at 200 °C for 60 min under microwave irradiation. The mixture was evaporated and the residue purified by column chromatography eluting with dichloromethane: ethyl acetate (98:2- 80:20) to give the title compound (1.27 g, >100%; containing triphenylphosphine) as a pale-brown powder. The crude product was used in the next step without further purification. LCMS: 66% (254 nm), Rt 1.430, ESMS m/z 220 (M-H)-.
  • Step 1 A mixture of 2-bromo-l-fluoro-3 -nitrobenzene (610 mg, 2.77 mmol), 4-(4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2-yl)-indan-l-one (Preparation 7-1 , 858 mg, 3.33 mmol), potassium carbonate (2M aq.
  • Step 1 A mixture of trifluoromethanesulfonic acid 5-nitro-l-oxoindan-4-yl ester (Preparation 8-1, 390 mg, 1.20 mmol), 2-methoxyphenyl boronic acid (273 mg, 1.80 mmol), 2 M potassium carbonate (1.2 mL, 2.4 mmol) and ⁇ , - bis(diphenylphosphino)ferrocene palladium(II) dichloride (44 mg, 0.06 mmol) in 1,4- dioxane (5 mL) was stirred at 100 °C for 2 h. The mixture was diluted with dichloromethane (20 mL) and water (20 mL) and the layers were separated.
  • Step 2 A mixture of 4-(2-methoxyphenyl)-5-nitroindan-l-one (Preparation 14a-l, 300 mg, 1.05 mmol) and triphenylphosphine (694 mg, 2.65 mmol) in chlorobenzene (4.5 mL) was irradiated in a microwave reactor at 200 °C for 1 h. The precipitate was collected and washed with diethyl ether (6 mL) to afford the title compound (160 mg, 0.64 mmol, 60%) as a brown powder.
  • Step 1 To a solution of 3-bromo-4-nitrobenzoic acid (2.5 g, 10.16 mmol) in a mixture of toluene (10 mL) and N,N-dimethylformamide (0.1 mL) was added thionyl chloride (2.21 mL, 30.48 mmol) and the mixture was stirred at 60 °C for 4 h. The reaction mixture was evaporated to afford the crude acid chloride (2.6 g). A portion of the residue (1.3 g, 4.92 mmol) was taken up in toluene (5 mL) and to this solution was added aqueous ammonia (5 mL, 25% v/v). The mixture was stirred at room temperature for 30 min.
  • Step 2 A mixture of 3-bromo-4-nitrobenzamide (Preparation 15a-l , 1.0 g, 4.08 mmol), 4-(4,4,5,5-tetramethyl-[l ,3,2] dioxaborolan-2-yl)-indan-l-one (Preparation 7-1 , 1.37 g, 5.3 1 mmol), l ,l'-0z diphenylphosphino)ferrocene palladium(II) dichloride (150 mg, 0.20 mmol) and aqueous potassium carbonate (2 M, 4.10 mL, 8.20 mmol) in 1 ,4-dioxane (27 mL) was irradiated at 100 °C in a microwave reactor for 45 min.
  • Step 1 A mixture of 3-bromo-4-nitrobenzoic acid (1.0 g, 4.07 mmol), 4- (4,4,5,5-tetramethyl-[l ,3,2]-dioxaborolan-2-yl)-indan-l-one (Preparation 7-1 , 1.16 g, 4.47 mmol), l,r-6w(diphenylphosphino)ferrocene palladium(II) dichloride (150 mg, 0.20 mmol) and 2 M aqueous potassium carbonate (4.06 mL) in 1,4-dioxane (25 mL) was stirred at 100 °C for 16 h.
  • Step 2 To a suspension of 4-nitro-3-(l-oxoindan-4-yl)-benzoic acid (Preparation 16a-l , 1.04 g, 3.52 mmol) in ethanol (10.5 mL) was added concentrated sulfuric acid (0.144 mL). The resulting mixture was stirred at 80 °C for 16 h in a sealed vial and poured into water (30 mL). The precipitate was collected by filtration and washed with a large excess of water to afford the title compound (481 mg, 1.48 mmol, 42%) as a yellow solid.
  • Step 3 A mixture of 4-nitro-3-(l-oxo-indan-4-yl)-benzoic acid ethyl ester (Preparation 16b-l, 455 mg, 1.40 mmol) and triphenylphosphine (917 mg, 3.50 mmol) in chlorobenzene (5 mL) was irradiated in a microwave reactor at 200°C for 1.5 h. The precipitate was collected and washed with hexane (5 mL) to afford the title compound (275 mg, 0.94 mmol, 63%) as a light brown powder.
  • Step 1 A mixture of 9-bromo-l,2-dihydro-6H-cyclopenta[c]carbazol-3-one (Preparation 19-1, 1.0 g, 3.33 mmol), 2-bromo-l,l-diethoxyethane (1.36 mL, 10.0 mrnol) and cesium carbonate (3.26 g, 10.0 mmol) in N,N-dimethylformamide (10 mL) was stirred at 80 °C for 3 h.
  • Step 2 A solution of 9-bromo-6-(2,2-diethoxy-ethyl)-l,2-dihydro-6H- cyclopenta[c]carbazol-3-one (Preparation 20a- 1, 1.0 g, 2.40 mmol) in trifluoroacetic acid (8.6 mL) and water (640 ⁇ ) was stirred at room temperature for 1 h and evaporated. The residue was triturated with water (10 mL), collected, washed with water (2 x 5 mL) and diethyl ether (10 mL) to give title compound (0.77 g, 2.33 mmol, 93%) as an off-white powder.
  • LCMS inconclusive; hydrate, hemiacetal and aldehyde masses detected, TLC: OK.
  • Step 3 A mixture of (9-bromo-3-oxo-2,3-dihydro-lH-cyclopenta[c]carbazol- 6-yl)-acetaldehyde (Preparation 20b-l, 190 mg, 0.56 mmol) and piperidine (56 ⁇ , 0.56 mmol) in dichloromethane (3.8 mL) was stirred at room temperature for 10 min, then was cooled to 0 °C and sodium triacetoxyborohydride (475 mg, 2.24 mmol) was added. The reaction was stirred at 0 °C for 1 h and at room temperature for 2 h, and poured into water (30 mL).
  • Step 1 The mixture of 10-fluoro-l,2-dihydro-6H-cyclopenta[c]carbazol-3- one (100 mg, 0.42 mmol), 2-chloro-N,N-diethylethylamine hydrochloride (108 mg, 0.63 mmol) and cesium carbonate (410 mg, 1.26 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 16 h, then at 50 °C for 6 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate and evaporated.
  • Step 1 To a solution of 6-(2-diethylaminoethyl)-l,2-dihydro-6H- cyclopenta[c]carbazol-3-one (Preparation 19-2, 100 mg, 0.31 mmol) in dichloromethane (2.0 mL) at 0 °C was added sodium-azide (41 mg, 0.62 mmol) and methanesulfonic acid (0.33 mL, 5.12 mmol). The mixture was stirred at 0 °C for 30 min, then warned to room temperature and stirred for 2.5 h. The mixture was diluted with dichloromethane (5 mL) and water (5 mL).
  • aqueous layer was neutralized to pH 7 by addition of 10% aqueous sodium hydroxide.
  • the aqueous layer was extracted with dichloromethane (2 x 5 mL) and the combined organic layers were dried over sodium sulfate and evaporated to afford the title compound (70 mg, 0.21 mmol, 67%) as an off-white solid.
  • the product was used without further purification.
  • Step 2 To a solution of 7-(2-diethylaminoethyl)-2,3-dihydro-lH,7H- pyrido[3,4-c]carbazol-4-one (Compound 3a-l, 70 mg, 0.21 mmol) in dichloromethane (1.4 mL) at 0 °C was added aluminum chloride (138 mg, 1.04 mmol). To this mixture was added acetyl chloride (81 mg, 1.04 mmol) in five portions over 5 min. The mixture was stirred at room temperature for 30 min. The mixture was diluted with dichloromethane (1.4 mL) and the stirring was continued for 30 min.
  • the reaction mixture was partitioned between IN hydrochloric acid (10 mL) and dichloromethane (10 mL). The aqueous layer was adjusted to pH 8 by the addition of solid sodium carbonate and extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over magnesium sulfate and evaporated. The crude product was triturated with diethyl ether (2 mL) to afford the title compound (46 mg, 0.12 mmol, 58%) as an off-white powder.
  • Step 1 A mixture of 9-acetyl-l,2-dihydro-6H-cyclopenta[c]carbazol-3-one (Preparation 17-1, 500 mg, 1.90 mmol), 1,3-dibromopropane (1.95 mL, 19.0 mmol) and cesium carbonate (2.47 g, 7.60 mmol) in N,N-dimethylformamide (25 mL) was stirred at 50 °C for 1 h. The mixture was poured into water (125 mL) and the precipitate collected.
  • Step 2 A mixture of 9-acetyl-6-(3-bromo-propyl)-l,2-dihydro-6H- cyclopenta[c]carbazol-3-one (Compound 4a- 1, 100 mg, 0.26 mmol), cyclopropylamine (55 ⁇ , 0.78 mmol) and cesium carbonate (338 mg, 1.04 mmol) in N,JV-dimethylformamide (2 mL) was stirred at 50 °C for 72 h. The mixture was poured into water (10 mL) and the precipitate collected. The crude material was purified by column chromatography eluting with chloroform: methanol (95:5) to afford the title compound as the free base.
  • Step 1 A mixture of 9-acetyl-l,2-dihydro-6H-cyclopenta[c]carbazol-3-one (Preparation 17-1, 281 mg, 1.07 mmol), methanesulfonic acid 2-(tert-butoxycarbonyl- methyl-amino)-ethyl ester (541 mg, 2.13 mmol) and cesium carbonate (1.39 g, 4.28 mmol)
  • Step 1 A mixture of 9-acetyl-l ,2-dihydro-6H-cyclopenta[c]carbazol-3-one (Preparation 17-1 , 1.70 g, 6.46 mmol), 2-bromo-l ,l-diethoxy ethane (2.65 mL, 19.4 mmol) and cesium carbonate (6.31 g, 19.4 mmol) in N, N-dimethylformamide (17 mL) was stirred at 80 °C for 2 h.
  • Step 2 A solution of 9-acetyl-6-(2,2-diethoxyethyl)-l,2-dihydro-6H- cyclopenta[c]carbazol-3-one (Compound 8a-l , 1.20 g, 3.16 mmol) in trifluoroacetic acid (1 1.3 mL) was stirred at room temperature for 1 h. The mixture was evaporated and the residue triturated with water (10 mL). The solid was washed with water (1 x 10 mL) and diethyl ether (1 x 10 mL) to give the title compound (0.75 g, 2.46 mmol, 78%) as an off- white powder.
  • LCMS inconclusive; hydrate, hemiacetal and aldehyde masses detected, TLC: OK.
  • Step 3 A mixture of (9-acetyl-3-oxo-2,3-dihydro-lH-cyclopenta[c]carbazol- 6-yl)-acetaldehyde (Compound 8b-l , 100 mg, 0.33 mmol) and piperidine (28 mg, 0.33 mmol) in dichloromethane (2 mL) was stirred at room temperature for 10 min. The mixture was then cooled to 0 °C and sodium triacetoxyborohydride (279 mg, 1.32 mmol) was added. The mixture was stirred at 0 °C for 1 h and room temperature for 2 h.
  • the reaction mixture was poured into water (15 mL) and extracted with dichloromethane (3 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over magnesium sulfate and evaporated. The residue was purified by column chromatography eluting with dichloromethane.methanol (100:0 ⁇ 95:5). The product was triturated with diethyl ether (ca. 1 mL) to afford the title compound (26 mg, 0.07 mmol, 21%) as a white powder.
  • Step 1 To a solution of 7-(2-diethylaminoethyl)-2,3-dihydro-lH,7H- pyrido[3,4-c]carbazol-4-one (Compound 3a-l , 215 mg, 0.64 mmol) in N,N- dimethylformamide (3 mL) was added sodium hydride (60% dispersion in mineral oil, 44 mg, 1.92 mmol) and the mixture stirred at room temperature for 15 min. The mixture was cooled to 0 °C and methyl iodide (48 ⁇ , 0.77 mmol) was added. The mixture stirred at 0 °C for 1 h.
  • Step 2 To a solution of 7-(2-diethylaminoethyl)-3-methyl-2,3-dihydro- lH,7H-pyrido[3,4-c]carbazol-4-one (Compound lOa-1, 200 mg, 0.57 mmol) in dichloromethane (4 mL) was added aluminum chloride (380 mg, 2.85 mmol) and acetyl chloride (180 mg, 2.29 mmol) and the mixture stirred at room temperature for 1 h. The reaction mixture was poured into ice water (4 mL) and the mixture made basic to pH 8 by addition of 20% aqueous sodium carbonate. The reaction mixture was diluted with chloroform (10 mL) and layers were separated.
  • Aluminum chloride 380 mg, 2.85 mmol
  • acetyl chloride 180 mg, 2.29 mmol
  • Compound 12-1 9-Acetyl-6-(2-diethylaminoethyl)-2-methyl-l,2-dihydro- 6H-pyrrolo[3,4-c]carbazol-3-one.
  • EXAMPLE 16 [00220] Compound 16-1. 6-(2-Diethylaminoethyl)-9-(l -methyl- lH-pyrazol-4-yl)- 1,2- dihydro-6H-cyclopenta[c]carbazol-3-one.
  • Step 1 A mixture of 9-bromo-6-(2-diethylaminoethyl)-l,2-dihydro-6H- cyclopenta[c]carbazol-3-one (Preparation 19-1, 2.00 g, 5.01 mmol), &w-pinacolato-diboron (2.54 g, 10.02 mmol), potassium acetate (1.47 g, 15.03 mmol) and 1,1'- 6w(diphenylphosphino)ferrocene palladium(II) dichloride (183 mg, 0.05 mmol) in 1,4- dioxane (30 mL) was heated to reflux for 5 h under argon.
  • EXAMPLE 18 [00227] Compound 18-1. 6-(2-Diethylaminoethyl)-9-oxazol-2-yl-l,2-dihydro-6H- cyclopenta[c]carbazol-3-one hydrochloride.
  • This example shows a table of the compounds of the present invention and their activity towards three different Fungal species (i.e., C. albicans, C. glabrata, and A. fumigatus) and also various cancer cell lines.
  • the MIC for 95% inhibition of growth is divided into 4 categories: A ⁇ 5 ⁇ , B 5-10 ⁇ , C >10 ⁇ , D ⁇ 40% growth inhibition at 20 ⁇ .
  • Positive controls were 20uM concentration of CBL100 and 1 mg/ml of Amphotericin B. Negative control was 0.2% DMSO solution. Percentile of reduction of cells comparing with DMSO control taken as 100% was calculated after subtraction of background (broth without cells) for each PLX compound. Experiments were done in quadriplicates and repeated at least twice. PLX compounds with average inhibition of C. albicans growth >50% were taken for secondary screening.
  • PLX compounds In parallel toxicity of PLX compounds was assessed on non-tumor (MT2 - in vitro transformed lymphoblast cells; and NKE-hTERT - immortalized kidney epithelial cells) and rumor (RCC45 - renal cell carcinoma; and RAW264 - leukemia cell line) cells according to SOP 2-18 (Appendix X). These assays were run only for compounds passed primary screening on C. albicans. Briefly, mammalian cells were plated in 96 well plates at 5X10 3 /well in lOOul of standard medium.

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Abstract

La présente invention concerne des composés carbazole de formule (I), qui peuvent être utilisés pour le traitement d'infections virales, à protozoaires, ou microbiennes, et du cancer. 
PCT/RU2013/000683 2013-08-07 2013-08-07 Composés carbazole et leurs méthodes d'utilisation WO2015020553A1 (fr)

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