HRP20171186T1 - Derivati n-((1h-indol-3-il)-alkil)-4-benzil)benzamida i n-((1h-pirolo[2,3b]piridin-3-il)-alkil)-4-benzil)benzamida kao inhibitori nakupljanja alfa sinukleina za liječenje neurodegenerativnih poremećaja - Google Patents
Derivati n-((1h-indol-3-il)-alkil)-4-benzil)benzamida i n-((1h-pirolo[2,3b]piridin-3-il)-alkil)-4-benzil)benzamida kao inhibitori nakupljanja alfa sinukleina za liječenje neurodegenerativnih poremećaja Download PDFInfo
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- HRP20171186T1 HRP20171186T1 HRP20171186TT HRP20171186T HRP20171186T1 HR P20171186 T1 HRP20171186 T1 HR P20171186T1 HR P20171186T T HRP20171186T T HR P20171186TT HR P20171186 T HRP20171186 T HR P20171186T HR P20171186 T1 HRP20171186 T1 HR P20171186T1
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- heterocyclic
- alkyl
- alkenyl
- alkynyl
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- -1 1h-indol-3-yl Chemical group 0.000 title claims 14
- 208000015122 neurodegenerative disease Diseases 0.000 title claims 5
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 title 2
- 230000002776 aggregation Effects 0.000 title 1
- 238000004220 aggregation Methods 0.000 title 1
- 102000003802 alpha-Synuclein Human genes 0.000 title 1
- 108090000185 alpha-Synuclein Proteins 0.000 title 1
- 239000003112 inhibitor Substances 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims 44
- 125000003342 alkenyl group Chemical group 0.000 claims 39
- 125000000304 alkynyl group Chemical group 0.000 claims 38
- 125000005842 heteroatom Chemical group 0.000 claims 31
- 229910052717 sulfur Inorganic materials 0.000 claims 31
- 125000000623 heterocyclic group Chemical group 0.000 claims 23
- 229910052799 carbon Inorganic materials 0.000 claims 20
- 229910052760 oxygen Inorganic materials 0.000 claims 20
- 150000001875 compounds Chemical class 0.000 claims 19
- 125000006270 aryl alkenylene group Chemical group 0.000 claims 17
- 229910052757 nitrogen Inorganic materials 0.000 claims 17
- 125000003118 aryl group Chemical group 0.000 claims 16
- 229910052736 halogen Inorganic materials 0.000 claims 12
- 150000002367 halogens Chemical class 0.000 claims 11
- 125000004432 carbon atom Chemical group C* 0.000 claims 10
- 229910052739 hydrogen Inorganic materials 0.000 claims 10
- 239000001257 hydrogen Substances 0.000 claims 10
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 7
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 7
- 201000011240 Frontotemporal dementia Diseases 0.000 claims 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 5
- 150000003839 salts Chemical class 0.000 claims 5
- 239000012453 solvate Substances 0.000 claims 5
- 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims 4
- 125000006591 (C2-C6) alkynylene group Chemical group 0.000 claims 4
- JXYGLMATGAAIBU-UHFFFAOYSA-N indol-3-ylmethylamine Chemical class C1=CC=C2C(CN)=CNC2=C1 JXYGLMATGAAIBU-UHFFFAOYSA-N 0.000 claims 4
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical compound C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 claims 4
- BGYVXTDDIGWPDV-UHFFFAOYSA-N 5-[[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino]-N-[2-(5-methyl-1H-indol-3-yl)ethyl]pyrimidine-2-carboxamide Chemical compound COC=1C=C2C(=NC=NC2=CC=1OCCCN1CCOCC1)NC=1C=NC(=NC=1)C(=O)NCCC1=CNC2=CC=C(C=C12)C BGYVXTDDIGWPDV-UHFFFAOYSA-N 0.000 claims 3
- BNFIIPJAQLIMMN-UHFFFAOYSA-N 6-amino-n-[2-(5-chloro-1h-indol-3-yl)ethyl]-5-[(2,6-dichlorophenyl)methoxy]pyridine-3-carboxamide Chemical compound NC1=NC=C(C(=O)NCCC=2C3=CC(Cl)=CC=C3NC=2)C=C1OCC1=C(Cl)C=CC=C1Cl BNFIIPJAQLIMMN-UHFFFAOYSA-N 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 claims 3
- 125000004122 cyclic group Chemical group 0.000 claims 3
- 239000003814 drug Substances 0.000 claims 3
- 150000004677 hydrates Chemical class 0.000 claims 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims 3
- 125000004434 sulfur atom Chemical group 0.000 claims 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 2
- OOIAXMPVZJKJHK-UHFFFAOYSA-N 3-(1h-indol-3-yl)propan-1-amine Chemical compound C1=CC=C2C(CCCN)=CNC2=C1 OOIAXMPVZJKJHK-UHFFFAOYSA-N 0.000 claims 2
- JBFLPLZLHHYVTG-UHFFFAOYSA-N 6-amino-5-[(2,6-dichlorophenyl)methoxy]-n-[2-(5-hydroxy-1h-indol-3-yl)ethyl]pyridine-3-carboxamide Chemical compound NC1=NC=C(C(=O)NCCC=2C3=CC(O)=CC=C3NC=2)C=C1OCC1=C(Cl)C=CC=C1Cl JBFLPLZLHHYVTG-UHFFFAOYSA-N 0.000 claims 2
- 208000024827 Alzheimer disease Diseases 0.000 claims 2
- 208000011990 Corticobasal Degeneration Diseases 0.000 claims 2
- 206010067889 Dementia with Lewy bodies Diseases 0.000 claims 2
- 201000010374 Down Syndrome Diseases 0.000 claims 2
- 208000009829 Lewy Body Disease Diseases 0.000 claims 2
- 208000001089 Multiple system atrophy Diseases 0.000 claims 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims 2
- 208000014060 Niemann-Pick disease Diseases 0.000 claims 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- 208000018737 Parkinson disease Diseases 0.000 claims 2
- 208000027089 Parkinsonian disease Diseases 0.000 claims 2
- 206010034010 Parkinsonism Diseases 0.000 claims 2
- 208000000609 Pick Disease of the Brain Diseases 0.000 claims 2
- 208000030886 Traumatic Brain injury Diseases 0.000 claims 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims 2
- 210000000349 chromosome Anatomy 0.000 claims 2
- 229940079593 drug Drugs 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 208000033510 neuroaxonal dystrophy Diseases 0.000 claims 2
- 208000002593 pantothenate kinase-associated neurodegeneration Diseases 0.000 claims 2
- 239000003880 polar aprotic solvent Substances 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 2
- 201000002212 progressive supranuclear palsy Diseases 0.000 claims 2
- 230000009529 traumatic brain injury Effects 0.000 claims 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 150000001298 alcohols Chemical class 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 239000010949 copper Substances 0.000 claims 1
- 229910052802 copper Inorganic materials 0.000 claims 1
- 239000007822 coupling agent Substances 0.000 claims 1
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 150000004820 halides Chemical class 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 229960003966 nicotinamide Drugs 0.000 claims 1
- 235000005152 nicotinamide Nutrition 0.000 claims 1
- 239000011570 nicotinamide Substances 0.000 claims 1
- 239000012038 nucleophile Substances 0.000 claims 1
- 229910052763 palladium Inorganic materials 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- 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
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
-
- 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
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- 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
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- 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
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Claims (17)
1. Spoj s formulom (Al) ili njegov stereoizomer, enantiomer ili tautomer,
[image]
naznačen time da,
- E je neovisno odabran od CR3; i N;
- svaki R1, R3, R4 i R6 je neovisno odabran od vodika; halogena; -OH; -OR10; -SH; -SR10; -S(O)R11; -S(O)2R11; -SO2NR12R13; trifluorometil; trifluorometoksi; nitro; -NHC(O)R10; -NHS(O)2R10; -NHC(O)NR12R13; -NR10C(O)R10; -NR10S(O)2R10; -NR10C(O)NR12R13; -NR12R13; -cijano; -COOH; -COOR10; -C(O)NR12R13; -C(O)R11; alkil; alkenil; alkiml; aril; heterocikal; arilalkilen; arilalkenilen; arilalkinilen; heterociklički-alkilen; heterociklički-alkenilen; i heterociklički-alkinilen;
* i pri čemu navedeni alkil, alkenil, alkinil, aril, heterocikal, arilalkilen, arilalkenilen, arilalkinilen, heterociklički-alkilen, heterociklički-alkenilen ili heterociklički-alkinilen, proizvoljno obuhvaća jedan ili više heteroatoma u skupini alkil(en), alkenil(en) ili alkinil(en), navedeni heteroatomi su odabrani od atoma O, S i N;
* i pri čemu navedeni alkil, alkenil, alkinil, aril, heterocikal, arilalkilen, arilalkenilen, arilalkinilen, heterociklički-alkilen, heterociklički-
alkenilen ili heterociklički-alkinilen može biti nesupstituiran ili supstituiran s jednim ili više Z;
* i pri čemu ugljikov atom ili heteroatom za navedeni alkil, alkenil, alkinil, aril, heterocikal, arilalkilen, arilalkenilen, arilalkinilen, heterociklički-alkilen, heterociklički-alkenilen ili heterociklički-alkinilen, može biti oksidiran da tvori C=O, C=S, N=O, N=S, S=O ili S(O)2;
- R2 je odabran od vodika; alkila; alkenila; i alkinila;
- R5 je neovisno odabran od halogena; -OH; -OR10; -SH; -SR10; -S(O)R"; -S(O)2R"; -SO2NR12R13; trifluorometil; trifluorometoksi; nitro; -NHC(O)R10; -NHS(O)2R10; -NHC(O)NR12R13; -NR10C(O)R10; -NR10S(O)2R'0; -NR10C(O)NR12R13; -NR12R13; -cijano; -COOH; -COOR10; -C(O)NR12R13; -C(O)Rn; alkil; alkenil; alkinil; aril; heterocikal; arilalkilen; arilalkenilen; arilalkinilen; heterociklički-alkilen; heterociklički-alkenilen; i heterociklički-alkinilen;
* i pri čemu navedeni alkil, alkenil, alkinil, aril, heterocikal, arilalkilen, arilalkenilen, arilalkinilen, heterociklički-alkilen, heterociklički-alkenilen ili heterociklički-alkinilen, proizvoljno obuhvaća jedan ili više heteroatoma u skupini alkil(en), alkenil(en) ili alkinil(en), navedeni heteroatomi su odabrani od atoma O, S i N;
* i pri čemu navedeni alkil, alkenil, alkinil, aril, heterocikal, arilalkilen, arilalkenilen, arilalkinilen, heterociklički-alkilen, heterociklički-alkenilen ili heterociklički-alkinilen može biti nesupstituiran ili supstituiran s jednim ili više Z;
* i pri čemu ugljikov atom ili heteroatom za navedeni alkil, alkenil, alkinil, aril, heterocikal, arilalkilen, arilalkenilen, arilalkinilen, heterociklički-alkilen, heterociklički-alkenilen ili heterociklički-alkinilen, može biti oksidiran da tvori C=O, C=S, N=O, N=S, S=O ili S(O)2;
- nje odabran od 1; 0; i 2;
- svaki od Y1 Y2, Y3, Y4 i Y5 je neovisno odabran od CZ1; N; i NR101; pri čemu su barem dva od Y1, Y2, Y3, Y4 i Y5 odabrani od CZ1;
- L je neovisno odabran od C1-6alkilena; -O-; -NH-; -NR10-; C2-6alkenilena; C2-6alkinilena;
* i pri čemu svaki navedeni C1-6alkilen, C2-6alkenilen ili C2-6alkinilen proizvoljno obuhvaća jedan ili više heteroatoma, navedeni heteroatomi su odabrani od heteroatoma koji sadrže O, S i N;
* i pri čemu svaki navedeni C1-6alkilen, C2-6alkenilen ili C2-6alkinilen, može biti nesupstituiran ili supstituiran s jednim ili više Z2;
* i pri čemu ugljikov atom ili heteroatom iz navedenog C1-6alkilena, C2-6 ealkenilena ili C2-6alkinilena, može biti oksidiran da tvori C=O, C=S, N=O, N=S, S=O ili S(O)2;
- B predstavlja cikličku strukturu koja je odabrana od arila; cikloalkila; cikloalkenila; cikloalkinila; i heterocikla;
- m je odabran od 0; 1; 2; 3; 4 i 5;
- svaki R8 je neovisno odabran od vodika; halogena; alkila; alkenila; alkinila; -OH; -OR20; -SH; -SR20; -S(O)R21; -S(O)2R21; -SO2NR22R23; trifluorometila; trifluorometoksi; nitro; -NHC(O)R20; -NHS(O)2R20; -NHC(O)NR22R23; -NR20C(O)R20; -NR10S(O)2R20; -NR20C(O)NR22R23; -NR22R23; -cijano; -COOH; -COOR20; -C(O)NR22R23; i -C(O)R21;
* i pri čemu navedeni alkil, alkenil i alkinil proizvoljno obuhvaća jedan ili više heteroatoma, navedeni heteroatomi su odabrani od atoma O, S i N;
* i pri čemu navedeni alkil, alkenil i alkinil može biti nesupstituiran ili supstituiran s jednim ili više Z2;
* i pri čemu ugljikov atom ili heteroatom za navedeni alkil, alkenil i alkinil, može biti oksidiran da tvori C=O, C=S, N=O, N=S, S=O ili S(O)2;
- svaki Z je neovisno odabran od halogena;-OH;-OR10 ;-SH;-SR10 ;-S(O)R11; -S(O)2R11; -SO2NRI2R13; trifluorometila; trifluorometoksi; nitro; -NHC(O)R10; -NHS(O)2R10; -NHC(O)NR12R13; -NR10C(O)R10; -NR10S(O)2R10; -NR10C(O)NR12R13; -NR12R13; -cijano; -COOH; -COOR10; -C(O)NR12R13; i -C(O)R11;
- svaki Z1 je neovisno odabran od vodika; alkila; i Z2;
- svaki Z2 je neovisno odabran od halogena; -OH; -OR20; -SH; -SR20; -S(O)R21; -S(O)2R21; -SO2NR22R23; trifluorometila; trifluorometoksi; nitro; -NHC(O)R20; -NHS(O)2R20; -NHC(O)NR22R23; -NR20C(O)R20; -NR20S(O)2R20; -NR20C(O)NR22R23; -NR22R23; -cijano; -COOH; -COOR20; -C(O)NR22R23; i -C(O)R21;
- svaki R10 je neovisno odabran od alkila; alkenila; alkinila; arila; heterocikla; arilalkilena; arilalkenilena; arilalkinilena; heterocikličkog-alkilena; heterocikličkog-alkenilena i heterocikličkog-alkinilena;
* i pri čemu navedeni alkil, alkenil, alkinil, aril, heterocikal, arilalkilen, arilalkenilen, arilalkinilen, heterociklički-alkilen, heterociklički-alkenilen ili heterociklički-alkinilen proizvoljno sadrže jedan ili više heteroatoma u skupini alkil(en), alkenil(en) ili alkinil(en), navedeni heteroatom se bira od O, S i N;
* i pri čemu ugljikov atom ili heteroatom za navedeni alkil, alkenil, alkinil, aril, heterocikal, arilalkilen, arilalkenilen, arilalkinilen, heterociklički-alkilen, heterociklički-alkenilen ili heterociklički-alkinilen, može biti oksidiran da tvori C=O, C=S, N=O, N=S, S=O ili S(O)2;
- svaki R101 je neovisno odabran od vodika i R1 ;
- svaki R11 je neovisno odabran od hidroksila; alkila; alkenila; alkinila; arila; heterocikla; arilalkilena; arilalkenilena; arilalkinilena; heterocikličkog-alkilena; heterocikličkog-alkenilena i heterocikličkog-alkinilena;
* i pri čemu navedeni alkil, alkenil, alkinil, aril, heterocikal, arilalkilen, arilalkenilen, arilalkinilen, heterociklički-alkilen, heterociklički-alkenilen ili heterociklički-alkinilen proizvoljno sadrže jedan ili više heteroatoma u skupini alkil(en), alkenil(en) ili alkinil(en), navedeni heteroatom se bira od O, S i N;
* i pri čemu ugljikov atom ili heteroatom za navedeni alkil, alkenil, alkinil, aril, heterocikal, arilalkilen, arilalkenilen, arilalkinilen, heterociklički-alkilen, heterociklički-alkenilen ili heterociklički-
alkinilen, može biti oksidiran da tvori C=O, C=S, N=O, N=S, S=O ili S(O)2;
- svaki R12 i R13 je neovisno odabran od vodika; alkila; alkenila; alkinila; arila; heterocikla; arilalkilena; arilalkenilena; arilalkinilena; heterocikličkog-alkilena; heterocikličkog-alkenilena i heterocikličkog-alkinilena;
* i pri čemu navedeni alkil, alkenil, alkinil, aril, heterocikal, arilalkilen, arilalkenilen, arilalkinilen, heterociklički-alkilen, heterociklički-alkenilen ili heterociklički-alkinilen proizvoljno sadrže jedan ili više heteroatoma u skupini alkil(en), alkenil(en) ili alkinil(en), navedeni heteroatom se bira od O, S i N;
* i pri čemu ugljikov atom ili heteroatom za navedeni alkil, alkenil, alkinil, aril, heterocikal, arilalkilen, arilalkenilen, arilalkinilen, heterociklički-alkilen, heterociklički-alkenilen ili heterociklički-alkinilen, može biti oksidiran da tvori C=O, C=S, N=O, N=S, S=O ili S(O)2;
* i pri čemu R12 i R13 se mogu uzeti zajedno tako da tvore (4-, 5-, 6-, ili 7-člani) heterocikal koji može biti nesupstiruiran ili supstituiran;
- svaki R20 je neovisno odabran od alkila; alkenila; i alkinila;
* i pri čemu navedeni alkil, alkenil, alkinil proizvoljno sadrže jedan ili više heteroatoma u skupini alkil, alkenil ili alkinil, navedeni heteroatom se bira od O, S i N;
* i pri čemu ugljikov atom ili heteroatom za navedeni alkil, alkenil, alkinil može biti oksidiran da tvori C=O, C=S, N=O, N=S, S=O ili S(O)2;
- svaki R21 je neovisno odabran od hidroksila; alkila; alkenila; i alkinila;
* i pri čemu navedeni alkil, alkenil ili alkinil proizvoljno sadrže jedan ili više heteroatoma u skupini alkil, alkenil ili alkinil, navedeni heteroatom se bira od O, S i N;
* i pri čemu ugljikov atom ili heteroatom za navedeni alkil, alkenil ili alkinil može biti oksidiran da tvori C=O, C=S, N=O, N=S, S=O ili S(O)2;
- svaki R22 i R23 je neovisno odabran od vodika; alkila; alkenila; i alkinila;
* i pri čemu navedeni alkil, alkenil ili alkinil proizvoljno sadrže jedan ili više heteroatoma u skupini alkil, alkenil ili alkinil, navedeni heteroatom se bira od O, S i N;
* i pri čemu ugljikov atom ili heteroatom za navedeni alkil, alkenil ili alkinil može biti oksidiran da tvori C=O, C=S, N=O, N=S, S=O ili S(O)2;
* i pri čemu R22 i R23 se mogu uzeti zajedno tako da tvore (4-, 5-, 6-, ili 7-člani) ne-aromatski heterocikal koji može biti nesupstituiran ili supstituiran;
ili njihov solvat, hidrat, ili njihova sol;
pod uvjetom da navedeni spoj nije 6-amino-5-(2,6-diklorobenziloksi)-N-(2-(5-
hidroksi-1H-indol-3-il)etil)nikotinamid; 6-amino-N-(2-(5-kloro-1H-indol-3-
il)etil)-5-(2,6-diklorobenziloksi)nikotinamid; i 5-[[6-metoksi-7-(3-
morfolinopropoksi)kinazolin-4-il]amino]-N-[2-(5-metil-1H-indol-3-
il)etil]pirimidin-2-karboksamid.
2. Spoj prema zahtjevu 1, naznačen time da ima strukturnu formulu (A2) ili (A3)
[image]
[image]
pri čemu R1, R2, R3, R4, R5, R6, R8, Y1, Y2, Y3, Y4, Y5, L, B, m i n imaju isto značenje kao što je definirano u zahtjevu 1.
3. Spoj prema zahtjevu 1, naznačen time da ima strukturnu formulu (B1), (B2) ili (B3),
[image]
[image]
pri čemu E, R1, R2, R3, R4, R5, R6, R8, Y1 Y2, Y3, Y4, Y5, L, B, m i n imaju isto značenje kao stoje definirano u zahtjevu 1.
4. Spoj prema bilo kojem od zahtjeva 1 do 3, naznačen time da ima strukturnu formulu (D1), (D2), (D3) ili (D4),
[image]
[image]
pri čemu E, R1, R2, R3, R4, R5, R6, R8, Y1 Y2, Y3, Y4, Y5, B, m i n imaju isto značenje kao stoje definirano u zahtjevu 1.
5. Spoj prema bilo kojem od zahtjeva 1 do 4, naznačen time da B je aril i R8 je odabran od vodika, halogena -OH, cijano, C1-6alkil, C-6alkoksi, trifluorometila; trifluorometoksi.
6. Spoj prema bilo kojem od zahtjeva 1 do 3, naznačen time da L je C1-6alkilen, proizvoljno supstituiran s jednim ili više supstituenata koji je svaki neovisno odabran od halogena; C1-6alkil; haloC1-6alkil; haloC1-6alkiloksi.
7. Spoj prema bilo kojem od zahtjeva 1 do 6, naznačen time da svaki od R , R1, R3, R4 i R6 su vodik.
8. Spoj prema zahtjevu 1, naznačen time da ima strukturnu formulu (I1), (I2), ili (I3)
[image]
pri čemu
nje odabran od 1; 0; i 2
- R5 je odabran od halogena; -OH; -OR10; trifluorometila; trifluorometoksi; cijano;
- C(O)R11; C1-6alkil; C6-10aril; i heterocikal;
- svaki od V1 i Y5 je neovisno odabran od CZ1 i N;
- svaki Y4 je CZ1;
- svaki Z1 je neovisno odabran od vodika i halogena;
- L je neovisno odabran od -O-; -NH-; -NR10-; C1-6alkilena; -CH2-NH-; i
- CH2-NH-CH2-;
- B predstavlja cikličku strukturu koja je odabrana C3-8cikloalkila; C6-10loarila; i heterocikla;
- m je odabran od 0; 1; i 2;
- svaki R je neovisno odabran od halogena; C1-6alkila; -OH; C1-6alkoksi; trifluorometila; trifluorometoksi; i cijano;
- svaki R10 je C1-6alkil;
- svaki R11 jeC1-6alkil;
i njihovi izomeri, solvati, hidrati ili njihove soli.
9. Spoj prema zahtjevu 1, naznačen time da ima strukturnu formulu (J1), (J2), (J3), ili (J4)
[image]
[image]
pri čemu
- R5 je odabran od halogena; -OH; -OR10; trifluorometila; trifluorometoksi; cijano;
- C(O)R11; C1-6alkil; C6-10aril; i heterocikal;
- L je neovisno odabran od -O-; -NH-; -NR10-; C1-6alkilen; -CH2-NH-; i
- CH2-NH-CH2-;
- B predstavlja cikličku strukturu koja je odabrana C3-8cikloalkila; C6-10arila; i heterocikla;
- m je odabran od 0; 1; i 2;
- svaki R8 je neovisno odabran od halogena; C1-6alkila; -OH; C1-6alkoksi; trifluorometila; trifluorometoksi; i cijano;
- svaki R10 je C1-6alkil;
- svaki R11 je C1-6alkil;
i njihovi izomeri, solvati, hidrati ili njihove soli.
10. Farmaceutski pripravak naznačen time da sadrži jednu ili više farmaceutski prihvatljivih pomoćnih tvari i terapeutski učinkovitu količinu spoja prema bilo kojem od zahtjeva 1 do 9.
11. Spoj prema bilo kojem od zahtjeva 1 do 9 ili farmaceutski pripravak prema zahtjevu 8, naznačen time daje za uporabu kao lijek.
12. Spoj ili farmaceutski pripravak prema zahtjevu 11, ili 6-amino-5-(2,6-diklorobenziloksi)-N-(2-(5-hidroksi-1H- indol-3-il)etil)nikotinamid; ili 6-amino-N-(2-(5-kloro-1H-indol-3-il)etil)-5-(2,6-diklorobenziloksi)nikotinamid, ili 5-[[6-metoksi-7-(3-morfolinopropoksi)kinazolin-4-il]amino]-N-[2-(5-metil-1H-indol-3-il)etil]pirimidin-2-karboksamid; naznačen time da je lijek za prevenciju ili liječenje neurodegenerativnih poremećaja.
13. Spoj ili farmaceutski pripravak prema zahtjevu 12, naznačen time da je neurodegenerativni poremećaj odabran iz skupa koji čine Alzheimerova bolest, Pickova bolest, kortikobazalna degeneracija, progresivna supranuklearna paraliza, frontotemporalna demencija, parkinsonizam (povezan s kromosomom 17, FTDP-17), Parkinsonova bolest, difuzna bolest Lewyevih tjelešaca, traumatska ozljeda mozga, amiotrofna lateralna skleroza, Niemann-Pickova bolest, Niemann- Hallervorden-Spatzov sindrom, Downov sindrom, neuroaksonalna distrofija, te multipla sistemska atrofija.
14. Spoj s formulom (VI) ili njegov stereoizomer, enantiomer ili tautomer,
[image]
pri čemu R1, R2, R3, R4, R5, R6, Y1, Y2, Y3, Y4, Y5, L, i n, su svaki kako je definirano u bilo kojem od zahtjeva 1-9; i LG je izlazna skupina odabrana od halogenog atoma ili sulfonata; ili njegov solvat, hidrat, ili njegova sol.
15. Postupak za pripravu spojeva prema bilo kojem od zahtjeva 1 do 9, te njihovih izomera, solvata, hidrata ili njihovih soli, naznačen time da obuhvaća sljedeće korake:
reakciju supstituiranog ili nesupstituiranog (1H-indol-3-il)metanamina, 2-(1H-indol-3-il)etanamina ili 3-(1H-indol-3-il)propan-1-amina s pravilno supstituiranim derivatom šestero članog prstena koji
nosi funkciju kiselog halogenida u polarnom aprotičnom otapalu u prisutnosti jake baze na temperaturi od između -10°C do 100°C;
reakciju supstituiranog ili nesupstituiranog (1H-indol-3-il)metanamina, 2-(1H-indol-3-il)etanamina ili 3-(1H-indol-3-il)propan-1-amina s pravilno supstituiranim derivatom šestero članog prstena koji nosi jednu funkciju karboksilne kiseline u polarnom aprotičnom otapalu u prisutnosti sredstva za vezanje za stvaranje peptidne veze na temperaturi između 0°C do 50°C; i
- proizvoljno reakciju spoja dobivenog u prethodnom koraku pri čemu šestero člani prsten nosi radikal -CH2LG, pri čemu LG je izlazna skupina, s pogodnim nukleofilima (npr. amini, alkoholi) i u prisutnosti jake baze ili s derivatima kao što su boronska kiselina, stanan ili organocinkovim derivatima u prisutnosti paladijevog ili bakrovog katalizatora.
16. Uporaba spoja prema bilo kojem od zahtjeva 1 do 9, ili 6-amino-5-(2,6-diklorobenziloksi)-N-(2-(5-hidroksi-Lh- indol-3-il)etil)nikotinamida; ili 6-amino-N-(2-(5-kloro-1H-indol-3-il)etil)-5-(2,6-diklorobenziloksi)nikotinamida; ili 5-[[6-metoksi-7-(3-morfolinopropoksi)kinazolin-4-il]amino]-N-[2-(5-metil-1H-indol-3-il)etil]pirimidin-2- karboksamida; naznačena time da je za proizvodnju lijeka za prevenciju ili liječenje neurodegenerativnih poremećaja.
17. Uporaba spoja prema zahtjevu 16, naznačena time da je neurodegenerativni poremećaj odabran iz skupa koji čine Alzheimerova bolest, Pickova bolest, kortikobazalna degeneracija, progresivna supranuklearna paraliza, frontotemporalna demencija, parkinsonizam (povezan s kromosomom 17, FTDP-17), Parkinsonova bolest, difuzna bolest Lewyevih tjelešaca, traumatska ozljeda mozga, amiotrofna lateralna skleroza, Niemann-Pickova bolest, Niemann- Hallervorden-Spatzov sindrom, Downov sindrom, neuroaksonalna distrofija, te multipla sistemska atrofija.
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| GBGB1021103.5A GB201021103D0 (en) | 2010-12-13 | 2010-12-13 | New compounds for the treatment of neurodegenerative diseases |
| EP11805450.1A EP2651888B1 (en) | 2010-12-13 | 2011-12-13 | N-((1H-indol-3-yl)-alkyl)-4-benzyl)benzamide and N-((1H-pyrrolo[2,3-b]pyridin-3-yl)-alkyl)-4-benzyl)benzamide derivatives as alpha synuclein aggregation inhibitors for the treatment of neurodegenerative disorders |
| PCT/EP2011/072568 WO2012080221A1 (en) | 2010-12-13 | 2011-12-13 | New compounds for the treatment of neurodegenerative diseases |
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| JP (1) | JP6050241B2 (hr) |
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| DK (1) | DK2651888T3 (hr) |
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| GB201021104D0 (en) | 2010-12-13 | 2011-01-26 | Univ Leuven Kath | Novel compounds for the treatment of neurodegenerative diseases |
| GB201021103D0 (en) | 2010-12-13 | 2011-01-26 | Univ Leuven Kath | New compounds for the treatment of neurodegenerative diseases |
| KR20160106627A (ko) * | 2013-12-30 | 2016-09-12 | 라이프에스씨아이 파마슈티컬스, 인크. | 치료적 억제 화합물 |
| BR112016017344B1 (pt) | 2014-01-29 | 2023-05-16 | Ucb Biopharma Sprl | Composto de heteroaril amida, sua composição farmacêutica, seu uso, e método de interferir ou de prevenir, retardar, inverter, ou inibir a agregação da proteína ou peptídeo numa célula |
| CN104744353B (zh) * | 2015-03-31 | 2017-11-24 | 山东友帮生化科技有限公司 | 2‑氨基‑3‑碘‑5‑氯吡啶的合成方法 |
| CN105130978B (zh) * | 2015-07-22 | 2017-11-21 | 中国人民解放军军事医学科学院基础医学研究所 | 一种化合物及其在帕金森疾病方面的应用 |
| US10975066B2 (en) | 2015-07-29 | 2021-04-13 | UCB Biopharma SRL | Bis-heteroaryl derivatives as modulators of protein aggregation |
| MA46589A (fr) | 2016-10-24 | 2019-08-28 | Yumanity Therapeutics Inc | Composés et utilisations de ces derniers |
| BR112019011931A2 (pt) | 2017-01-26 | 2019-10-29 | Ucb Biopharma Sprl | derivados de alcóxi bis-heteroarila como moduladores da agregação de proteína |
| MA47370A (fr) | 2017-01-26 | 2021-03-24 | UCB Biopharma SRL | Dérivés bis-hétéroaryliques en tant que modulateurs de l'agrégation des protéines |
| CA3045221A1 (en) | 2017-01-26 | 2018-08-02 | Ucb Biopharma Sprl | Bicyclic bis-heteroaryl derivatives as modulators of protein aggregation |
| WO2018158160A1 (en) | 2017-02-28 | 2018-09-07 | Universitat Autonoma De Barcelona | (nitro-phenyl)-nitropyridine compounds for treating synucleinopathies |
| WO2019025424A1 (en) | 2017-08-04 | 2019-02-07 | Universitat Autonoma De Barcelona | COMPOUNDS FOR TREATING SYNUCLEINOPATHIES |
| CA3083000A1 (en) | 2017-10-24 | 2019-05-02 | Yumanity Therapeutics, Inc. | Compounds and uses thereof |
| WO2019161917A1 (en) | 2018-02-23 | 2019-08-29 | Universitat Autonoma De Barcelona | 4-substituted 1-ethenylsulfonyl-2-nitrobenzene compounds for treating synucleinopathies |
| FI3860998T3 (fi) | 2018-10-05 | 2024-03-27 | Annapurna Bio Inc | Yhdisteitä ja koostumuksia apj-reseptorin aktiivisuuteen liittyvien tautitilojen hoitoon |
| CN114174273A (zh) * | 2019-03-22 | 2022-03-11 | 优曼尼蒂治疗公司 | 化合物和其用途 |
| WO2021025723A1 (en) * | 2019-08-02 | 2021-02-11 | Acelot, Inc. | Small molecule drugs and related methods for treatment of diseases related to tdp-43, alpha-synuclein, huntingtin's protein and tau protein oligomer formation |
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| US3345376A (en) * | 1963-11-06 | 1967-10-03 | Upjohn Co | Polyhydro-6-methoxy-1-(3, 4, 5-trimethoxyphenyl)-9h-pyrido[3, 4-b]indoles |
| IL130169A (en) * | 1999-05-27 | 2006-08-20 | Neurim Pharma 1991 | Indole derivatives, and pharmaceutical preparations, skin protection preparations, and cosmetics containing them |
| US6306890B1 (en) * | 1999-08-30 | 2001-10-23 | Vanderbilt University | Esters derived from indolealkanols and novel amides derived from indolealkylamides that are selective COX-2 inhibitors |
| GB9922171D0 (en) * | 1999-09-21 | 1999-11-17 | Zeneca Ltd | Chemical compounds |
| CA2411165A1 (en) * | 2000-05-02 | 2002-12-11 | Meiji Seika Kaisha, Ltd. | Novel indole derivatives exhibiting chymase-inhibitory activities and process for preparation thereof |
| DOP2002000332A (es) * | 2001-02-14 | 2002-08-30 | Warner Lambert Co | Inhibidores de piridina de metaloproteinasas de la matriz |
| OA13151A (en) | 2003-02-26 | 2006-12-13 | Sugen Inc | Aminoheteroaryl compounds as protein kinase inhibitors. |
| US7795295B2 (en) | 2004-07-01 | 2010-09-14 | The Regents Of The University Of California | Small molecule inhibition of PDZ-domain interaction |
| CA2588389A1 (en) * | 2004-11-23 | 2006-06-22 | Ptc Therapeutics, Inc. | Substituted phenols as active agents inhibiting vegf production |
| JP2009501709A (ja) | 2005-07-12 | 2009-01-22 | バイエル・クロツプサイエンス・エス・アー | 新規ベンゾヘテロシクリルエチルベンズアミド誘導体 |
| EP2149552A1 (de) * | 2008-07-30 | 2010-02-03 | Bayer Schering Pharma AG | 5,6 substituierte Benzamid-Derivate als Modulatoren des EP2-Rezeptors |
| EP2403835A1 (en) * | 2009-03-03 | 2012-01-11 | Pfizer Inc. | Novel phenyl imidazoles and phenyl triazoles as gamma-secretase modulators |
| GB0910003D0 (en) * | 2009-06-11 | 2009-07-22 | Univ Leuven Kath | Novel compounds for the treatment of neurodegenerative diseases |
| ES2360435B1 (es) * | 2009-10-30 | 2012-05-04 | Consejo Superior De Investigaciones Cientificas (Csic) (70%) | Derivados de biss (aralquil) amino y sistemas (6+5)-heteroaromaticos y su uso en el tratamiento de patologias neurodegenerativas, incluida la enfermedad de alzheimer |
| JPWO2012042621A1 (ja) | 2010-09-29 | 2014-02-03 | 味の素株式会社 | 塩味増強剤 |
| KR20140009251A (ko) | 2010-11-15 | 2014-01-22 | 애브비 인코포레이티드 | Ｎａｍｐｔ 및 ｒｏｃｋ 억제제 |
| GB201021103D0 (en) | 2010-12-13 | 2011-01-26 | Univ Leuven Kath | New compounds for the treatment of neurodegenerative diseases |
| GB201021104D0 (en) | 2010-12-13 | 2011-01-26 | Univ Leuven Kath | Novel compounds for the treatment of neurodegenerative diseases |
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| US20130274260A1 (en) | 2013-10-17 |
| DK2651888T3 (en) | 2017-08-28 |
| SI2651888T1 (sl) | 2017-10-30 |
| CN103261156B (zh) | 2016-12-28 |
| JP2013544872A (ja) | 2013-12-19 |
| US9266832B2 (en) | 2016-02-23 |
| CN103261156A (zh) | 2013-08-21 |
| EP2651888A1 (en) | 2013-10-23 |
| EP2651888B1 (en) | 2017-05-17 |
| GB201021103D0 (en) | 2011-01-26 |
| CA2819171C (en) | 2020-02-18 |
| CA2819171A1 (en) | 2012-06-21 |
| WO2012080221A1 (en) | 2012-06-21 |
| HUE033277T2 (en) | 2017-11-28 |
| JP6050241B2 (ja) | 2016-12-21 |
| ES2637288T3 (es) | 2017-10-11 |
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