WO2023140369A1 - Phosphoric acid derivatives - Google Patents

Phosphoric acid derivatives Download PDF

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Publication number
WO2023140369A1
WO2023140369A1 PCT/JP2023/001813 JP2023001813W WO2023140369A1 WO 2023140369 A1 WO2023140369 A1 WO 2023140369A1 JP 2023001813 W JP2023001813 W JP 2023001813W WO 2023140369 A1 WO2023140369 A1 WO 2023140369A1
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optionally substituted
ring
cancer
compound
pharmaceutically acceptable
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PCT/JP2023/001813
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French (fr)
Inventor
Hajime Takashima
Eiji Honda
Tomonori Taguri
Jun Ozawa
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Prism BioLab Co., Ltd.
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Publication of WO2023140369A1 publication Critical patent/WO2023140369A1/en

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    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present invention relates to a phosphoric acid derivative . More specifically, the present invention relates to a phosphoric acid derivative having inhibitory activities on cancer cell proliferation .
  • Cancer is the leading cause of death in animals and humans .
  • Many chemotherapeutic agents effective against cancer and tumor cells have been developed . However, they are not always effective against all types of cancers and tumors, and sometimes show the side effect of destroying normal cells . There is still a need for the development of a pharmaceutical product that shows cancer cell-specific effects and causes fewer side effects .
  • the present invention aims to provide a compound having inhibitory activities on cancer cell proliferation .
  • the present inventors have conducted intensive studies in an attempt to solve the aforementioned problems and found that a compound having a particular structure shows a superior inhibitory activities on cancer cell proliferation, and completed the present invention .
  • a compound represented by the following formula ( I ) wherein Q 1 is represented by any of the following formulas ( II-l ) to ( II- 6) :
  • Q 1a is a hydrogen atom, or 1 to 3 same or different alkyls ;
  • W 1 is an optionally substituted alkylene or an optionally substituted cycloalkylene;
  • X 1 is -OPO 3 H 2 or hydrogen atom
  • R 2 is an optionally substituted alkyl, an optionally substituted cycloalkylalkyl, or an optionally substituted arylalkyl ;
  • Q 3 is an optionally substituted divalent group derived from an aryl ring, or an optionally substituted divalent group derived from a heteroaryl ring;
  • W 3 is a single bond, an optionally substituted alkylene, or an optionally substituted alkynylene;
  • X 3 is hydrogen atom or hydroxy when X 1 is -OPO 3 H 2 , or is -OPO 3 H 2 when X 1 is hydrogen atom;
  • R 4 is an optionally substituted alkyl, or an optionally substituted cycloalkylalkyl ;
  • R 5 is a hydrogen atom, or an optionally substituted alkyl, or a pharmaceutically acceptable salt thereof .
  • Q 1 is represented by any of the following formulas (III-l ) to (III-3) : r
  • R 2 is an optionally substituted alkyl ;
  • W 3 is a single bond, or an optionally substituted alkynylene;
  • Q 3 is an optionally substituted divalent group derived from a heteroaryl ring
  • R 4 is an optionally substituted alkyl
  • R 5 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.
  • R 2 is neopentyl
  • Q 3 is a divalent group derived from thiazole ring, benzothiazole ring, thiazolo [5, 4-b] pyridine ring, or quinoxaline ring; the thiazole ring, benzothiazole ring, thiazolo [5, 4-b] pyridine ring, or quinoxaline ring may be substituted by substituent (s) selected from a hydroxy group, a methyl group and a cyano group; and R 4 is isobutyl or 2-ethylbutyl, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound of any of [1] to [3] or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier or diluent.
  • composition of [4] wherein the composition comprises an effective amount of the compound.
  • a method of treating or preventing a cancer comprising administering to a subject in need thereof the compound of any of [1] to [3] or a pharmaceutically acceptable salt thereof, or a composition of [4] or [5] , in an amount effective to treat or prevent the cancer.
  • An agent for treating or preventing a cancer comprising a compound of any of [1] to [3] or a pharmaceutically acceptable salt thereof.
  • the compound of the formula (I) of the present invention inhibits cancer cell proliferation and thus can be used for treating various cancers and tumors. [Brief Description of the Drawings]
  • Fig. 1 shows a NMR (300 MHz, CDCI 3 ) data of F-04.
  • Fig. 2 shows a NMR (300 MHz, CDCI 3 ) data of F-08- intl .
  • Fig. 3 shows a 2 H NMR (300 MHz, CDCI 3 ) data of F-08- int2.
  • Fig. 4 shows a T H NMR (300 MHz, CDCI 3 ) data of F-08.
  • Fig. 5 shows a X H NMR (300 MHz, CDCI 3 ) data of F-10-
  • Fig. 6 shows a X H NMR (300 MHz, CDCI 3 ) data of F-10.
  • Fig. 7 shows a X H NMR (300 MHz, CDCI 3 ) data of ID-02.
  • Fig. 8 shows a 1 H NMR (300 MHz, CDCI 3 ) data of ID-08.
  • Optionally substituted means that a given radical may consist of only hydrogen substituents through available valencies or may further comprise one or more non-hydrogen substituents through available valencies.
  • a non-hydrogen substituent may be any substituent that may be bound to an atom of the given radical that is specified to be substituted.
  • substituents include, but are not limited to, -R 6 , -OR 6 , -COR 6 , -COOR 6 , -OCOR 6 , -CONR 6 R 7 , -NR 6 R 7 , - NR 7 COR 6 , -NR 7 COOR 6 , -SR 6 , -SO 2 R 6 , -SO 2 NR 6 R 7 , -SO 2 OR e , -OSO 2 R 6 , - NHC (NHR 6 ) NR 7 , -NHC(NH 2 )NH, -CN, -NO 2 , halogen and methylenedioxy, wherein R 6 and R 7 are independently selected from hydrogen, linear or branched chain, cyclic or noncyclic, substituted or unsubstituted, alkyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl moieties.
  • substituents include, but
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Halo means fluoro, chloro, bromo or iodo.
  • Alkyl means a linear or branched, saturated, aliphatic radical having a chain of carbon atoms .
  • C X-Y alkyl is typically used where X and Y indicate the number of carbon atoms in the chain.
  • the number of carbon atoms in the chain is preferably 1 to 10 (Ci-io) , more preferably 1 to 6 (C 1-6 ) , further preferably 1 to 4 (C1-4) .
  • Non-exclusive examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, tert-butylmethyl, diethylethyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, and the like .
  • Alkoxy means an oxygen moiety having a further alkyl substituent .
  • C X-Y alkoxy is typically used where X and Y indicate the number of carbon atoms in the chain .
  • the number of carbon atoms in the chain is preferably 1 to 10 (C 1-10 ) , more preferably 1 to 6 (C 1-6 ) •
  • Non-exclusive examples of alkoxy include methoxy, ethoy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, tert pentoxy, hexyloxy, isohexyloxy, and the like .
  • Alkenyl means a linear or branched, carbon chain that contains at least one carbon-carbon double bond.
  • C X-Y alkenyl is typically used where X and Y indicate the number of carbon atoms in the chain .
  • the number of carbon atoms in the chain is preferably 2 to 10 (C 2-10 ) , more preferably 2 to 6 (C 2-6 ) •
  • Non-exclusive examples of alkenyl include ethenyl (vinyl) , allyl, isopropenyl, 2 -methylallyl, 1 -pentenyl, hexenyl, heptenyl, 1- propenyl, 2-butenyl, 2-methyl-2-butenyl , and the like .
  • Alkynyl means a linear or branched, carbon chain that contains at least one carbon-carbon triple bond.
  • C X-Y alkynyl is typically used where X and Y indicate the number of carbon atoms in the chain .
  • the number of carbon atoms in the chain is preferably 2 to 10 (C 2-10 ) , more preferably 2 to 6 (C 2-6 ) .
  • Non-exclusive examples of alkynyl include ethynyl, propargyl , 3- methyl-l-pentynyl, 2-heptynyl and the like .
  • Alkylene unless indicated otherwise, means a linear or branched, saturated, aliphatic, polyvalent carbon chain .
  • C X-Y alkylene is typically used where X and Y indicate the number of carbon atoms in the chain .
  • the number of carbon atoms in the chain is preferably 1 to 10 (C 1-10 ) , more preferably 1 to 6 (C 1-6 ) •
  • Non-exclusive examples of alkylene include methylene (-CH 2 -) , ethylene (-CH 2 CH 2 -) , methylmethylene (-CH (CH 3 ) -) , 1, 2-propylene (- CH 2 CH (CH 3 ) -) , 1 , 3-propylene ( -CH 2 CH 2 CH 2 - ) , 1, 2-butylene ( - CH 2 CH (CH 2 CH 3 ) -) , 1, 3-butylene ( -CH 2 CH 2 CH (CH 3 ) -) , 1 , 4-butylene ( - CH 2
  • Alkynylene means a linear or branched, carbon chain (divalent ) that contains at least one carbon-carbon triple bond.
  • C X-Y alkynylene is typically used where X and Y indicate the number of carbon atoms in the chain .
  • the number of carbon atoms in the chain is preferably 2 to 10 (C 2-10 ) , more preferably 2 to 6 (C 2-6 ) -
  • Non-exclusive examples of alkynylene include ethynylene, propargylene, 3-methyl-l-pentynylene, 2-heptynylene and the like .
  • Cycloalkylene unless indicated otherwise, means a non- aromatic, saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring radical (divalent) .
  • C X-Y cycloalkylene is typically used where X and Y indicate the number of carbon atoms in the ring assembly.
  • the number of carbon atoms in the ring is preferably 3 to 10 (C 3-10 ) , more preferably 3 to 8 (C 3-8 ) ⁇
  • cycloalkylene include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclohexenylene, 2 , 5- cyclohexadienylene, bicyclo [2 . 2 . 2 ] octylene, adamantan-l-ylene, decahydronaphthylene, bicyclo [2 . 2 . 1 ] hept-l-ylene, and the like .
  • Heteroatom refers to an atom that is not a carbon atom and hydrogen atom. Particular examples of heteroatoms include, but are not limited to nitrogen, oxygen, and sulfur .
  • Aryl ring means a monocyclic or polycyclic ring wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring .
  • C X-Y aryl ring is typically used where X and Y indicate the number of carbon atoms in the ring assembly.
  • the number of carbon atoms in the ring is preferably 6 to 14 (C 6-14 ) , more preferably 6 to 10 (C 6-10 ) •
  • Non-exclusive examples of aryl ring include benzene, naphthalene, anthracene, phenanthrene, acenaphthylene, indene and the like .
  • Aryl means a monocyclic or polycyclic radical wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring .
  • C X-Y aryl is typically used where X and Y indicate the number of carbon atoms in the ring assembly .
  • the number of carbon atoms in the ring is preferably 6 to 14 (C 6-14 ) , more preferably 6 to 10 (C 6-10 ) •
  • Non-exclusive examples of aryl include phenyl, naphthyl, indenyl, azulenyl, biphenyl , fluorenyl , anthracenyl, phenalenyl and the like .
  • “Aryl” may partially be hydrogenated.
  • Non-exclusive examples of partially hydrogenated aryl include tetrahydronaphthyl, indanyl and the like .
  • Allene means divalent radical derived from the above- mentioned aryl ring .
  • Heteroaryl ring means a monocyclic or polycyclic aromatic ring wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon .
  • X-Y membered heteroaryl ring is typically used where X and Y indicate the number of carbon atoms and heteroatoms in the ring assembly .
  • the number of carbon atoms and heteroatoms in the ring is preferably 5 to 14 , more preferably 5 to 10.
  • Monocyclic heteroaryl rings include, but are not limited to, cyclic aromatic rings having five or six ring atoms, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon .
  • Non-exclusive examples of monocyclic heteroaryl ring of this invention include, but are not limited to, furan, imidazole, thiazole, isothiazole, isoxazole, oxadiazole, oxazole, 1 , 2 , 3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, 1, 3, 4-thiadiazole, triazole and tetrazole .
  • Heteroaryl ring also includes, but is not limited to, bicyclic or tricyclic rings, wherein the heteroaryl ring is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, and another monocyclic heteroaryl or heterocycloalkyl ring .
  • Non-exclusive examples of bicyclic or tricyclic heteroaryl ring include, but are not limited to, benzofuran (ex . benzo [b] furan) , benzothiophene (ex . benzo [b] thiophene) , benzimidazole, benzotriazine (ex .
  • thieno [2 , 3-c] pyridine, thieno [3, 2- b]pyridine, thieno [2, 3-b] pyridine) indolizine, quinoline, isoquinoline, phthalazine, quinoxaline, cinnoline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, pyrazolopyridine (ex. pyrazolo [1, 5-a] pyridine) , imidazopyrimidine (ex.
  • bicyclic or tricyclic heteroaryl rings can be attached to the parent molecule through either the heteroaryl group itself or the aryl, cycloalkyl, or heterocycloalkyl group to which it is fused.
  • Heteroaryl means monovalent radical derived from the above-mentioned heteroaryl ring .
  • Heteroarylene means divalent radical derived from the above-mentioned heteroaryl ring .
  • Cycloalkyl means a non-aromatic, saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring radical .
  • C X-Y cycloalkyl is typically used where X and Y indicate the number of carbon atoms in the ring assembly.
  • the number of carbon atoms in the ring is preferably 3 to 10 (C3-10) r more preferably 3 to 8 (C3-8) •
  • Non-exclusive examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2 , 5-cyclohexadienyl , bicyclo [2 . 2 . 2 ] octyl, adamantan-l-yl, decahydronaphthyl, bicyclo [2 . 2 . 1] hept-l-yl, and the like .
  • Heterocycloalkyl means cycloalkyl, as defined in this Application, provided that one or more of the atoms forming the ring is a heteroatom selected, independently from N, 0, or S .
  • "X-Y membered heterocycloalkyl” is typically used where X and Y indicate the number of carbon atoms and heteroatoms in the ring assembly .
  • the number of carbon atoms and heteroatoms in the ring is preferably 3 to 10 , more preferably 3 to 8 .
  • Non- exclusive examples of heterocycloalkyl include piperidyl, 4- morpholyl, 4-piperazinyl, pyrrolidinyl , perhydropyrrolidinyl,
  • arylalkyl means linear or branched alkyl group which is substituted by one or more aryl groups , such as benzyl ,
  • Heteroarylalkyl means linear or branched alkyl group which is substituted by one or more heteroaryl groups .
  • Cycloalkylalkyl means linear or branched alkyl group which is substituted by one or more cycloalkyl group (e . g . , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,
  • Heterocycloalkylalkyl means linear or branched alkyl group which is substituted by one or more heterocycloalkyl groups .
  • Alkylthio means thio radical ( -S) substituted with a liner or branched alkyl group .
  • Non-exclusive examples of alkylthio include methylthio, ethylthio, propylthio and the like .
  • Alkylsulfonyl means sulfonyl radical (-SO2-) substituted with a liner or branched alkyl group .
  • Non-exclusive examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like .
  • “Monocyclic ring” as used herein refers to a monocyclic, saturated or unsaturated carbocyclic ring or a monocyclic, saturated or unsaturated heterocyclic ring .
  • "X-membered monocyclic ring” is typically used where X indicate the number of carbon atoms and heteroatoms in the ring .
  • the number of carbon atoms and heteroatoms in the ring is preferably 4 to 7 , more preferably 5 or 6.
  • “Monocyclic heterocyclic ring” means a monocyclic, aromatic or nonaromatic ring wherein at least one ring atom is a heteroatom (preferably S, N or 0) and the remaining ring atoms are carbon .
  • the nitrogen atoms can be optionally quaternerized and the sulfur atoms can be optionally oxidized.
  • Non-exclusive examples of monocyclic saturated carbocyclic ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and the like .
  • Non-exclusive examples of monocyclic unsaturated carbocyclic ring include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, benzene, and the like .
  • Non-exclusive examples of monocyclic saturated heterocyclic ring include pyrrolidine, piperidine, morpholine, piperazine, 1, 3-dioxane, 1 , 4-dioxane and the like .
  • Non-exclusive examples of monocyclic unsaturated heterocyclic ring include pyrazole, dihydro-pyrrole, pyrrole, dihydro-pyrazole, imidazole, thiophene, thiazole, isothiazole, thiadiazole, furan, oxazole, isoxazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like .
  • "Protected derivatives” means derivatives of compound in which a reactive site or sites are blocked with protecting groups . A comprehensive list of suitable protecting groups can be found in T . W. Greene, Protecting Groups in Organic Synthesis , 5th edition, John Wiley & Sons, Inc . 2014 .
  • leaving group means an atom or a group of atoms, which is detached from the reaction substrate in substitution reactions, elimination reactions, or the like .
  • the "leaving group” for example, a halogen atom (e . g . , a chlorine atom, a bromine atom, an iodine atom etc . ) , Ci-6 alkylsulfonyloxy (e . g . , methanesulfonyl oxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy etc . ) , C 6-10 arylsulfonyloxy (e . g .
  • Ci-6 alkylsulfonyl e . g . , methanesulfonyl, ethanesulfonyl etc . ) and the like are used.
  • “Isomers” mean any compound having identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space . Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers” . Stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes "optical isomers” . A carbon atom bonded to four nonidentical substituents is termed a "chiral center” . A compound with one chiral center has two enantiomeric forms of opposite chirality.
  • a mixture of the two enantiomeric forms is termed a "racemic mixture” .
  • a compound that has more than one chiral center has 2 n-1 enantiomeric pairs , where n is the number of chiral centers .
  • Compounds with more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture” .
  • a stereoisomer may be characterized by the absolute configuration of that chiral center . Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center .
  • Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog .
  • Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art ( e. g. , see “Advanced Organic Chemistry", 4th edition, March, Jerry, John Wiley & Sons, New York, 1992 ) .
  • the compounds of the present invention may include these isomers .
  • "Animal” includes humans , non-human mammals ( e . g.
  • Disease specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i . e . , the "side effects" of such therapy.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use .
  • “Pharmaceutically acceptable salt” or “salt” means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity.
  • Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- ( 4-hydroxybenzoyl ) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2- ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,
  • Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases .
  • Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide .
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like .
  • Amount effective to treat means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease .
  • Amount effective to prevent means that amount which, when administered to an animal for preventing a disease, is sufficient to effect such prophylaxis for the disease .
  • Effective amount equals to "amount effective to treat” and “amount effective to prevent” .
  • Treatment or “treat” means any administration of the compound of the present invention and includes :
  • Q 1 is represented by any of the following formulas ( II-l) to ( II-
  • Q 1a is a hydrogen atom, or 1 to 3 same or different alkyls ;
  • W 1 is an optionally substituted alkylene or an optionally substituted cycloalkylene;
  • X 1 is -OPO 3 H 2 or hydrogen atom;
  • R 2 is an optionally substituted alkyl, an optionally substituted cycloalkylalkyl, or an optionally substituted arylalkyl;
  • Q 3 is an optionally substituted divalent group derived from an aryl ring, or an optionally substituted divalent group derived from a heteroaryl ring;
  • W 3 is a single bond, an optionally substituted alkylene, or an optionally substituted alkynylene;
  • X 3 is hydrogen atom or hydroxy when X 1 is -OPO 3 H 2 , or is -OPO 3 H 2 when X 1 is hydrogen atom;
  • R 4 is an optionally substituted alkyl, or an optionally substituted cycloalkylalkyl ;
  • R 5 is a hydrogen atom, or an optionally substituted alkyl, or a pharmaceutically acceptable salt thereof is disclosed .
  • Q 1a is a hydrogen atom, or 1 to 3 same or different alkyls .
  • alkyl include methyl , ethyl , propyl, isopropyl , butyl, tert-butylmethyl, diethylethyl, sec- butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, tert- pentyl, hexyl, isohexyl and the like .
  • Q 1 in the formula ( I ) Q 1a is a hydrogen atom.
  • W 1 is an optionally substituted alkylene or an optionally substituted cycloalkylene .
  • substituents include alkyl, halogen, -CN, and -OH .
  • an optionally substituted alkylene include methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, neopentylene, tert-pentylene, aminomethylene, aminoethylene, aminopropylene, aminobutylene, carboxymethylene, carboxyethylene, carboxypropylene, carboxybutylene, carbamoylmethylene, carbamoylethylene, carbamoylpropylene, carbamoylbutylene, methoxymethylene, methoxyethylene, methoxypropylene, methoxybutylene, methyl thiomethylene, methylthioethylene, methylthioethylene, methylthioethylene, methylthi
  • W 1 is alkylene (e . g. , isopropylene, butylene) , or cycloalkylene (e . g . , cyclopropylene) .
  • R 2 is an optionally substituted alkyl , an optionally substituted cycloalkylalkyl, or an optionally substituted arylalkyl .
  • substituents include alkyl, halogen, -CN, and -OH .
  • Examples of an optionally substituted alkyl group include methyl , ethyl , propyl , isopropyl , butyl, isobutyl, sec-butyl, tert-butyl , pentyl, isopentyl , neopentyl , tert-pentyl, tert-butylmethyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, carboxymethyl, carboxyethyl, carboxypropyl , carboxybutyl, carbamoylmethyl, carbamoylethyl, carbamoylpropyl , carbamoylbutyl , methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, hydroxymethyl, hydroxyethyl , hydroxypropyl,
  • Examples of an optionally substituted cycloalkylalkyl group include cyclopropylmethyl, fluorocyclopropylmethyl, chlorocyclopropylmethyl , bromocyclopropylmethyl , iodocyclopropylmethyl, methylcyclopropylmethyl, 1, 1- dime thy Icyclopropylmethyl , 1 , 2 -dimethylcyclopropylmethyl , hydroxycyclopropylmethyl , methoxycyclopropylmethyl , ethoxycyclopropylmethyl , methoxycarbonylcyclopropylmethyl , methylcarbamoylcyclopropylmethyl , cyclopropylethyl , cyclohexylmethyl, cyclopropylhexyl and the like .
  • Examples of an arylalkyl group include unsubstituted arylalkyl or arylalkyl having an alkyl group such as benzyl, a-methylbenzyl, phenethyl, a-methylphenethyl, a, a-dimethylbenzyl, a, a-dimethylphenethyl, 4- methylphenethyl, 4 -methylbenzyl , 4-isopropylbenzyl and the like; arylalkyl having an aryl group or an arylalkyl group such as 4- benzylbenzyl, 4 -phenethylbenzyl, 4-phenylbenzyl and the like; arylalkyl having a substituted oxy group such as 4- methoxybenzyl, 4 -n- tetradecyloxybenzyl, 4-n-heptadecyloxybenzyl ,
  • R 2 is alkyl (e . g. , tert-butylmethyl ) .
  • Q 3 is an optionally substituted divalent group derived from an aryl ring, or an optionally substituted divalent group derived from a heteroaryl ring .
  • "Divalent optionally substituted group derived from an aryl ring” means a divalent optionally substituted group formed by removing two hydrogen atoms from an aryl ring .
  • "Divalent optionally substituted group derived from a heteroaryl ring” means a divalent optionally substituted group formed by removing two hydrogen atoms from a heteroaryl ring . Examples of substituents include alkyl, halogen, -CN, and -OH .
  • Examples of an optionally substituted aryl ring include, benzene, naphthalene, anthracene, phenanthrene, acenaphthylene, indene and the like .
  • Examples of an optionally substituted heteroaryl ring include furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1, 2 , 3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, 1, 3, 4- thiadiazole, triazole, tetrazole, benzofuran, benzothiazole, benzothiophene, benzimidazole, benzotriazine, pyridopyrimidine, pyridopyrazine, pyridopyridazine, pyridotriazine, benzothiadiazole, fur
  • thiazolo [5, 4-b] pyridine) imidazopyridine, quinazoline, thienopyridine, indolizine, quinoline, isoquinoline, phthalazine, quinoxaline, cinnoline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, pyrazolopyridine, imidazopyrimidine, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, pyrrolopyridazine, triazolopyridine, pteridine, purine, carbazole, acridine, perimidine, 1, 10 -phenanthroline, phenoxathiin, phenoxazine, phenothiazine, phenazine and the like .
  • Q 3 is an optionally substituted divalent group derived from a heteroaryl ring (e . g . , thiazole ring, benzothiazole ring, thiazolo [ 5, 4- b] pyridine ring, or quinoxaline ring) .
  • W 3 is a single bond, an optionally substituted alkylene, or an optionally substituted alkynylene . Examples of substituents include alkyl, halogen, - CN, and -OH .
  • Examples of an optionally substituted alkylene include methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, neopentylene, tert-pentylene, aminomethylene, aminoethylene, aminopropylene, aminobutylene, carboxymethylene, carboxyethylene, carboxypropylene, carboxybutylene, carbamoylmethylene, carbamoylethylene, carbamoylpropylene, carbamoylbutylene, methoxymethylene, methoxyethylene, methoxypropylene, methoxybutylene, methylthiomethylene, methylthioethylene, methylthioethylene, methylthiopropylene, methylthiobutylene, hydroxymethylene, hydroxyethylene, hydroxypropylene, hydroxybutylene, ethoxycarbonylmethylene, ethoxycarbonylethylene, benzy
  • W 3 is a single bond or an optionally substituted alkylene (e . g . , ethynylene) .
  • R 4 is an optionally substituted alkyl, or an optionally substituted cycloalkylalkyl .
  • substituents include alkyl, halogen, -CN, and -OH .
  • Examples of an optionally substituted alkyl group include methyl, ethyl, propyl, isopropyl , butyl, isobutyl, sec-butyl, tert-butyl , pentyl, isopentyl, neopentyl, tert-pentyl, 2- ethylbutyl , aminomethyl, aminoethyl, aminopropyl, aminobutyl, carboxymethyl, carboxyethyl, carboxypropyl , carboxybutyl, carbamoylmethyl, carbamoylethyl, carbamoylpropyl, carbamoylbutyl, methoxymethyl , methoxyethyl, methoxypropyl, methoxybutyl, methylthiomethyl , methylthioethyl, methylthiopropyl, methylthiobutyl , hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybut
  • Examples of an optionally substituted cycloalkylalkyl group include cyclopropylmethyl, fluorocyclopropylmethyl, chlorocyclopropylmethyl , bromocyclopropylmethyl , iodocyclopropylmethyl, methylcyclopropylmethyl , 1, 1- dimethylcyclopropylmethyl, 1 , 2-dimethylcyclopropylmethyl, hydroxycyclopropylmethyl , methoxycyclopropylmethyl , ethoxycyclopropylmethyl , methoxycarbonylcyclopropylmethyl , methylcarbamoylcyclopropylmethyl , cyclopropylethyl , cyclohexylmethyl , cyclopropylhexyl and the like .
  • R 5 is a hydrogen atom, or an optionally substituted alkyl .
  • substituents include alkyl, halogen, -CN, and -OH .
  • an optionally substituted alkyl group include methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carbamoylmethyl, carbamoylethyl, carbamoylpropyl, carbamoylbutyl , methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methylthiomethyl, methylthioe
  • R 5 is a hydrogen atom.
  • Q 1 is represented by any of the following formulas ( III-l ) to ( III-3) :
  • R 2 is an optionally substituted alkyl ( same as defined above) ;
  • W 3 is a single bond, or an optionally substituted alkynylene ( same as defined above) ;
  • Q 3 is an optionally substituted divalent group derived from a heteroaryl ring ( same as defined above) ;
  • R 4 is an optionally substituted alkyl ( same as defined above) ;
  • R 5 is a hydrogen atom.
  • W 1 is n-butylene, i-propylene or cyclopropylene
  • R 2 is neopentyl
  • Q 3 is a divalent group derived from thiazole ring, benzothiazole ring, thiazolo [ 5, 4-b] pyridine ring, or quinoxaline ring
  • the thiazole ring, benzothiazole ring, thiazolo [5 , 4-b] pyridine ring, or quinoxaline ring may be substituted by substituent (s ) selected from a hydroxy group, a methyl group and a cyano group
  • R 4 is isobutyl or 2-ethylbutyl .
  • ACONH4 ammonium acetate
  • DIAD diisopropyl azodicarboxylate
  • DIPEA N, N-diisopropylethylamine
  • HATU 1- [bis (dimethylamino) methylene] -1H-1, 2, 3-triazolo [4,5- b] pyridinium 3-oxide hexafluorophosphate
  • OTHP(THPO) ( tetrahydro-21f-pyran-2-yl ) oxy p-TsOH: p-toluenesulfonic acid
  • TBS tert-butyldimethylsilyl tBu: tert-butyl
  • Trt trityl
  • R A1 is an alkyl group such as methyl and ethyl
  • PG 1 is an amino-protecting group that can be deprotected under acidic condition
  • R 2 , R 5 and Q 1 are as defined above
  • R A1 , R 5 , Q 1 and PGi are as defined above
  • Intermediate [B] PG 2 is an amino-protecting group which can be deprotected under conditions other than acidic condition, and R 2 is as defined above
  • Examples of PGi include tert-butoxycarbonyl (Boc) , trityl (Trt ) and the like .
  • Examples of PG 2 include benzyloxycarbonyl (Cbz ) , f luorenylmethyloxycarbonyl ( Fmoc) , trifluoroacetyl, phthaloyl, formyl and the like .
  • Condensing reagents and reaction conditions can be applied.
  • HATU and DMT- MM are preferable as the condensing reagent
  • DMF, MeOH, THF and the like are preferable as the solvent
  • the reaction temperature is preferably from 0 °C to the boiling point of the solvent .
  • PG 2 In the deprotection reaction of PG 2 , a generally known reaction condition can be applied according as the kind of PG 2 .
  • PG 2 in the formula is an Fmoc group
  • a deprotection reaction using piperidine or DBU as a deprotecting reagent in AcOEt, THF or DCM as a solvent is preferable .
  • PG 2 is a Cbz group
  • a deprotection reaction using a palladium catalyst such as Pd (OH) 2, Pd/C or the like in methanol, ethanol or THF as a solvent under H 2 atmosphere is preferable .
  • the reaction temperature is preferably 0 °C to the temperature of the boiling point of the solvent .
  • Step 2 Synthesis of Intermediate [D] Intermediate [D] ( PG 3 is an amino-protecting group which can be deprotected under conditions other than acidic condition, and Q 1 , R 2 , R 4 and R 5 are as defined above) can be synthesized by an amidation condensation reaction of [ Int-a] and Intermediate [C] ( PG 3 and R 4 are as defined above) , followed by a ring closure reaction in the presence of an acid.
  • amidation condensation reaction generally known condensing reagents and reaction conditions can be applied.
  • DMT-MM or HATU is preferable as the condensing reagent, DMF, MeOH, THF or the like is preferable as the solvent, and the reaction temperature is preferably 0 °C to the boiling point of the solvent .
  • the acid to be used for the ring closure reaction formic acid is preferable and formic acid can also be used as the solvent .
  • the reaction temperature is preferably 0 °C to the boiling point of the solvent .
  • [Int-b] ( PG 4 is a hydroxy-protecting group, and W 1 , Q 1 , R 2 , R 4 , R 5 and PG 3 are as defined above ) can be synthesized by the reaction of alkylation reaction using Intermediate [D] and Intermediate [E] (LG is a leaving group, and PG 4 and W 1 are as defined above) in the presence of base .
  • Triethylamine, Hunig' s base, pyridine, DBU, sodium carbonate, potassium carbonate, sodium methoxide and potassium tert-butoxide are preferable as bases .
  • THF, MeCN, chloroform, DCM, DCE, DMF and DMSO are preferable as solvents .
  • the reaction temperature is preferably 0 °C to the temperature of the boiling point of the solvent .
  • [Int-b2 ] can be synthesized by the following method.
  • Sodium triacetoxyborohydride, sodium cyanoborohydride, sodium tetrahydroborate, lithium tetrahydroborate, THF-borane complex, pyridine-borane complex, picoline-borane complex and the like are preferable as the reducing reagent, MeOH, THF, chloroform, DCM, DCE and the like are preferable as solvent, and the reaction temperature is preferably from 0 °C to the boiling point of the solvent .
  • [ Int-c] ( W 1 , Q 1 , R 2 , R 4 , R 5 and PG 3 are as defined above) can be synthesized by an appropriate deprotection reaction of PG 4 according as the kind of PG 4 .
  • PG 4 is a 2- tetrahydropyranyl group
  • p-TsOH and methanol is used as an acid and solvent, respectively.
  • the reaction temperature is preferably 0 °C to the temperature of the boiling point of the solvent .
  • [ Int-d] ( W 1 , Q 1 , R 2 , R 4 , R 5 and PG 3 are as defined above) can be synthesized by a reaction of [ Int-c] and di-tert-butyl diisopropylphosphoramidite, followed by the treatment of oxidation reagent such as hydrogen peroxide .
  • oxidation reagent such as hydrogen peroxide .
  • DCM, DCE, THF and the like are preferable as the solvent, and the reaction temperature is preferably -80 °C to the temperature of the boiling point of the solvent .
  • [ Int-e] (W 1 , Q 1 , R 2 , R 4 , and R 5 are as defined above) can be synthesized by an appropriate deprotection reaction of PG 3 according as the kind of PG 3 .
  • PG 3 is a Cbz group
  • a deprotection reaction using a palladium catalyst such as Pd (OH) 2 , Pd/C or the like in methanol, ethanol or THF as a solvent under H 2 atmosphere is preferable .
  • PG 3 is an Fmoc group
  • a deprotection reaction using piperidine or DBU as a deprotecting reagent in AcOEt , THF or dichloromethane as a solvent is preferable . Both groups can also be deprotected by hydrolysis reaction .
  • the reaction temperature is preferably 0 °C to the temperature of the boiling point of the solvent .
  • [ Int-f ] (W 1 , Q 1 , R 2 , R 4 , and R 5 are as defined above) can be synthesized by an amidation condensation reaction using intermediate [ Int-e] and diethylphosphonoacetic acid.
  • amidation condensation reaction generally known condensing reagents and conditions can be applied.
  • HATH and CIP are preferable as the condensing reagent
  • DMF, DCM, DCE, THF and the like are preferable as the solvent
  • the reaction temperature is preferably from 0 °C to the boiling point of the solvent .
  • [ Int-g] (W 1 , Q 1 , R 2 , R 4 , R 5 , Q 3 , W 3 and X 3 are as defined above) can be synthesized by Horner-Wadsworth-Emmons (HWE) reaction using [ Int-f] and intermediate [ F] in the presence of a base reagent and in the presence or absence of lithium salt such as lithium bromide and lithium chloride .
  • HWE Horner-Wadsworth-Emmons
  • Triethylamine, Hunig' s base, DBU, potassium carbonate, sodium methoxide, sodium hydride and LDA are preferable as bases, and THE, chloroform, DCM, DCE, 1, 2 -dimethoxyethane, methanol, ethanol and DMSO are preferable as solvents .
  • the reaction temperature is preferably -78 °C to the temperature of the boiling point of the solvent .
  • Compound [ I ] (the formulae are as defined above) can be by the deprotection reaction of t-butyl groups . Acidic conditions are used for the reaction and formic acid is preferable . Formic acid can also be used as the solvent .
  • Intermediate [ Int-m] ( PG' is a protecting group of carboxylic acid and R 4 is as defined above) can be synthesized by Mitsunobu reaction from Intermediate [Int-1] using N- hydroxyphthalimide, triphenylphosphine and DIAD.
  • Mitsunobu amination reaction generally known reagents and conditions can be applied other than triphenylphosphine and DIAD.
  • [ Int-1] is a chiral compound, the stereochemistry of the obtained [Int-m] is converted.
  • the reaction temperature is preferably from 0 °C to the boiling point of the solvent .
  • Intermediate [ Int-o] ( PG' , PG 3 and R 4 are as defined above) can be synthesized by generally known reagents and conditions according as the kind of PG 3 .
  • Preferable amino-protecting groups PG 3 are Cbz and Fmoc groups .
  • Other protecting groups that are not deprotected by acetic condition are also available .
  • the reaction temperature is preferably from 0 °C to the boiling point of the solvent .
  • the protecting group in each step is not limited to the protecting group .
  • deprotection can be performed in any step .
  • the compound synthesized in each step of the reaction may be directly used in the next reaction without isolation . Under the conditions of Steps 2 and 12 , the ring closure reaction and the deprotection reaction may proceed simultaneously.
  • the compound to be obtained in the cyclization reaction can be isolated and purified by a conventional method such as extraction, water-washing, acid washing, alkali washing, crystallization, recrystallization, and silica gel column chromatography .
  • the compounds of the present invention, salts thereof and derivatives thereof are excellent in pharmacological action selectivity, safety (various toxicities and safety pharmacology) , pharmacokinetic performance, physicochemical property and the like, and therefore the usefulness as active ingredients of medicaments can be confirmed.
  • tests concerning pharmacological action selectivity include, but not be limited to, inhibition or activation assays on various pharmacological target receptors, inhibition assays on various pharmacological target enzymes, ion channels or transporters, cell tests to be used for the evaluation for various pharmacological action, and the like.
  • tests concerning safety include, but not be limited to, the following list including cytotoxic tests (e.g., tests using HL60 cells, hepatocytes, etc., and the like) , genotoxicity tests (e.g., Ames test, mouse lymphoma TK test, chromosomal aberration test, micronucleus test and the like) , skin sensitization tests (e.g., Buehler method, GPMT method, APT method, LLNA test and the like) , skin photosensitization tests (e.g., Adjuvant and Strip method and the like) , eye irritation tests (e.g., single instillation, short-term continuation instillation, repetitive instillation and the like) , safety pharmacology tests for the cardiovascular system (e.g., telemetry method, APD method, hERG inhibition assay and the like) , safety pharmacology tests for the central nervous system (e.g., FOB method, modified version of Irwin method and the like
  • tests concerning pharmacokinetic performance include, but not be limited to, the following list including cytochrome P450 enzyme inhibition or induction tests, cell permeability tests (e.g., tests using CaCO-2 cells, MDCK cells etc., and the like) , drug transporter ATPase assay, oral absorption tests, blood concentration transition measurement tests, metabolism tests (e.g., stability test, metabolite molecular species test, reactivity test and the like) , solubility tests (e.g., solubility test based on turbidity method and the like), and the like.
  • cytochrome P450 enzyme inhibition or induction tests include cell permeability tests (e.g., tests using CaCO-2 cells, MDCK cells etc., and the like) , drug transporter ATPase assay, oral absorption tests, blood concentration transition measurement tests, metabolism tests (e.g., stability test, metabolite molecular species test, reactivity test and the like) , solubility tests (e.g., so
  • tests concerning physicochemical property include, but not be limited to, the following list including chemical stability test (e.g., stability test using HPLC etc., and the like) , partition coefficient (e.g., partition test using octanol phase/water phase and the like) , ionization constant test, crystallization test, and the like.
  • chemical stability test e.g., stability test using HPLC etc., and the like
  • partition coefficient e.g., partition test using octanol phase/water phase and the like
  • ionization constant test e.g., crystallization test, crystallization test, and the like.
  • a method for treating cancer by administration of the compound of the present invention is provided.
  • the compound of the present invention has an action of inhibiting proliferation of cancer cells and may be used for treating cancer.
  • test compound here is a compound described in the present specification, that is, the compound of the present invention.
  • test compounds are tested at several different concentrations, and the concentrations are partly selected according to the assay conditions.
  • the compound of the present invention may be used for suppressing cancer cells, and therefore, is useful for controlling cell proliferation.
  • the compound of the present invention may also be used favorably for inducing apoptosis of cells.
  • the present invention provides pharmaceutical compositions containing the compound of the present invention. These compositions may be used in various methods (e.g., treatment of cancer) of the present invention as described in detail below.
  • the pharmaceutical composition of the present invention is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical) , transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral (particularly, intravenous), intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose .
  • pH may be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide .
  • the parenteral preparation can be enclosed in ampoules , disposable syringes or multiple dose vials made of glass or plastic .
  • compositions suitable for inj ectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile inj ectable solutions or dispersion .
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline ( PBS) .
  • the composition must be sterile and should be fluid to the extent that easy syringability exists . It must be stable under the conditions of manufacture and storage • and must be preserved against the contaminating action of microorganisms such as bacteria and fungi .
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol , polyol (for example, glycerol , propylene glycol, and liquid polyethylene glycol, and the like) , and suitable mixtures thereof .
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants .
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like .
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition .
  • Prolonged absorption of the inj ectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin .
  • Sterile inj ectable solutions can be prepared by incorporating the active compound, e . g . , the compound of the present invention in the required amount, in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization .
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a dispersion medium and the required other ingredients from those enumerated above .
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-f iltered solution thereof .
  • Oral compositions generally include an inert diluent or an edible carrier . They can be enclosed in gelatin capsules or compressed into tablets .
  • the active compound can be incorporated with excipients and used in the form of tablets , troches , or capsules .
  • Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
  • Pharmaceutically compatible binding agents , and/or adjuvant materials can be included as part of the composition .
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature : a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes ; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring .
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser that contains a suitable propellant, e . g . , a gas such as carbon dioxide, or a nebulizer .
  • a suitable propellant e . g . , a gas such as carbon dioxide, or a nebulizer .
  • Systemic administration can also be by transmucosal or transdermal means .
  • penetrants appropriate to the barrier to be permeated are used in the formulation .
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents , bile salts , and fusidic acid derivatives .
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories .
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art .
  • the compounds can also be prepared in the form of suppositories (e . g . , with conventional suppository bases such as cocoa butter and other glycerides ) or retention enemas for rectal delivery.
  • suppositories e . g .
  • conventional suppository bases such as cocoa butter and other glycerides
  • retention enemas for rectal delivery.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems .
  • a controlled release formulation including implants and microencapsulated delivery systems .
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters , and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art .
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals , Inc .
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens ) can also be used as pharmaceutically acceptable carriers . These can be prepared according to methods known to those skilled in the art, for example, as described in U . S . Patent No . 4 , 522 , 811.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subj ect to be treated; each unit containing a 5 predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier .
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals .
  • a pharmaceutical composition of the present invention is one suitable for oral administration in unit dosage form such as a tablet or capsule that contains from about 1 mg to about 1 g of the compound of this invention .
  • a pharmaceutical composition of the present invention is one suitable for intravenous , subcutaneous or intramuscular inj ection .
  • a patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of about 1 pg/kg to about 1 g/kg of the compound of the present invention .
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus inj ection or by continuous infusion over a period of time .
  • a patient will receive a daily oral dose approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • the compound of the present invention can be administered intravenously (particularly preferably, by continuous drip infusion or rapid intravenous administration) to mammals inclusive of human .
  • the dose is selected appropriately depending on various factors such as the body weight and/or age of patients, and/or the degree of the symptom and an administration route .
  • the dose of the compound of the formula ( I ) for intravenous administration is generally in the range of 1 to 10000 mg/day/m 2 human body surface area, preferably in the range of 1 to 5000 mg/day/m 2 human body surface area, and more preferably 10 to 5000 mg/day/m 2 human body surface area .
  • the pharmaceutical composition containing the compound of present invention can be used for treatment of disease, especially cancer.
  • the present invention provides methods for inhibiting tumor growth .
  • Such methods comprise the step of administering to a subj ect (e . g . , a mammalian subj ect ) having a tumor a compound or a composition of the present invention in an amount effective to inhibit tumor growth .
  • a compound or composition inhibits tumor growth if the tumor sizes are statistically significantly smaller in subjects with the treatment of the compound or composition than those without the treatment .
  • the inhibitory effect of a particular compound or composition of the present invention on tumor growth was characterized to the binding inhibition of eIF4E (eukaryotic translation initiation factor 4E) and eIF4G eukaryotic translation initiation factor 4G) by m7GTP pull-down assay and proximity ligation assay. Translation can be inhibited by blocking the binding of eIF4E to elF4G. The binding of a particular compound to eIF4E was also observed by NMR measurements .
  • eIF4E eukaryotic translation initiation factor 4E
  • eIF4G eukaryotic translation initiation factor 4G eukaryotic translation initiation factor 4G
  • the inhibitory effect of a particular compound or composition of the present invention on tumor growth may be characterized by any appropriate methods known in the art. For instance, the effect of the compound or composition on survivin expression may be measured. Compounds or compositions down- regulate survivin expression are likely to have inhibitory effects on tumor growth.
  • assays using tumor cell lines e.g., soft agar assays using SW480 cells
  • animal models for tumor growth e.g., nude mice grafted with tumor cells and Min mouse model
  • Other exemplary animal models or xenografts for tumor growth include those for breast cancer (Guo et al, Cancer Res.
  • the compound or composition that inhibits tumor growth may be administrated into a subj ect with a tumor via an appropriate route depending on, for example, the tissue in which the tumor resides .
  • the appropriate dosage may be determined using knowledge and technigues known in the art as described above .
  • the effect of the treatment of the compound or composition on tumor growth may also be monitored using methods known in the art . For instance, various methods may be used for monitoring the progression and/or growth of colorectal cancer, including colonoscopy, sigmoidoscopy, biopsy, computed tomograph, ultrasound, magnetic resonance imaging, and positron emission tomography . Methods for monitoring the progression and/or growth of ovarian cancer include, for example, ultrasound, computed tomography, magnetic resonance imaging, chest X-ray, laparoscopy, and tissue sampling .
  • the present invention provides a method for treating or preventing cancer .
  • Such methods comprise the step of administering to a subj ect in need thereof a compound or composition of the present invention in an amount effective to treat or prevent cancer in the subj ect .
  • Treating cancer is understood to encompass reducing or eliminating cancer progression, e . g . , cancer growth and metastasis .
  • Preventing cancer is understood to encompass preventing or delaying the onset of cancer .
  • Various types of cancer may be treated or prevented by the present invention .
  • a subj ect in need of treatment may be a human or non-human primate or other animal with various types of cancer .
  • a subj ect in need of prevention may be a human or non- human primate or other animal that is at risk for developing cancer .
  • Methods for diagnosing cancer and screening for individuals with high risk of cancer are known in the art and may be used in the present invention .
  • colorectal cancer may be diagnosized by fecal occult blood test, sigmoidoscopy, colonoscopy, barium enema with air contrast, and virtual colonoscopy .
  • An individual with high risk of colorectal cancer may have one or more colorectal cancer risk factors such as a strong family history of colorectal cancer or polyps , a known family history of hereditary colorectal cancer syndromes, a personal history of adenomatous polyps , and a personal history of chronic inflammatory bowel disease .
  • colorectal cancer risk factors such as a strong family history of colorectal cancer or polyps , a known family history of hereditary colorectal cancer syndromes, a personal history of adenomatous polyps , and a personal history of chronic inflammatory bowel disease .
  • the compound of the present invention useful in cancer treatment or prevention may be identified by appropriate methods known in the art . Methods that may be used to select compounds for inhibitory effect on tumor (or cancer cells ) growth (or proliferation) as described above may also be used .
  • the route of administration, the dosage of a given compound, the effectiveness of the treatment may be determined using knowledge and techniques known in the art . Factors that may be considered in making such a determination include, for example, type and stage of the cancer to be treated.
  • the compound of the present invention useful in cancer treatment and prevention may be administered in combination with other anti-neoplastic agent .
  • the anti-neoplastic agent refers to a compound that inhibits tumor growth .
  • the other anti-neoplastic agent include alkylating agents such as thiotepa and CYTOXAN (RTM) cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone) ; a camptothecin ( including the synthetic analogue topotecan) ; bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues) ; cryptophycins (particularly cryptophycin 1
  • calicheamicin especially calicheamicin gammall and calicheamicin omegall ( see, e . g . , Agnew, Chem Inti . Ed. Engl . 33 : 183-186 ( 1994 ) ) ; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores ) , aclacinomysins, actinomycin, authramycin, azaserine, bleomycins , cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, ADRLAM
  • TAXOL paclitaxel
  • ABRAXANE Cremophor-f ree
  • albumin-engineered nanoparticle formulation of paclitaxel American Pharmaceutical Partners, Schaumberg, Illinois
  • TAXOTERE RTM doxetaxel
  • chloranbucil GEMZAR (RTM) gemcitabine
  • 6-thioguanine mercaptopurine
  • methotrexate platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16) ; ifosfamide; mitoxantrone; vincristine; NAVELBINE (RTM) vinorelbine; novantrone; teniposide; edatrex
  • CMOS complementary metal-oxide-semiconductor
  • DMFO dif luorometlhylornithine
  • retinoids such as retinoic acid
  • capecitabine and pharmaceutically acceptable salts, acids or derivatives of any of the above .
  • examples of the other anti-neoplastic agent also include anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs ) , including, for example, tamoxifen (including NOLVADEX (RTM) tamoxifen) , raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON toremifene; aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as , for example, 4 ( 5 ) -imidazoles , aminoglutethimide, MEGASE (RTM) megestrol acetate, AROMASIN (RTM) exemestane, formestane, fadrozole, RIVISOR (RTM) vorozole, FEMARA (RTM)
  • ANGIOZYME ribozyme
  • a HER2 expression inhibitor such as gene therapy vaccines , for example, ALLOVECTIN (RTM) vaccine, LEUVECTIN (RTM) vaccine, and VAXID (RTM) vaccine; PROLEUKIN (RTM) rIL-2 ; LURTOTECAN (RTM) topoisomerase 1 inhibitor; ABARELIX (RTM) rmRH; and pharmaceutically acceptable salts, acids or derivatives of any of the above .
  • examples of the other anti-neoplastic agent also include a "growth inhibitory agent" referring to a compound or composition which inhibits growth of a cell in vitro and/or in vivo .
  • the growth inhibitory agent may be one which significantly reduces the percentage of cells in S phase .
  • growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase) , such as agents that induce G1 arrest and M-phase arrest .
  • Classical M- phase blockers include the vincas (vincristine and vinblastine) , TAXOL (RTM) , and topo II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin .
  • DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5- f luorouracil, and ara-C .
  • examples of the other anti-neoplastic agent also include a "molecular target drug” that blocks the proliferation and metastasis of cancer by interfering with specific molecules involved in carcinogenesis (the process by which normal cells become cancer cells ) , tumor growth, or tumor spread.
  • kinase inhibitors that inhibit kinase activity on tumors , including, for example, imatinib, erlotinib, gefitinib, sunitinib, sorafenib, dasatinib, nilotinib; antibodies that bind to the cell surface molecule on tumor cells or to the growth factor and the like such as, for example, ibritumomab, cetuximab, trastuzumab, panitumumab, bevacizumab, rituximab; and proteasome inhibitors that inhibit the proteasome which regulates protein expression and function by degradation of ubiquitinylated proteins, such as bortezomib; and pharmaceutically acceptable salts , acids or derivatives of any of above .
  • the compound of the present invention administered in combination with an anti-neoplastic agent does not necessarily require that the compound and the anti-neoplastic aqent be administered concurrently.
  • the compound and the agent may be administered separately as long as at a time point, they both have effects on same cancer cells .
  • the administration mode may be exemplified by ( 1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the other anti-neoplastic agent, (2 ) simultaneous administration through the same administration route of two preparations obtained by separately formulating the compound of the present invention and the other anti-neoplastic agent, ( 3 ) administration with a time interval through the same administration route of two preparations obtained by separately formulating the compound of the present invention and the other anti-neoplastic agent, ( 4 ) simultaneous administration through different administration routes of two preparations obtained by separately formulating the compound of the present invention and the other anti-neoplastic agent, ( 5 ) administration with a time interval through different administration routes of two preparations obtained by separately formulating the compound of the present invention and the other anti-neoplastic agent (e .
  • the amount of the other anti- neoplastic agent to be administered can be appropriately selected with reference to the clinically used dosage .
  • the mixing ratio of the compound of the present invention and the other anti-neoplastic agent can be appropriately selected in accordance with the subj ect of administration, administration route, disease to be treated, symptoms, combination, and the like .
  • the present invention provides methods for promoting apoptosis in cancer cells .
  • Such methods comprise the step of contacting cancer cells with the compound of the present invention in an amount effective to promote apoptosis in these cells .
  • a compound promotes apoptosis if the number of cancer cells undergoing apoptosis is statistically significantly larger in the presence of the compound than that in the absence of the compound .
  • Such compounds may be identified by methods known in the art (e . g . , measuring caspase activities and/or cell death) using cultured cancer cell lines, xenografts, or animal cancer models .
  • the compound is more active in promoting apoptosis in cancer cells than in normal cells .
  • Cancer cells treatable by the present method may be from various tissue origins .
  • 1 H NMR was measured using Bruker AVANCE III 300 or Bruker AVANCE III HD 400.
  • Topspin (Bruker, trade name) and the like were used .
  • Method A or B Mass spectrometric analysis was performed using the following Method A or B : (Method A) System: Shimadzu UFLC/MS System (Shimazu-2020 mass spectrometer) Column : CDS column for the chromatography column Eluents : A (water with 0. 04% TFA) and B (acetonitrile with 0. 04% TFA) (Method B) System: Shimadzu UFLC/MS System (Shimazu-2020 mass spectrometer) Column: CDS column for the chromatography column Eluents: A (5 mM ACONH 4 in water) and B (5 mM ACONH 4 in acetonitrile)
  • Biotage Initiator was used for organic microwave synthesis .
  • a mixed suspension of A-02 (14 g) , B-01 (18 g) , HATU (22 g) and DIEA (11 mL) in THE (0.20 L) was stirred for 2 hours at room temperature.
  • B-01 (1.5 g) , HATU (1.7 g) and DIEA (1 mL) the reaction mixture was stirred for another 1 hour.
  • the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted by AcOEt twice.
  • D-MEM High Glucose with L-Glutamine and Phenol Red (Wako, Cat. No. : 044-29765) Fetal Bovine Serum (FBS; Life Technologies, Cat. No. : 26140-079) penicillin-streptomycin solution (*100) (Wako, Cat. No. : 168- 23191) lOxD-PBS (-) (Wako, Cat. No. : 048-29805) 0.25w/v% Trypsin-1 mmol/1 EDTA*4Na Solution with Phenol Red (Wako, Cat. No. : 201-16945)
  • Respective cells were cultured under the following conditions. Where necessary, they were passaged. proliferation medium: D-MEM + 10% FBS culture environment : 37 °C, 5% CO2 seeding density: 5. 0 x 10 5 cells/25 cm 2
  • a DMSO solution of the test substance was prepared by serially diluting (common ratio 2 ) each test substance with DMSO .
  • Normalized values calculated by the following formula 2 from the absorbances of each sample at 492 nm and 630 nm and the absorbances of the blank were used as the absorbances in the above-mentioned formula 1 .
  • normalized value (ABS 492 nm-630 nm) (ABSsa 492 nm-ABSsa 630 nm) - (ABSbl 492 nm-ABSbl 630 nm)
  • ABSsa 492 absorbance of each sample at wavelength 492 nm
  • ABSsa 630 absorbance of each sample at wavelength 630 nm
  • ABSbl 492 absorbance of blank corresponding to each sample at wavelength 630 nm formula 2
  • the analysis was performed by using nplr package on R (The R Foundation for Statistical Computing) and estimating the logistic regression curve ( 4-parameter) .
  • the compound of the present invention inhibits cancer cell proliferation, and thus can be used for treating diseases such as cancer .
  • the compound of the present invention shows inhibitory activities on cancer cell proliferation by itself and also acts as a prodrug in vivo, showing anticancer activity in an in vivo mouse model . It is also highly soluble and can be administered intravenously.

Abstract

A compound of the formula ( I ) : wherein each symbol is as defined in the DESCRIPTION, or a pharmaceutically acceptable salt thereof has a superior inhibitory activities on cancer cell proliferation.

Description

DESCRIPTION
Title of the Invention : PHOSPHORIC ACID DERIVATIVES [Technical Field]
The present invention relates to a phosphoric acid derivative . More specifically, the present invention relates to a phosphoric acid derivative having inhibitory activities on cancer cell proliferation . [Background Art]
Cancer is the leading cause of death in animals and humans . Many chemotherapeutic agents effective against cancer and tumor cells have been developed . However, they are not always effective against all types of cancers and tumors, and sometimes show the side effect of destroying normal cells . There is still a need for the development of a pharmaceutical product that shows cancer cell-specific effects and causes fewer side effects .
[SUMMARY OF THE INVENTION]
[ Problems to be Solved by the Invention]
The present invention aims to provide a compound having inhibitory activities on cancer cell proliferation . [Means of Solving the Problems]
The present inventors have conducted intensive studies in an attempt to solve the aforementioned problems and found that a compound having a particular structure shows a superior inhibitory activities on cancer cell proliferation, and completed the present invention .
That is , the present invention relates to the following . [ 1] A compound represented by the following formula ( I ) :
Figure imgf000002_0001
wherein Q1 is represented by any of the following formulas ( II-l ) to ( II- 6) :
Figure imgf000003_0001
Q1a is a hydrogen atom, or 1 to 3 same or different alkyls ; W1 is an optionally substituted alkylene or an optionally substituted cycloalkylene;
X1 is -OPO3H2 or hydrogen atom;
R2 is an optionally substituted alkyl, an optionally substituted cycloalkylalkyl, or an optionally substituted arylalkyl ;
Q3 is an optionally substituted divalent group derived from an aryl ring, or an optionally substituted divalent group derived from a heteroaryl ring;
W3 is a single bond, an optionally substituted alkylene, or an optionally substituted alkynylene;
X3 is hydrogen atom or hydroxy when X1 is -OPO3H2, or is -OPO3H2 when X1 is hydrogen atom; R4 is an optionally substituted alkyl, or an optionally substituted cycloalkylalkyl ; and
R5 is a hydrogen atom, or an optionally substituted alkyl, or a pharmaceutically acceptable salt thereof .
[2 ] The compound of [ 1] , wherein
Q1 is represented by any of the following formulas (III-l ) to (III-3) :
Figure imgf000003_0002
r
R2 is an optionally substituted alkyl ; W3 is a single bond, or an optionally substituted alkynylene;
Q3 is an optionally substituted divalent group derived from a heteroaryl ring;
R4 is an optionally substituted alkyl; and
R5 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.
[3] The compound of [1] or [2], wherein W1 is n-butylene, i-propylene or cyclopropylene;
R2 is neopentyl,
Q3 is a divalent group derived from thiazole ring, benzothiazole ring, thiazolo [5, 4-b] pyridine ring, or quinoxaline ring; the thiazole ring, benzothiazole ring, thiazolo [5, 4-b] pyridine ring, or quinoxaline ring may be substituted by substituent (s) selected from a hydroxy group, a methyl group and a cyano group; and R4 is isobutyl or 2-ethylbutyl, or a pharmaceutically acceptable salt thereof.
[4] A pharmaceutical composition comprising a compound of any of [1] to [3] or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier or diluent.
[5] The pharmaceutical composition of [4] , wherein the composition comprises an effective amount of the compound.
[6] A method of treating or preventing a cancer, comprising administering to a subject in need thereof the compound of any of [1] to [3] or a pharmaceutically acceptable salt thereof, or a composition of [4] or [5] , in an amount effective to treat or prevent the cancer.
[7] An agent for treating or preventing a cancer, comprising a compound of any of [1] to [3] or a pharmaceutically acceptable salt thereof.
[8] The compound according to any of [1] to [3] or a pharmaceutically acceptable salt thereof, or. the composition of [4] or [5] for the use as a medicament for treating or preventing a cancer.
[Effect of the Invention] .
The compound of the formula (I) of the present invention inhibits cancer cell proliferation and thus can be used for treating various cancers and tumors. [Brief Description of the Drawings]
[Fig. 1] Fig. 1 shows a NMR (300 MHz, CDCI3) data of F-04. [Fig. 2] Fig. 2 shows a NMR (300 MHz, CDCI3) data of F-08- intl .
[Fig. 3] Fig. 3 shows a 2H NMR (300 MHz, CDCI3) data of F-08- int2.
[Fig. 4] Fig. 4 shows a TH NMR (300 MHz, CDCI3) data of F-08.
[Fig. 5] Fig. 5 shows a XH NMR (300 MHz, CDCI3) data of F-10-
Intl .
[Fig. 6] Fig. 6 shows a XH NMR (300 MHz, CDCI3) data of F-10.
[Fig. 7] Fig. 7 shows a XH NMR (300 MHz, CDCI3) data of ID-02.
[Fig. 8] Fig. 8 shows a 1H NMR (300 MHz, CDCI3) data of ID-08.
[Description of Embodiments] Definition
Unless otherwise stated, the following terms used in the specification and claims shall have the following meanings for the purposes of this Application.
"Lower", unless indicated otherwise, means that the number of the carbon atoms constituting the given radicals is between one and six.
"Optionally substituted", unless otherwise stated, means that a given radical may consist of only hydrogen substituents through available valencies or may further comprise one or more non-hydrogen substituents through available valencies. In general, a non-hydrogen substituent may be any substituent that may be bound to an atom of the given radical that is specified to be substituted. Examples of substituents include, but are not limited to, -R6, -OR6, -COR6, -COOR6, -OCOR6, -CONR6R7, -NR6R7, - NR7COR6, -NR7COOR6, -SR6, -SO2R6, -SO2NR6R7, -SO2ORe, -OSO2R6, - NHC (NHR6) NR7, -NHC(NH2)NH, -CN, -NO2, halogen and methylenedioxy, wherein R6 and R7 are independently selected from hydrogen, linear or branched chain, cyclic or noncyclic, substituted or unsubstituted, alkyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl moieties. Preferable examples of substituents include, but are not limited to, alkyl, halogen, -CN, and -OH.
"Halogen" means fluorine, chlorine, bromine or iodine. "Halo" means fluoro, chloro, bromo or iodo. "Alkyl" means a linear or branched, saturated, aliphatic radical having a chain of carbon atoms . CX-Y alkyl is typically used where X and Y indicate the number of carbon atoms in the chain. The number of carbon atoms in the chain is preferably 1 to 10 (Ci-io) , more preferably 1 to 6 (C1-6) , further preferably 1 to 4 (C1-4) . Non-exclusive examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, tert-butylmethyl, diethylethyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, and the like .
"Alkoxy" means an oxygen moiety having a further alkyl substituent . CX-Y alkoxy is typically used where X and Y indicate the number of carbon atoms in the chain . The number of carbon atoms in the chain is preferably 1 to 10 (C1-10) , more preferably 1 to 6 (C1-6) • Non-exclusive examples of alkoxy include methoxy, ethoy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, tert pentoxy, hexyloxy, isohexyloxy, and the like .
"Alkenyl" means a linear or branched, carbon chain that contains at least one carbon-carbon double bond. CX-Y alkenyl is typically used where X and Y indicate the number of carbon atoms in the chain . The number of carbon atoms in the chain is preferably 2 to 10 (C2-10) , more preferably 2 to 6 (C2-6) • Non- exclusive examples of alkenyl include ethenyl (vinyl) , allyl, isopropenyl, 2 -methylallyl, 1 -pentenyl, hexenyl, heptenyl, 1- propenyl, 2-butenyl, 2-methyl-2-butenyl , and the like .
"Alkynyl" means a linear or branched, carbon chain that contains at least one carbon-carbon triple bond. CX-Y alkynyl is typically used where X and Y indicate the number of carbon atoms in the chain . The number of carbon atoms in the chain is preferably 2 to 10 (C2-10) , more preferably 2 to 6 (C2-6) . Non- exclusive examples of alkynyl include ethynyl, propargyl , 3- methyl-l-pentynyl, 2-heptynyl and the like .
"Alkylene", unless indicated otherwise, means a linear or branched, saturated, aliphatic, polyvalent carbon chain . CX-Y alkylene is typically used where X and Y indicate the number of carbon atoms in the chain . The number of carbon atoms in the chain is preferably 1 to 10 (C1-10) , more preferably 1 to 6 (C1-6) • Non-exclusive examples of alkylene include methylene (-CH2-) , ethylene (-CH2CH2-) , methylmethylene (-CH (CH3) -) , 1, 2-propylene (- CH2CH (CH3) -) , 1 , 3-propylene ( -CH2CH2CH2- ) , 1, 2-butylene ( - CH2CH (CH2CH3) -) , 1, 3-butylene ( -CH2CH2CH (CH3) -) , 1 , 4-butylene ( - CH2CH2CH2CH2-) , 2-methyltetramethylene (-CH2CH (CH3) CH2CH2- ) , pentamethylene (-CH2CH2CH2CH2CH2- ) , 1, 2 , 3-propanetriyl, 1 , 3, 3- propanetriyl and the like .
"Alkynylene" means a linear or branched, carbon chain (divalent ) that contains at least one carbon-carbon triple bond. CX-Y alkynylene is typically used where X and Y indicate the number of carbon atoms in the chain . The number of carbon atoms in the chain is preferably 2 to 10 (C2-10) , more preferably 2 to 6 (C2-6) - Non-exclusive examples of alkynylene include ethynylene, propargylene, 3-methyl-l-pentynylene, 2-heptynylene and the like .
"Cycloalkylene", unless indicated otherwise, means a non- aromatic, saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring radical (divalent) . CX-Y cycloalkylene is typically used where X and Y indicate the number of carbon atoms in the ring assembly. The number of carbon atoms in the ring is preferably 3 to 10 (C3-10) , more preferably 3 to 8 (C3-8) ■ Non-exclusive examples of cycloalkylene include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclohexenylene, 2 , 5- cyclohexadienylene, bicyclo [2 . 2 . 2 ] octylene, adamantan-l-ylene, decahydronaphthylene, bicyclo [2 . 2 . 1 ] hept-l-ylene, and the like .
"Heteroatom" refers to an atom that is not a carbon atom and hydrogen atom. Particular examples of heteroatoms include, but are not limited to nitrogen, oxygen, and sulfur .
"Aryl ring" means a monocyclic or polycyclic ring wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring . CX-Y aryl ring is typically used where X and Y indicate the number of carbon atoms in the ring assembly. The number of carbon atoms in the ring is preferably 6 to 14 (C6-14) , more preferably 6 to 10 (C6-10) • Non-exclusive examples of aryl ring include benzene, naphthalene, anthracene, phenanthrene, acenaphthylene, indene and the like .
"Aryl" means a monocyclic or polycyclic radical wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring . CX-Y aryl is typically used where X and Y indicate the number of carbon atoms in the ring assembly . The number of carbon atoms in the ring is preferably 6 to 14 (C6-14) , more preferably 6 to 10 (C6-10) • Non-exclusive examples of aryl include phenyl, naphthyl, indenyl, azulenyl, biphenyl , fluorenyl , anthracenyl, phenalenyl and the like . "Aryl" may partially be hydrogenated. Non-exclusive examples of partially hydrogenated aryl include tetrahydronaphthyl, indanyl and the like .
"Arylene" means divalent radical derived from the above- mentioned aryl ring .
"Heteroaryl ring" means a monocyclic or polycyclic aromatic ring wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon . "X-Y membered heteroaryl ring" is typically used where X and Y indicate the number of carbon atoms and heteroatoms in the ring assembly . The number of carbon atoms and heteroatoms in the ring is preferably 5 to 14 , more preferably 5 to 10. Monocyclic heteroaryl rings include, but are not limited to, cyclic aromatic rings having five or six ring atoms, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon . The nitrogen atoms can be optionally quaternerized and the sulfur atoms can be optionally oxidized. Non-exclusive examples of monocyclic heteroaryl ring of this invention include, but are not limited to, furan, imidazole, thiazole, isothiazole, isoxazole, oxadiazole, oxazole, 1 , 2 , 3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, 1, 3, 4-thiadiazole, triazole and tetrazole . "Heteroaryl ring" also includes, but is not limited to, bicyclic or tricyclic rings, wherein the heteroaryl ring is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, and another monocyclic heteroaryl or heterocycloalkyl ring . Non-exclusive examples of bicyclic or tricyclic heteroaryl ring include, but are not limited to, benzofuran (ex . benzo [b] furan) , benzothiophene (ex . benzo [b] thiophene) , benzimidazole, benzotriazine (ex . benzo [e] [ 1 , 2 , 4 ] triazine, benzo [d] [ 1 , 2 , 3] triazine) , pyridopyrimidine (ex . pyrido [ 4 , 3-d] pyrimidine, pyrido [3 , 4- d] pyrimidine, pyrido [3, 2-d] pyrimidine, pyrido [2, 3-d] pyrimidine) , pyridopyrazine (ex. pyrido [3, 4-b] pyrazine, pyrido [2,3- b]pyrazine) , pyridopyridazine (ex. pyrido [2, 3-c] pyridazine, pyrido [3, 4-c] pyridazine, pyrido [4, 3-c] pyridazine, pyrido[3,2- c] pyridazine) , pyridotriazine (ex. pyrido [2, 3-d] [1, 2, 3] triazine, pyrido [3, 4-d] [1, 2, 3] triazine, pyrido [4, 3-d] [1, 2, 3] triazine, pyrido [3, 2-d] [1, 2, 3] triazine, pyrido [3, 4-e] [1, 2, 4] triazine, pyrido [3, 2-e] [1, 2, 4] triazine) , benzothiadiazole (ex. benzo [c] [1, 2, 5] thiadiazole) , furopyridine (ex. furo[3,2- b] pyridine, furo [3, 2-c] pyridine, furo [2, 3-c] pyridine, furo [2, 3- b]pyridine) , oxazolopyridine (ex. oxazolo [4 , 5-b] pyridine, oxazolo [4 , 5-c] pyridine, oxazolo [5, 4-c] pyridine, oxazolo [5, 4- b]pyridine), thiazolopyridine (ex. thiazolo [4, 5-b] pyridine, thiazolo [4, 5-c] pyridine, thiazolo [5, 4-c] pyridine, thiazolo [5, 4- b]pyridine) , imidazopyridine (ex. imidazo [1, 2-a] pyridine, imidazo [4, 5-c] pyridine, imidazo [1, 5-a] pyridine) , quinazoline, thienopyridine (ex. thieno [2 , 3-c] pyridine, thieno [3, 2- b]pyridine, thieno [2, 3-b] pyridine) , indolizine, quinoline, isoquinoline, phthalazine, quinoxaline, cinnoline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, pyrazolopyridine (ex. pyrazolo [1, 5-a] pyridine) , imidazopyrimidine (ex. imidazo [1, 2-a] pyrimidine, imidazo [1,2- c] pyrimidine, imidazo [1, 5-a] pyrimidine, imidazo [1,5- c] pyrimidine) , pyrrolopyridine (ex. pyrrolo [2, 3-b] pyridine, pyrrolo [2, 3-c] pyridine, pyrrolo [3, 2-c] pyridine, pyrrolo [3, 2- b]pyridine) , pyrrolopyrimidine (ex. pyrrolo [2 , 3-d] pyrimidine, pyrrolo [3, 2-d] pyrimidine, pyrrolo [1, 2-c] pyrimidine, pyrrolo [1, 2- a] pyrimidine) , pyrrolopyrazine (ex. pyrrolo [2, 3-b] pyrazine, pyrrolo [1, 2-a] pyrazine) , pyrrolopyridazine (ex. pyrrolo[l,2- b] pyridazine) , triazolopyridine (ex. triazolo [1, 5-a] pyridine) , pteridine, purine, carbazole, acridine, perimidine, 1,10- phenanthroline, phenoxathiin, phenoxazine, phenothiazine, phenazine and the like. The bicyclic or tricyclic heteroaryl rings can be attached to the parent molecule through either the heteroaryl group itself or the aryl, cycloalkyl, or heterocycloalkyl group to which it is fused. "Heteroaryl" means monovalent radical derived from the above-mentioned heteroaryl ring .
"Heteroarylene" means divalent radical derived from the above-mentioned heteroaryl ring .
"Cycloalkyl" means a non-aromatic, saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring radical . CX-Y cycloalkyl is typically used where X and Y indicate the number of carbon atoms in the ring assembly. The number of carbon atoms in the ring is preferably 3 to 10 (C3-10) r more preferably 3 to 8 (C3-8) • Non-exclusive examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2 , 5-cyclohexadienyl , bicyclo [2 . 2 . 2 ] octyl, adamantan-l-yl, decahydronaphthyl, bicyclo [2 . 2 . 1] hept-l-yl, and the like .
"Heterocycloalkyl" means cycloalkyl, as defined in this Application, provided that one or more of the atoms forming the ring is a heteroatom selected, independently from N, 0, or S . "X-Y membered heterocycloalkyl" is typically used where X and Y indicate the number of carbon atoms and heteroatoms in the ring assembly . The number of carbon atoms and heteroatoms in the ring is preferably 3 to 10 , more preferably 3 to 8 . Non- exclusive examples of heterocycloalkyl include piperidyl, 4- morpholyl, 4-piperazinyl, pyrrolidinyl , perhydropyrrolidinyl,
1. 4-diazaperhydroepinyl, 1 , 3-dioxanyl, 1 , 4-dioxanyl, and the like .
Moreover, the above-mentioned definitions can apply to groups wherein the above-mentioned substituents are connected . For example, "arylalkyl" means linear or branched alkyl group which is substituted by one or more aryl groups , such as benzyl ,
1 -phenylethyl, 2 -phenylethyl, 3 -phenylpropyl, 1 -naphthylmethyl,
2-naphthylmethyl and the like . "Heteroarylalkyl" means linear or branched alkyl group which is substituted by one or more heteroaryl groups .
"Cycloalkylalkyl" means linear or branched alkyl group which is substituted by one or more cycloalkyl group (e . g . , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,
2. 5-cyclohexadienyl, bicyclo [2 . 2 . 2 ] octyl, adamantan-l-yl, decahydronaphthyl, bicyclo [2 . 2 . 1] hept-l-yl ) . "Heterocycloalkylalkyl" means linear or branched alkyl group which is substituted by one or more heterocycloalkyl groups .
"Alkylthio" means thio radical ( -S) substituted with a liner or branched alkyl group . Non-exclusive examples of alkylthio include methylthio, ethylthio, propylthio and the like .
"Alkylsulfonyl" means sulfonyl radical (-SO2-) substituted with a liner or branched alkyl group . Non-exclusive examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like .
"Monocyclic ring" as used herein refers to a monocyclic, saturated or unsaturated carbocyclic ring or a monocyclic, saturated or unsaturated heterocyclic ring . "X-membered monocyclic ring" is typically used where X indicate the number of carbon atoms and heteroatoms in the ring . The number of carbon atoms and heteroatoms in the ring is preferably 4 to 7 , more preferably 5 or 6. "Monocyclic heterocyclic ring" means a monocyclic, aromatic or nonaromatic ring wherein at least one ring atom is a heteroatom (preferably S, N or 0) and the remaining ring atoms are carbon . The nitrogen atoms can be optionally quaternerized and the sulfur atoms can be optionally oxidized.
Non-exclusive examples of monocyclic saturated carbocyclic ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and the like .
Non-exclusive examples of monocyclic unsaturated carbocyclic ring include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, benzene, and the like .
Non-exclusive examples of monocyclic saturated heterocyclic ring include pyrrolidine, piperidine, morpholine, piperazine, 1, 3-dioxane, 1 , 4-dioxane and the like .
Non-exclusive examples of monocyclic unsaturated heterocyclic ring include pyrazole, dihydro-pyrrole, pyrrole, dihydro-pyrazole, imidazole, thiophene, thiazole, isothiazole, thiadiazole, furan, oxazole, isoxazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like . "Protected derivatives" means derivatives of compound in which a reactive site or sites are blocked with protecting groups . A comprehensive list of suitable protecting groups can be found in T . W. Greene, Protecting Groups in Organic Synthesis , 5th edition, John Wiley & Sons, Inc . 2014 .
"Leaving group" means an atom or a group of atoms, which is detached from the reaction substrate in substitution reactions, elimination reactions, or the like . As the "leaving group", for example, a halogen atom (e . g . , a chlorine atom, a bromine atom, an iodine atom etc . ) , Ci-6 alkylsulfonyloxy (e . g . , methanesulfonyl oxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy etc . ) , C6-10 arylsulfonyloxy (e . g . , benzenesulfonyloxy, p-toluenesulfonyloxy etc . ) , Ci-6 alkylsulfonyl (e . g . , methanesulfonyl, ethanesulfonyl etc . ) and the like are used.
"Isomers" mean any compound having identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space . Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers" . Stereoisomers that are not mirror images of one another are termed "diastereomers" and stereoisomers that are nonsuperimposable mirror images are termed "enantiomers" or sometimes "optical isomers" . A carbon atom bonded to four nonidentical substituents is termed a "chiral center" . A compound with one chiral center has two enantiomeric forms of opposite chirality. A mixture of the two enantiomeric forms is termed a "racemic mixture" . A compound that has more than one chiral center has 2n-1 enantiomeric pairs , where n is the number of chiral centers . Compounds with more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture" . When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center . Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center . Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog . Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art ( e. g. , see "Advanced Organic Chemistry", 4th edition, March, Jerry, John Wiley & Sons, New York, 1992 ) . The compounds of the present invention may include these isomers . "Animal" includes humans , non-human mammals ( e . g. , mice, rats , dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals ( e. g. , birds, and the like) . "Disease" specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i . e . , the "side effects" of such therapy.
"Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use .
"Pharmaceutically acceptable salt" or "salt" means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- ( 4-hydroxybenzoyl ) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2- ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2 . 2 . 2 ] oct-2-ene-l- carboxylic acid, glucoheptonic acid, 4 , 4 ' -methylenebis ( 3- hydroxy-2-ene-l-carboxylic acid) , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, trifluoroacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like .
Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases . Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide . Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like .
"Amount effective to treat" means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease .
"Amount effective to prevent" means that amount which, when administered to an animal for preventing a disease, is sufficient to effect such prophylaxis for the disease .
"Effective amount" equals to "amount effective to treat" and "amount effective to prevent" .
"Treatment" or "treat" means any administration of the compound of the present invention and includes :
( 1 ) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease,
(2 ) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i . e . , arresting further development of the pathology and/or symptomatology) , or
( 3 ) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased ( i . e . , reversing the pathology and/or symptomatology) .
It is noted in regard to all of the definitions provided herein that the definitions should be interpreted as being open ended in the sense that further substituents beyond those specified may be included.
In one aspect of the present invention, a compound represented by the following formula ( I ) :
Figure imgf000015_0001
wherein
Q1 is represented by any of the following formulas ( II-l) to ( II-
6) :
Figure imgf000015_0002
Q1a is a hydrogen atom, or 1 to 3 same or different alkyls ; W1 is an optionally substituted alkylene or an optionally substituted cycloalkylene; X1 is -OPO3H2 or hydrogen atom;
R2 is an optionally substituted alkyl, an optionally substituted cycloalkylalkyl, or an optionally substituted arylalkyl;
Q3 is an optionally substituted divalent group derived from an aryl ring, or an optionally substituted divalent group derived from a heteroaryl ring;
W3 is a single bond, an optionally substituted alkylene, or an optionally substituted alkynylene;
X3 is hydrogen atom or hydroxy when X1 is -OPO3H2, or is -OPO3H2 when X1 is hydrogen atom;
R4 is an optionally substituted alkyl, or an optionally substituted cycloalkylalkyl ; and
R5 is a hydrogen atom, or an optionally substituted alkyl, or a pharmaceutically acceptable salt thereof is disclosed .
In one embodiment of the formulas ( II-l ) to (II-6) of Q1 in the formula ( I ) , Q1a is a hydrogen atom, or 1 to 3 same or different alkyls . Examples of alkyl include methyl , ethyl , propyl, isopropyl , butyl, tert-butylmethyl, diethylethyl, sec- butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, tert- pentyl, hexyl, isohexyl and the like .
In another embodiment of the formulas ( II-l) to ( II-6) of
Q1 in the formula ( I ) , Q1a is a hydrogen atom.
In one embodiment of the formula ( I ) , W1 is an optionally substituted alkylene or an optionally substituted cycloalkylene . Examples of substituents include alkyl, halogen, -CN, and -OH . Examples of an optionally substituted alkylene include methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, neopentylene, tert-pentylene, aminomethylene, aminoethylene, aminopropylene, aminobutylene, carboxymethylene, carboxyethylene, carboxypropylene, carboxybutylene, carbamoylmethylene, carbamoylethylene, carbamoylpropylene, carbamoylbutylene, methoxymethylene, methoxyethylene, methoxypropylene, methoxybutylene, methyl thiomethylene, methylthioethylene, methylthiopropylene, methylthiobutylene, hydroxymethylene, hydroxyethylene, hydroxypropylene, hydroxybutylene, ethoxycarbonylmethylene, ethoxycarbonylethylene, benzyloxymethylene, benzyloxyethylene, benzyloxypropylene, benzyloxybutylene, guanidinomethylene, guanidinoethylene, guanidinopropylene, 4-hydroxy-3- ( hydroxymethyl ) butylene, hydroxyethoxyethylene, pyrimidinylmethylene and the like . Examples of an optionally substituted cycloalkylene include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, adamant ylene and the like .
In another embodiment of the formula ( I ) , W1 is alkylene (e . g. , isopropylene, butylene) , or cycloalkylene (e . g . , cyclopropylene) .
In one embodiment of the formula ( I ) , R2 is an optionally substituted alkyl , an optionally substituted cycloalkylalkyl, or an optionally substituted arylalkyl . Examples of substituents include alkyl, halogen, -CN, and -OH . Examples of an optionally substituted alkyl group include methyl , ethyl , propyl , isopropyl , butyl, isobutyl, sec-butyl, tert-butyl , pentyl, isopentyl , neopentyl , tert-pentyl, tert-butylmethyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, carboxymethyl, carboxyethyl, carboxypropyl , carboxybutyl, carbamoylmethyl, carbamoylethyl, carbamoylpropyl , carbamoylbutyl , methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, hydroxymethyl, hydroxyethyl , hydroxypropyl, hydroxybutyl , ethoxycarbonylmethyl, ethoxycarbonylethyl, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, benzyloxybutyl, guanidinomethyl, guanidinoethyl, guanidinopropyl and the like . Examples of an optionally substituted cycloalkylalkyl group include cyclopropylmethyl, fluorocyclopropylmethyl, chlorocyclopropylmethyl , bromocyclopropylmethyl , iodocyclopropylmethyl, methylcyclopropylmethyl, 1, 1- dime thy Icyclopropylmethyl , 1 , 2 -dimethylcyclopropylmethyl , hydroxycyclopropylmethyl , methoxycyclopropylmethyl , ethoxycyclopropylmethyl , methoxycarbonylcyclopropylmethyl , methylcarbamoylcyclopropylmethyl , cyclopropylethyl , cyclohexylmethyl, cyclopropylhexyl and the like . Examples of an arylalkyl group include unsubstituted arylalkyl or arylalkyl having an alkyl group such as benzyl, a-methylbenzyl, phenethyl, a-methylphenethyl, a, a-dimethylbenzyl, a, a-dimethylphenethyl, 4- methylphenethyl, 4 -methylbenzyl , 4-isopropylbenzyl and the like; arylalkyl having an aryl group or an arylalkyl group such as 4- benzylbenzyl, 4 -phenethylbenzyl, 4-phenylbenzyl and the like; arylalkyl having a substituted oxy group such as 4- methoxybenzyl, 4 -n- tetradecyloxybenzyl, 4-n-heptadecyloxybenzyl ,
3. 4 -dimethoxybenzyl, 4 -methoxymethylbenzyl, 4- vinyloxymethylbenzyl, 4 -benzyloxybenzyl, 4-phenethyloxybenzyl and the like; arylalkyl having a hydroxyl group such as 4- hydroxybenzyl, 4-hydroxy-3-methoxybenzyl and the like; arylalkyl having a halogen atom such as 4-fluorobenzyl, 3-chlorobenzyl,
3. 4-dichlorobenzyl and the like; 2-furfuryl, diphenylmethyl , 1- naphthylmethyl, 2 -naphthylmethyl and the like . In another embodiment of the formula ( I ) , R2 is alkyl (e . g. , tert-butylmethyl ) .
In one embodiment of the formula ( I ) , Q3 is an optionally substituted divalent group derived from an aryl ring, or an optionally substituted divalent group derived from a heteroaryl ring . "Divalent optionally substituted group derived from an aryl ring" means a divalent optionally substituted group formed by removing two hydrogen atoms from an aryl ring . "Divalent optionally substituted group derived from a heteroaryl ring" means a divalent optionally substituted group formed by removing two hydrogen atoms from a heteroaryl ring . Examples of substituents include alkyl, halogen, -CN, and -OH . Examples of an optionally substituted aryl ring include, benzene, naphthalene, anthracene, phenanthrene, acenaphthylene, indene and the like . Examples of an optionally substituted heteroaryl ring include furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1, 2 , 3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, 1, 3, 4- thiadiazole, triazole, tetrazole, benzofuran, benzothiazole, benzothiophene, benzimidazole, benzotriazine, pyridopyrimidine, pyridopyrazine, pyridopyridazine, pyridotriazine, benzothiadiazole, furopyridine, oxazolopyridine, thiazolopyridine (e . g . , thiazolo [5, 4-b] pyridine) , imidazopyridine, quinazoline, thienopyridine, indolizine, quinoline, isoquinoline, phthalazine, quinoxaline, cinnoline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, pyrazolopyridine, imidazopyrimidine, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, pyrrolopyridazine, triazolopyridine, pteridine, purine, carbazole, acridine, perimidine, 1, 10 -phenanthroline, phenoxathiin, phenoxazine, phenothiazine, phenazine and the like .
In another embodiment of the formula ( I ) , Q3 is an optionally substituted divalent group derived from a heteroaryl ring (e . g . , thiazole ring, benzothiazole ring, thiazolo [ 5, 4- b] pyridine ring, or quinoxaline ring) . In one embodiment of the formula ( I ) , W3 is a single bond, an optionally substituted alkylene, or an optionally substituted alkynylene . Examples of substituents include alkyl, halogen, - CN, and -OH . Examples of an optionally substituted alkylene include methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, neopentylene, tert-pentylene, aminomethylene, aminoethylene, aminopropylene, aminobutylene, carboxymethylene, carboxyethylene, carboxypropylene, carboxybutylene, carbamoylmethylene, carbamoylethylene, carbamoylpropylene, carbamoylbutylene, methoxymethylene, methoxyethylene, methoxypropylene, methoxybutylene, methylthiomethylene, methylthioethylene, methylthiopropylene, methylthiobutylene, hydroxymethylene, hydroxyethylene, hydroxypropylene, hydroxybutylene, ethoxycarbonylmethylene, ethoxycarbonylethylene, benzyloxymethylene, benzyloxyethylene, benzyloxypropylene, benzyloxybutylene, guanidinomethylene, guanidinoethylene, guanidinopropylene and the like . Examples of an optionally substituted alkynylene include ethynylene, propargylene, 3-methyl-l-pentynylene, 2-heptynylene and the like .
In another embodiment of the formula ( I ) , W3 is a single bond or an optionally substituted alkylene (e . g . , ethynylene) .
In one embodiment of the formula ( I ) , R4 is an optionally substituted alkyl, or an optionally substituted cycloalkylalkyl . Examples of substituents include alkyl, halogen, -CN, and -OH . Examples of an optionally substituted alkyl group include methyl, ethyl, propyl, isopropyl , butyl, isobutyl, sec-butyl, tert-butyl , pentyl, isopentyl, neopentyl, tert-pentyl, 2- ethylbutyl , aminomethyl, aminoethyl, aminopropyl, aminobutyl, carboxymethyl, carboxyethyl, carboxypropyl , carboxybutyl, carbamoylmethyl, carbamoylethyl, carbamoylpropyl, carbamoylbutyl, methoxymethyl , methoxyethyl, methoxypropyl, methoxybutyl, methylthiomethyl , methylthioethyl, methylthiopropyl, methylthiobutyl , hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, benzyloxymethyl, benzyloxyethyl , benzyloxypropyl, benzyloxybutyl, guanidinomethyl, guanidinoethyl, guanidinopropyl and the like . Examples of an optionally substituted cycloalkylalkyl group include cyclopropylmethyl, fluorocyclopropylmethyl, chlorocyclopropylmethyl , bromocyclopropylmethyl , iodocyclopropylmethyl, methylcyclopropylmethyl , 1, 1- dimethylcyclopropylmethyl, 1 , 2-dimethylcyclopropylmethyl, hydroxycyclopropylmethyl , methoxycyclopropylmethyl , ethoxycyclopropylmethyl , methoxycarbonylcyclopropylmethyl , methylcarbamoylcyclopropylmethyl , cyclopropylethyl , cyclohexylmethyl , cyclopropylhexyl and the like .
In another embodiment of the formula ( I ) , R« is an optionally substituted alkyl (e . g . , isobutyl, 2-ethylbutyl) .
In one embodiment of the formula ( I ) , R5 is a hydrogen atom, or an optionally substituted alkyl . Examples of substituents include alkyl, halogen, -CN, and -OH . Examples of an optionally substituted alkyl group include methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carbamoylmethyl, carbamoylethyl, carbamoylpropyl, carbamoylbutyl , methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, hydroxymethyl, hydroxyethyl , hydroxypropyl, hydroxybutyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, benzyloxybutyl, guanidinomethyl, guanidinoethyl, guanidinopropyl and the like .
In another embodiment of the formula ( I ) , R5 is a hydrogen atom.
In another embodiment of the formula ( I ) ,
Q1 is represented by any of the following formulas ( III-l ) to ( III-3) :
Figure imgf000020_0001
R2 is an optionally substituted alkyl ( same as defined above) ; W3 is a single bond, or an optionally substituted alkynylene ( same as defined above) ; Q3 is an optionally substituted divalent group derived from a heteroaryl ring ( same as defined above) ; R4 is an optionally substituted alkyl ( same as defined above) ; and
R5 is a hydrogen atom.
In further another embodiment of the formula ( I ) ,
W1 is n-butylene, i-propylene or cyclopropylene;
R2 is neopentyl, Q3 is a divalent group derived from thiazole ring, benzothiazole ring, thiazolo [ 5, 4-b] pyridine ring, or quinoxaline ring; the thiazole ring, benzothiazole ring, thiazolo [5 , 4-b] pyridine ring, or quinoxaline ring may be substituted by substituent (s ) selected from a hydroxy group, a methyl group and a cyano group; and R4 is isobutyl or 2-ethylbutyl .
In the following, a compound having the formula ( I ) is to be also referred to as "the compound of the present invention" .
The general synthesis of the compound of the present invention is described in the following "Production Method" . Abbreviations used in the Production Method and Examples are as follows .
AcOEt (EtOAc) : ethyl acetate
AcOH : acetic acid
ACONH4 : ammonium acetate
Boc : tert-buthoxycarbonyl
( BOC ) 20 : di-tert-butyl dicarbonate
Cbz : benzyloxycarbonyl
CIP : 2-chloro-l, 3-dimethylimidazolidinium hexafluorophosphate DBU : 1, 8-diazabicyclo [ 5. 4 . 0] undec-7-ene DCE : dichloroethane
DCM: dichloromethane
DIAD: diisopropyl azodicarboxylate
DIEA ( DIPEA) : N, N-diisopropylethylamine
DMF: N, N-dimethyl formamide DMSO : dimethylsulfoxide DMT-MM: 4- (4, 6-dimethoxy-l, 3, 5-triazin-2-yl) -4- methylmorpholinium chloride EtOH: ethanol
Fmoc : 9-f luorenylmethyloxycarbonyl
HATU : 1- [bis (dimethylamino) methylene] -1H-1, 2, 3-triazolo [4,5- b] pyridinium 3-oxide hexafluorophosphate
LDA: lithium diisopropylamide LG: leaving group MeCN: acetonitrile
MeOH: methanol n-BuLi: n-butyllithium NEt3: triethylamine OEt(EtO) : ethoxy OMe(MeO) : methoxy OtBu(tBuO) : tert-butoxy
OTHP(THPO) : ( tetrahydro-21f-pyran-2-yl ) oxy p-TsOH: p-toluenesulfonic acid
Pd/C: palladium-carbon
PG: protecting group
Ph: phenyl
PPh3: triphenylphosphine rt : room temperature
TBS: tert-butyldimethylsilyl tBu: tert-butyl
TEA: trifluoroacetic acid
THE: tetrahydrofuran
Trt: trityl
Production Method
The synthesis method will be explained using the formula
(I) compounds (hereinafter, it will also be referred to as compound [I] ) .
When X1 is -OPO3H2, compound [I] can by synthesized according as the following scheme. [Intermediate C]
[ ]
Figure imgf000023_0001
ep
[Intermediate E]
Figure imgf000023_0002
Figure imgf000023_0003
Figure imgf000023_0004
[Step 1] Synthesis of [ Int-a]
[Int-a] ( RA1 is an alkyl group such as methyl and ethyl, PG1 is an amino-protecting group that can be deprotected under acidic condition, and R2, R5 and Q1 are as defined above) can be synthesized by an amidation condensation reaction using Intermediate [A] ( RA1 , R5, Q1 and PGi are as defined above) and Intermediate [B] ( PG2 is an amino-protecting group which can be deprotected under conditions other than acidic condition, and R2 is as defined above) , followed by an appropriate deprotection reaction of PG2. Examples of PGi include tert-butoxycarbonyl (Boc) , trityl (Trt ) and the like . Examples of PG2 include benzyloxycarbonyl (Cbz ) , f luorenylmethyloxycarbonyl ( Fmoc) , trifluoroacetyl, phthaloyl, formyl and the like . In the amidation condensation reaction, generally known condensing reagents and reaction conditions can be applied. HATU and DMT- MM are preferable as the condensing reagent, DMF, MeOH, THF and the like are preferable as the solvent, and the reaction temperature is preferably from 0 °C to the boiling point of the solvent . In the deprotection reaction of PG2, a generally known reaction condition can be applied according as the kind of PG2. When PG2 in the formula is an Fmoc group, a deprotection reaction using piperidine or DBU as a deprotecting reagent in AcOEt, THF or DCM as a solvent is preferable . When PG2 is a Cbz group, a deprotection reaction using a palladium catalyst such as Pd (OH) 2, Pd/C or the like in methanol, ethanol or THF as a solvent under H2 atmosphere is preferable . The reaction temperature is preferably 0 °C to the temperature of the boiling point of the solvent .
[Step 2 ] Synthesis of Intermediate [D] Intermediate [D] ( PG3 is an amino-protecting group which can be deprotected under conditions other than acidic condition, and Q1, R2, R4 and R5 are as defined above) can be synthesized by an amidation condensation reaction of [ Int-a] and Intermediate [C] ( PG3 and R4 are as defined above) , followed by a ring closure reaction in the presence of an acid. In the amidation condensation reaction, generally known condensing reagents and reaction conditions can be applied. DMT-MM or HATU is preferable as the condensing reagent, DMF, MeOH, THF or the like is preferable as the solvent, and the reaction temperature is preferably 0 °C to the boiling point of the solvent . As the acid to be used for the ring closure reaction, formic acid is preferable and formic acid can also be used as the solvent . The reaction temperature is preferably 0 °C to the boiling point of the solvent .
[Step 3] Synthesis of [Int-b] / [Int-b2 ]
[Int-b] ( PG4 is a hydroxy-protecting group, and W1, Q1, R2, R4, R5 and PG3 are as defined above ) can be synthesized by the reaction of alkylation reaction using Intermediate [D] and Intermediate [E] (LG is a leaving group, and PG4 and W1 are as defined above) in the presence of base . Triethylamine, Hunig' s base, pyridine, DBU, sodium carbonate, potassium carbonate, sodium methoxide and potassium tert-butoxide are preferable as bases . THF, MeCN, chloroform, DCM, DCE, DMF and DMSO are preferable as solvents . The reaction temperature is preferably 0 °C to the temperature of the boiling point of the solvent .
[Int-b2 ] can be synthesized by the following method.
[Intermediate E2]
Figure imgf000025_0001
[Int-b2]
[ Int-b2 ] ( PG4, W1, Q1 , R2, R4, R5 and PG3 are as defined above ) can be synthesized by reductive amination reaction using Intermediate [D] and intermediate [E2 ] ( PG4 and W1 are as defined above) . In the reductive amination reaction, generally known reducing reagents and conditions can be applied. Sodium triacetoxyborohydride, sodium cyanoborohydride, sodium tetrahydroborate, lithium tetrahydroborate, THF-borane complex, pyridine-borane complex, picoline-borane complex and the like are preferable as the reducing reagent, MeOH, THF, chloroform, DCM, DCE and the like are preferable as solvent, and the reaction temperature is preferably from 0 °C to the boiling point of the solvent .
[Step 4] Synthesis of [ Int-c]
[ Int-c] ( W1, Q1, R2, R4, R5 and PG3 are as defined above) can be synthesized by an appropriate deprotection reaction of PG4 according as the kind of PG4. For example, when PG4 is a 2- tetrahydropyranyl group, p-TsOH and methanol is used as an acid and solvent, respectively. The reaction temperature is preferably 0 °C to the temperature of the boiling point of the solvent .
[Step 5] Synthesis of [ Int-d]
[ Int-d] ( W1, Q1, R2, R4, R5 and PG3 are as defined above) can be synthesized by a reaction of [ Int-c] and di-tert-butyl diisopropylphosphoramidite, followed by the treatment of oxidation reagent such as hydrogen peroxide . DCM, DCE, THF and the like are preferable as the solvent, and the reaction temperature is preferably -80 °C to the temperature of the boiling point of the solvent . [Step 6] Synthesis of [ Int-e]
[ Int-e] (W1, Q1, R2, R4, and R5 are as defined above) can be synthesized by an appropriate deprotection reaction of PG3 according as the kind of PG3. When PG3 is a Cbz group, a deprotection reaction using a palladium catalyst such as Pd (OH) 2, Pd/C or the like in methanol, ethanol or THF as a solvent under H2 atmosphere is preferable . When PG3 is an Fmoc group, a deprotection reaction using piperidine or DBU as a deprotecting reagent in AcOEt , THF or dichloromethane as a solvent is preferable . Both groups can also be deprotected by hydrolysis reaction . The reaction temperature is preferably 0 °C to the temperature of the boiling point of the solvent .
[Step 7] Synthesis of [Int-f]
[ Int-f ] (W1, Q1, R2, R4, and R5 are as defined above) can be synthesized by an amidation condensation reaction using intermediate [ Int-e] and diethylphosphonoacetic acid. In the amidation condensation reaction, generally known condensing reagents and conditions can be applied. HATH and CIP are preferable as the condensing reagent, DMF, DCM, DCE, THF and the like are preferable as the solvent, and the reaction temperature is preferably from 0 °C to the boiling point of the solvent . [Step 8 ] Synthesis of [ Int-g]
[ Int-g] (W1, Q1, R2, R4, R5, Q3, W3 and X3 are as defined above) can be synthesized by Horner-Wadsworth-Emmons (HWE) reaction using [ Int-f] and intermediate [ F] in the presence of a base reagent and in the presence or absence of lithium salt such as lithium bromide and lithium chloride . In this reaction, generally known bases and conditions can be applied. Triethylamine, Hunig' s base, DBU, potassium carbonate, sodium methoxide, sodium hydride and LDA are preferable as bases, and THE, chloroform, DCM, DCE, 1, 2 -dimethoxyethane, methanol, ethanol and DMSO are preferable as solvents . The reaction temperature is preferably -78 °C to the temperature of the boiling point of the solvent .
[Step 9] Synthesis of Compound [ I ]
Compound [ I ] (the formulae are as defined above) can be by the deprotection reaction of t-butyl groups . Acidic conditions are used for the reaction and formic acid is preferable . Formic acid can also be used as the solvent .
When X1 is hydrogen, compound [ I ] can by synthesized according as the following scheme .
Figure imgf000028_0002
Figure imgf000028_0001
[Step 11] Synthesis of [ Int-h]
[ Int-h] ( RA1 is an alkyl group such as methyl and ethyl, and R2, R5 , W1 and Q1 are as defined above) can be synthesized in the same manner as [Step-1 ] .
[Step 12 ] Synthesis of Intermediate [D]
Intermediate [D] ( PG3 is an amino-protecting group which can be deprotected under conditions other than acidic condition, and Q1, W1, R2, R4 and R5 are as defined above) can be synthesized in the same manner as [Step-2 ] . [Step 13] Synthesis of Intermediate [ Int-i]
Intermediate [ Int-i ] (W1, Q1, R2, R4 and R5 are as defined above) can be synthesized in the same manner as [Step-6] . [Step 14 ] Synthesis of Intermediate [ Int-j ]
Intermediate [ Int-j ] (W1, Q1, R2, R4 and R5 are as defined above) can be synthesized in the same manner as [Step-7 ] . [Step 15] Synthesis of Intermediate [ Int-k]
Intermediate [ Int-k] (W1, Q1, R2, R4, R5, Q3, and W3 are as defined above ) can be synthesized in the same manner as [Step- 81 .
[Step 16] Synthesis of Compound [ I ]
Compound [ I ] (the formulae are as defined above) can be synthesized in the same manner as [Step-9] .
Intermediate [C] can be synthesized from intermediate
[ Int-1] by the following scheme .
Figure imgf000029_0001
Figure imgf000029_0002
Step 23
Figure imgf000029_0003
Step 24
[Intermediate C]
Figure imgf000029_0004
[Step 21 ] Synthesis of Intermediate [ Int-m]
Intermediate [ Int-m] ( PG' is a protecting group of carboxylic acid and R4 is as defined above) can be synthesized by Mitsunobu reaction from Intermediate [Int-1] using N- hydroxyphthalimide, triphenylphosphine and DIAD. In the Mitsunobu amination reaction, generally known reagents and conditions can be applied other than triphenylphosphine and DIAD. When [ Int-1] is a chiral compound, the stereochemistry of the obtained [Int-m] is converted. The reaction temperature is preferably from 0 °C to the boiling point of the solvent .
[Step 22 ] Synthesis of Intermediate [ Int-n]
Intermediate [ Int-n] ( PG' and R4 are as defined above) can be synthesized using hydrazine . Generally known conditions can be applied, and the reaction temperature is preferably from - 80 °C to the boiling point of the solvent . [Step 23] Synthesis of Intermediate [ Int-o]
Intermediate [ Int-o] ( PG' , PG3 and R4 are as defined above) can be synthesized by generally known reagents and conditions according as the kind of PG3. Preferable amino-protecting groups PG3 are Cbz and Fmoc groups . Other protecting groups that are not deprotected by acetic condition are also available . The reaction temperature is preferably from 0 °C to the boiling point of the solvent .
[Step 24 ] Synthesis of Intermediate [C]
Intermediate [C] ( PG3 and R4 are as defined above) can be synthesized by an appropriate deprotection reaction of PG' according as the kind of PG' . When PG' is a tert -butyl group, acidic conditions such as formic acid is preferable . The reaction temperature is preferably from 0 °C to the boiling point of the solvent .
The protecting group in each step is not limited to the protecting group . When R2, R4, R5, Q1 or Q3 has a protected functional group, deprotection can be performed in any step . The compound synthesized in each step of the reaction may be directly used in the next reaction without isolation . Under the conditions of Steps 2 and 12 , the ring closure reaction and the deprotection reaction may proceed simultaneously.
The compound to be obtained in the cyclization reaction can be isolated and purified by a conventional method such as extraction, water-washing, acid washing, alkali washing, crystallization, recrystallization, and silica gel column chromatography .
Furthermore, continuing the explanation, the compounds of the present invention, salts thereof and derivatives thereof are excellent in pharmacological action selectivity, safety (various toxicities and safety pharmacology) , pharmacokinetic performance, physicochemical property and the like, and therefore the usefulness as active ingredients of medicaments can be confirmed.
Examples of tests concerning pharmacological action selectivity include, but not be limited to, inhibition or activation assays on various pharmacological target receptors, inhibition assays on various pharmacological target enzymes, ion channels or transporters, cell tests to be used for the evaluation for various pharmacological action, and the like.
Examples of tests concerning safety include, but not be limited to, the following list including cytotoxic tests (e.g., tests using HL60 cells, hepatocytes, etc., and the like) , genotoxicity tests (e.g., Ames test, mouse lymphoma TK test, chromosomal aberration test, micronucleus test and the like) , skin sensitization tests (e.g., Buehler method, GPMT method, APT method, LLNA test and the like) , skin photosensitization tests (e.g., Adjuvant and Strip method and the like) , eye irritation tests (e.g., single instillation, short-term continuation instillation, repetitive instillation and the like) , safety pharmacology tests for the cardiovascular system (e.g., telemetry method, APD method, hERG inhibition assay and the like) , safety pharmacology tests for the central nervous system (e.g., FOB method, modified version of Irwin method and the like) , safety pharmacology tests for the respiratory system (e.g., measurement method using a respiratory function measuring apparatus, measurement method using a blood gas analyzer and the like) , general toxicity tests, and the like.
Examples of tests concerning pharmacokinetic performance include, but not be limited to, the following list including cytochrome P450 enzyme inhibition or induction tests, cell permeability tests (e.g., tests using CaCO-2 cells, MDCK cells etc., and the like) , drug transporter ATPase assay, oral absorption tests, blood concentration transition measurement tests, metabolism tests (e.g., stability test, metabolite molecular species test, reactivity test and the like) , solubility tests (e.g., solubility test based on turbidity method and the like), and the like. Examples of tests concerning physicochemical property include, but not be limited to, the following list including chemical stability test (e.g., stability test using HPLC etc., and the like) , partition coefficient (e.g., partition test using octanol phase/water phase and the like) , ionization constant test, crystallization test, and the like.
In other embodiment, a method for treating cancer by administration of the compound of the present invention is provided. The compound of the present invention has an action of inhibiting proliferation of cancer cells and may be used for treating cancer.
The test compound here is a compound described in the present specification, that is, the compound of the present invention. Typically, test compounds are tested at several different concentrations, and the concentrations are partly selected according to the assay conditions.
The compound of the present invention may be used for suppressing cancer cells, and therefore, is useful for controlling cell proliferation. The compound of the present invention may also be used favorably for inducing apoptosis of cells.
In other aspects, the present invention provides pharmaceutical compositions containing the compound of the present invention. These compositions may be used in various methods (e.g., treatment of cancer) of the present invention as described in detail below.
The pharmaceutical composition of the present invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical) , transmucosal, and rectal administration. Solutions or suspensions (e.g., injection) used for parenteral (particularly, intravenous), intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose . In addition, pH may be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide . The parenteral preparation can be enclosed in ampoules , disposable syringes or multiple dose vials made of glass or plastic .
Pharmaceutical compositions suitable for inj ectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile inj ectable solutions or dispersion . For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline ( PBS) . In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists . It must be stable under the conditions of manufacture and storage • and must be preserved against the contaminating action of microorganisms such as bacteria and fungi . The carrier can be a solvent or dispersion medium containing, for example, water, ethanol , polyol ( for example, glycerol , propylene glycol, and liquid polyethylene glycol, and the like) , and suitable mixtures thereof . The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants . Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like . In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition . Prolonged absorption of the inj ectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin .
Sterile inj ectable solutions can be prepared by incorporating the active compound, e . g . , the compound of the present invention in the required amount, in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization . Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a dispersion medium and the required other ingredients from those enumerated above . In the case of sterile powders for the preparation of sterile inj ectable solutions , the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-f iltered solution thereof .
Oral compositions generally include an inert diluent or an edible carrier . They can be enclosed in gelatin capsules or compressed into tablets . For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets , troches , or capsules .
Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents , and/or adjuvant materials can be included as part of the composition . The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature : a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes ; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring .
For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser that contains a suitable propellant, e . g . , a gas such as carbon dioxide, or a nebulizer .
Systemic administration can also be by transmucosal or transdermal means . For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation . Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents , bile salts , and fusidic acid derivatives . Transmucosal administration can be accomplished through the use of nasal sprays or suppositories . For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art .
The compounds can also be prepared in the form of suppositories (e . g . , with conventional suppository bases such as cocoa butter and other glycerides ) or retention enemas for rectal delivery.
In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems . Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters , and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art . The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals , Inc . Liposomal suspensions ( including liposomes targeted to infected cells with monoclonal antibodies to viral antigens ) can also be used as pharmaceutically acceptable carriers . These can be prepared according to methods known to those skilled in the art, for example, as described in U . S . Patent No . 4 , 522 , 811.
It can be advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage . Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subj ect to be treated; each unit containing a 5 predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier . The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals .
For instance, in certain embodiments, a pharmaceutical composition of the present invention is one suitable for oral administration in unit dosage form such as a tablet or capsule that contains from about 1 mg to about 1 g of the compound of this invention . In some other embodiments , a pharmaceutical composition of the present invention is one suitable for intravenous , subcutaneous or intramuscular inj ection . A patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of about 1 pg/kg to about 1 g/kg of the compound of the present invention . The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus inj ection or by continuous infusion over a period of time . Alternatively a patient will receive a daily oral dose approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
Preferably, the compound of the present invention can be administered intravenously (particularly preferably, by continuous drip infusion or rapid intravenous administration) to mammals inclusive of human .
In the case, the dose is selected appropriately depending on various factors such as the body weight and/or age of patients, and/or the degree of the symptom and an administration route . For example, the dose of the compound of the formula ( I ) for intravenous administration is generally in the range of 1 to 10000 mg/day/m2 human body surface area, preferably in the range of 1 to 5000 mg/day/m2 human body surface area, and more preferably 10 to 5000 mg/day/m2 human body surface area .
The pharmaceutical composition containing the compound of present invention can be used for treatment of disease, especially cancer.
In one aspect, the present invention provides methods for inhibiting tumor growth . Such methods comprise the step of administering to a subj ect (e . g . , a mammalian subj ect ) having a tumor a compound or a composition of the present invention in an amount effective to inhibit tumor growth . A compound or composition inhibits tumor growth if the tumor sizes are statistically significantly smaller in subjects with the treatment of the compound or composition than those without the treatment .
The inhibitory effect of a particular compound or composition of the present invention on tumor growth was characterized to the binding inhibition of eIF4E (eukaryotic translation initiation factor 4E) and eIF4G eukaryotic translation initiation factor 4G) by m7GTP pull-down assay and proximity ligation assay. Translation can be inhibited by blocking the binding of eIF4E to elF4G. The binding of a particular compound to eIF4E was also observed by NMR measurements .
The inhibitory effect of a particular compound or composition of the present invention on tumor growth may be characterized by any appropriate methods known in the art. For instance, the effect of the compound or composition on survivin expression may be measured. Compounds or compositions down- regulate survivin expression are likely to have inhibitory effects on tumor growth. In addition, assays using tumor cell lines (e.g., soft agar assays using SW480 cells) and animal models for tumor growth (e.g., nude mice grafted with tumor cells and Min mouse model) may also be used to evaluate the inhibitory effect on tumor growth of a given compound or composition as described in detail in the examples. Other exemplary animal models or xenografts for tumor growth include those for breast cancer (Guo et al, Cancer Res. 62: 4678-84, 2002; Lu et al, Breast Cancer Res. Treat. 57: 183-92, 1999) , pancreatic cancer (Bouvet et al, Cancer Res. 62: 1534-40, 2002) , ovarian tumor (Nilsson et al, Cancer Chemother. Pharmacol. 49: 93- 100, 2002; Bao et al, Gynecol. Oncol. 78: 373-9, 2000) , melanoma (Demidem et al, Cancer Res. 61: 2294-300, 2001), colorectal cancer (Brown et al, Dig. Dis. Sci. 45: 1578-84, 2000; Tsunoda et al, Anticancer Res. 19: 1149-52, 1999; Cao et al, Clin. Cancer Res. 5: 267-74, 1999; Shawler et al, J. Immunother. Emphasis Tumor Immunol. 17: 201-8, 1995; McGregor et al, Dis. Colon. Rectum. 36: 834-9, 1993; Verstijnen et al, Anticancer Res. 8: 1193-200, 1988), hepatocellular cancer (Labonte et al, Hepatol . Res . 18 : 72-85, 2000 ) , and gastric cancer (Takahashi et al, Int . J. Cancer 85 : 243-7 , 2000 ) .
The compound or composition that inhibits tumor growth may be administrated into a subj ect with a tumor via an appropriate route depending on, for example, the tissue in which the tumor resides . The appropriate dosage may be determined using knowledge and technigues known in the art as described above . The effect of the treatment of the compound or composition on tumor growth may also be monitored using methods known in the art . For instance, various methods may be used for monitoring the progression and/or growth of colorectal cancer, including colonoscopy, sigmoidoscopy, biopsy, computed tomograph, ultrasound, magnetic resonance imaging, and positron emission tomography . Methods for monitoring the progression and/or growth of ovarian cancer include, for example, ultrasound, computed tomography, magnetic resonance imaging, chest X-ray, laparoscopy, and tissue sampling .
In a related aspect, the present invention provides a method for treating or preventing cancer . Such methods comprise the step of administering to a subj ect in need thereof a compound or composition of the present invention in an amount effective to treat or prevent cancer in the subj ect . Treating cancer is understood to encompass reducing or eliminating cancer progression, e . g . , cancer growth and metastasis . Preventing cancer is understood to encompass preventing or delaying the onset of cancer . Various types of cancer may be treated or prevented by the present invention . They include, but are not limited to, lung cancer, breast cancer, colorectal cancer, stomach cancer, pancreatic cancer, liver cancer, uterus cancer, ovarian cancer, gliomas, melanoma, lymphoma, and leukemia . A subj ect in need of treatment may be a human or non-human primate or other animal with various types of cancer .
A subj ect in need of prevention may be a human or non- human primate or other animal that is at risk for developing cancer . Methods for diagnosing cancer and screening for individuals with high risk of cancer are known in the art and may be used in the present invention . For instance, colorectal cancer may be diagnosized by fecal occult blood test, sigmoidoscopy, colonoscopy, barium enema with air contrast, and virtual colonoscopy . An individual with high risk of colorectal cancer may have one or more colorectal cancer risk factors such as a strong family history of colorectal cancer or polyps , a known family history of hereditary colorectal cancer syndromes, a personal history of adenomatous polyps , and a personal history of chronic inflammatory bowel disease .
The compound of the present invention useful in cancer treatment or prevention may be identified by appropriate methods known in the art . Methods that may be used to select compounds for inhibitory effect on tumor (or cancer cells ) growth (or proliferation) as described above may also be used . The route of administration, the dosage of a given compound, the effectiveness of the treatment may be determined using knowledge and techniques known in the art . Factors that may be considered in making such a determination include, for example, type and stage of the cancer to be treated.
The compound of the present invention useful in cancer treatment and prevention may be administered in combination with other anti-neoplastic agent . The anti-neoplastic agent refers to a compound that inhibits tumor growth .
Specific examples of the other anti-neoplastic agent include alkylating agents such as thiotepa and CYTOXAN (RTM) cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone) ; a camptothecin ( including the synthetic analogue topotecan) ; bryostatin; callystatin; CC-1065 ( including its adozelesin, carzelesin and bizelesin synthetic analogues) ; cryptophycins (particularly cryptophycin 1 and cryptophycin 8 ) ; dolastatin; duocarmycin (including the synthetic analogues, KW- 2189 and CB1-TM1 ) ; eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e . g. , calicheamicin, especially calicheamicin gammall and calicheamicin omegall ( see, e . g . , Agnew, Chem Inti . Ed. Engl . 33 : 183-186 ( 1994 ) ) ; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores ) , aclacinomysins, actinomycin, authramycin, azaserine, bleomycins , cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, ADRLAMYCIN (RTM) doxorubicin ( including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2- pyrrolino-doxorubicin and deoxydoxorubicin) , epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalarnycin, olivomycins, peplomycin, potf iromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5- fluorouracil ( 5-FU) , tegafur, raltitrexed; folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxif luridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol , mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; def of amine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins ; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet ; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK (RTM) polysaccharide complex (JHS Natural Products , Eugene, Oreg . ) ; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2 , 2 ' , 2"- trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine) ; urethan; vindesine; dacarbazine; mannomustine; mitobronitol ; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C") ; cyclophosphamide; thiotepa; taxoids, e . g . , TAXOL (RTM) paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N . J. ) , ABRAXANE (RTM) Cremophor-f ree, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Illinois ) , and TAXOTERE (RTM) doxetaxel (Rhne-Poulenc Rorer, Antony, France) ; chloranbucil; GEMZAR (RTM) gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16) ; ifosfamide; mitoxantrone; vincristine; NAVELBINE (RTM) vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e . g . , CPT-11 ) ; topoisomerase inhibitor RFS 2000 ; dif luorometlhylornithine ( DMFO) ; retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above .
In addition, examples of the other anti-neoplastic agent also include anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs ) , including, for example, tamoxifen (including NOLVADEX (RTM) tamoxifen) , raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON toremifene; aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as , for example, 4 ( 5 ) -imidazoles , aminoglutethimide, MEGASE (RTM) megestrol acetate, AROMASIN (RTM) exemestane, formestane, fadrozole, RIVISOR (RTM) vorozole, FEMARA (RTM) letrozole, and ARIMIDEX (RTM) anastrozole; and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1 , 3-dioxolane nucleoside cytosine analog) ; antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in abherant cell proliferation, such as , for example, PKC-alpha, Ralf and H-Ras ; ribozymes such as a VEGF expression inhibitor (e . g . , ANGIOZYME (RTM) ribozyme) and a HER2 expression inhibitor; vaccines such as gene therapy vaccines , for example, ALLOVECTIN (RTM) vaccine, LEUVECTIN (RTM) vaccine, and VAXID (RTM) vaccine; PROLEUKIN (RTM) rIL-2 ; LURTOTECAN (RTM) topoisomerase 1 inhibitor; ABARELIX (RTM) rmRH; and pharmaceutically acceptable salts, acids or derivatives of any of the above .
Moreover, examples of the other anti-neoplastic agent also include a "growth inhibitory agent" referring to a compound or composition which inhibits growth of a cell in vitro and/or in vivo . Thus, the growth inhibitory agent may be one which significantly reduces the percentage of cells in S phase . Examples of growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase) , such as agents that induce G1 arrest and M-phase arrest . Classical M- phase blockers include the vincas (vincristine and vinblastine) , TAXOL (RTM) , and topo II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin . Those agents that arrest G1 also spill over into S-phase arrest , for example, DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5- f luorouracil, and ara-C .
Furthermore, examples of the other anti-neoplastic agent also include a "molecular target drug" that blocks the proliferation and metastasis of cancer by interfering with specific molecules involved in carcinogenesis (the process by which normal cells become cancer cells ) , tumor growth, or tumor spread. Specific examples of the "molecular target drug" include kinase inhibitors that inhibit kinase activity on tumors , including, for example, imatinib, erlotinib, gefitinib, sunitinib, sorafenib, dasatinib, nilotinib; antibodies that bind to the cell surface molecule on tumor cells or to the growth factor and the like such as, for example, ibritumomab, cetuximab, trastuzumab, panitumumab, bevacizumab, rituximab; and proteasome inhibitors that inhibit the proteasome which regulates protein expression and function by degradation of ubiquitinylated proteins, such as bortezomib; and pharmaceutically acceptable salts , acids or derivatives of any of above .
Further information can be found in The Molecular Basis of Cancer, Mendelsohn and Israel, eds . , Chapter 1, entitled "Cell cycle regulation, oncogenes, and antineoplastic drugs" by Murakami et al . (W B Saunders : Philadelphia, 1995 ) , especially p . 13.
The compound of the present invention administered in combination with an anti-neoplastic agent does not necessarily require that the compound and the anti-neoplastic aqent be administered concurrently. The compound and the agent may be administered separately as long as at a time point, they both have effects on same cancer cells .
For example, the administration mode may be exemplified by ( 1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the other anti-neoplastic agent, (2 ) simultaneous administration through the same administration route of two preparations obtained by separately formulating the compound of the present invention and the other anti-neoplastic agent, ( 3 ) administration with a time interval through the same administration route of two preparations obtained by separately formulating the compound of the present invention and the other anti-neoplastic agent, ( 4 ) simultaneous administration through different administration routes of two preparations obtained by separately formulating the compound of the present invention and the other anti-neoplastic agent, ( 5 ) administration with a time interval through different administration routes of two preparations obtained by separately formulating the compound of the present invention and the other anti-neoplastic agent (e . g . , administration in order of the compound of the present invention and then the other anti-neoplastic agent, or administration in the reverse order) , or the like . The amount of the other anti- neoplastic agent to be administered can be appropriately selected with reference to the clinically used dosage . The mixing ratio of the compound of the present invention and the other anti-neoplastic agent can be appropriately selected in accordance with the subj ect of administration, administration route, disease to be treated, symptoms, combination, and the like .
In a further related aspect , the present invention provides methods for promoting apoptosis in cancer cells . Such methods comprise the step of contacting cancer cells with the compound of the present invention in an amount effective to promote apoptosis in these cells . A compound promotes apoptosis if the number of cancer cells undergoing apoptosis is statistically significantly larger in the presence of the compound than that in the absence of the compound . Such compounds may be identified by methods known in the art (e . g . , measuring caspase activities and/or cell death) using cultured cancer cell lines, xenografts, or animal cancer models . Preferably, the compound is more active in promoting apoptosis in cancer cells than in normal cells . Cancer cells treatable by the present method may be from various tissue origins .
The following non-limiting examples illustrate the compounds , compositions, and methods of use of this invention . [Examples ]
The present invention is explained in more detail in the following by referring to Production Examples, Examples, Reference Examples and Experimental Examples ; however, the scope of the present invention is not limited thereto .
In the Examples, 1H NMR was measured using Bruker AVANCE III 300 or Bruker AVANCE III HD 400. For the analysis , Topspin (Bruker, trade name) and the like were used .
Mass spectrometric analysis was performed using the following Method A or B : (Method A) System: Shimadzu UFLC/MS System (Shimazu-2020 mass spectrometer) Column : CDS column for the chromatography column Eluents : A (water with 0. 04% TFA) and B (acetonitrile with 0. 04% TFA) (Method B) System: Shimadzu UFLC/MS System (Shimazu-2020 mass spectrometer) Column: CDS column for the chromatography column Eluents: A (5 mM ACONH4 in water) and B (5 mM ACONH4 in acetonitrile)
Biotage Initiator was used for organic microwave synthesis .
Column chromatography was performed using flash purification system of SHOKO Scientific Purif-espoir 2 and Biotage Isolera One using n-hexane-AcOEt and/or AcOEt-MeOH with a gradient as an eluent. One or several columns selected from prepacked cartridge columns listed in below were used for purification depending on the amount and purity of sample: SiO2: CHROMATOREX Q-PACK SI30 (SIZE10, SIZE20, SIZE60 and SIZE200) , Biotage SNAP KP-Sil (10g, 25g and 50g) , Biotage Rening Cartridges (5g, 10g, 30g, 45g and 80g) NHSiO2: CHROMATOREX Q-PACK NH60 (SIZE10, SIZE20, SIZE60 and SIZE200) , CHROMATOREX Q-PACK DNH600 (SIZE20, SIZE60 and SIZE200) Preparative HPLC (prep-HPLC) was performed using Waters FractionLynx system. General prep-HPLC condition (AcOH) : Column: C30-UG 25 mmID*150 mmL, 5 pm Mobile phase A: water with 0.10% v/v acetic acid Mobile phase B: acetonitrile UV detection wavelength: 220 nm Flow rate: 25ml/min Temperature: room temperature Gradient time table: 0 min B=x%, A=100-x% 0.01 - 10.99 min linear gradient 11.00 min B=y%, A=100-y% 11.01 - 11.20 min B=y%, A=100-y% 11.21 - 13.00 min B=100% 13.01 - 15.00 min B=z%, A=100-z% x, y and z values depend on the kind of compounds. General prep-HPLC condition (TFA) : Column: L-Column2 ODS 20 mmID*150 mmL, 5 pm Mobile phase A: water with 0.10% v/v TFA Mobile phase B: acetonitrile with 0.10% v/v TFA UV detection wavelength: 220 nm Flow rate: 20 ml /min Temperature: room temperature
Gradient time table:
0 min B=x%, A=100-x%
0.01 - 6.99 min linear gradient
7.00 min B=y%, A=100-y%
7.01 - 10.99 min B=100%
11.00 - 12.00 min B=z%, A=100-z% x, y and z values depend on the kind of compounds.
Compounds ID-01 to ID-13 listed in Tables 1 and 2 were synthesized according to the below methods or a known method using the Intermediates A, B, C, D, E and F (Int. A, Int. B, Int. C, Int. D, Int. E and Int. F) .
[Table 1]
Figure imgf000047_0001
[Table 2]
Figure imgf000048_0001
Intermediates A listed in the Table 1 are known compounds or were synthesized according to a known method or a method below.
Production Example 1: Synthesis of Intermediate A-01
Figure imgf000049_0002
To a solution of l-methylpiperidin-4-one (10 g) and 2,2- diethoxyethan-l-amine (12 g) in THE (100 mL) was added 5% Wt palladium-carbon (1.0 g, 5% Wt) . The mixture was stirred overnight under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated to give A-01 (19 g) as gray oil.
LCMS (method A) : m/z = 231.4 [M+H]+.
Production Example 2: Synthesis of Intermediate A-02
Figure imgf000049_0001
To a solution of tert-butyl (S)— 3—
( (methylsulfonyl) oxy) pyrrolidine-l-carboxylate (26 g) in MeCN (0.25 L) was added 2, 2-diethoxyethan-l-amine (66 g) . After stirring for 3.5 days at 60°C, the reaction mixture was cooled to room temperature and the precipitated solid was filtered out. The obtained filtrate was concentrated in vacuo and purified by column chromatography (SiO2, n-hexane: AcOEt = 75:25-0:100 and AcOEt:MeOH = 100:0-80:20, gradient) to give A-02 (18 g) as light yellow syrup.
LCMS (method A) : m/z = 303.1[M+H]+.
Intermediate B-01 listed in the Table 1 is a known compound .
Intermediate C listed in the Table 1 is known compounds or were synthesized according to a known method or a method below.
Production Example 3: Synthesis of Intermediate C-01
Figure imgf000050_0001
3-1) Synthesis of Intermediate C-01-intl
To a solution of tert-butyl (S) -2-hydroxy-4- methylpentanoate (200 g, 1.1 mol) in THE (2.0 L) was added PPhs (341 g, 1.3 mol) and 2-hydroxyisoindoline-l, 3-dione (196 g, 1.2 mol) under nitrogen. The mixture was cooled to 0°C and added dropwise DEAD (226 g, 1.3 mol) . The mixture was stirred for 3 hours at room temperature. The mixture was concentrated at 40 - 45 °C, the residue was added MTBE (4.0 L) and stirred for 30 min. Filtered, the filtrate was washed with H2O (2.0 L) and brine (1.0 L) , dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluted with Heptane: EtOAc = 10: 1 to afford C-01-intl (284 g, 78% yield) as a white solid. 1H NMR (DMSO-d6) δ 8.03 - 7.76 (m, 4H) , 4.64 (dd, J = 7.9, 5.9 Hz, 1H), 1.84 (tdd, J = 14.1, 10.5, 6.4 Hz, 2H) , 1.63 (ddd, J = 13.8, 7.7, 5.9 Hz, 1H) , 1.45 - 1.25 (m, 9H) , 0.95 (dt, J = 40.2, 20.1 Hz, 6H) . 3-2) Synthesis of Intermediate C-01-int2
To a solution of C-01-intl (280 g, 840 mmol) in MeOH (2.8 L) was added NH2NH2 -^0 (125 g, 2.5 mol) at 20°C. A white solid appeared after 10 mins, then the mixture was stirred for 2 hours. The mixture was filtered, and the filtrate was concentrated at 45°C. The residue was diluted with DCM (2.8 L) and 5% NaHCO3 solution (2.8 L) . The separated organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluted with Heptane: EtOAc = 20: 1 to afford compound C-01-int2 (165 g, 96% crude yield) as a colorless oil.
1H NMR (CDC13) 5 5.48 (s, 2H) , 4.01 (dd, J = 9.3, 4.6 Hz, 1H) , 1.81 - 1.64 (m, 1H), 1.57 - 1.29 (m, 11H) , 0.86 (dd, J = 6.6, 2.0 Hz, 6H) .
3-3) Synthesis of Intermediate C-01-int3
To a solution of C-01-int2 (160 g, 787 mmol) and pyridine (62 g, 787 mmol) in DCM (3.2 L) was added dropwise Cbz-Cl (273 g, 1.6 mol) at 0°C. The mixture was stirred for 2 hours at room temperature. The mixture was poured into H2O (1.6 L) . Separated, the organic phase was washed with brine (1.6 L) , dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluted with Heptane: EtOAc = 10: 1 to afford C-01-int3 (259 g, 93% yield) as a colorless oil . 1H NMR (DMSO-d6) 5 10.50 (s, 1H) , 7.51 - 7.21 (m, 5H) , 5.31 - 4.93 (m, 2H) , 4.16 (dd, J = 8.8, 4.8 Hz, 1H) , 1.77 (dt, J = 13.5, 6.6 Hz, 1H), 1.53 (ddd, J = 14.4, 8.8, 5.8 Hz, 1H) , 1.45 - 1.32 (m, 10H) , 1.11 (s, 2H) , 0.94 - 0.80 (m, 6H) . 3-4) Synthesis of Intermediate C-01
To a solution of TEA (521 g, 4.5 mol) in DCM (771 mL, 3 V) was added dropwise a solution of C-01-int3 (257 g, 762 mmol) in DCM (514 ml) at room temperature. The mixture was stirred for 16 hours. The mixture was concentrated at 30 °C until no more distillation was observed. The crude product was diluted with MTBE (2.5 L) and adjusted the pH to 9-10 with 10% Na2CO3 aqueous solution. Then separated, the aqueous layer was adjusted to pH =1-2 with a 4 mol/L HC1 aqueous solution and extracted with DCM (2.5 L x 2) . The combined organic layers were washed with brine (2.5 L) , dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluted with DCM: MeOH= 50: 1 to afford C-01 (154 g, 73% yield) as a yellow oil. 1H NMR (DMSO-d6) δ 10.49 (s, 1H) , 7.46 - 7.26 (m, 5H) , 5.24 - 4.95 (m, 2H) , 4.24 (dd, J = 9.1, 4.4 Hz, 1H) , 1.95 - 1.69 (m, 1H), 1.56 (ddd, J = 14.4, 9.1, 5.5 Hz, 1H) , 1.46 - 1.35 (m, 1H) , 0.89 (t, J = 6.5 Hz, 6H) . Intermediates D listed in the Table 1 are known compounds or were synthesized according to a known method or a method below.
Production Example 4: Synthesis of Intermediate D-02
Figure imgf000052_0001
4-1) Synthesis of Intermediate D-02-intl
A mixed suspension of A-02 (14 g) , B-01 (18 g) , HATU (22 g) and DIEA (11 mL) in THE (0.20 L) was stirred for 2 hours at room temperature. After addition of B-01 (1.5 g) , HATU (1.7 g) and DIEA (1 mL) , the reaction mixture was stirred for another 1 hour. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted by AcOEt twice. The organic layer was concentrated in vacuo and purified by column chromatography (SiO2, n-hexane: AcOEt = 95:5-50:50, gradient) . The obtained material was further purified by column chromatography (NHSiO2, n-hexane : AcOEt = 50:50) to give D-02-intl (21 g) as colorless gum.
LCMS (method A) : m/ z = 674.4 [M+Na] +.
4-2) Synthesis of Intermediate D-02-int2
To a solution of D-02-intl (20 g) in MeOH (0.25 L) was added piperidine (25 mL) . After stirring for 4 hours at room temperature, the reaction mixture was concentrated to about a half volume and the obtained precipitates were filtered out. The obtained filtrate was concentrated in vacuo and purified by column chromatography (SiO2, n-hexane : AcOEt = 50:50-0:100 and AcOEt :MeOH = 100:0-80:20, gradient) to give D-02-int2 (8.2 g) as slightly yellow oil.
LCMS (method A) : m/z = 430.3[M+H]+, 384.3 [M-EtOH+H] +. 4-3) Synthesis of Intermediate D-02-int3
A mixture solution of D-02-int2 (9.5 g) , C-01 (7.4 g) and DMT -MM (7.3 g) in MeOH (0.10 L) was stirred for 1 hour at room temperature. After addition of DMT-MM (1.5 g) , the reaction mixture was stirred for another 1 hour. After concentrated to about one third volume, the mixture was poured into saturated aqueous sodium bicarbonate solution and extracted by AcOEt twice. The organic layer was concentrated in vacuo and purified by column chromatography (SiO2, n-hexane : AcOEt = 94:6-50:50, gradient) to give D-02-int3 (15 g) as colorless syrup. LCMS (method A) : m/z = 715.5 [M+Na] +, 647.4 [M-EtOH+H] +. 4-4) Synthesis of Intermediate D-02
A solution D-02-int3 (15 g) in formic acid (0.10 L) was stirred for 22 hours at 60 °C. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The residue was dissolved in AcOEt and washed with a mixture of aqueous sodium bicarbonate solution and aqueous sodium carbonate solution. The organic layer was concentrated in vacuo and purified by column chromatography (NHSiO2, n-hexane : AcOEt = 50:50-0:100 and AcOEt:MeOH = 100:0-40:60, gradient) to give D-02 (8.8 g) as light yellow amorphous. LCMS (method A) : m/z = 501.3 [M+H] +.
Intermediate E-01 listed in the Table 2 is a known compound.
Intermediates F listed in the Table 2 are known compounds or were synthesized according to a known method or a method below.
Production Example 5: Synthesis of Intermediate F-04
Figure imgf000053_0001
5-1) Synthesis of Intermediate F-04-intl
To a suspension of benzo [d] thiazol-5-ol (0.50 g) in DCM (20 mL) and THF (5 mL) were added 3, 4-dihydro-2H-pyran (0.80 mL) , p-TsOH monohydrate (30 mg) . After stirring for 5 hours at room temperature, the mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with chloroform twice. The organic layer was concentrated in vacuo and purified by column chromatography (SiO2, n-hexane : AcOEt =75:25-30:70, gradient) to give F-04-intl (0.73 g) as colorless syrup .
LCMS (method B) : m/z = 236.1[M+H]+. 5-2) Synthesis of Intermediate F-04
To a solution of F-04-intl (0.73 g) in THE (15 mL) was added n-BuLi (2.8 mol/L) in hexane (1.2 mL) at -70 °C under nitrogen atmosphere. After stirring for 30 minutes, a solution of DMF (0.27 g) in THF (1 mL) was added. After stirring for another 30 minutes at the same temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride solution, warmed to room temperature and extracted with AcOEt twice. The organic layer was concentrated in vacuo and purified by column chromatography (SiO2, n-hexane : AcOEt =94:6-50:50, gradient) to give F-04 (0.64 g) as a yellow solid. (300 MHz, CDCI3) data of F-04 is shown in Fig 1. Production Example 6: Synthesis of Intermediate F-06
Figure imgf000054_0001
To a stirred mixture of 4-bromothiazole-2-carbaldehyde (96 mg) in MeCN (4 mL) were added hex-5-yn-l-ol (98 mg) , copper(I) iodide (9.5 mg), triethylamine (0.51 g) and tetrakis (triphenylphosphine) palladium (0) (58 mg) . After stirring for 2 hours at 60 °C under microwave irradiation, the reaction mixture was cooled to room temperature. The precipitated solid was filtered out, and the resulting filtrate was concentrated in vacuo and purified by column chromatography (SiO2, n-Hexane: AcOEt = 100:0-50:50, gradient) to give F-06 (46 mg) as light yellow syrup. LCMS (method A) : m/z=210.0 [M+H]+. Production Example 7 : Synthesis of Intermediate F-08
Figure imgf000055_0001
7-1) Synthesis of Intermediate F-08-intl
To a mixture of 5- (trimethylsilyl) pent-4-yn-l-ol (0.79 g) and IH-tetrazole (0.53 g) in THF (5 mL) /DCM (5 mL) was added di- tert-butyl diisopropylphosphoramidite (2.1 g) at room temperature. After stirring for 1 hour at same temperature, the mixture was cooled to -5°C and added hydrogen peroxide (0.98 g, 35% Wt) in one portion. After stirring at same temperature for 2 hours, the resulting mixture was added 10% aqueous sodium thiosulfate solution (20 mL) and DCM (20 mL) . The organic layer was separated, washed with 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiCh, Hexane: AcOEt = 100:0-75:25, gradient) to give F-08-intl ( 1.0 g) as colorless oil. XH NMR (300 MHz, CDCI3) data of F-08-intl is shown in Fig 2. 7-2) Synthesis of Intermediate F-08-int2
To a stirred solution of F-08-intl (0.51 g) in THF (10 mL) was added triethylamine trihydrofluoride (0.37 g) at room temperature. The resulting mixture was stirring at 60 °C for 1.5 hours under microwave irradiation. The solution was concentrated in vacuo. The residue was added saturated aqueous sodium bicarbonate solution (10 mL) and AcOEt (20 mL) . The organic layer was separated and washed with brine, dried over NaaSCh, concentrated in vacuo. The residue was purified by column chromatography (SiO2, Hexane:AcOEt = 100:0-50:50, gradient) to give F-08-int2 (0.39 g) as colorless oil.
1H NMR (300 MHz, CDCI3) data of F-08-int2 is shown in Fig 3. 7-3) Synthesis of Intermediate F-08
To a stirred mixture of 4-bromothiazole-2-carbaldehyde (96 mg) in MeCN (4 mL) were added F-08-int2 (170 mg) , copper(I) iodide (9.5 mg) , tetrakis (triphenylphosphine) palladium(O) (58 mg) and triethylamine (0.51 g) . After stirring for 2 hours at 62 °C under microwave irradiation, the reaction mixture was cooled to room temperature. The precipitated solid was filtered out, and the resulting filtrate was concentrated in vacuo and purified by column chromatography (SiO2, n-Hexane : AcOEt = 100:0-
50:50, gradient) to give F-08 (0.12 g) as light yellow syrup. :H NMR (300 MHz, CDCI3) data of F-08 is shown in Fig 4.
Production Example 8: Synthesis of Intermediate F-10
Figure imgf000056_0001
8-1) Synthesis of Intermediate F-10-intl
To a mixture of benzo [d] thiazol-5-ol (0.30 g) and 1H- tetrazole (0.28 g) in THE (5 mL) /DCM (5 mL) was added di-tert- butyl diisopropylphosphoramidite (1.1 g) at room temperature. After stirring for 1 hour at same temperature, the mixture was cooled to 0°C and added hydrogen peroxide (0.58 g) in one portion. After stirring at same temperature for 40 minutes, the resulting mixture was added 10% aqueous sodium thiosulfate solution (20 mL) and DCM (10 mL) . The organic layer was separated, washed with 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Hexane: AcOEt = 100:0-75:25, gradient) to give F-10-intl (0.50 g) as colorless oil. 1H NMR (300 MHz, CDCI3) data of F-10-intl is shown in Fig 5. 8-2) Synthesis of Intermediate F-10
To a solution of F-10-intl (0.50 g) in THF (8 mL) was added LDA (1.1 mol/L) in hexane (1.6 mL) at -78°C under nitrogen atmosphere. After stirring for 30 minutes, a solution of DMF (0.16 g) in THF (1 mL) was added. After stirring for another 13 minutes at the same temperature, the reaction mixture was gradually wormed to room temperature for 2 hours. After which, the resulting mixture was quenched with saturated aqueous ammonium chloride solution and extracted with AcOEt twice. The organic layer was concentrated in vacuo and purified by column chromatography (SiCh, n-hexane: AcOEt =100:0-50:50, gradient) to give F-10 (0.35 g) as a colorless oil.
NMR (300 MHz, CDCI3) data of F-10 is shown in Fig 6. Compounds ID-01 to ID-21 listed in the Table 3 can be synthesized according to a known method, methods described in the general synthesis section or a method below. Example 1: Synthesis of Intermediate ID-02
Figure imgf000058_0001
Exl-1) Synthesis of Intermediate ID-02-Intl
A mixture suspension of D-02 (7.4 g) , 2- (4- bromobutoxy) tetrahydro-2H-pyran (E-01, 3.9 g) , sodium carbonate (4.7 g) and sodium iodide (2.2 g) in DMSO (0.10 L) was stirred for 1 hours at 70°C. After addition of 2- (4- bromobutoxy) tetrahydro-2H-pyran (0.36 g) , the reaction mixture was stirred for another 30 minutes. After cooled to room temperature, the mixture was poured into saturated aqueous sodium bicarbonate solution and extracted by AcOEt three times . The organic layer was concentrated in vacuo and purified by column chromatography (SiO2, AcOEt :MeOH = 100:0-70:30, gradient) followed by further purification by column chromatography (SiO2, AcOEt:MeOH = 100:0-85:15, gradient) to give ID-02-intl (6.2 g) as light yellow syrup.
LCMS (method A) : m/z = 657.5[M+H]+.
Exl-2) Synthesis of Intermediate ID-02-int2
To a stirred solution of ID-02-intl (12 g) in MeOH (19 mL) was added TsOH monohydrate (5.5 g) at room temperature. After 15 hours, the solvent was removed under reduced pressure. The residue was transferred to a separating funnel with hexane/EtOAc (1/5) and saturated aqueous sodium bicarbonate solution. The two-phase mixture was partitioned, extracted with hexane/EtOAc (1/5) once. The combined organic layer was dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography (NH silica, hexane:AcOEt = 100:0-0:100, gradient) to give ID-02-int2 (8.7 g) as light yellow amorphous. LCMS (method A) : m/ z = 573.4 [M+H]+. Exl-3) Synthesis of Intermediate ID-02-int3
To a stirred mixture of ID-02-int2 (8.7 g) and 1H- tetrazole (2.7 g) in CH2CI2 (25 mL) was added dropwise di-tert-butyl diisopropylphosphoramidite (6.4 g) at room temperature. After one hour the mixture was cooled with an ice bath, and aqueous hydrogen peroxide (35%, 3.3 mL) was added dropwise. After one hour sodium sulfite (5.8 g) in water (30 mL) was added. The mixture was transferred to a separating funnel with CH2CI2 and saturated aqueous sodium bicarbonate solution. The two-phase mixture was partitioned, extracted with EtOAc twice. The combined organic layer was dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography (SiO2, AcOEt :MeOH = 100:0-80:20, gradient) to give ID-02-int3 (8.7 g) as light yellow syrup. LCMS (method A) : m/z = 765.4 [M+H]+.
Exl-4) Synthesis of Intermediate ID-02-int4
The mixture of ID-02-int3 (8.7 g) and Pd/C (5.0% Wt, 0.46 g) in THF (11 mL) was stirred under hydrogen atmosphere at room temperature. After 5 hours hydrogen was removed. The mixture was diluted with EtOAc and passed through Celite pad to remove Pd/C. The filtrate was concentrated in vacuo to give crude ID- 02-int4 (6.8 g) , which was used in the next reaction without further purification.
LCMS (method A) : m/z = 631.5[M+H]+.
Exl-5) Synthesis of Intermediate ID-02-int5
To a stirred mixture of crude ID-02-int4 (6.8 g) , 2- (diethoxyphosphoryl) acetic acid (2.2 g) , and DIPEA (2.3 mL) in CH2CI2 (11 mL) was added HATU (4.9 g) at room temperature. After 5 hours the solvent was removed under reduced pressure. The residue was transferred to a separating funnel with EtOAc and water. The two-phase mixture was partitioned, extracted with EtOAc twice. The combined organic layer was washed with saturated aqueous sodium bicarbonate solution once and then saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo to give crude ID-02-int5 (12 g) as yellow amorphous. The crude mixture was used in the next reaction without further purification. LCMS (method A) : m/z = 809.5 [M+H]+. Exl-6) Synthesis of Intermediate ID-02-int6
To a stirred mixture of crude ID-02-int5 (12 g) , lithium bromide (1.1 g) , benzo [d] thiazole-2-carbaldehyde (1.9 g) in THE (16 mL) was added triethylamine (1.8 mL) at room temperature. After 14 hours the mixture was transferred to a separating funnel with EtOAc and water. The two-phase mixture was partitioned, extracted with EtOAc twice. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography (SiO2, AcOEt:MeOH = 100:0- 75:25, gradient) to give ID-02-int6 (5.6 g) as yellow syrup. LCMS (method A) : m/z = 818.5 [M+H]+. Exl-7) Synthesis of Intermediate ID-02
ID-02-int6 (5.6 g) was dissolved in formic acid (25 mL) and the solution was stirred at 40 °C. After one hour the volatiles were removed under reduced pressure. The residue was purified by column chromatography (SiO2, AcOEt:MeOH = 50:50- 0:100, gradient) to give ID-02 (3.5 g) as light yellow solid. LCMS (method A) : m/z = 706.3 [M+H] + .
1H NMR (300 MHz, CDCI3) data of ID-02 is shown in Fig 7.
Example 2: Synthesis of Intermediate ID-08
Figure imgf000061_0001
Ex2-1) Synthesis of Intermediate ID-08-intl
To a stirred solution of D-08 (1.7 g) in THF (15 mL) was added 10% palladium-carbon (0.85 g) . The resulting mixture was stirred under hydrogen atmosphere (balloon pressure) for 2 hours at room temperature. After the reaction completed, palladium- carbon was filtered and removed by Celite pad. The filtrate was concentrated under reduced pressure to give ID-08-intl (1.3 g) as a white solid, which was used in the next reaction without any purification.
LCMS (method A) : m/z = 423.3 [M+H] +.
Ex2-2) Synthesis of Intermediate ID-08-int2
To a stirred solution of ID-08-intl (1.3 g) in DCE (15 mL) were added 2- (diethoxyphosphoryl) acetic acid (0.89 g) , DIEA (1.3 mL) and HATU (1.8 g) . The reaction mixture was stirred for 16 hours at room temperature. After stirring, the mixture was added 30 mL of saturated aqueous sodium bicarbonate solution and 30 mL of DCM. The organic layer was separated, washed with 30 mL of brine, dried over Na2SO4 and concentrated in vacuo. The crude mixture was purified by column chromatography (NHSiCL, AcOEt:MeOH = 100:0-40:60, gradient) to give ID-08-int2 (1.5 g) as colorless amorphous.
LCMS (method B) : m/z = 601.5 [M+H]+.
Ex2-3) Synthesis of Intermediate ID-08-int3
To a stirred solution of ID-08-int2 (30 mg) , F-08 (29 mg) and lithium bromide (13 mg) in THE (4 mL) was added triethylamine (30 mg) in one portion. After stirring for 0.5 hour at room temperature, the mixture was added 10 mL of water and 20 mL of ethyl acetate. The organic layer was separated, washed with 30 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, AcOEt:MeOH = 100:0-50:50, gradient) to give ID-08-int3 (33 mg) as a white solid.
LCMS (method A) : m/z = 834.5 [M+H]+.
Ex2-4) Synthesis of Intermediate ID-08
In a round bottom flask, ID-08-int3 (33 mg) was added formic acid (6.1 g) at room temperature. After stirring at 45°C for 1- hour, formic acid was concentrated in vacuo. The residue was purified by prep-HPLC (condition (AcOH) : B=30 to 80%) . The collected fraction was concentrated in vacuo to give ID-08 (22 mg) as a pale-yellow amorphous powder.
LCMS (method B) : m/z = 722.3 [M+H]+.
1H NMR (300 MHz, CD3OD) data of ID-08 is shown in Fig 8.
Chemical structures of compounds ID-01 to ID-21 are shown in Table 3 (Table 3-1 to Table 3-4) .
[Table 3-1]
Figure imgf000063_0001
[Table 3-2]
Figure imgf000064_0001
[Table 3-3]
Figure imgf000065_0001
[Table 3-4]
Figure imgf000066_0001
Chemical names of compounds ID-01 to ID-21 are listed as below:
ID-01
4- (4- ( (3R, 6S, 9aS) -1- ( (E) -3- (benzo [d] thiazol-2- yl) acryloyl) -3-isobutyl-6-neopentyl-4 , 7- dioxohexahydropyrazino [2, 1-c] [1,2,4] oxadiazin-8 (1H) - yl) piperidin-l-yl) butyl dihydrogen phosphate ID-02
4- ( (R) -3- ( (3R, 6S, 9aS) -1- ( (E) -3- (benzo [d] thiazol-2- yl) acryloyl) -3-isobutyl-6-neopentyl-4 , 7- dioxohexahydropyrazino [2 , 1-c] [1, 2, 4] oxadiazin-8 (1H) - yl) pyrrolidin-l-yl) butyl dihydrogen phosphate ID-03
4- ( (S) -3- ( (3R, 6S, 9aS) -1- ( (E) -3- (benzo [d] thiazol-2- yl) acryloyl) -3-isobutyl-6-neopentyl-4 z 7- dioxohexahydropyrazino [2, 1-c] [1,2,4] oxadiazin-8 (1H) - yl) pyrrolidin-l-yl) butyl dihydrogen phosphate ID-04
4- ( (R) -3- ( (3R, 6S, 9aS) -1- ( (E) -3- (5-hydroxybenzo [d] thiazol- 2-yl) acryloyl) -3-isobutyl-6-neopentyl-4 , 7- dioxohexahydropyrazino [2, 1-c] [1,2,4] oxadiazin-8 (1H) - yl) pyrrolidin-l-yl) butyl dihydrogen phosphate ID-05
4- (3- ( (3R, 6S, 9aS) -1- ( (E) -3- (5-hydroxybenzo [d] thiazol-2- yl) acryloyl) -3-isobutyl-6-neopentyl-4 , 7- dioxohexahydropyrazino [2, 1-c] [1,2,4] oxadiazin-8 (1H) -yl) azetidin- 1-yl) butyl dihydrogen phosphate ID-06
4- ( (R) -3- ( (3R, 6S, 9aS) -1- ( (E) -3- (4- ( 6-hydroxyhex-l-yn-l- yl) thiazol-2-yl) acryloyl) -3-isobutyl-6-neopentyl-4 , 7- dioxohexahydropyrazino [2, 1-c] [1,2,4] oxadiazin-8 (1H) - yl) pyrrolidin-l-yl) butyl dihydrogen phosphate ID-07
4- ( (R) -3- ( (3R, 6S, 9aS) -1- ( (E) -3- (4- (7-hydroxyhept-l-yn-l- yl) thiazol-2-yl) acryloyl) -3-isobutyl-6-neopentyl-4 , 7- dioxohexahydropyrazino [2, 1-c] [1,2,4] oxadiazin-8 (1H) - yl) pyrrolidin-l-yl) butyl dihydrogen phosphate ID-08
5- (2- ( (E) -3- ( (3R, 6S, 9aS) -3-isobutyl-8- ( 1- isopropylpiperidin-4-yl) -6-neopentyl-4 , 7- dioxohexahydropyrazino [2, 1-c] [1, 2,4] oxadiazin-1 (6H) -yl) -3- oxoprop-l-en-l-yl) thiazol-4-yl) pent-4-yn-l-yl dihydrogen phosphate
ID-09
6-(2-( (E)-3-( (3R,6S,9aS)-3-isobutyl-8-(l- isopropylpiperidin-4-yl) -6-neopentyl-4 , 7- dioxohexahydropyrazino [2, 1-c] [1,2,4] oxadiazin-1 (6H) -yl) -3- oxoprop-l-en-l-yl) thiazol-4-yl) hex-5-yn-l-yl dihydrogen phosphate
ID-10
2- ( (E) -3- ( (3R, 6S, 9aS) -3-isobutyl-8- ( 1-isopropylpiperidin- 4-yl) -6-neopentyl-4 , 7-dioxohexahydropyrazino [2, 1- c] [1, 2, 4] oxadiazin-1 (6H) -yl) -3-oxoprop-l-en-l- yl) benzo [d] thiazol-5-yl dihydrogen phosphate ID-11
2- ( (E) -3- ( (3R, 6S, 9aS) -8- (l-cyclopropylpiperidin-4-yl) -3- isobutyl-6-neopentyl-4, 7-dioxohexahydropyrazino [2, 1- c] [1,2,4] oxadia zin-1 ( 6H) -yl) -3 -oxoprop- 1-en-l- yl) benzo [d] thiazol-5-yl dihydrogen phosphate ID-12 4- ( (R) -3- ( (3R, 6S, 9aS) -1- ( (E) -3- (4- (5-hydroxypent-l-yn-l- yl) -5-methylthiazol-2-yl) acryloyl) -3-isobutyl-6-neopentyl-4 , 7- dioxohexahydropyrazino [2, 1-c] [1,2,4] oxadiazin-8 (1H) - yl) pyrrolidin-l-yl) butyl dihydrogen phosphate ID-13
4- ( (R) -3- ( (3R, 6S, 9aS) -1- ( (E) -3- ( 6-hydroxythiazolo [5, 4- b] pyridin-2-yl) acryloyl) -3-isobutyl-6-neopentyl-4 , 7- dioxohexahydropyrazino [2, 1-c] [1,2,4] oxadiazin-8 (1H) - yl) pyrrolidin-l-yl) butyl dihydrogen phosphate ID-14
4- ( (R) -3- ( (3R, 6S, 9aS) -3- (2-ethylbutyl) -6-neopentyl-4 , 7- dioxo-1- ( (E) -3- (quinoxalin-2-yl) acryloyl) hexahydropyrazino [2, 1- c] [1, 2, 4] oxadiazin-8 (1H) -yl) pyrrolidin-l-yl) butyl dihydrogen phosphate
ID-15
4- ( (R) -3- ( (3R, 6S, 9aS) -1- ( (E) -3- (4-cyano-5- (prop-l-yn-1- yl) thiazol-2-yl) acryloyl) -3- (2-ethylbutyl) -6-neopentyl-4 , 7- dioxohexahydropyrazino [2, 1-c] [1,2,4] oxadiazin-8 (1H) - yl) pyrrolidin-l-yl) butyl dihydrogen phosphate ID-16
4- ( (S) -3- ( (3R, 6S, 9aS) -1- ( (E) -3- (4 -hydroxybenzo [d] thiazol- 2-yl) acryloyl) -3-isobutyl-6-neopentyl-4 , 7- dioxohexahydropyrazino [2, 1-c] [1,2,4] oxadiazin-8 (1H) - yl) pyrrolidin-l-yl) butyl dihydrogen phosphate ID-17
2- ( (3- (2- ( (E) -3- ( (3R, 6S, 9aS) -3-isobutyl-8- (1- isopropylpiperidin-4-yl ) -6-neopentyl-4 , 7- dioxohexahydropyrazino [2, 1-c] [1,2,4] oxadiazin-1 (6H) -yl) -3- oxoprop-l-en-l-yl) thiazol-4-yl) prop-2-yn-l-yl) oxy) ethyl dihydrogen phosphate ID-18
6- (2- ( (E) -3- ( (3R, 6S, 9aS) -3- (cyclopropylmethyl) -8- (1- isopropylpiperidin-4-yl) -6-neopentyl-4 , 7- dioxohexahydropyrazino [2, 1-c] [1,2,4] oxadiazin-1 (6H) -yl) -3- oxoprop-l-en-l-yl) thiazol-4-yl) hex-5-yn-l-yl dihydrogen phosphate ID-19 5- (5-ethynyl-2- ( (E) -3- ( (3R, 6S, 9aS) -3-isobutyl-8- (1- isopropylpiperidin-4-yl) -6-neopentyl-4 , 7- dioxohexahydropyrazino [2, 1-c] [1,2,4] oxadiazin-1 (6H) -yl) -3- oxoprop-l-en-l-yl) thiazol-4-yl) pent-4-yn-l-yl dihydrogen phosphate ID-20
3- ( (2- ( (E) -3- ( (3R, 6S, 9aS) -3-isobutyl-8- ( 1- isopropylpiperidin-4-yl) -6-neopentyl-4 , 7- dioxohexahydropyrazino [2, 1-c] [1,2,4] oxadiazin-1 (6H) -yl) -3- oxoprop-l-en-l-yl ) benzo [d] thiazol-5-yl ) oxy) propyl dihydrogen phosphate ID-21
5- (5-ethynyl-2- ( (E) -3- ( (3R, 6S, 9aS) -3-isobutyl-8- (1- methylpiperidin-4-yl) -6-neopentyl-4 , 7- dioxohexahydropyrazino [2, 1-c] [1,2,4] oxadiazin-1 ( 6H) -yl) -3- oxoprop-l-en-l-yl) thiazol-4-yl) pent-4-yn-l-yl dihydrogen phosphate Experimental Example: MTS assay on Panc-1 (Human Pancreas Carcinoma cell line) (Materials and methods)
1. Cell cell line name: PANC-1 derived from: human pancreas glandular cancer purchased from: ATCC product code : CRL- 1469
2. Cell culture
2.1 Reagent for cell culture
D-MEM (High Glucose) with L-Glutamine and Phenol Red (Wako, Cat. No. : 044-29765) Fetal Bovine Serum (FBS; Life Technologies, Cat. No. : 26140-079) penicillin-streptomycin solution (*100) (Wako, Cat. No. : 168- 23191) lOxD-PBS (-) (Wako, Cat. No. : 048-29805) 0.25w/v% Trypsin-1 mmol/1 EDTA*4Na Solution with Phenol Red (Wako, Cat. No. : 201-16945)
2.2 Culture conditions
Respective cells were cultured under the following conditions. Where necessary, they were passaged. proliferation medium: D-MEM + 10% FBS culture environment : 37 °C, 5% CO2 seeding density: 5. 0 x 105 cells/25 cm2
2 . 3 Measurement sample solvent control substance : DMSO (HYBRI-MAX®, Sigma-Aldrich Corp . ) test substance : Example compound ( ID-01 - ID-13 )
A DMSO solution of the test substance was prepared by serially diluting (common ratio 2 ) each test substance with DMSO .
2 . 4 Measurement and analysis
A solvent control substance sample and a test substance sample were exposed to a human pancreatic cancer-derived cell line (PANC-1) , and the survival rate of the cell 6 days later was measured by the MTS method . The measurement was performed 3 times and the average thereof was adopted. The survival rate of the cell in each test substance sample was calculated by the following formula 1 with the value at exposure of the solvent control substance sample as 100% survival rate . survival rate ( % ) = 100*absorbance of each test substance sample/absorbance of solvent control substance sample formula 1
Normalized values calculated by the following formula 2 from the absorbances of each sample at 492 nm and 630 nm and the absorbances of the blank were used as the absorbances in the above-mentioned formula 1 . normalized value (ABS 492 nm-630 nm) = (ABSsa 492 nm-ABSsa 630 nm) - (ABSbl 492 nm-ABSbl 630 nm)
ABSsa 492 : absorbance of each sample at wavelength 492 nm ABSsa 630 : absorbance of each sample at wavelength 630 nm ABSbl 492 : absorbance of blank corresponding to each sample at wavelength 630 nm formula 2 The analysis was performed by using nplr package on R (The R Foundation for Statistical Computing) and estimating the logistic regression curve ( 4-parameter) .
The results are shown in Table 4 .
[Table 4 ]
Figure imgf000071_0001
[ INDUSTRIAL APPLICABILITY]
The compound of the present invention inhibits cancer cell proliferation, and thus can be used for treating diseases such as cancer . The compound of the present invention shows inhibitory activities on cancer cell proliferation by itself and also acts as a prodrug in vivo, showing anticancer activity in an in vivo mouse model . It is also highly soluble and can be administered intravenously.
Although only some exemplary embodiments of this invention have been described in detail above, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention . Accordingly, all such modifications are intended to be included within the scope of this invention .
This application is based on US provisional patent application No . 63/300, 324 ( filing date : January 18 , 2022 ) filed in US, the contents of which are incorporated in full herein .

Claims

1. A compound represented by the following formula ( I ) :
Figure imgf000072_0001
wherein
Q1 is represented by any of the following formulas ( II-l) to ( II- 6) :
Figure imgf000072_0002
wherein Q1a is a hydrogen atom, or 1 to 3 same or different alkyls, and * indicates a binding site; W1 is an optionally substituted alkylene or an optionally substituted cycloalkylene; X1 is -OPO3H2 or hydrogen atom;
R2 is an optionally substituted alkyl, an optionally substituted cycloalkylalkyl, or an optionally substituted arylalkyl ; Q3 is an optionally substituted divalent group derived from an aryl ring, or an optionally substituted divalent group derived from a heteroaryl ring;
W3 is a single bond, an optionally substituted alkylene, or an optionally substituted alkynylene; X3 is hydrogen atom or hydroxy when X1 is -OPO3H2, or is -OPO3H2 when X1 is hydrogen atom; R4 is an optionally substituted alkyl, or an optionally substituted cycloalkylalkyl ; and
R5 is a hydrogen atom, or an optionally substituted alkyl , or a pharmaceutically acceptable salt thereof .
2 . The compound according to claim 1 , wherein
Q1 is represented by any of the following formulas ( III-l) to ( III-3) :
Figure imgf000073_0001
(wherein * indicates a binding site) ;
R2 is an optionally substituted alkyl;
W3 is a single bond, or an optionally substituted alkynylene; Q3 is an optionally substituted divalent group derived from a heteroaryl ring; R4 is an optionally substituted alkyl ; and
R5 is a hydrogen atom, or a pharmaceutically acceptable salt thereof .
3. The compound according to claim 1 or 2 , wherein W1 is n-butylene, i-propylene or cyclopropylene;
R2 is neopentyl, Q3 is a divalent group derived from thiazole ring, benzothiazole ring, thiazolo [ 5, 4-b] pyridine ring, or quinoxaline ring; the thiazole ring, benzothiazole ring, thiazolo [5, 4-b] pyridine ring, or quinoxaline ring may be substituted by substituent ( s ) selected from a hydroxy group, a methyl group and a cyano group; and R4 is isobutyl or 2-ethylbutyl, or a pharmaceutically acceptable salt thereof .
4 . A pharmaceutical composition comprising a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof , and optionally a pharmaceutically acceptable carrier or diluent .
5. The pharmaceutical composition according to claim 4 , wherein the composition comprises an effective amount of the compound.
6. A method of treating or preventing a cancer, comprising administering to a subj ect in need thereof a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, in an amount effective to treat or prevent the cancer .
7 . A method of treating or preventing a cancer, comprising administering to a subj ect in need thereof a composition according to claim 4 , in an amount effective to treat or prevent the cancer .
8 . An agent for treating or preventing a cancer, comprising a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof .
9. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof for the use as a medicament for treating or preventing a cancer .
10. A compound according to claim 4 for the use as a medicament for treating or preventing a cancer.
PCT/JP2023/001813 2022-01-18 2023-01-17 Phosphoric acid derivatives WO2023140369A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009148192A1 (en) * 2008-06-06 2009-12-10 Prism Biolab Corporation Alpha helix mimetics and methods relating thereto
US20150175615A1 (en) * 2013-12-25 2015-06-25 Eisai R&D Management Co., Ltd. (6S,9aS)-N-Benzyl-6-[(4-hydroxyphenyl)methyl]-4,7-dioxo-8-(methyl)-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide compound
WO2022014724A1 (en) * 2020-07-16 2022-01-20 Prism BioLab Co., Ltd. Novel heterocyclic compounds
WO2022075486A1 (en) * 2020-10-10 2022-04-14 Prism BioLab Co., Ltd. Novel bicyclic compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009148192A1 (en) * 2008-06-06 2009-12-10 Prism Biolab Corporation Alpha helix mimetics and methods relating thereto
US20150175615A1 (en) * 2013-12-25 2015-06-25 Eisai R&D Management Co., Ltd. (6S,9aS)-N-Benzyl-6-[(4-hydroxyphenyl)methyl]-4,7-dioxo-8-(methyl)-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide compound
WO2022014724A1 (en) * 2020-07-16 2022-01-20 Prism BioLab Co., Ltd. Novel heterocyclic compounds
WO2022075486A1 (en) * 2020-10-10 2022-04-14 Prism BioLab Co., Ltd. Novel bicyclic compounds

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