WO2019235501A1 - Inhibiteur d'histone désacétylase - Google Patents

Inhibiteur d'histone désacétylase Download PDF

Info

Publication number
WO2019235501A1
WO2019235501A1 PCT/JP2019/022248 JP2019022248W WO2019235501A1 WO 2019235501 A1 WO2019235501 A1 WO 2019235501A1 JP 2019022248 W JP2019022248 W JP 2019022248W WO 2019235501 A1 WO2019235501 A1 WO 2019235501A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
substituted
unsubstituted
pharmaceutically acceptable
ring
Prior art date
Application number
PCT/JP2019/022248
Other languages
English (en)
Japanese (ja)
Inventor
孝禎 鈴木
幸裕 伊藤
敏史 東條
周作 内田
Original Assignee
塩野義製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 塩野義製薬株式会社 filed Critical 塩野義製薬株式会社
Publication of WO2019235501A1 publication Critical patent/WO2019235501A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a compound having a HDAC2 inhibitory action and useful as a therapeutic or prophylactic agent for diseases involving HDAC2, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing them.
  • Histone acetylation which is known as a representative example of epigenetics control, is controlled by the function of histone acetylase (HAT) and histone deacetylase (HDAC).
  • HAT histone acetylase
  • HDAC histone deacetylase
  • HDACs are known to use a variety of proteins such as histones as substrates, and HDACs based on histones are generally thought to negatively regulate the expression of specific gene regions by histone deacetylation. Yes.
  • HDACs control different gene groups for each subtype. It is known that HDAC2 belonging to class I is mainly involved in the control of gene groups related to nerve function. Non-clinical studies have shown that inhibition of HDAC2 enhances transcription of genes related to nerve function, resulting in enhancement of nerve function (Non-Patent Document 1). HDAC2 is known to be upregulated in Alzheimer's dementia patients and model mice. Therefore, it is suggested that HDAC2 may be involved in the formation of the disease state by excessively suppressing gene transcription in the nervous system (Non-patent Document 2). Furthermore, since it has been reported that specific inhibition of HDAC2 in Alzheimer's disease model mice has an effect of improving impaired cognitive function, HDAC2 is a promising drug discovery target for Alzheimer-type dementia.
  • Non-Patent Document 3 reports suggesting that HDAC2 is also associated with other neurological diseases such as schizophrenia and depression, and HDAC2 inhibitors are expected to be widely applicable to neurodegenerative and psychiatric disorders.
  • All HDAC inhibitors currently in clinical use are non-selective HDAC inhibitors that are indicated for cancer and inhibit multiple HDAC subtypes. These are known to cause side effects that are commonly observed with other anticancer agents, including thrombocytopenia. In order to clarify the mechanism of such side effects, a plurality of non-clinical studies have been conducted, and it has been revealed that inhibition of HDAC1 and 2 simultaneously causes suppression of cell proliferation (Non-patent Document 5).
  • Patent Documents 1 to 4 and Non-Patent Documents 6 to 8 describe HDAC inhibitors, but the substantially disclosed compounds have structures different from the compounds of the present invention.
  • An object of the present invention is a compound having a HDAC2 inhibitory action and preferably high HDAC2 / HDAC1 selectivity, and useful as a therapeutic or prophylactic agent for a disease related to HDAC2, or a pharmaceutically acceptable salt thereof, and the like It is to provide a pharmaceutical composition.
  • the present invention relates to the following.
  • R 1 is substituted or unsubstituted furyl, substituted or unsubstituted pyridyl, or halogen.
  • R 1 is substituted or unsubstituted furyl.
  • R 1 is a group represented by the following: Wherein n is an integer from 0 to 2; each R 3 is independently halogen or substituted or unsubstituted alkyl.
  • R 1 is a group represented by the following: (In the formula, each symbol has the same meaning as (4) above) The compound according to (1) above, or a pharmaceutically acceptable salt thereof. (6) The compound according to (4) or (5) above, wherein n is 0, or a pharmaceutically acceptable salt thereof. (7) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (6), wherein -L- is -SO 2- . (8) The compound according to any one of (1) to (7) above, wherein R 2 is phenyl, or a pharmaceutically acceptable salt thereof. (9) Compounds shown below: Or a pharmaceutically acceptable salt thereof. (10) A pharmaceutical composition comprising the compound according to any one of (1) to (9) above, or a pharmaceutically acceptable salt thereof. (11) The pharmaceutical composition according to the above (10), which is an HDAC2 inhibitor. (12) An HDAC2 inhibitor comprising the compound according to any one of (1) to (9) above, or a pharmaceutically acceptable salt thereof.
  • the compound according to the present invention has an inhibitory action on HDAC2, and is useful as a therapeutic and / or prophylactic agent for diseases involving HDAC2.
  • Halogen includes fluorine atom, chlorine atom, bromine atom, and iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.
  • Alkyl includes straight or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , Isooctyl, n-nonyl, n-decyl and the like.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. Further preferred examples include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
  • Alkenyl has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl Etc.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl and butenyl.
  • Alkynyl has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Furthermore, you may have a double bond in arbitrary positions. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
  • Alkylene is a straight or branched divalent hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Includes groups. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
  • alkenylene refers to a carbon number of 2 to 15, preferably 2 to 10, more preferably 2 to 6 and even more preferably 2 to 4 having one or more double bonds at an arbitrary position. And a linear or branched divalent hydrocarbon group.
  • vinylene, propenylene, butenylene, pentenylene, hexenylene and the like can be mentioned.
  • Alkynylene refers to carbon atoms of 2 to 15, preferably 2 to 10, more preferably 2 to 6, more preferably 2 to 4 carbon atoms having one or more triple bonds at any position.
  • a linear or branched divalent hydrocarbon group is included.
  • aromatic carbocyclic group means a cyclic aromatic hydrocarbon group having one or more rings.
  • aromatic carbocyclic group includes phenyl.
  • aromatic carbocycle means a ring derived from the above “aromatic carbocyclic group”.
  • a preferred embodiment of the “aromatic carbocycle” includes a benzene ring.
  • non-aromatic carbocyclic group means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings.
  • the “non-aromatic carbocyclic group” having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more non-aromatic carbocyclic groups.
  • the “non-aromatic carbocyclic group” includes a group which forms a bridge as described below or a group which forms a spiro ring.
  • the monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms.
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like can be mentioned.
  • the non-aromatic carbocyclic group having 2 or more rings preferably has 8 to 20 carbon atoms, more preferably 8 to 16 carbon atoms.
  • 8 to 20 carbon atoms more preferably 8 to 16 carbon atoms.
  • indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned.
  • Non-aromatic carbocyclic ring means a ring derived from the above “non-aromatic carbocyclic group”.
  • “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring To do.
  • the aromatic heterocyclic group having two or more rings includes those in which the ring in the above “aromatic carbocyclic group” is condensed to a monocyclic or two or more aromatic heterocyclic groups, You may have in any ring.
  • the monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members.
  • Examples of the 5-membered aromatic heterocyclic group include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, and the like.
  • Examples of the 6-membered aromatic heterocyclic group include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like.
  • the bicyclic aromatic heterocyclic group is preferably 8 to 10 members, more preferably 9 or 10 members.
  • indolyl isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazoazolyl, benzoxadiazolyl, benzoisodiazolyl Ril, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl, etc.
  • the aromatic heterocyclic group having 3 or more rings is preferably 13 to 15 members.
  • Examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.
  • “Aromatic heterocycle” means a ring derived from the above “aromatic heterocyclic group”.
  • the monocyclic aromatic heterocyclic ring is preferably 5 to 8 members, more preferably 5 or 6 members.
  • Examples of the 5-membered aromatic heterocycle include pyrroline ring, imidazoline ring, pyrazoline ring, triazole ring, tetrazole ring, furan ring, thiophene ring, isoxazole ring, oxazole ring, oxadiazole ring, isothiazole ring, thiazole ring. And thiadiazole ring.
  • 6-membered aromatic heterocycle examples include a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, and a triazine ring.
  • the bicyclic aromatic heterocyclic group is preferably 8 to 10 members, more preferably 9 or 10 members.
  • the aromatic heterocycle having 3 or more rings is preferably 13 to 15 members.
  • Examples thereof include a carbazole ring, acridine ring, xanthene ring, phenothiazine ring, phenoxathiin ring, phenoxazine ring, dibenzofuran ring and the like.
  • Non-aromatic heterocyclic group means a monocyclic or bicyclic or more non-aromatic cyclic group having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring Means.
  • the non-aromatic heterocyclic group having 2 or more rings is a monocyclic or 2 or more non-aromatic heterocyclic group, the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and / Or each condensed ring in the “aromatic heterocyclic group” is condensed, and further, the ring in the above “aromatic heterocyclic group” is condensed to a monocyclic or two or more non-aromatic carbocyclic group The bond may be present in any ring.
  • non-aromatic heterocyclic group includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members.
  • Examples of the 3-membered non-aromatic heterocyclic group include thiranyl, oxiranyl, and aziridinyl.
  • Examples of the 4-membered non-aromatic heterocyclic group include oxetanyl and azetidinyl.
  • Examples of the 5-membered non-aromatic heterocyclic group include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, thiolanyl and the like. Can be mentioned.
  • 6-membered non-aromatic heterocyclic group examples include dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl , Hexahydropyrimidinyl, dioxazinyl, thiinyl, thiazinyl and the like.
  • Examples of the 7-membered non-aromatic heterocyclic group include hexahydroazepinyl, tetrahydrodiazepinyl, and oxepanyl.
  • the non-aromatic heterocyclic group having 2 or more rings is preferably 8 to 20 members, more preferably 8 to 10 members.
  • indolinyl, isoindolinyl, chromanyl, isochromanyl and the like can be mentioned.
  • Non-aromatic heterocyclic ring means a ring derived from the above “non-aromatic heterocyclic group”.
  • Trialkylsilyl means a group in which the above three “alkyls” are bonded to a silicon atom.
  • the three alkyl groups may be the same or different.
  • trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.
  • alkyloxy has the same meaning as the above “alkyl”.
  • alkenyl part of “alkenyloxy”, “alkenylcarbonyloxy”, “alkenylcarbonyl”, “alkenyloxycarbonyl”, “alkenylsulfanyl”, “alkenylsulfinyl” and “alkenylsulfonyl” has the same meaning as the above “alkenyl”.
  • alkynyl part of “alkynyloxy”, “alkynylcarbonyloxy”, “alkynylcarbonyl”, “alkynyloxycarbonyl”, “alkynylsulfanyl”, “alkynylsulfinyl” and “alkynylsulfonyl” has the same meaning as the above “alkynyl”.
  • substituent of “substituted alkyl” include the following substituent group ⁇ .
  • the carbon atom at any position may be bonded to one or more groups selected from the following substituent group ⁇ .
  • Substituent group ⁇ halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, cyano, and nitro.
  • Substituent group B halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, penta Fluorothio, trialkylsilyl, Alkyloxy optionally substituted with substituent group ⁇ , alkenyloxy optionally substituted with substituent group ⁇ , alkynyloxy optionally substituted with substituent group ⁇ , substituted with substituent group ⁇ Alkylcarbonyloxy which may be substituted, alkenylcarbonyloxy which may be substituted with substituent group ⁇ , alkynylcarbonyloxy which may be substituted with substituent group ⁇ , alkylcarbonyl which may be substituted with substituent
  • substituent of the ring constituent atom of “cyclohexenyl” of “substituted cyclohexenyl” include the following substituent group C. Any ring-constituting atom may be bonded to one or more groups selected from the following substituent group C. Substituent group C: each substituent and oxo defined as substituent group B.
  • non-aromatic carbocycle When “non-aromatic carbocycle”, “non-aromatic heterocycle”, “non-aromatic carbocyclic group” and “non-aromatic heterocyclic group” are substituted with “oxo”, as follows: It means a ring in which two hydrogen atoms on a carbon atom are substituted.
  • R 1 , R 2 and -L- in the compound represented by the formula (I) are shown below.
  • Examples of the compound represented by the formula (I) include all combinations of the specific examples shown below.
  • R 1 is a hydrogen atom, halogen, substituted or unsubstituted furyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyridyl, substituted or unsubstituted phenyl Or substituted or unsubstituted cyclohexenyl (hereinafter referred to as A-1).
  • R 1 is a hydrogen atom, halogen, substituted or unsubstituted furyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrrolyl, substituted thienyl, substituted or unsubstituted pyridyl, substituted or unsubstituted phenyl, or substituted or Unsubstituted cyclohexenyl (hereinafter referred to as A-2).
  • R 1 is preferably substituted or unsubstituted furyl, substituted or unsubstituted pyridyl, or halogen. (Hereinafter referred to as A-3).
  • R 1 is more preferably substituted or unsubstituted furyl (hereinafter referred to as A-4).
  • R 1 is more preferably furyl optionally substituted with one or more groups selected from substituent group B (hereinafter referred to as A-5).
  • R 1 is particularly preferably a group shown below: (Wherein n is an integer of 0 to 2; each R 3 is independently halogen or substituted or unsubstituted alkyl) (hereinafter referred to as A-6).
  • R 1 is particularly preferably a group shown below: (Wherein n is an integer of 0 to 2; each R 3 is independently an alkyl optionally substituted with a substituent group ⁇ , or a halogen) (Hereinafter referred to as A-7).
  • R 1 is particularly preferably a group shown below: (Wherein n and R 3 are the same as A-6) (hereinafter referred to as A-8). R 1 is particularly preferably a group shown below: Wherein n is 0 or 1, and R 3 is alkyl optionally substituted with substituent group ⁇ , Or halogen) (hereinafter referred to as A-9). R 1 is particularly preferably a group shown below: (Hereinafter referred to as A-10). R 1 is particularly preferably a group shown below: (Hereinafter referred to as A-11).
  • —L— is —SO 2 —, —SO—, —S—, or —CH 2 — (hereinafter referred to as B-1).
  • B-1 —L— is preferably —SO 2 —, —SO—, or —S— (hereinafter referred to as B-2).
  • B-2 —SO—
  • B-3 —L— is preferably —CH 2 — (hereinafter referred to as B-4).
  • —L— is particularly preferably —SO 2 — (hereinafter referred to as B-5).
  • R 2 is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 6-membered aromatic heterocyclic group (hereinafter referred to as C-1).
  • R 2 is preferably phenyl optionally substituted with one or more groups selected from substituent group B, or 6-membered optionally substituted with one or more groups selected from substituent group B
  • An aromatic heterocyclic group hereinafter referred to as C-2).
  • R 2 is more preferably substituted or unsubstituted phenyl (hereinafter referred to as C-3).
  • R 2 is particularly preferably phenyl optionally substituted with one or more groups selected from Substituent Group B (hereinafter referred to as C-4).
  • R 2 is particularly preferably phenyl (hereinafter referred to as C-5).
  • the compounds of formula (I) are not limited to specific isomers, but all possible isomers (eg keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers) , Rotamers, etc.), racemates or mixtures thereof.
  • One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively.
  • isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compound represented by the formula (I) also includes a compound substituted with such an isotope.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I).
  • a “radiolabeling method” for producing the “radiolabeled substance” is also encompassed in the present invention, and the “radiolabeled substance” is useful as a metabolic pharmacokinetic study, a research in a binding assay, and / or a diagnostic tool. It is.
  • the radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art.
  • the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by catalytic dehalogenation reaction using tritium. In this method, a tritium gas is reacted with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that.
  • Other suitable methods for preparing tritium labeled compounds can be referred to “Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”.
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • Examples of the pharmaceutically acceptable salt of the compound represented by the formula (I) include, for example, a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), Calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, Quinoline etc.) and amino acid salts, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, propionic acid) , Trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, Maleic acid, fumaric acid, mandelic
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.), a co-crystal and / or a crystal polymorph.
  • a solvate for example, hydrate etc.
  • co-crystals and polymorphs may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I).
  • solvent molecules for example, water molecules
  • a crystal polymorph may be formed by recrystallizing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • “Co-crystal” means that the compound or salt represented by the formula (I) and the counter molecule are present in the same crystal lattice, and may contain any number of counter molecules.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • a prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included.
  • a method for selecting and producing an appropriate prodrug derivative is described in, for example, “Design of Prodrugs, Elsevier, Amsterdam, 1985”. Prodrugs may themselves have activity.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group
  • prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or by reacting with a condensing agent.
  • the compound represented by the formula (I) can be produced, for example, by the general synthesis method shown below. Any of the starting materials and reaction reagents used in these syntheses are commercially available or can be prepared according to methods well known in the art using commercially available compounds. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
  • the compounds of the present invention can be synthesized with reference to techniques known in the art. In the following steps, when there are substituents that hinder the reaction (for example, hydroxy, mercapto, amino, formyl, carbonyl, carboxyl, etc.), Protective Groups in Organic Synthesis, Theodora W Greene (John Wiley & Sons), etc.
  • reaction time reaction temperature, solvent, reagent, protecting group, etc. are all merely examples, and are not particularly limited as long as the reaction is not hindered.
  • the compound represented by the formula (I) can be produced, for example, by the following synthesis route.
  • dicyclohexylcarbodiimide carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDCI, 4- (4,6-dimethoxy-1,3,5, -triazin-2-yl) -4-
  • Examples thereof include methylmorpholinium chloride and HATU, and 1 to 5 molar equivalents can be used with respect to compound (ii).
  • the reaction temperature is ⁇ 20 ° C. to 60 ° C., preferably 0 ° C. to 30 ° C.
  • the reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
  • the reaction solvent include DMF, DMA, NMP, tetrahydrofuran, dioxane, dichloromethane, acetonitrile and the like, and these can be used alone or in combination.
  • Compound (v) can be obtained by reacting compound (iv) with compound (iii) in the presence of a metal catalyst and an additive.
  • a metal catalyst include copper (II) sulfate pentahydrate, copper (II) acetate, Ru (OAc) 2 (PPh 3 ) 2 , RuCl 2 (PPh 3 ) 3 and the like, with respect to compound (iii) 0.001 to 1.0 molar equivalent can be used.
  • additives include sodium ascorbate, tris [(1-benzyl-1H-1,2,3-triazol-4-yl) methyl] amine, tetrabutylammonium bromide, tetrabutylammonium iodide, etc. 1 to 10 molar equivalents can be used with respect to (iii).
  • Compound (iv) can be used at 1 to 10 molar equivalents relative to compound (iii).
  • the reaction temperature is 0 ° C. to the reflux temperature of the solvent, and optionally under microwave irradiation.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • reaction solvent examples include tetrahydrofuran, toluene, DMF, dioxane, dimethyl sulfoxide, acetonitrile, methanol, ethanol, water and the like, and these can be used alone or in combination.
  • Compound (vii) can be obtained by reacting compound (v) with boronic acid (vi) in the presence of a metal catalyst and a base.
  • a metal catalyst include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium and the like. 0.001 to 0.5 molar equivalent can be used with respect to compound (v).
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, phosphorus
  • Examples thereof include potassium oxyhydrogen, and 1 to 10 molar equivalents can be used with respect to compound (v).
  • Boronic acid (vi) can be used in an amount of 1 to 10 molar equivalents relative to compound (v).
  • the reaction temperature is 20 ° C. to the reflux temperature of the solvent, and optionally under microwave irradiation.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • the reaction solvent include tetrahydrofuran, toluene, DMF, dioxane, water and the like, and these can be used alone or in combination.
  • Compound (I) can be obtained by reacting compound (vii) with an acid or a Lewis acid.
  • the acid include hydrochloric acid-ethyl acetate, hydrochloric acid-methanol, hydrochloric acid-dioxane, sulfuric acid, formic acid, trifluoroacetic acid and the like.
  • the Lewis acid include trimethylsilyl iodide, BBr 3 , AlCl 3 , BF 3. (Et 2 O) and the like, and 1 to 10 molar equivalents can be used with respect to the compound (vii).
  • the reaction temperature is 0 ° C. to 60 ° C., preferably 0 ° C. to 20 ° C.
  • the reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
  • the reaction solvent include methanol, ethanol, water, acetone, acetonitrile, DMF and the like, and these can be used alone or in combination.
  • the method described in Journal of Medicinal Chemistry 2012, Vol. 55, pages 9562-9575 can be used as a reference.
  • the compound according to the present invention has an HDAC2 inhibitory action, it is useful as a therapeutic and / or prophylactic agent for diseases involving HDAC2.
  • the term “therapeutic agent and / or prophylactic agent” includes a symptom improving agent.
  • the disease involving HDAC2 include cancer and neurological disease, and preferably neurological disease.
  • the neurological diseases include central nervous diseases (for example, neurodegenerative diseases).
  • central nervous system diseases include Alzheimer's disease, Alzheimer's dementia, Alzheimer's senile dementia, mild cognitive impairment (MCI), memory loss, attention deficit symptoms related to Alzheimer's disease, neurodegeneration related to Alzheimer's disease, mixed Dementia of mixed vascular origin, dementia of degenerative origin, presenile dementia, senile dementia, dementia related to Parkinson's disease, vascular dementia, frontotemporal dementia, stroke , Progressive supranuclear palsy, cerebral cortex basal ganglia degeneration, schizophrenia, delirium, attention, deficit disorder (ADD), schizophrenic disorder, Rubinstein-Tevi syndrome, depression, mania, attention deficit disorder, drug epilepsy , Dementia, autism, fierceness, blunt emotion, anxiety, post-traumatic stress disorder (PTSD), psychosis, Examples include personality disorder, bipolar disorder, unipolar affective disorder, obsessive compulsive disorder, eating disorder, post-traumatic stress disorder, hypersensitivity, adolescent behavioral disorder and disinhibition, particularly preferably Alzheimer'
  • the compound of the present invention has not only an HDAC2 inhibitory action but also a usefulness as a medicine, and has any or all of the following excellent characteristics.
  • the rate constant k ⁇ 1 (HDAC2 k ⁇ 1 ) in HDAC2 inhibition is smaller than the rate constant k ⁇ 1 (HDAC1 k ⁇ 1 ) in HDAC1 inhibition.
  • the rate constant k ⁇ 2 (HDAC2 k ⁇ 2 ) in HDAC2 inhibition is smaller than the rate constant k ⁇ 2 (HDAC1 k ⁇ 2 ) in HDAC1 inhibition.
  • the inhibitory effect on CYP enzymes is weak.
  • CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc. is weak.
  • Good pharmacokinetics such as high bioavailability and moderate clearance.
  • composition of the present invention can be administered either orally or parenterally.
  • parenteral administration include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop, and intravaginal administration.
  • solid preparations for internal use eg, tablets, powders, granules, capsules, pills, films, etc.
  • liquids for internal use eg, suspensions, emulsions, elixirs, syrups
  • the tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, and powders and granules are dry syrups
  • the capsule may be a soft capsule, a microcapsule or a sustained release capsule.
  • injections, drops, external preparations eg eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coating agents, mouthwashes, enemas
  • Any commonly used dosage form such as an ointment, a plaster, a jelly, a cream, a patch, a patch, a powder for external use, a suppository and the like can be suitably administered.
  • the injection may be an emulsion such as O / W, W / O, O / W / O, W / O / W type.
  • Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
  • the pharmaceutical composition can be obtained by changing the effective amount, dosage form and / or various pharmaceutical additives of the compound of the present invention as appropriate, so that it can be used for pediatric, elderly, critically ill patients or surgery. You can also
  • the pediatric pharmaceutical composition is preferably administered to a patient under the age of 12 or 15 years. Also, the pediatric pharmaceutical composition can be administered to patients less than 27 days after birth, 28 to 23 months after birth, 2 to 11 years old, or 12 to 17 years old or 18 years old.
  • the elderly pharmaceutical composition is preferably administered to a patient over 65 years of age.
  • the dose of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc., but when administered orally, usually 0.05 to 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day.
  • parenteral administration although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
  • the compound of the present invention can be used in combination with a concomitant drug for the purpose of enhancing the action of the compound or reducing the dose of the compound.
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference.
  • Proton nuclear magnetic resonance spectra 1 H NMR
  • carbon nuclear magnetic resonance spectra 13 C NMR
  • the chemical shift ( ⁇ ) is expressed in parts per million compared to the internal standard tetramethylsilane.
  • Electrospray ionization (ESI) mass spectra were recorded on a BRUKER HCTplus mass spectrometer. Reagents and solvents were purchased from Aldrich, Merck, Nacalai Tesque, Tokyo Chemical Industry, Wako Pure Chemical Industries, Kishida Chemical, Kanto Chemical, and used without purification. Flash column chromatography was performed using silica gel purchased from Merck silica gel. Further, when NMR data is shown, there are cases where not all measured peaks are described.
  • Step 1 Synthesis of Compound 27 To a solution of compound 24 (157.7 mg, 1.08 mmol) in N, N-dimethylformamide (10 ml), compound 26 (353.8 mg, 3.27 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide Hydrochloride (271.3 mg, 1.42 mmol) and 1-hydroxybenzotriazole monohydrate (176.2 mg, 1.30 mmol) were added, and the mixture was stirred at room temperature for 13 hours. The reaction solution was diluted with a saturated aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated.
  • Step 2 Synthesis of Compound I-001 In a mixed solvent of dimethyl sulfoxide (8 mL) and water (2 mL), compound 27 (173.2 mg, 0.733 mmol), copper (II) sulfate pentahydrate (95.1 mg, 0.381 mmol), sodium ascorbate ( 151.6 mg, 0.765 mmol) and compound 25 (221.3 mg, 1.12 mmol) were added and stirred at 50 ° C. for 13 hours. The reaction mixture was filtered through a Celite (registered trademark) pad, brine was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated.
  • Celite registered trademark
  • Step 1 Synthesis of Compound 19 To a tetrahydrofuran solution (15 ml) of compound 18 (3.013 g, 13.8 mmol) was added di-tert-butyl dicarbonate (6.053 g, 27.7 mmol) and dimethylaminopyridine (348.1 mg, 2.850 mmol). The mixture was further stirred at room temperature for 18 hours. The reaction mixture was concentrated, tetrahydrofuran (15 mL) and 2 mol / L aqueous sodium hydroxide solution (15 mL) were added to the obtained residue, and the mixture was heated with stirring under reflux for 3 hr.
  • di-tert-butyl dicarbonate 6.053 g, 27.7 mmol
  • dimethylaminopyridine 348.1 mg, 2.850 mmol
  • Step 3 Synthesis of Compound 21
  • Compound 20 (256.1 mg, 0.892 mmol) in N, N-dimethylformamide solution (10 ml) was added compound 24 (151.8 mg, 1.04 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Salt (232.5 mg, 1.21 mmol) and 1-hydroxybenzotriazole monohydrate (151.3 mg, 1.12 mmol) were sequentially added, and the mixture was stirred at room temperature for 13.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated.
  • Step 4 Synthesis of Compound 22 To a mixed solvent of dimethyl sulfoxide (8 mL) and water (2 mL), compound 21 (326.4 mg, 0.786 mmol), copper (II) sulfate pentahydrate (93.6 mg, 0.375 mmol), sodium ascorbate ( 144.3 mg, 0.728 mmol) and compound 25 (227.5 mg, 1.15 mmol) were added and stirred at 50 ° C. for 18.5 hours. The reaction mixture was filtered through a Celite (registered trademark) pad, brine was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated.
  • Celite registered trademark
  • Step 5 Synthesis of Compound I-012
  • sodium carbonate 68.4 mg, 0.645 mmol
  • tri (o-tolyl) phosphine 26.0 mg, 0.0854 mmol
  • 2-furanylboronic acid 62.1 mg, 0.555 mmol
  • Nitrogen gas was blown into the reaction solution for 5 minutes, tetrakis (triphenylphosphine) palladium (30.6 mg, 0.0265 mmol) was added, and the mixture was heated to reflux for 17 hours.
  • the rate constant and the rate constant k- 2 indicate the rate constant when returning from the stable complex to the original complex. Furthermore, K i represents an inhibition constant, and K i * represents an apparent inhibition constant when a structural change occurs in a more stable complex after formation of the enzyme-inhibitor complex.
  • HDAC1 (SignalChem, H83-30G), HDAC2 (SignalChem, H84-30G), fluorescent substrate (AcLGK (Ac) -AMC), kinetic HDAC assay developer (BPS, # 53029), HDAC assayBPS # 5 Using. Using an HDAC assay buffer, a 2 ng / ⁇ L enzyme solution and a developer solution (diluted 20 times) were prepared.
  • a fluorescent substrate was dissolved using an assay buffer containing 5% DMSO to prepare a 200 ⁇ M substrate solution.
  • an inhibitor solution was prepared using an assay buffer containing 10% DMSO.
  • 20 ⁇ L of the enzyme solution was added to a mixture of 10 ⁇ L of the inhibitor solution, 20 ⁇ L of the substrate solution, and 50 ⁇ L of the developer solution.
  • the release of the fluorophore in each well was detected by measuring the fluorescence and continuously recorded every 2 minutes.
  • Grapfit 7.0 software the concentration of the enzyme reaction product was calculated using fluorescence data obtained by subtracting the background value, and it was confirmed whether the calculated value could be approximated to equation (2).
  • CYP inhibition test O-deethylation of 7-ethoxyresorufin (CYP1A2), a typical substrate metabolic reaction of the major human CYP5 species (CYP1A2, 2C9, 2C19, 2D6, 3A4), Methyl-hydroxylation (CYP2C9), mephenytoin 4′-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadine hydroxylation (CYP3A4) are used as indicators. The degree of inhibition by the compound of the present invention is evaluated.
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points) .
  • resorufin CYP1A2 metabolite
  • a fluorescent multilabel counter or LC / MS / MS
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxylated The body (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite) are quantified by LC / MS / MS. The dilution concentration and the dilution solvent are changed as necessary.
  • a control solution (100%) was obtained by adding only DMSO, which is a solvent in which the compound was dissolved, instead of the compound of the present invention to the reaction solution, and the residual activity (%) was calculated.
  • IC 50 is calculated by inverse estimation.
  • the CYP3A4 inhibition of the compound of the present invention is a test for evaluating the mechanism based inhibition (MBI) ability from the enhancement of the inhibitory action resulting from the metabolic reaction of the compound of the present invention. Pooled human liver microsomes are used to evaluate CYP3A4 inhibition using midazolam (MDZ) 1-hydroxylation as an indicator.
  • MBI mechanism based inhibition
  • reaction conditions are as follows: substrate, 10 ⁇ mol / L MDZ; pre-reaction time, 0 or 30 minutes; substrate metabolic reaction time, 2 minutes; reaction temperature, 37 ° C .; pooled human liver microsomes, 0.5 mg / mL during pre-reaction, 0.05 mg / mL at the time of reaction (at 10-fold dilution); concentration at the time of pre-reaction of the compound of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points).
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound was dissolved, instead of the compound of the present invention to the reaction solution, and calculating the residual activity (%) when each concentration of the compound of the present invention was added, Using the concentration and the inhibition rate, IC is calculated by inverse estimation using a logistic model.
  • Preincubation 0 min IC / Preincubation 30 min IC is the Shifted IC value, and if the Shifted IC is 1.5 or more, it is “Positive”, and if the Shifted IC is 1.0 or less, it is “Negative”.
  • Administration method Oral administration is forcibly administered into the stomach with an oral sonde. Intravenous administration is performed from the tail vein using a syringe with an injection needle.
  • Evaluation item Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS.
  • Statistical analysis The plasma concentration-time curve area (AUC) was calculated by the non-linear least square method for plasma compound concentration transition, and the dose ratio and AUC ratio of the oral administration group and intravenous administration group were calculated. From the above, the bioavailability (BA) of the compound of the present invention is calculated. The dilution concentration and the dilution solvent are changed as necessary.
  • Test Example 6 Metabolic stability test
  • a commercially available pooled human liver microsome is reacted with the compound of the present invention for a certain period of time, and the residual ratio is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver.
  • a commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver.
  • the compound of the present invention in the supernatant was quantified by LC / MS / MS or solid phase extraction (SPE) / MS, and the remaining amount of the compound of the present invention after the reaction was defined as 100% at 0 minutes. calculate.
  • the hydrolysis reaction is carried out in the absence of NADPH, the glucuronic acid conjugation reaction is carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation is carried out thereafter.
  • the dilution concentration and dilution solvent are changed as necessary.
  • Micro F buffer (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, citrate Bacteria were suspended in sodium dihydrate: 0.25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L, and 120 mL Exposure medium (biotin: 8 ⁇ g / mL, histidine: 0.2 ⁇ g / mL, Glucose: MicroF buffer containing 8 mg / mL). For the TA100 strain, add 3.10 to 3.42 mL of bacterial solution to 120 to 130 mL of Exposure medium to prepare a test bacterial solution.
  • Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at a 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 ⁇ g / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 ⁇ L of the test bacterial solution (under the metabolic activation conditions, 498 ⁇ L of the test bacterial solution and S9 mix 90 ⁇ L of the mixture) and incubate with shaking at 37 ° C.
  • the cell was held at a membrane potential of ⁇ 80 mV by the whole cell patch clamp method, and after giving a leak potential of ⁇ 50 mV, depolarization stimulation of +20 mV for 2 seconds, further records the I Kr induced repolarization stimulated when given 2 seconds -50 mV.
  • the extracellular solution in which the compound of the invention is dissolved at the target concentration is applied to the cells for 7 minutes or longer at room temperature.
  • the absolute value of the maximum tail current is measured based on the current value at the holding membrane potential by using analysis software (QPatch Assay software; Sophion Bioscience A / S). Further, the maximum tail current after application of the compound of the present invention relative to the maximum tail current after application of the medium is calculated as an inhibition rate, and the influence of the compound of the present invention on I Kr is evaluated. The dilution concentration and the dilution solvent are changed as necessary.
  • the composition of JP-1 solution is as follows. Add water to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL.
  • the composition of JP-2 solution is as follows. 1 volume of water is added to 1 volume of 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water to 1000 mL.
  • Test Example 8 Powder solubility test
  • JP-1 solution 2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to make 1000 mL
  • JP-2 solution potassium dihydrogen phosphate 3 .40 g and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water to make 1000 mL, add 1 volume of water to 1 volume
  • 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (1.08 g of TCA to JP -2 solution is added to make 100 mL) 200 ⁇ L at a time.
  • the compound of the present invention When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C. for 1 hour, the mixture is filtered, and 100 ⁇ L of methanol is added to 100 ⁇ L of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Check for bubbles and deposits, seal and shake. The compound of the present invention is quantified using HPLC by the absolute calibration curve method. The dilution concentration and the dilution solvent are changed as necessary.
  • Test Example 9 The mutagenicity of the compound of the present invention is evaluated by the Ames test using Salmonella typhimurium TA98, TA100, TA1535, TA1537, and Escherichia coli WP2uvrA as test strains.
  • Salmonella typhimurium TA98, TA100, TA1535, TA1537, and Escherichia coli WP2uvrA as test strains.
  • a DMSO solution of the compound of the present invention 0.5 mL of S9mix is mixed under metabolic activation conditions, and 0.5 mL of a phosphate buffer and 0.1 mL of a test bacterial solution are mixed under non-metabolic activation conditions, and histidine and biotin are mixed.
  • Test Example 10 Photohemolysis test
  • the compound of the present invention is dissolved at a desired concentration, and mixed with 0.1 to 0.0008% concentration of erythrocyte suspension (2.5 v / v%) prepared from sheep defibrinated blood on a microplate, and ultraviolet fluorescent.
  • Light irradiation (10 J / cm 2 , 290 to 400 nm) was performed in the UVA and UVB regions using a lamp (GL20SE lamp, Sankyo Electric and FL20S-BLB lamp, Panasonic). Collect the mixture after the light irradiation and centrifuge.
  • the supernatant after centrifugation is collected and transferred to a microplate, and then the absorbance (540 or 630 nm) of the supernatant is measured and a determination based on the absorbance is performed.
  • Absorbance at 540 and 630 nm is an indicator of biological membrane damage (photohemolysis rate%) and lipid membrane peroxidation (methemoglobin production), respectively.
  • the case where the photohemolysis rate is less than 10% and the amount of change in absorbance at 630 nm is less than 0.05 is ( ⁇ )
  • the photohemolysis rate is 10% or more
  • the amount of change in absorbance at 630 nm is 0.
  • the case of 05 or more is defined as (+).
  • the compound of the present invention is added to one side of a transwell (registered trademark, CORNING) obtained by monolayer culture of human MDR1-expressing cells or parent cells, and allowed to react for a certain period of time.
  • a transwell registered trademark, CORNING
  • the membrane permeability coefficient was calculated from the axial side to the basolateral side (A ⁇ B) and from the basolateral side to the apical side (B ⁇ A), and the Efflux Ratio (ER; Calculate the ratio of B ⁇ A and A ⁇ B membrane permeability coefficient).
  • the Efflux Ratio (ER value) between the MDR1-expressing cell and the parent cell is compared to determine whether the compound of the present invention is a P-gp substrate.
  • the compounds of the invention may be administered topically by any conventional route, in particular enterally, for example orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injections or suspensions.
  • it can be administered as a pharmaceutical composition in the form of a lotion, gel, ointment or cream, or in the form of a nasal or suppository.
  • a pharmaceutical composition comprising a compound of the invention in free form or in the form of a pharmaceutically acceptable salt, together with at least one pharmaceutically acceptable carrier or diluent, is mixed in a conventional manner, It can be produced by granulation or coating methods.
  • an oral composition can be a tablet, granule, or capsule containing an excipient, a disintegrant, a binder, a lubricant and the like and an active ingredient.
  • the injectable composition may be a solution or suspension, may be sterilized, and may contain preservatives, stabilizers, buffering agents, and the like.
  • the compound according to the present invention has an HDAC2 inhibitory action and is considered to be useful as a therapeutic and / or prophylactic agent for diseases or conditions involving HDAC2.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un nouveau composé ayant une activité inhibitrice de HDAC2. L'invention concerne un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci. (Dans la formule, R1 représente un atome d'hydrogène, un atome d'halogène, un groupe furyle substitué ou non substitué, ou similaire ; -L- représente -SO2-, -SO-, -S- ou -CH2- ; et R2 représente un groupe phényle substitué ou non substitué, ou un groupe hétérocyclique aromatique à six chaînons substitué ou non substitué.)
PCT/JP2019/022248 2018-06-06 2019-06-05 Inhibiteur d'histone désacétylase WO2019235501A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2018108464 2018-06-06
JP2018-108464 2018-06-06

Publications (1)

Publication Number Publication Date
WO2019235501A1 true WO2019235501A1 (fr) 2019-12-12

Family

ID=68770962

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2019/022248 WO2019235501A1 (fr) 2018-06-06 2019-06-05 Inhibiteur d'histone désacétylase

Country Status (1)

Country Link
WO (1) WO2019235501A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011089995A1 (fr) * 2010-01-21 2011-07-28 公立大学法人名古屋市立大学 Dérivé de l'acide hydroxamique et inhibiteur de hdac8 l'utilisant
JP2012510512A (ja) * 2008-12-03 2012-05-10 マサチューセッツ インスティテュート オブ テクノロジー 記憶を推進するためのｈｄａｃ２の阻害
JP2013170164A (ja) * 2012-02-23 2013-09-02 Nagoya City Univ 新規アミド化合物及びその用途
JP2014523857A (ja) * 2011-04-28 2014-09-18 ザ ブロード インスティテュート， インコーポレイテッド ヒストンデアセチラーゼ阻害剤
JP2016017040A (ja) * 2014-07-07 2016-02-01 ＴＡＫ−Ｃｉｒｃｕｌａｔｏｒ株式会社 ヒドロキサム酸誘導体及びｈｄａｃ８阻害剤
WO2017007756A1 (fr) * 2015-07-06 2017-01-12 Rodin Therapeutics, Inc Inhibiteurs hétéro-halogéno d'histone désacétylase

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012510512A (ja) * 2008-12-03 2012-05-10 マサチューセッツ インスティテュート オブ テクノロジー 記憶を推進するためのｈｄａｃ２の阻害
WO2011089995A1 (fr) * 2010-01-21 2011-07-28 公立大学法人名古屋市立大学 Dérivé de l'acide hydroxamique et inhibiteur de hdac8 l'utilisant
JP2014523857A (ja) * 2011-04-28 2014-09-18 ザ ブロード インスティテュート， インコーポレイテッド ヒストンデアセチラーゼ阻害剤
JP2013170164A (ja) * 2012-02-23 2013-09-02 Nagoya City Univ 新規アミド化合物及びその用途
JP2016017040A (ja) * 2014-07-07 2016-02-01 ＴＡＫ−Ｃｉｒｃｕｌａｔｏｒ株式会社 ヒドロキサム酸誘導体及びｈｄａｃ８阻害剤
WO2017007756A1 (fr) * 2015-07-06 2017-01-12 Rodin Therapeutics, Inc Inhibiteurs hétéro-halogéno d'histone désacétylase

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BRESSI, J. C. ET AL.: "Exploration of the HDAC2 foot pocket: Synthesis and SAR of substituted N- (2-aminophenyl) benzamides", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 20, no. 10, 2010101, pages 3142 - 3145, XP027036806, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2010.03.091 *
DONG, G. ET AL.: "Small Molecule Inhibitors Simultaneously Targeting Cancer Metabolism and Epigenetics: Discovery of Novel Nicotinamide Phosphoribosyltransferase (NAMPT) and Histone Deacetylase (HDAC) Dual Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 60, no. 19, 8 September 2017 (2017-09-08), pages 7965 - 7983, XP055661360, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.7b00467 *
TOJO, TOSHIFUMI ET AL.: "The invention of inhibitors showing kinetic HDAC2 selectivity", ABSTRACTS OF ANNUAL CONFERENCE OF THE PHARMACEUTICAL SOCIETY OF JAPAN, vol. 137, March 2017 (2017-03-01) *
WAGNER, F. F. ET AL.: "Kinetically selective inhibitors of hi stone deacety lase 2 (HDAC2) as cognition enhancers", CHEMICAL SCIENCE, vol. 6, no. 1, 2015, pages 804 - 815, XP055300906, ISSN: 2041-6520, DOI: 10.1039/C4SC02130D *

Similar Documents

Publication Publication Date Title
JP6618120B2 (ja) ＴｒｋＡ阻害活性を有する複素環および炭素環誘導体
JP6643773B2 (ja) 新規アルキレン誘導体
JP7060298B1 (ja) Ｍｇａｔ２阻害活性を有する縮合環誘導体
JP6632532B2 (ja) オートタキシン阻害活性を有するピリミジノン誘導体
WO2010113848A1 (fr) Dérivé isothiourée ou dérivé isourée ayant une activité inhibitrice de bace1
WO2017135399A1 (fr) Hétérocycle contenant de l'azote ayant une activité inhibitrice de trka et dérivé carbocyclique
JP6579549B2 (ja) Ｈｉｖ複製阻害作用を有する３環性複素環誘導体
JPWO2013146754A1 (ja) Ｔｒｐｖ４阻害活性を有する芳香族複素５員環誘導体
WO2016159082A1 (fr) Dérivé à cycle condensé à 9 chaînons
WO2018079759A1 (fr) Hétérocycle fusionné ayant une activité inhibitrice de trka et dérivé carbocycle fusionné
JP7068743B2 (ja) Ｍｇａｔ２阻害活性を有する縮合環誘導体を含有する医薬組成物
KR20100135266A (ko) Ｎｐｙ ｙ５ 수용체 길항 작용을 갖는 화합물
KR20220105425A (ko) 티아졸로피리딘 또는 이의 약학적으로 허용 가능한 염 및 이의 용도
JP2019182806A (ja) 二環性複素環誘導体およびそれらを含有する医薬組成物
JPWO2017110841A1 (ja) Ｍｇａｔ２阻害活性を有する非芳香族複素環誘導体
WO2021117759A1 (fr) Inhibiteur d'histone désacétylase comprenant un groupe hétérocyclique aromatique contenant de l'azote
WO2019235501A1 (fr) Inhibiteur d'histone désacétylase
WO2017033966A1 (fr) Dérivé de pyrazole condensé substitué par un 5-carbonylaminoalkyle ayant une activité inhibitrice d'autotaxine
WO2020145369A1 (fr) Dérivé de dihydropyrazolopyrazinone présentant une activité inhibitrice sur mgat2
WO2024063140A1 (fr) Composé monocyclique ayant une activité agoniste du récepteur glp-1
WO2023106310A1 (fr) Dérivé hétérocyclique aromatique ayant une activité agoniste du récepteur glp-1
JP2017128518A (ja) Ｓｍｓ２阻害活性を有するセラミド誘導体
WO2023033018A1 (fr) Dérivé hétérocyclique condensé présentant une action inhibitrice de la réplication du vih
JP2022016394A (ja) Ｍｇａｔ２阻害活性を有するジヒドロピラゾロピラジノン誘導体を含有する医薬組成物
JP2020186182A (ja) 標的蛋白質分解誘導化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19815350

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19815350

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP