WO2011058582A1 - Inhibiteurs d'histone déacétylase pour le traitement d'infections fongiques - Google Patents

Inhibiteurs d'histone déacétylase pour le traitement d'infections fongiques Download PDF

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WO2011058582A1
WO2011058582A1 PCT/IN2010/000738 IN2010000738W WO2011058582A1 WO 2011058582 A1 WO2011058582 A1 WO 2011058582A1 IN 2010000738 W IN2010000738 W IN 2010000738W WO 2011058582 A1 WO2011058582 A1 WO 2011058582A1
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adamant
thiazol
group
oxoethyl
hydroxyamino
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PCT/IN2010/000738
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Sridharan Rajagopal
Selvakumar Thangapazham
Maneesh Paul-Satyaseela
Gopalan Balasubramanian
Solanki Shakti Singh
Bharathimohan Kuppusamy
Virendra Kachhadia
Vinoth Kumar Chenniappan
Karthikeyan Ganesan
Shridhar Narayanan
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Orchid Research Laboratories Ltd.
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Publication of WO2011058582A1 publication Critical patent/WO2011058582A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • 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
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • bridged compounds of the formula (I) their analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof.
  • compositions and methods to treat fungal infection are also the compositions and methods to treat fungal infection. These compounds are selective HDAC inhibitors that act as inherent antifungal compounds or augment the activity of other antifungal compounds such as azoles.
  • Fungal infections are not as frequent as bacterial or viral infections, but have nonetheless been increasing in incidence in the human population over the past several years. This trend is largely as a consequence of increased number of cancer and immunocompromised patients who, owing to weakened immune system and the chronic nature of the diseases, are at greater risk.
  • the fungi, like bacteria have unique characteristics, distinct from their mammalian hosts, but at the same time they being eukaryotic like mammals, are much more complex organisms. Consequently, only a few drugs are aimed at interfering with cell division and have limited use. Most antifungal drugs are targeted to the cell membrane.
  • C. albicans infection The principal predisposing factors for C. albicans infection are diabetes mellitus, general debility, immunodeficiency, indwelling catheters, antibiotics that alter normal bacterial flora and corticosteroids. Of these the infection of the skin occurs in moist, warm parts of the body such as the axilla, intergluteal folds, groin, or inframammary folds; it is most common in the obese and diabetic individuals. Interdigital web infection is common among those that work in wet conditions. (Jawetz Microbiology 19 th ed; Antimicrobial Agents and Chemotherapy, 2002: 46(1 1): 3532- 3539).
  • Candidiasis is treated with antifungal azoles such as topical agents and oral or intravenous fluconazole and itraconazole.
  • antifungal azoles such as topical agents and oral or intravenous fluconazole and itraconazole.
  • the major limitation of antifungal azoles is their lack of fungicidal activity.
  • yeasts provide a reservoir for the development of Azole resistance. (Antimicrobial Agents and Chemotherapy 2002; 46:3532-3539).
  • Azole class of antifungal agents includes the imidazoles (clotrimazole, miconazole, and ketoconazole) and the triazoles (fluconazole, itraconazole, isavucanazole, ravucanazole, posoconazole, voriconazole and terconazole).
  • Azoles interfere with the biosynthesis of major fungal membrane component ergosterol by inhibiting sterol C14-demethylation of cytochrome P-450 3-A dependent enzyme 14-a-lanosterol-demethylase, one of the about 20 enzymes involved in the biosynthesis of ergosterol. Inhibition of this critical enzyme in the ergosterol synthesis pathway leads to the depletion of ergosterol in the cell membrane and accumulation of toxic intermediate sterols, causing increased membrane permeability and inhibition of fungal growth. Azole antifungals can also inhibit many mammalian cytochrome P450-dependent enzymes involved in hormone synthesis or drug metabolism.
  • fungi rely on endogenous ergosterol biosynthesis, in contrast to mammalian cells that have the ability to incorporate exogenous sterol. This property may account for the selectivity of the azoles against fungi. (Lorian V. Antibiotics in Laboratory medicine. 4 th ed; Crit. Rev. Biochem. Mol. Biol. 1999: 34: 159-166; Curr. Opin. Microbiol. 2001 , 4:540-545).
  • Azole resistance has been documented in several species of Candida.
  • the proposed mechanisms include alteration of 14-a-demethylase and upregulation of genes that encode for efflux pumps.
  • Azoles In vitro, Azoles not only fail to kill but also fail to suppress growth of Candida completely, resulting in trailing growth as observed in broth microdilution assays. (Antimicrobial Agents and Chemotherapy, 2002; 46:3532- 3539)
  • HDACs Histone deacetylases
  • Histone deacetylases are validated targets for anticancer and antiprotozoal therapy.
  • the chromatin at any given point of time is controlled by opposing actions of two types of enzymes: Histone acetyltransferases, which transfer an acetyl group from acetyl CoA to an ⁇ -amino group of lysine residues of histones loosening the nucleosomes, and HDACs that catalyze the hydrolysis of acetamides by removing acetyl groups and lead to the compaction of chromatin (The Oncologist, 2003; 8:389-391).
  • Inhibitors of HDAC selectively induce cellular differentiation, growth arrest and apoptosis in a broad spectrum of tumor cells, without affecting normal cells, which contributes to their known low-level of toxicity compared to other anticancer agents. (Curr. Med. Chem. 2005; 5:529-560).
  • HDACs are conserved in yeast. Five histone deacetylase genes (HDA1, RPD3, HOS1, HOS2, and HOS3) have been cloned from Candida albicans and characterized. Sequence analysis and comparison with 12 additional fungal deacetylases resulted in a phylogenetic tree composed of three major groups as shown in figure- 1.
  • Figure-1 Journal of Bacteriology 2001. 183:4614 - 4625
  • All the values are above 77%, suggesting that the nodes are significant and reflect the correct phylogeny.
  • Proteins from different fungal species are indicated by two-letter prefixes: Ca, Candida albicans; An, Aspergillus nidulans; Sc, Saccharomyces cerevisiae; and Sp, Schizosaccharomyces pombe.
  • the deacetylase with the highest homology to each C. albicans deacetylase is the S. cerevisiae homolog. (J. Bact. 2001 ; 183: 4614-4625).
  • C. albicans genome sequence encodes three proteins with >50% identity over much of their lengths to TSA (Trichostatin-A)-sensitive human and S. cerevisiae histone deacetylases(HDAs).
  • TSA Trichostatin-A
  • HDAs S. cerevisiae histone deacetylases
  • HDA1 and HDA6 of S. cerevisiae are examples of closely related human homologs. It is therefore anticipated that TSA and other HDAC inhibitors would affect C. albicans gene expression in some manner.
  • Some HDAC inhibitors have no effect on C albicans growth under optimal conditions, but they have clear effects on C albicans trailing growth commonly observed with azoles.
  • HDAC inhibitor MGCD290 was found to be a potent, fungal selective potentiator of several azole antifungals in Aspergillus and Candida species including C. glabrata and also it was found to potentiate azole resistant C. glabrata mutant (WO 2008/021944). MGCD290 has entered the phase I clinical trials for determining the ⁇ safety profile.
  • Hu et al “US20080139673A1”, describes how HDAC inhibitors interact with antifungal azole compounds to potentiate the activity of such compounds.
  • One objective herein is to provide bridged compounds of the formula (I) and their analogs, tautomeric forms, stereoisomers, polymorphs, intermediates, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, prodrugs, metabolites and complexes thereof.
  • the invention relates to compositions and methods to treat fungal infection. These compounds are selective HDAC inhibitors, that act as inherent antifungal compounds or that augments/potentiates the activity of other antifungal compounds such as azoles.
  • the present invention pertains to the bridged compounds of the formula (I),
  • R represents substituted or unsubstituted adamantyl, adamantylalkenylidene, aza-adamantyl, homoaza-adamantyl, noradamantyl, homoadamantyl, protoadamantyl or heteroadamantyl;
  • X represents a bond, or the groups selected from alkenylene, alkynylene, heterocycloalkyl, -OCONR 9 -, -NR 9 COO-, -NR 9 CONR 5 -, -CONR 9 -, -NR 9 CO-, -NR 9 -, -0-, -S-, -SO- -CO-, -S0 2 - -OS0 2 NR 9 -, -NR 9 S0 2 NR 5 -, -NR 9 S0 2 0- -CONR 9 CONR 5 -, -CONR 9 S0 2 NR 5 -, -CONR ⁇ R ⁇ O- -S0 2 NR 9 CONR 5 - -CONR 9 CR 7 R 8 CONR 9 -, -NR 9 COCR 7 R 8 NR 9 CO-, -NR 9 CR 7 R 8 CONR 9 -, and -NR 9 COCR 7 R 8 0-;
  • a and B independently represent a bond, -CO-, -S0 2 - or substituted or unsubstituted groups selected from alkylene, alkenylene, alkynylene, arylene, arylalkylene and heteroarylene;
  • R 1 represents substituted or unsubstituted arylene or heteroarylene
  • R 2 represents -OR 3 , ortho substituted aniline, amino aryl or amino heteroaryl, which may be optionally substituted, wherein R represents hydrogen, optionally substituted groups selected from alkyl, aryl, heterocyclyl and -COR 6 , wherein R 6 represents optionally substituted groups selected from alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl;
  • E 1 and E 2 independently represent hydrogen, aryl, alkyl or halogens
  • n is an integer selected from 1 to 2;
  • the present invention pertains to the bridged compounds of the formula la),
  • R 1 represents thiazolyl or phenylene
  • R 2 represents -OR 3 , wherein R 3 represents hydrogen, optionally substituted groups selected from alkyl, aryl, heterocyclyl and -COR 6 , wherein R 6 represents optionally substituted groups selected from alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl;
  • E 1 and E 2 independently represent hydrogen, or halogens
  • n is an integer selected from 1 to 2;
  • R represents substituted or unsubstituted adamantyl, adamantylalkenylidene, aza-adamantyl, homoaza-adamantyl and noradamantyl;
  • X represents a bond, or the groups selected from alkenylene, alkynylene, -OCONR 9 -, -NR 9 COO-, -NR 9 CONR 5 -, -CONR 9 -, -NR 9 CO-, -NR 9 -, -0-, -S-, -CONR'WCO- -CONR 9 CR 7 R 8 CONR 9 -, -NR 9 CR 7 R 8 CONR 9 - and
  • a and B independently represent a bond, -CO-, -S0 2 - ; or substituted or unsubstituted groups selected from alkylene, alkenylene, alkynylene, arylene, arylalkylene and heteroarylene; and R 5 , R 7 , R 8 and R 9 are as defined earlier;
  • the present invention pertains to the bridged compounds of the formula (lb),
  • E and E independently represent hydrogen or halogens
  • R 1 represents thiazolyl or phenylene
  • R represents substituted or unsubstituted adamantyl, adamantylalkenylidene, aza-adamantyl, homoaza-adamantyl, noradamantyl, homoadamantyl, protoadamantyl and heteroadamantyl;
  • linker A-X-B is selected from the group consisting of
  • the compound of formula (I) can be its derivatives, analogs, tautomeric forms, stereoisomers, diastereomers, geometrical isomers, polymorphs, solvates, intermediates, metabolites, prodrugs or pharmaceutically acceptable salts and compositions.
  • solvates may be hydrates or comprising of other solvents of crystallization such as alcohols.
  • alkyl refers to straight or branched aliphatic hydrocarbon groups having the specified number of carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms, which are attached to the rest of the molecule by a single atom, which may be optionally substituted by one or more substituents.
  • Preferred alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like.
  • alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, having the specified number of carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms, which may be optionally substituted by one or more substituents.
  • Preferred alkylene groups include, without limitation, methylene, ethylene, propylene, butylene and the like.
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched chain having about 2 to 10 carbon atoms, preferably 2-6 carbon atoms, which may be optionally- substituted by one or more substituents.
  • Preferred alkenyl groups include, without limitation, ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-l-propenyl, 1- butenyl, 2-butenyl and the like.
  • alkenylene refers to a linear divalent aliphatic hydrocarbon radical containing a carbon-carbon double bond and which may be straight or branched chain having about 2 to 10 carbon atoms, preferably 2-6 carbon atoms, which may be optionally substituted by one or more substituents.
  • Preferred alkenylene groups include, without limitation, ethenylene, propenylene, butenylene and the like.
  • alkynyl refers to a straight or branched hydrocarbyl radicals having at least one carbon-carbon triple bond and having in the range of 2-12 carbon atoms, preferably 2-6 carbon atoms, which may be optionally substituted by one or more substituents.
  • Preferred alkynyl groups include, without limitation, ethynyl, propynyl, butynyl and the like.
  • alkynylene refers to a straight or branched divalent hydrocarbyl radicals having at least one carbon-carbon triple bond and having in the range of 2-12 carbon atoms, preferably 2-6 carbon atoms, which may be optionally substituted by one or more substituents.
  • Preferred alkynylene groups include, without limitation, ethynylene, propynylene, butynylene, pentynylene and the like.
  • cycloalkyl refers to non-aromatic mono or polycyclic ring system of about 3 to 12 carbon atoms, which may be optionally substituted by one or more substituents.
  • the polycyclic ring denotes hydrocarbon systems containing two or more ring systems with one or more ring carbon atoms in common i.e. a spiro, fused or bridged structures.
  • Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, perhydronaphthyl, adamantyl, homoadamantyl, noradamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups e.g spiro [4.4] non-2-yl and the like.
  • cycloalkenyl refers to a non-aromatic cyclic ring radical containing about 3 to 8 carbon atoms with at least one carbon-carbon double bond, which may be optionally substituted by one or more substituents.
  • Preferred cycloalkenyl groups include, without limitation, cyclopropenyl, cyclopentenyl and the like.
  • heterocyclyl refers to a stable 3 to 15 membered ring radical, which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be monocyclic, bicyclic or tricyclic ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated.
  • Preferred heterocyclyl groups include, without limitation, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, homopiperazinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidon
  • heteroaryl refers to an aromatic heterocyclic ring radical as defined above.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of stable structure.
  • heteroarylene also refers to divalent heteroaryl.
  • heterocycloalkyl refers to a hydrocarbyl radical having alkyl group attached to the heterocyclyl ring.
  • aryl refers to aromatic radicals having 6 to 14 carbon atoms, which may be optionally substituted by one or more substituents.
  • Preferred aryl groups include, without limitation, phenyl, naphthyl, indanyl, biphenyl and the like.
  • arylene also refers to aryl.
  • Preferred arylene groups include, without limitation, phenylene, naphthylene, biphenylene and the like
  • heterocyclantyl refers to one or more carbon atoms in the adamantane ring replaced by nitrogen, oxygen or sulfur.
  • adamantylalkenylidene refers to a hydrocarbyl radical having alkenylidene group attached to the adamantyl ring.
  • alkenylidene refers to a bivalent hydrocarbon group having one or more double bonds formed by mono or dialkenyl substitution of methylene.
  • Typical alkenylidene radicals include, but are not limited to, ethenylidene, prop-l-en-l-ylidene, prop-2-en-l-ylidene, but-l-en-l-ylidene, but-2-en-l-ylidene, but-3-en-l-ylidene, buta- 1,3-dien-l-ylidene; cyclobut-2-en-l-ylidene.
  • alkoxy refers to an alkyl group attached via an oxygen linkage to the rest of the molecule, which may be optionally substituted by one or more substituents.
  • Preferred alkoxy groups include, without limitation, -OCH 3; -OC 2 H 5 and the like.
  • alkylamino refers to an alkyl group attached via an amino linkage to the rest of the molecule.
  • Preferred alkylamino group include, without limitation, methyamino, ethylamino, propylamino, isopropylamino and the like.
  • arylalkoxy refers to an alkoxy group attached to an aryl substituent.
  • Preferred arylalkoxy groups include, without limitation, phenylmethyl ether and the like.
  • cycloalkyloxy refers to cycloalkyl group attached via an oxygen linkage to the rest of the molecule
  • Preferred cycloalkyloxy groups include, wthout limitation, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and the like.
  • haloalkoxy refers to a group resulting from the replacement of one or more hydrogen atoms from a C 1-4 alkoxy group with one or more halogen atoms, which can be the same or different.
  • Preferred haloalkoxy groups include, without limitation, -trifluoromethoxy, fluoromethoxy and the like.
  • haloalkyl refers to an halogen group attached via an alkyl linkage to the rest of the molecule, which may be optionally substituted by one or more substituents.
  • Preferred haloalkyl groups include, without limitation, -CH 2 Cl j -C 2 H 5 C1 and the like.
  • bridged means a saturated bicyclic or tricyclic ring system.
  • Bicyclic ring systems are exemplified by a cycloalkyl group, as defined herein, in which two non-adjacent carbon atoms of the cycloalkyl group are linked by an alkylene bridge of 1-3 carbon atoms.
  • Representative examples of bicyclic ring systems include, but are not limited to, bicyclo [3.1.1] heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1] nonane.
  • Tricyclic ring systems are exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms.
  • Representative examples of tricyclic- ring systems include, but are not limited to, tricyclo[3.3.1.0 3 ' 7 Jnonane and tricyclo[3.3.1.1 3 ' 7 Jdecane (adamantane).
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • analog refers to a chemical compound that is structurally similar to another but differs slightly in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group.
  • An analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
  • metabolite refers to compositions that result from a metabolic process. Examples of the results of metabolism on the compounds of the present invention include addition of -OH, hydrolysis and cleavage.
  • stereoisomers refers to a chemical compound or molecule made from a parent compound by one or more chemical reactions such as, by oxidation, hydrogenation, alkylation, esterification, halogenation and the like.
  • the stereoisomers are isomers that differ in the arrangement of their atoms in space.
  • Compounds disclosed herein may exist as single stereoisomers, racemates and or mixtures of enantiomers and/or diastereomers.
  • Stereoisomers include geometrical isomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the subject matter described.
  • the methods for determination of stereochemistry, preparation and separation of the stereoisomers are well known in the art. (e.g., see “Advanced Organic Chemistry", 4th edition, March, Jerry, John Wiley & Sons, New York, 1992).
  • phrases “pharmaceutically acceptable” refers to compounds or compositions that are physiologically tolerable and do not typically produce allergic or similar untoward reaction, including but not limited to gastric upset or dizziness when administered to mammal.
  • Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn and the like; salts of organic bases such as N, N'-diacetylethylenediamine, glucamine, triethylamine, choline, dicyclohexylamine, benzylamine, trialkylamine, thiamine, guanidine, diethanolamine, cc-phenylethylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, ammonium, substituted ammonium salts, aluminum salts and the like.
  • inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn and the like
  • salts of organic bases such as N, N'-diacetylethylenediamine, glucamine, triethylamine, choline
  • Salts also include amino acid salts such as glycine, alanine; cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc.
  • Salts may include acid addition salts, where appropriate, which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • prodrugs refers to any pharmacologically inactive or less active compound which, when metabolized or chemically transformed by a mammalian system is converted into a pharmacologically active compound of formula (I) of the present invention.
  • some of prodrugs are esters of the compound of formula (I), during metabolysis; the ester group is cleaved to form the active compound of formula (I).
  • a general overview of prodrug is provided in H Surya Prakash Rao, Capping Drugs: Development of Prodrugs, Resonance, 2003, vol. 8, 19- 27.
  • the compounds described herein can also be prepared in any solid or liquid physical form, for example the compound can be in a crystalline form, in amorphous form and have any particle size.
  • the compound particles may be micronized or nanoized, or may be agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical forms.
  • the compounds described herein may also exhibit polymorphism.
  • This invention further includes different polymorphs of the compounds of the present invention.
  • polymorph refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point and the like.
  • histone deacetylase and "HDAC” are intended to refer to any one of a family of enzymes that remove acetyl groups from the ⁇ -amino groups of lysine residues at the N-terminus of a histone. Unless otherwise indicated by context, the term “histone” is meant to refer to any histone protein, including HI, H2A, H2B, H3, H4 and H5, from any species. Human HDAC proteins or gene products include but are not limited to, HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9 and HDAC-10.
  • the histone deacetylase can also be derived from a protozoal or fungal source.
  • histone deacetylase inhibitor is used to identify a compound having structure as defined herein, which is capable of interacting with histone deacetylase and inhibiting its enzymatic activity. Inhibiting histone deacetylase enzymatic activity means reducing the ability of histone deacetylase to remove an acetyl group from histone. Such inhibition is specific, i.e. histone deacetylase inhibitor reduces the ability of histone deacetylase to remove an acetyl group from histone at a concentration that is lower than the concentration of inhibitor that is required to produce another, unrelated biological effect.
  • the present invention provides compounds, composition thereof and methods for selectively enhancing fungal sensitivity to antifungal compounds.
  • inhibitors of histone deacetylase are more active against a fungal histone deacetylase than a plant or mammalian histone deacetylase; preferably the inhibitory activity is specific for fungal histone deacetylase.
  • antifungal agent is a substance capable of inhibiting or preventing the growth, viability and/or reproduction of a fungal cell.
  • Preferable antifungal agent is a broad spectrum antifungal agent.
  • an antifungal agent can also be specific to one or more species of fungus.
  • Preferable antifungal agents are ergosterol synthesis inhibitor and include, but are not limited to azoles and phenpropimorph.
  • Preferred azoles include imidazoles and triazoles.
  • Further preferred antifungal agents include, but are not limited to, ketoconazole, itraconazole, fluconazole, voriconazole, posaconazole, ravuconazole and miconazole.
  • phenpropimorph is an ergosterol synthesis inhibitor, but acts on the ergosterol reductase (ERG24) step of the synthesis pathway.
  • Terbinafine is also an ergosterol inhibitor, but acts on squalene epoxidase (ERG1) step.
  • compound of the present invention shows inherent activity against fungal species or synergistic activity with an antifungal agent against a fungal species, preferably at concentrations of inhibitor not toxic to mammalian cells.
  • antifungal agents are azole antifungal agents.
  • Such combinations, and compositions thereof, can be used to selectively treat fungal infections.
  • the compounds of the present invention are also useful in the medicament for inhibiting HDAC in a fungal cell.
  • the compounds of the present invention are also useful in preparing a medicament for reducing resistance of a fungal cell to an antifungal agent, in a mammal suffering from the said fungal infection.
  • TSA trichostatin A
  • sodium butyrate sodium butyrate
  • trapoxin sodium butyrate
  • HDAC inhibitors have been tested as an agent to enhance the sensitivity of selected fungal species to azole antifungal agents. Only TSA was able to enhance the sensitivity of Candida albicans. (Antimicrobial Agents and Chemotherapy 2002; 46:3532-3539). However, the concentration of TSA required was higher than those toxic to mammalian cells. A major problem with current antifungal formulations is their toxicity to the infected host. The therapeutic index is preferably selective to the targeted fungus without being toxic to the host. Drawbacks to current antifungal agents, such as the azoles, include development of resistance, possible drug-drug interactions and possible toxic liver effects.
  • Representative compounds include:
  • Step 1 NH 2 OH.HCl, KOH and MeOH.
  • the said process for the preparation of the compounds of formula (I) comprises of the following:
  • Step-1 Treating the compound of formula (2) with hydroxylamine HC1 or R 2 NH 2 in presence of inorganic base such as KOH and the like to give compound of formula (I).
  • inorganic base such as KOH and the like
  • the compound of formula (2) includes other alkyl esters such as ethyl, isopropyl, t-butyl and the like.
  • DIPEA Diisopropylethylamine
  • DCM Dichloromethane
  • CDI Carbonyldiimidazole
  • THF Tetrahydrofuran
  • Step 1 Conditions: EDCI, HOBt, DIPEA and DCM
  • Step 1 Conditions: Carbonyldiimidazole (CDI), Triethylamine (TEA) and
  • Step 1 Conditions: CH 3 S0 3 H,
  • Step 2 Conditions: H 2 S0 4 , MeOH.
  • Step 1 Conditions: Trifluoroacetic anhydride (TFAA), TEA, P 2 S 5 .
  • Step 2 Conditions: H 2 S0 4 , MeOH.
  • Step 1 Conditions: NaH, Pd/C.
  • Step 2 Conditions: KOH, Oxalyl chloride, TMSdiazomethane, TEA, Silver benzoate.
  • the compound of formula (In) was further one carbon homologated (Arndt eistert reaction) to yield the compound of general formula (2).
  • Step 1 Conditions: NaH or K 2 C0 3
  • Step 1 Condition 1: W is Br, Z is NH 2 , Potassium carbonate, DMF
  • W is CI
  • Z is NH 2 TEA
  • DCM Reacting the compound of formula (la) with the compound of formula (lr) in presence of base such as TEA and the like and the solvent such as DCM and the like to yield the compound of formula (2).
  • LAH Lithium Aluminium Hydride
  • THF 250 mL
  • methyl adamantane-l-carboxylate 21.8 g, 1 12 mmol
  • EtOAc 100 mL
  • water 20 mL
  • Reaction mixture was filtered and filtrate was dried over anhydrous sodium sulphate, solvent was distilled out and dried to afford the pure product (17 g, 91% yield).
  • Example 1 Synthesis of adamant-l-ylmethyl ⁇ 4-[2-(hydroxyamino)-2-oxoethyl]- l,3-thiazol-2-yl ⁇ carbamate
  • Step-I Preparation of methyl (2-amino-l,3-thiazol-4-yl)acetate hydrochloride
  • Step-II Preparation of methyl (2- ⁇ [(adamant-l-ylmethoxy)carbonyl]amino ⁇ -l,3- thiazol-4-yl)acetate:
  • Triphosgene (0.145 g, 0.49 mmol) was dissolved in DCM (1 mL).
  • Adamant- 1- ylmethanol(I-3) (0.25 g, 1.5 mmol) and DIPEA (0.32 mL, 1.9 mmol) in DCM (2 mL) was added dropwise slowly at RT under stirring.
  • methyl (2-amino- l,3-thiazol-4-yl)acetate hydrochloride salt (0.256 g, 1.5 mmol) and DIPEA (0.32 mL, 1.9 mmol) in DCM (2 mL) was added and stirred for 30 minutes.
  • Example 12 Synthesis of 7V- ⁇ 4-[2-(hydroxyamino)-2-oxoethyl]-l,3-thiazol-2- yl ⁇ adamantane-l-carboxamide.
  • Step-I Preparation of methyl ⁇ 2-[(adamant-l-ylcarbonyl)amino]-l,3-thiazol-4- yljacetate:
  • Step-II Preparation of N- ⁇ 4-[2-(hydroxyainino)-2-oxoethyl]-l,3-thiazol-2- yl ⁇ adamantane-l-carboxamide:
  • adamantane-l-carboxylic acid (I- 1) (0.250 g, 1.4 mmol) is coupled with ethyl (2-amino-l,3-thiazol-4-yl)(oxo)acetate to give ethyl ⁇ 2-[(adamant-l-ylcarbonyl)amino]-l,3-thiazol-4-yl ⁇ (oxo)acetate.
  • Step-II Preparation of ethyl ⁇ 2-[(adamant-l-ylcarbonyl)amino]-l,3-thiazol-4- yl ⁇ (difluoro)acetate:
  • Step-III Preparation of N- ⁇ 4-[l,l-difluoro-2-(hydroxyamino)-2-oxoethyl]-l,3- thiazol-2-yl ⁇ adamantane-l-carboxamide:
  • Step-I Preparation of ethyl (2- ⁇ [(adamant-l-ylamino)carbonyl]amino ⁇ -l,3- thiazol-4-yl)acetate:
  • Step-II Preparation of 2-(2- ⁇ [(adamant-l-ylamino)carbonyl]amino ⁇ -l,3-thiazol-4- yl)-N-hydroxyacetamide:
  • Step-I Preparation of methyl ⁇ 2-[(bromoacetyl)amino]-l,3-thiazol-4-yl ⁇ acetate:
  • Step-II Preparation of methyl (2- ⁇ [(adamant-l-ylamino)acetyI]amino ⁇ -l,3- thiazol-4-yl)acetate:
  • Step-III Preparation of methyl [2-( ⁇ [(adamant-l- ylcarbonyl)amino] acety l ⁇ amino)-l ,3-thaizol-4-yl] acetate:
  • Step-IV Preparation of N-[2-( ⁇ 4-[2-(hydroxyamino)-2-oxoethyl]-l,3-thiazol-2- yl ⁇ amino)-2-oxoethyl]adamantane-l-carboxamide:
  • Step-II Preparation of methyl 2-[4'-(adamant-l-yl)biphenyl-4-yl]acetate:
  • Step-I Preparation of ethyl ⁇ 2-[4-(adamant-l-yl)butyl]-l,3-thiazol-4-yl ⁇ acetate:
  • Step-IV Preparation of ethyl ⁇ 4-[4-(adamant-l-yl)butyl]phenyl ⁇ acetate:
  • Step-V Preparation of 2- ⁇ 4-[4-(adamant-l-yl)butyl]phenyl ⁇ -N- hydroxyacetamide:
  • Step-I Preparation of l-(3-bromo ropyl)adamantane:
  • Step-II Preparation of methyl ⁇ 4-(3-[adamant-l-yl]propyloxy)phenyl ⁇ acetate:
  • Step-III Preparation of 2- ⁇ 4-[3-(adamant-l-y.)propoxy]phenyl ⁇ -N- hydroxyacetamide:
  • Step-II Preparation of 2-(4- ⁇ [3-(adamant-l-yl)propylamino]sulfonyl ⁇ phenyl)-N- hydroxy acetamide:
  • Step-II Preparation of 2-(4- ⁇ [(3-(adamant-l-yl)propyIamino]methyI ⁇ phenyI)-7V- hydroxy acetamide:
  • Compounds to be tested are prepared in concentrations that are four-fold higher than required to correct the dilution factor. While adding the compounds, the final DMSO concentration should be ⁇ 0.5%.
  • An azole is serially two-fold diluted in a 96- well plate, an equal volume of the predetermined concentration of HDAC- inhibitor(HDACi) is added to each well, and the inoculum is added to each well and plates incubated for 24 h and 48 h in ambient temperature.
  • antifungal agent (azole) is added to row A in column 1 and serially diluted two-fold to rows B through G in column 1.
  • Row H serves as antifungal-free control.
  • the HDAC-inhibitor is added to column 2 and serially diluted two-fold to columns 3 through 8 in row A.
  • Column 9 serves as organism control and column 10 serves as HDAC-inhibitor-free control.
  • Antifungal agent from each row is dispensed from column 2 through column 8 in their respective rows.
  • HDAC-inhibitor from each column is dispensed from row B through row G in their respective columns and mixed well.
  • MIC Minimum inhibitory concentration
  • Synergy determined by the checker-board method, is defined as >4-fold deerease in MIC of the Azole in combination with the HDAC-inhibitor relative to the Azole alone.
  • test compounds were binding to the fungal HDACs
  • an HDAC enzymatic assay was carried out using the Fluorogenic Class I HDAC substrate, Boc-Lys(Ac)-AMC.
  • yeast cell pellets were washed with sterile autoclaved water and resuspended in lysis buffer at pH 7.9 containing glass beads. Cells were lysed and centrifuged and the supernatant was incubated with test compounds in DMSO, diluted in assay buffer to appropriate concentrations along with substrate and incubated for 1 h. Reactions were terminated by the addition of TSA/SAHA and developed by the addition of developer and left at 37 °C for 15 minutes, before reading the plates in fluorimeter, Spectramax Gemini XS (Molecular Devices). Ex 360 Em 460.
  • Hos2 Binding to one of the purified HDACs, Hos2, was studied by cloning, expressing and purifying the Hos2 protein. Briefly, Hos2 enzymatic assay was carried out using the Fluorogenic Class I HDAC substrate, Boc-Lys (Ac)-AMC. Test compounds were dissolved in DMSO and diluted in HDAC assay buffer.
  • SRB Assay cell viability assay in human cancer cell lines: The DU145 cells (human prostate cancer cell line) were seeded in 96 well tissue culture plates and after overnight adherence, incubated with the indicated concentration of test compound, then plate was incubated for 48 h at 37 °C in C0 2 and after that ice cold 30% TCA (10% of the well) was added to each well of the plate (for fixing adherence cells) and incubated at 4 °C for an hour, then plates were washed with slow running tap water.
  • SRB sulforhodamine B
  • Table -6 Inhibition of cancer cell growth.
  • hPBMC human peripheral blood mononuclear cells

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Abstract

La présente invention concerne des composés pontés de formule (I), leurs analogues, des formes tautomères, des stéréoisomères, des isomères géométriques, des polymorphes, des hydrates, des solvates, des sels pharmaceutiquement acceptables, des compositions pharmaceutiques, des métabolites et des promédicaments de ceux-ci. L'invention concerne des compositions et des procédés pour traiter une infection fongique. Ces composés sont des inhibiteurs sélectifs de HDAC qui agissent en tant que composés antifongiques intrinsèques ou augmentent l'activité d'autres composés antifongiques tels que des azoles.
PCT/IN2010/000738 2009-11-16 2010-11-12 Inhibiteurs d'histone déacétylase pour le traitement d'infections fongiques WO2011058582A1 (fr)

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EP3769757A3 (fr) * 2013-10-18 2021-10-06 The General Hospital Corporation Imagerie d'histone désacétylases au moyen d'un radiotraceur à l'aide de la tomographie par émission de positrons
US11548893B2 (en) 2017-07-15 2023-01-10 Arisan Therapeutics Inc. Enantiomerically pure adamantane carboxamides for the treatment of filovirus infection
US11793827B2 (en) 2021-01-25 2023-10-24 Brii Biosciences, Inc. Adenosine derivative and pharmaceutical composition comprising the same
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US8314119B2 (en) 2006-11-06 2012-11-20 Abbvie Inc. Azaadamantane derivatives and methods of use
US8987453B2 (en) 2006-11-06 2015-03-24 Abbvie Inc. Azaadamantane derivatives and methods of use
WO2012021982A1 (fr) * 2010-08-20 2012-02-23 Methylgene Inc. Agents antifongiques et leurs utilisations
US9464078B2 (en) 2010-09-23 2016-10-11 Abbvie Inc. Monohydrate of azaadamantane derivatives
CN102329245A (zh) * 2011-07-04 2012-01-25 武汉大学 具有抗禽流感病毒活性的金刚烷衍生物及其制备方法
WO2013041407A1 (fr) * 2011-09-19 2013-03-28 Cellzome Ag Acides hydroxamiques et récepteurs hdac6
EP3769757A3 (fr) * 2013-10-18 2021-10-06 The General Hospital Corporation Imagerie d'histone désacétylases au moyen d'un radiotraceur à l'aide de la tomographie par émission de positrons
US11938134B2 (en) 2017-03-10 2024-03-26 Eikonizo Therapeutics, Inc. Metalloenzyme inhibitor compounds
EP3609864A4 (fr) * 2017-04-11 2021-01-20 The General Hospital Corporation Inhibiteurs de hdac6 et agents d'imagerie
JP2020516628A (ja) * 2017-04-11 2020-06-11 ザ ジェネラル ホスピタル コーポレイション Ｈｄａｃ６阻害剤及び造影剤
CN110770206A (zh) * 2017-04-11 2020-02-07 通用医疗公司 Hdac6抑制剂和显像剂
WO2018191360A1 (fr) * 2017-04-11 2018-10-18 The General Hospital Corporation Inhibiteurs de hdac6 et agents d'imagerie
US11207431B2 (en) 2017-04-11 2021-12-28 The General Hospital Corporation HDAC6 inhibitors and imaging agents
AU2018250599B2 (en) * 2017-04-11 2022-05-26 The General Hospital Corporation HDAC6 inhibitors and imaging agents
CN110770206B (zh) * 2017-04-11 2022-11-25 通用医疗公司 Hdac6抑制剂
JP7183178B2 (ja) 2017-04-11 2022-12-05 ザ ジェネラル ホスピタル コーポレイション Ｈｄａｃ６阻害剤及び造影剤
US11890356B2 (en) 2017-04-11 2024-02-06 The General Hospital Corporation HDAC6 inhibitors and imaging agents
RU2646043C1 (ru) * 2017-06-09 2018-03-01 Федеральное государственное бюджетное образовательное учреждение высшего образования "Волгоградский государственный технический университет" (ВолгГТУ) Способ получения 3-(1-адамантил)пропановой кислоты
US11548893B2 (en) 2017-07-15 2023-01-10 Arisan Therapeutics Inc. Enantiomerically pure adamantane carboxamides for the treatment of filovirus infection
US11793827B2 (en) 2021-01-25 2023-10-24 Brii Biosciences, Inc. Adenosine derivative and pharmaceutical composition comprising the same

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