HRP20090439T1 - Supstituirani derivati propenil piperazina kao novi inhibitori histonske deacetilaze - Google Patents
Supstituirani derivati propenil piperazina kao novi inhibitori histonske deacetilaze Download PDFInfo
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- HRP20090439T1 HRP20090439T1 HR20090439T HRP20090439T HRP20090439T1 HR P20090439 T1 HRP20090439 T1 HR P20090439T1 HR 20090439 T HR20090439 T HR 20090439T HR P20090439 T HRP20090439 T HR P20090439T HR P20090439 T1 HRP20090439 T1 HR P20090439T1
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- 6alkyl
- hydrogen
- independently selected
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- phenyl
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- QWLWFCBWJIJQAY-UHFFFAOYSA-N 1-prop-1-enylpiperazine Chemical class CC=CN1CCNCC1 QWLWFCBWJIJQAY-UHFFFAOYSA-N 0.000 title 1
- 102000003964 Histone deacetylase Human genes 0.000 title 1
- 108090000353 Histone deacetylase Proteins 0.000 title 1
- 239000003112 inhibitor Substances 0.000 title 1
- -1 hydroxy, cyano, amino Chemical group 0.000 claims abstract 34
- 150000001875 compounds Chemical class 0.000 claims abstract 28
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 23
- 239000001257 hydrogen Substances 0.000 claims abstract 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract 16
- 125000003545 alkoxy group Chemical group 0.000 claims abstract 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract 13
- 150000002431 hydrogen Chemical class 0.000 claims abstract 13
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract 12
- 125000001624 naphthyl group Chemical group 0.000 claims abstract 12
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract 10
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract 10
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims abstract 9
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract 9
- 125000001424 substituent group Chemical group 0.000 claims abstract 9
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims abstract 9
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract 7
- 125000003118 aryl group Chemical group 0.000 claims abstract 7
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims abstract 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract 6
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims abstract 5
- 125000001425 triazolyl group Chemical group 0.000 claims abstract 5
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims abstract 4
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims abstract 3
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims abstract 3
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims abstract 3
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims abstract 3
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims abstract 3
- 125000000815 N-oxide group Chemical group 0.000 claims abstract 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims abstract 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract 3
- 125000002541 furyl group Chemical group 0.000 claims abstract 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract 3
- 125000002632 imidazolidinyl group Chemical group 0.000 claims abstract 3
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims abstract 3
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims abstract 3
- 125000001041 indolyl group Chemical group 0.000 claims abstract 3
- 125000001786 isothiazolyl group Chemical group 0.000 claims abstract 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims abstract 3
- 125000002971 oxazolyl group Chemical group 0.000 claims abstract 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims abstract 3
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims abstract 3
- 125000002755 pyrazolinyl group Chemical group 0.000 claims abstract 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims abstract 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract 3
- 125000001422 pyrrolinyl group Chemical group 0.000 claims abstract 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims abstract 3
- 150000003839 salts Chemical class 0.000 claims abstract 3
- 125000000335 thiazolyl group Chemical group 0.000 claims abstract 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims abstract 2
- 125000005883 dithianyl group Chemical group 0.000 claims abstract 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims abstract 2
- 125000001544 thienyl group Chemical group 0.000 claims abstract 2
- 125000004306 triazinyl group Chemical group 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 5
- 239000000543 intermediate Substances 0.000 claims 5
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims 2
- 125000000532 dioxanyl group Chemical group 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 125000000524 functional group Chemical group 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000000034 method Methods 0.000 claims 2
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims 2
- 125000001715 oxadiazolyl group Chemical group 0.000 claims 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims 2
- 125000003386 piperidinyl group Chemical group 0.000 claims 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims 2
- 125000004076 pyridyl group Chemical group 0.000 claims 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims 2
- 230000001131 transforming effect Effects 0.000 claims 2
- 125000005455 trithianyl group Chemical group 0.000 claims 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 claims 1
- ATFVTAOSZBVGHC-UHFFFAOYSA-N Glycolaldehyde dimer Chemical compound OC1COC(O)CO1 ATFVTAOSZBVGHC-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 claims 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims 1
- 125000002636 imidazolinyl group Chemical group 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 230000002062 proliferating effect Effects 0.000 claims 1
- 125000002098 pyridazinyl group Chemical group 0.000 claims 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 3
Classifications
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- 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
- 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Spoj formule (I), N-oksidnog oblika, njegove farmaceutski prihvatljive adicijske soli i njegovi stereokemijski izomerni oblici, naznačen time, dasvaki X je nezavisno N ili CH; R1 je fenil, naftalenil ili heterociklil; gdjesvaki od navedenih fenila ili naftalenila je ponekad supstituiran sa jednim ili dva supstituenta svaki nezavisno izabran među halo, C1-6alkila, C1-6alkiloksi, polihaloC1-6alkila, arila, hidroksi, cijano, amino, C1-6alkilkarbonilamino, C1-6alkilsulfonilamino, hidroksikarbonila, C1-6alkiloksikarbonila, hidroksiC1-6alkila, C1-6alkiloksimetila, aminometila, C1-6alkilaminometila, C1-6alkilkarbonilaminometila, C1-6alkilsulfonilaminometila, aminosulfonila, C1-6alkilaminosulfonila ili heterociklila; R2 je vodik, -CH2-R5, trifulorometil, -C(=O)-R6 ili -CH2-NR7R8; gdje svaki R5 je nezavisno izabran iz vodika, hidroksi, C1-6alkoksi, C1-6alkiloksiC1-6alkiloksi, C1-6alkilkarboniloksi, piperazinila, N-metilpiperazinila, morfolinila, tiomorfolinila, imidazolila ili triazolila; svaki R6 je nezavisno izabran među hidroksi, C1-6alkiloksi, amino ili mono- ili di(C1-6alkil)amino, C1-6cikloalkilamino, hidroksiC1-6alkilamino, piperazinila, mono- ili di(C1-6alkil)aminoC1-6alkilamino N-metilpiperazinila, morfolinila ili tiomorfolinila; svaki R7 i R8 su nezavisno izabrani među vodika, C1-6alkila, C1-6alkilkarbonila, C1-6alkilsulfonila ili mono- ili di(C1-4alkil)aminosulfonila; R3 je vodik, hidroksimetil, aminometil ili mono- ili di(C1-6alkil)aminometil; R4 je vodik ili C1-6alkil; aril u gore navedenom je fenil ili naftalenil; gdjesvaki navedeni fenil ili naftalenil je ponekad supstituiran sa jednim ili dva supstituenta svaki neovisno izabran među halo, C1-6alkila, C1-6alkoksi, trifluorometila, cijano ili hidroksikarbonila; igore navedeni heterociklil je furanil, tienil, pirolil, pirolinil, pirolidinil, dioksolil, oksazolil, tiazolil, imidazolil, imidazolidinil, pirazolil, pirazolinil, pirazolidinil, izoksazolil, izotiazolil, oksadiazolil, triazolil, tiadiazolil, piranil, piridinil, piperidinil, dioksanil, morfolinil, ditianil, tiomorfolinil, piradizinil, pirimidinil, pirazinil, piperazinil, triazinil, tritianil, indolizinil, indolil, indolinil, benzofuranil, benzotifenil, indazolil, benzimidazolil, bentatiazolil, purinil, kinolizinil, kinolinil, cinolinil, ftlazinil, kinazolinil, kinoksalinil ili naftiridinil; gdjesvaki navedeni heterocikal je ponekad supstituiran sa jednim ili više supstituenata, te je svaki nezavisno izabran među halo, C1-6alkila, C1-6alkoksi, C1-6alkiloksi, cijano, amino, mono- ili di(C1-4alkil)amino. Patent sadrži još 11 patentnih zahtjeva.
Claims (12)
1. Spoj formule (I),
[image]
N-oksidnog oblika, njegove farmaceutski prihvatljive adicijske soli i njegovi stereokemijski izomerni oblici, naznačen time, da
svaki X je nezavisno N ili CH;
R1 je fenil, naftalenil ili heterociklil; gdje
svaki od navedenih fenila ili naftalenila je ponekad supstituiran sa jednim ili dva supstituenta svaki nezavisno izabran među halo, C1-6alkila, C1-6alkiloksi, polihaloC1-6alkila, arila, hidroksi, cijano, amino, C1-6alkilkarbonilamino, C1-6alkilsulfonilamino, hidroksikarbonila, C1-6alkiloksikarbonila, hidroksiC1-6alkila, C1-6alkiloksimetila, aminometila, C1-6alkilaminometila, C1-6alkilkarbonilaminometila, C1-6alkilsulfonilaminometila, aminosulfonila, C1-6alkilaminosulfonila ili heterociklila;
R2 je vodik, -CH2-R5, trifulorometil, -C(=O)-R6 ili –CH2-NR7R8; gdje svaki R5 je nezavisno izabran iz vodika, hidroksi, C1-6alkoksi, C1-6alkiloksiC1-6alkiloksi, C1-6alkilkarboniloksi, piperazinila, N-metilpiperazinila, morfolinila, tiomorfolinila, imidazolila ili triazolila;
svaki R6 je nezavisno izabran među hidroksi, C1-6alkiloksi, amino ili mono- ili di(C1-6alkil)amino, C1-6cikloalkilamino, hidroksiC1-6alkilamino, piperazinila, mono- ili di(C1-6alkil)aminoC1-6alkilamino N-metilpiperazinila, morfolinila ili tiomorfolinila;
svaki R7 i R8 su nezavisno izabrani među vodika, C1-6alkila, C1-6alkilkarbonila, C1-6alkilsulfonila ili mono- ili di(C1-4alkil)aminosulfonila;
R3 je vodik, hidroksimetil, aminometil ili mono- ili di(C1-6alkil)aminometil;
R4 je vodik ili C1-6alkil;
aril u gore navedenom je fenil ili naftalenil; gdje
svaki navedeni fenil ili naftalenil je ponekad supstituiran sa jednim ili dva supstituenta svaki neovisno izabran među halo, C1-6alkila, C1-6alkoksi, trifluorometila, cijano ili hidroksikarbonila; i
gore navedeni heterociklil je furanil, tienil, pirolil, pirolinil, pirolidinil, dioksolil, oksazolil, tiazolil, imidazolil, imidazolidinil, pirazolil, pirazolinil, pirazolidinil, izoksazolil, izotiazolil, oksadiazolil, triazolil, tiadiazolil, piranil, piridinil, piperidinil, dioksanil, morfolinil, ditianil, tiomorfolinil, piradizinil, pirimidinil, pirazinil, piperazinil, triazinil, tritianil, indolizinil, indolil, indolinil, benzofuranil, benzotifenil, indazolil, benzimidazolil, bentatiazolil, purinil, kinolizinil, kinolinil, cinolinil, ftlazinil, kinazolinil, kinoksalinil ili naftiridinil; gdje
svaki navedeni heterocikal je ponekad supstituiran sa jednim ili više supstituenata, te je svaki nezavisno izabran među halo, C1-6alkila, C1-6alkoksi, C1-6alkiloksi, cijano, amino, mono- ili di(C1-4alkil)amino.
2. Spoj prema patentnom zahtjevu 1, naznačen time, da
svaki X je N; R1 je fenil ili fenil ponekad supstituiran sa halo, C1-6alkil, C1-6alikloksi, polihaloC1-6alkil ili aril; R2 je –CH2-R5 ili –C(=O)-R6; svaki R5 je nezavisno izabran iz vodika, hidroksi, C1-6alkiloksi,
C1-6alkiloksiC1-6alkiloksi, C1-6alkilkarboniloksi, N-metilpiperazinila, morfolinila ili imidazolila; svaki R6 je nezavisno izabran iz C1-6alkilamino, C1-6cikloalkilamino,
hidroskiC1-6alkilamino, di(C1-6alkil)aminoC1-6alkilamino ili morfolinila; R3 je vodik i R4 je vodik ili C1-6alkil.
3. Spoj prema patentnim zahtjevima1 i 2, naznačen time, da
svaki X je N; R1 je fenil ili fenil ponekad supstituiran sa halo; R2 je –CH2-R5; svaki R5 je nezavisno izabran iz vodika, hidroksi, C1-6alkiloksi ili C1-6alkilkarboniloksi; R3 je vodik i R4 je vodik.
4. Spoj prema patentnim zahtjevima 1, 2 i 3, naznačen time, da navedeni spoj je spoj br. 1, spoj br. 8, spoj br. 11, spoj br. 9, spoj br. 33, spoj br. 34, spoj br. 7 ili spoj br. 25.
[image]
5. Farmaceutski pripravak, naznačen time, da obuhvaća farmaceutski prihvatljive nosače i kao aktivni sastojak terapeutski učinkovitu količinu spoja prema zahtjevima od 1 do 4.
6. Proces pripremanja farmaceutskog pripravka prema zahtjevu 5, naznačen time, da su farmaceutski prihvatljivi nosači i spoj prema zahtjevima od 1 do 4 dobro izmiješani.
7. Spoj prema bilo kojem od zahtjeva od 1 do 4, naznačen time, da se upotrebljava kao lijek.
8. Upotreba spoja prema bilo kojem od zahtjeva od 1 do 4, naznačena time, da se koristi u proizvodnji lijeka za tretman proliferativnih bolesti.
9. Kombinacija, naznačena time, da sadrži anti-tumorski agens i inhibitor HDAC prema zahtjevima od 1 do 4.
10. Proces za pripremu spoja prema zahtjevu 1, naznačen time, da intermedijer sa formulom (II) reagira sa odgovarajućom kiselinom, a to dovodi do nastanka hidroksamske kiseline sa formulom (I).
[image]
11. Spoj sa formulom (V)
[image]
N-oksidnog oblika, njegove farmaceutski prihvatljive adicijske soli i njegovi stereokemijski izomerni oblici, naznačen time, da
svaki X je nezavisno N ili CH;
R1 je fenil, naftalenil ili heterociklil; gdje
svaki navedeni fenil ili naftalenil je ponekad supstituiran sa jednim ili dva supstituenta
svaki nezavisno izabran iz halo, C1-6alkila, C1-6alkiloksi, polihaloC1-6alkila, arila, hidroksi, cijano, amino, C1-6alkilkarbonilamino, C1-6alkilsulfonilamino, hidroksikarbonila, C1-6alkiloksikarbonila, hidroksiC1-6alkila, C1-6alkiloksimetila, aminometila, C1-6alkilaminometila, C1-6alkilkarbonilaminometila, C1-6alkilsulfonilaminometila, aminosulfonila, C1-6alkilaminosulfonila ili heterociklila;
R2 je vodik, -CH2-R5, trifluorometil, -C(=O)-R6 ili –CH2-NR7R8; gdje svaki R5 je nezavisno izabran iz vodika, hidroksi, C1-6alkiloksi, C1-6alkiloksiC1-6alkiloksi, C1-6alkilkarboniloksi, piperazinila, N-metilpiperazinila, morfolinila, tiomorfolinila, imidazolila ili triazolila;
svaki R6 je nezavisno izabran iz vodika, C1-6alkiloksi, amino ili mono- ili di(C1-6alkil)amino, C1-6cikloalkilamino, hidroksiC1-6alkilamino, piperazinila, mono- ili di(C1-6alkil)aminoC1-6alkilamino
N-metilpiperazinila, morfolinila ili tiomorfolinila;
svaki od R7 i R8 je nezavisno izabran od vodika, C1-6alkila, C1-6alkilkarbonila, C1-6alkilsulfonila ili mono- ili di(C1-4alkil)aminosulfonila;
R3 je vodik, hidroksimetil, aminometil ili mono- ili di(C1-6alkil)aminometil;
R4 je vodik ili C1-6alkil;
gore navedeni aril je fenil ili naftalenil; gdje
svaki navedeni fenil ili naftalenil je ponekad supstituiran sa jednim ili dva supstituenta svaki nezavisno izabran iz halo, C1-6alkila, C1-6alkiloksi, trifluorometila, cijano ili hidroksikarbonila; i
gore navedeni heterociklil je furanil, pirolil, pirolinil, pirolidinil, dioksolil, oksazolil, tiazolil, imidazolil, imidazolinil, imidazolidinil, pirazolil, pirazolinil, pirazolidinil, izoksazolil, izotiazolil, oksadiazolil, triazolil, tiadiazolil, piranil, piridinil, piperidinil, dioksanil, morfolinil, diatianil, tiomorfolinil, piridazinil, pirimidinil, pirazinil, piperazinil, tiazinil, tritianil, indolizinil, indolil, indolinil, benzofuranil, benzotiofenil, imidazolil, benzoimidazolil, benztiazolil, purinil, kinolizinil, kinolinil, cinolinil, ftlazinil, kinazolil, kinaksolinil ili naftiridinil; gdje
svaki navedeni heterocikal ponekad je supstituiran sa jednim ili dva supstituenta svaki nezavisno izabran iz halo, C1-6alkila, C1-6alkiloksi, cijano, amino ili mono- di(C1-4alkil)amino.
12. Proces za pripremanje spoja prema zahtjevu 11, naznačen time, da obuhvaća
a) pretvorbu spoja sa formulom (V), gdje R2 je –CH2OH i R4 je vodik, ovdje označenih kao spojevi sa formulom (V-a), u spojeve sa formulom (V) gdje R2 je različit od –CH2OH, ovdje označenog kao spoja (V-b), preko reakcije koja je poznata u stanju tehnike ili transformiranja funkcionalnih grupa, i
[image]
b) pripremanje spoja sa formulom (V-a) u jednom koraku uz pomoć reakcije intermedijera sa formulom (VI) sa 1,4-dioksan-2,5-diolom te odgovarajućom boronskom kiselinom (VII), gdje R1 je definiran ranije ili
[image]
c) pripremanje spoja sa formulom (V-b) uz pomoć reakcije intermedijera sa formulom (VI) sa odgovarajućim ketonom sa formulom (VIII), gdje R1 i R2 su definirani ranije
[image]
d) pripremanje spoja sa formulom (V), gdje R2 je –COOH ovdje označen kao spojevi sa formulom (V-c) u jednom koraku uz pomoć reakcije intermedijera sa formulom (VI) sa 2-okso-propanskom kiselinom i odgovarajućom boronskom kiselinom sa formulom (VII), gdje R1 je definiran ranije, u odgovarajućem otapalu uz dodatnu pretvorbu u intermedijere sa formulom (V) gdje R2 je –C(=O)-R6, preko reakcija koje su poznate u stanju tehnike ili transformiranjem funkcionalnih grupa
[image]
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP04077171 | 2004-07-28 | ||
| US59235704P | 2004-07-29 | 2004-07-29 | |
| PCT/EP2005/053611 WO2006010749A2 (en) | 2004-07-28 | 2005-07-25 | Substituted propenyl piperazine derivatives as novel inhibitors of histone deacetylase |
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| MXPA04007776A (es) | 2002-03-13 | 2004-10-15 | Janssen Pharmaceutica Nv | Derivados de sulfonilamino como nuevos inhibidores de histona deacetilasa. |
| BR0307606A (pt) | 2002-03-13 | 2004-12-21 | Janssen Pharmaceutica Nv | Derivados de piperazinila, piperidinila e morfolinila como inibidores de histona desacetilase |
| EA007272B1 (ru) | 2002-03-13 | 2006-08-25 | Янссен Фармацевтика Н. В. | Новые ингибиторы гистондеацетилазы |
| SG156687A1 (en) | 2004-07-28 | 2009-11-26 | Janssen Pharmaceutica Nv | Substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylase |
| EP1885710B1 (en) | 2005-05-18 | 2015-08-19 | Janssen Pharmaceutica N.V. | Substituted aminopropenyl piperidine or morpholine derivatives as novel inhibitors of histone deacetylase |
| WO2007049262A1 (en) * | 2005-10-27 | 2007-05-03 | Berand Limited | Methods and compositions for the promotion of neuronal growth and the treatment of asociality and affective disorders |
| JP5225104B2 (ja) | 2006-01-19 | 2013-07-03 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 新しい、ヒストンデアセチラーゼのインヒビターとしてのアミノフェニル誘導体 |
| CN101370803B (zh) | 2006-01-19 | 2012-12-12 | 詹森药业有限公司 | 作为组蛋白脱乙酰酶抑制剂的取代的吲哚基-烷基-氨基衍生物 |
| US8101616B2 (en) | 2006-01-19 | 2012-01-24 | Janssen Pharmaceutica N.V. | Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase |
| JP5247470B2 (ja) * | 2006-01-19 | 2013-07-24 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | ヒストンデアセチラーゼのインヒビターとしてのピリジン及びピリミジン誘導体 |
| EP1839656A1 (en) * | 2006-03-31 | 2007-10-03 | TopoTarget Germany AG | Use of valproic acid for the topical treatment of mild to moderate acne vulgaris |
| KR20100095430A (ko) * | 2007-11-02 | 2010-08-30 | 메틸진 인크. | 히스톤 탈아세틸화효소의 저해물질 |
| CN101723896B (zh) * | 2009-11-03 | 2012-10-31 | 山东大学 | 酪氨酸衍生物类组蛋白去乙酰化酶抑制剂及其应用 |
| WO2012117421A1 (en) | 2011-03-02 | 2012-09-07 | Orchid Research Laboratories Ltd | Histone deacetylase inhibitors |
| KR101419836B1 (ko) * | 2012-05-10 | 2014-07-16 | 서울대학교산학협력단 | Δ5-2-옥소피페라진 유도체를 포함하는 중간엽 줄기세포의 연골세포로의 분화 유도용 조성물 |
| KR101586045B1 (ko) | 2013-07-30 | 2016-01-15 | 충북대학교 산학협력단 | 신규 페닐티아졸 기반 히드록삼산 및 이를 유효성분으로 포함하는 항암용 조성물 |
| KR102132078B1 (ko) | 2018-09-20 | 2020-07-08 | 원광대학교산학협력단 | 방향족 화합물, 아민 및 친핵체를 이용한 3가지 성분 반응으로 1-에틸-4-페닐피페라진 유도체를 제조하는 방법 |
| KR20230155311A (ko) | 2022-05-03 | 2023-11-10 | 충북대학교 산학협력단 | 신규한 n-히드록시프로펜아미드 화합물 및 이를 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물 |
| KR20230155310A (ko) | 2022-05-03 | 2023-11-10 | 충북대학교 산학협력단 | 신규한 n-히드록시프로펜아미드 화합물 및 이를 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물 |
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| EA007272B1 (ru) * | 2002-03-13 | 2006-08-25 | Янссен Фармацевтика Н. В. | Новые ингибиторы гистондеацетилазы |
| BR0307606A (pt) * | 2002-03-13 | 2004-12-21 | Janssen Pharmaceutica Nv | Derivados de piperazinila, piperidinila e morfolinila como inibidores de histona desacetilase |
| ATE399012T1 (de) * | 2002-04-03 | 2008-07-15 | Topotarget Uk Ltd | Carbaminsäurederivate enthaltend eine piperazin verknüpfung als hdac-inhibitoren |
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