HRP20201171T1 - Derivati izoindolin-1-ona kao modulatori aktivnosti pozitivnog alosternog modulatora kolinergijskog muskarinskog m1 receptora za liječenje alzheimerove bolesti - Google Patents
Derivati izoindolin-1-ona kao modulatori aktivnosti pozitivnog alosternog modulatora kolinergijskog muskarinskog m1 receptora za liječenje alzheimerove bolesti Download PDFInfo
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- HRP20201171T1 HRP20201171T1 HRP20201171TT HRP20201171T HRP20201171T1 HR P20201171 T1 HRP20201171 T1 HR P20201171T1 HR P20201171T T HRP20201171T T HR P20201171TT HR P20201171 T HRP20201171 T HR P20201171T HR P20201171 T1 HRP20201171 T1 HR P20201171T1
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- optionally substituted
- halogen atom
- pharmaceutically acceptable
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- 208000024827 Alzheimer disease Diseases 0.000 title claims 4
- 238000011282 treatment Methods 0.000 title claims 4
- 102000007207 Muscarinic M1 Receptor Human genes 0.000 title 1
- 108010008406 Muscarinic M1 Receptor Proteins 0.000 title 1
- 230000001713 cholinergic effect Effects 0.000 title 1
- 230000000694 effects Effects 0.000 title 1
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical class C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 title 1
- 125000005843 halogen group Chemical group 0.000 claims 32
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 31
- 150000001875 compounds Chemical class 0.000 claims 18
- 150000003839 salts Chemical class 0.000 claims 18
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 17
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 16
- 125000002950 monocyclic group Chemical group 0.000 claims 16
- 125000001424 substituent group Chemical group 0.000 claims 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 6
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 4
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims 4
- 125000003118 aryl group Chemical group 0.000 claims 4
- 206010012289 Dementia Diseases 0.000 claims 3
- 206010067889 Dementia with Lewy bodies Diseases 0.000 claims 3
- 201000002832 Lewy body dementia Diseases 0.000 claims 3
- 208000002193 Pain Diseases 0.000 claims 3
- 208000018737 Parkinson disease Diseases 0.000 claims 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 3
- 238000011321 prophylaxis Methods 0.000 claims 3
- 201000000980 schizophrenia Diseases 0.000 claims 3
- 208000019116 sleep disease Diseases 0.000 claims 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- 229940079593 drug Drugs 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- WFSARWQASFQZMG-VXKWHMMOSA-N 4-fluoro-2-[(3S,4S)-4-hydroxyoxan-3-yl]-5-methyl-6-[(4-pyrazol-1-ylphenyl)methyl]-3H-isoindol-1-one Chemical compound FC1=C2CN(C(C2=CC(=C1C)CC1=CC=C(C=C1)N1N=CC=C1)=O)[C@H]1COCC[C@@H]1O WFSARWQASFQZMG-VXKWHMMOSA-N 0.000 claims 1
- PQTDWVGBNKIBKC-VXKWHMMOSA-N O[C@@H]1[C@H](CCCC1)N1C(C2=CC(=C(C(=C2C1)C)C)CC=1C=NC(=CC1)C)=O Chemical group O[C@@H]1[C@H](CCCC1)N1C(C2=CC(=C(C(=C2C1)C)C)CC=1C=NC(=CC1)C)=O PQTDWVGBNKIBKC-VXKWHMMOSA-N 0.000 claims 1
- TYTRQXGARQKALD-VXKWHMMOSA-N O[C@@H]1[C@H](COCC1)N1C(C2=CC(=C(C(=C2C1)C)C)CC1=CC=C(C=C1)OC)=O Chemical compound O[C@@H]1[C@H](COCC1)N1C(C2=CC(=C(C(=C2C1)C)C)CC1=CC=C(C=C1)OC)=O TYTRQXGARQKALD-VXKWHMMOSA-N 0.000 claims 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 125000003226 pyrazolyl group Chemical group 0.000 claims 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims 1
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- 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
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
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Claims (19)
1. Spoj, naznačen time, što je predstavljen formulom (I):
[image]
u kojoj
R1 je
(1) fenilna skupina, skupina C5-6 cikloalkil, 5- ili 6-člana monociklička ne-aromatska heterociklička skupina ili 5- ili 6-člana monociklička aromatska heterociklička skupina, od kojih je svaka proizvoljno supstituirana s 1 do 3 supstituenta koji su odabrani od
(i) halogenog atoma,
(ii) cijano skupine,
(iii) hidroksi skupine,
(iv) skupine C1-6 alkil proizvoljno supstituirane s 1 do 3 hidroksi skupine, i
(v) skupine C1-6 alkoksi, ili
(2) skupina C1-6 alkil proizvoljno supstituirana s 1 do 3 supstituenta koji su odabrani od
(i) hidroksi skupine, i
(ii) 3- do 14-člane ne-aromatske heterocikličke skupine;
R2 je
(1) vodikov atom,
(2) halogeni atom, ili
(3) skupina C1-6 alkil;
R3 je
(1) vodikov atom,
(2) halogeni atom,
(3) cijano skupina,
(4) skupina C1-6 alkil proizvoljno supstituirana s 1 do 3 halogena atoma,
(5) skupina C1-6 alkoksi, ili
(6) skupina C3-6 cikloalkil;
R4 je
(1) halogeni atom,
(2) cijano skupina,
(3) skupina C1-6 alkil,
(4) skupina C1-6 alkoksi proizvoljno supstituirana s 1 do 3 halogena atoma,
(5) karbamoil skupina,
(6) mono- ili di-C1-6 alkil-karbamoil skupina, ili
(7) 5- ili 6-člana monociklička aromatska heterociklička skupina proizvoljno supstituirana s 1 do 3 skupine C1-6 alkil; i
Prsten A je 6-člani aromatski prsten koji je proizvoljno dodatno supstituiran s 1 do 3 supstituenta, dodatno uz R4, odabrana od
(a) halogenog atoma,
(b) skupine C1-6 alkil, i
(c) skupine C1-6 alkoksi,
ili njegova farmaceutski prihvatljiva sol.
2. Spoj prema patentnom zahtjevu 1, naznačen time, što djelomična struktura predstavljena sa sljedećom formulom:
[image]
u formuli (I) je djelomična struktura predstavljena sa sljedećom formulom:
[image]
,
ili njegova farmaceutski prihvatljiva sol.
3. Spoj prema patentnom zahtjevu 1, naznačen time, što
R1 je
(1) fenilna skupina proizvoljno supstituirana s 1 do 3 supstituenta koji su odabrani od
(i) halogenog atoma, i
(ii) cijano skupine,
(2) skupina C5-6 cikloalkil proizvoljno supstituirana s 1 do 3 supstituenta koji su odabrani od
(i) hidroksi skupine,
(ii) skupine C1-6 alkil proizvoljno supstituirane s 1 do 3 hidroksi skupine, i
(iii) skupine C1-6 alkoksi,
(3) 5- ili 6-člana monociklička ne-aromatska heterociklička skupina proizvoljno supstituirana s 1 do 3 hidroksi skupine,
(4) 5- ili 6-člana monociklička aromatska heterociklička skupina proizvoljno supstituirana s 1 do 3 halogena atoma, ili
(5) skupina C1-6 alkil proizvoljno supstituirana s 1 do 3 supstituenta koji su odabrani od
(i) hidroksi skupine, i
(ii) 3- do 8-člane monocikličke ne-aromatske heterocikličke skupine;
R2 je
(1) vodikov atom,
(2) halogeni atom, ili
(3) skupina C1-6 alkil;
R3 je
(1) vodikov atom,
(2) halogeni atom,
(3) cijano skupina,
(4) skupina C1-6 alkil proizvoljno supstituirana s 1 do 3 halogena atoma,
(5) skupina C1-6 alkoksi, ili
(6) skupina C3-6 cikloalkil;
R4 je
(1) halogeni atom,
(2) cijano skupina,
(3) skupina C1-6 alkil,
(4) skupina C1-6 alkoksi proizvoljno supstituirana s 1 do 3 halogena atoma,
(5) karbamoil skupina,
(6) mono- ili di-C1-6 alkil-karbamoil skupina, ili
(7) 5- ili 6-člana monociklička aromatska heterociklička skupina proizvoljno supstituirana s 1 do 3 skupine C1-6 alkil; i
Prsten A je 6-člani aromatski prsten koji je proizvoljno dodatno supstituiran s 1 do 3 supstituenta, dodatno uz R4, odabrana od
(a) halogenog atoma,
(b) skupine C1-6 alkil, i
(c) skupine C1-6 alkoksi,
ili njegova farmaceutski prihvatljiva sol.
4. Spoj prema patentnom zahtjevu 3, naznačen time, što djelomična struktura predstavljena sa sljedećom formulom:
[image]
u formuli (I) je djelomična struktura predstavljena sa sljedećom formulom:
[image]
,
ili njegova farmaceutski prihvatljiva sol.
5. Spoj prema patentnom zahtjevu 1, naznačen time, što
R1 je
(1) fenilna skupina proizvoljno supstituirana s 1 do 3 supstituenta koji su odabrani od
(i) halogenog atoma, i
(ii) cijano skupine,
(2) skupina C5-6 cikloalkil proizvoljno supstituirana s 1 do 3 hidroksi skupine,
(3) 5- ili 6-člana monociklička ne-aromatska heterociklička skupina proizvoljno supstituirana s 1 do 3 hidroksi skupine,
(4) 5- ili 6-člana monociklička aromatska heterociklička skupina proizvoljno supstituirana s 1 do 3 halogena atoma, ili
(5) skupina C1-6 alkil proizvoljno supstituirana s 1 do 3 supstituenta koji su odabrani od
(i) hidroksi skupine, i
(ii) 3- do 8-člane monocikličke ne-aromatske heterocikličke skupine;
R2 je
(1) vodikov atom,
(2) halogeni atom, ili
(3) skupina C1-6 alkil;
R3 je
(1) vodikov atom,
(2) halogeni atom,
(3) cijano skupina,
(4) skupina C1-6 alkil proizvoljno supstituirana s 1 do 3 halogena atoma,
(5) skupina C1-6 alkoksi, ili
(6) skupina C3-6 cikloalkil;
R4 je
(1) halogeni atom,
(2) cijano skupina,
(3) skupina C1-6 alkil,
(4) skupina C1-6 alkoksi proizvoljno supstituirana s 1 do 3 halogena atoma,
(5) karbamoil skupina,
(6) mono- ili di-C1-6 alkil-karbamoil skupina, ili
(7) 5- ili 6-člana monociklička aromatska heterociklička skupina proizvoljno supstituirana s 1 do 3 skupine C1-6 alkil; i
Prsten A je 6-člani aromatski prsten koji je proizvoljno dodatno supstituiran s 1 do 3 supstituenta, dodatno uz R4, odabrana od
(a) halogenog atoma,
(b) skupine C1-6 alkil, i
(c) skupine C1-6 alkoksi,
ili njegova farmaceutski prihvatljiva sol.
6. Spoj prema patentnom zahtjevu 5, naznačen time, što djelomična struktura predstavljena sa sljedećom formulom:
[image]
u formuli (I) je djelomična struktura predstavljena sa sljedećom formulom:
[image]
,
ili njegova farmaceutski prihvatljiva sol.
7. Spoj prema patentnom zahtjevu 1, naznačen time, što
R1 je
(1) fenilna skupina proizvoljno supstituirana s 1 do 3 supstituenta koji su odabrani od
(i) halogenog atoma, i
(ii) cijano skupine,
(2) skupina C5-6 cikloalkil proizvoljno supstituirana s 1 do 3 hidroksi skupine,
(3) 5- ili 6-člana monociklička ne-aromatska heterociklička skupina proizvoljno supstituirana s 1 do 3 hidroksi skupine, ili
(4) skupina C1-6 alkil proizvoljno supstituirana s 1 do 3 supstituenta koji su odabrani od
(i) hidroksi skupine, i
(ii) 3- do 8-člane monocikličke ne-aromatske heterocikličke skupine;
R2 je
(1) vodikov atom,
(2) halogeni atom, ili
(3) skupina C1-6 alkil;
R3 je
(1) vodikov atom,
(2) halogeni atom,
(3) cijano skupina,
(4) skupina C1-6 alkil proizvoljno supstituirana s 1 do 3 halogena atoma,
(5) skupina C1-6 alkoksi, ili
(6) skupina C3-6 cikloalkil;
R4 je
(1) halogeni atom,
(2) cijano skupina,
(3) skupina C1-6 alkil,
(4) skupina C1-6 alkoksi proizvoljno supstituirana s 1 do 3 halogena atoma,
(5) mono- ili di-C1-6 alkil-karbamoil skupina, ili
(6) 5- ili 6-člana monociklička aromatska heterociklička skupina proizvoljno supstituirana s 1 do 3 skupine C1-6 alkil; i
Prsten A je 6-člani aromatski prsten koji je proizvoljno dodatno supstituiran s 1 do 3 supstituenta, dodatno uz R4, odabrana od
(a) halogenog atoma, i
(b) skupine C1-6 alkoksi,
ili njegova farmaceutski prihvatljiva sol.
8. Spoj prema patentnom zahtjevu 7, naznačen time, što djelomična struktura predstavljena sa sljedećom formulom:
[image]
u formuli (I) je djelomična struktura predstavljena sa sljedećom formulom:
[image]
,
ili njegova farmaceutski prihvatljiva sol.
9. Spoj prema patentnom zahtjevu 1, naznačen time, što
R1 je
(1) skupina C5-6 cikloalkil proizvoljno supstituirana s 1 do 3 hidroksi skupine, ili
(2) 5- ili 6-člana monociklička ne-aromatska heterociklička skupina proizvoljno supstituirana s 1 do 3 hidroksi skupine;
R2 je
(1) halogeni atom, ili
(2) skupina C1-6 alkil;
R3 je skupina C1-6 alkil;
R4 je
(1) skupina C1-6 alkil,
(2) skupina C1-6 alkoksi, ili
(3) 5- ili 6-člana monociklička aromatska heterociklička skupina; i
Prsten A je benzenov prsten ili piridinski prsten, od kojih je svaki nesupstituiran, dodatno uz R4,
ili njegova farmaceutski prihvatljiva sol.
10. Spoj prema patentnom zahtjevu 9, naznačen time, što djelomična struktura predstavljena sa sljedećom formulom:
[image]
u formuli (I) je djelomična struktura predstavljena sa sljedećom formulom:
[image]
,
ili njegova farmaceutski prihvatljiva sol.
11. Spoj prema patentnom zahtjevu 1, naznačen time, što
R1 je
(1) skupina cikloheksil supstituirana s jednom hidroksi skupinom, ili
(2) skupina tetrahidropiranil supstituirana s jednom hidroksi skupinom;
R2 je
(1) halogeni atom, ili
(2) skupina C1-6 alkil;
R3 je skupina C1-6 alkil;
R4 je
(1) skupina C1-6 alkil,
(2) skupina C1-6 alkoksi, ili
(3) skupina pirazolil; i
Prsten A je benzenov prsten ili piridinski prsten, od kojih je svaki nesupstituiran, dodatno uz R4,
ili njegova farmaceutski prihvatljiva sol.
12. Spoj prema patentnom zahtjevu 11, naznačen time, što djelomična struktura predstavljena sa sljedećom formulom:
[image]
u formuli (I) je djelomična struktura predstavljena sa sljedećom formulom:
[image]
,
ili njegova farmaceutski prihvatljiva sol.
13. Spoj prema patentnom zahtjevu 1, naznačen time, što je 2-[(3S,4S)-4-hidroksitetrahidro-2H-piran-3-il]-6-(4-metoksibenzil)-4,5-dimetil-2,3-dihidro-1H-izoindol-1-on, ili njegova farmaceutski prihvatljiva sol.
14. Spoj prema patentnom zahtjevu 1, naznačen time, što je 4-fluoro-2-[(3S,4S)-4-hidroksitetrahidro-2H-piran-3-il]-5-metil-6-[4-(1H-pirazol-1-il)benzil]-2,3-dihidro-1H-izoindol-1-on, ili njegova farmaceutski prihvatljiva sol.
15. Spoj prema patentnom zahtjevu 1, naznačen time, što je 2-((1S,2S)-2-hidroksicikloheksil)-4,5-dimetil-6-((6-metilpiridin-3-il)metil)izoindolin-1-on, ili njegova farmaceutski prihvatljiva sol.
16. Lijek, naznačen time, što sadrži spoj prema patentnom zahtjevu 1 ili njegovu farmaceutski prihvatljivu sol.
17. Lijek prema patentnom zahtjevu 16, naznačen time, što je sredstvo za profilaksu ili liječenje Alzheimerove bolesti, shizofrenije, boli, poremećaja spavanja, demencije kod Parkinsonove bolesti ili demencije s Lewyjevim tjelešcima.
18. Spoj prema patentnom zahtjevu 1 ili njegova farmaceutski prihvatljiva sol, naznačen time, što se koristi za profilaksu ili liječenje Alzheimerove bolesti, shizofrenije, boli, poremećaja spavanja, demencije kod Parkinsonove bolesti ili demencije s Lewyjevim tjelešcima.
19. Uporaba spoja prema patentnom zahtjevu 1 ili njegove farmaceutski prihvatljive soli, naznačena time, što je za proizvodnju sredstva za profilaksu ili liječenje Alzheimerove bolesti, shizofrenije, boli, poremećaja spavanja, demencije kod Parkinsonove bolesti ili demencije s Lewyjevim tjelešcima.
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| PCT/JP2015/062912 WO2015163485A1 (en) | 2014-04-23 | 2015-04-22 | Isoindoline-1-one derivatives as cholinergic muscarinic m1 receptor positive alloesteric modulator activity for the treatment of alzheimers disease |
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