HRP20171040T1 - Supstituirani biciklički dihidropirimidinoni i njihova uporaba za inhibiranje djelovanja elastaze neutrofila - Google Patents
Supstituirani biciklički dihidropirimidinoni i njihova uporaba za inhibiranje djelovanja elastaze neutrofila Download PDFInfo
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- 239000003112 inhibitor Substances 0.000 title claims 5
- 108010028275 Leukocyte Elastase Proteins 0.000 title 1
- 102000016799 Leukocyte elastase Human genes 0.000 title 1
- 125000002619 bicyclic group Chemical group 0.000 title 1
- 125000001424 substituent group Chemical group 0.000 claims 21
- 229910020008 S(O) Inorganic materials 0.000 claims 20
- 229910052760 oxygen Inorganic materials 0.000 claims 19
- 150000001875 compounds Chemical class 0.000 claims 16
- 125000000217 alkyl group Chemical group 0.000 claims 13
- 229910052717 sulfur Inorganic materials 0.000 claims 13
- 229910052736 halogen Inorganic materials 0.000 claims 12
- 150000002367 halogens Chemical class 0.000 claims 12
- 150000003839 salts Chemical class 0.000 claims 12
- 125000001072 heteroaryl group Chemical group 0.000 claims 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 10
- 125000000623 heterocyclic group Chemical group 0.000 claims 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims 5
- 125000001188 haloalkyl group Chemical group 0.000 claims 5
- 125000005347 halocycloalkyl group Chemical group 0.000 claims 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 4
- 229910052757 nitrogen Inorganic materials 0.000 claims 3
- 125000004076 pyridyl group Chemical group 0.000 claims 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 125000002950 monocyclic group Chemical group 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 102000003902 Cathepsin C Human genes 0.000 claims 1
- 108090000267 Cathepsin C Proteins 0.000 claims 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims 1
- 206010014950 Eosinophilia Diseases 0.000 claims 1
- 208000017189 Gastrointestinal inflammatory disease Diseases 0.000 claims 1
- 229940122236 Histamine receptor antagonist Drugs 0.000 claims 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims 1
- 239000013543 active substance Substances 0.000 claims 1
- 239000000808 adrenergic beta-agonist Substances 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 208000026935 allergic disease Diseases 0.000 claims 1
- 208000006682 alpha 1-Antitrypsin Deficiency Diseases 0.000 claims 1
- 239000005557 antagonist Substances 0.000 claims 1
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 claims 1
- 208000006673 asthma Diseases 0.000 claims 1
- 230000003454 betamimetic effect Effects 0.000 claims 1
- 239000000812 cholinergic antagonist Substances 0.000 claims 1
- 239000003246 corticosteroid Substances 0.000 claims 1
- 229960001334 corticosteroids Drugs 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 229940121647 egfr inhibitor Drugs 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 claims 1
- 230000001717 pathogenic effect Effects 0.000 claims 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims 1
- 206010039073 rheumatoid arthritis Diseases 0.000 claims 1
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Claims (15)
1. Spoj, naznačen time, da ima sljedeću formulu 1:
[image]
1
u kojoj
R1 je fenil ili peteročlani ili šesteročlani heteroaril, dok su jedan, dva ili tri elementa zamijenjena jednim elementom neovisno odabranim iz skupine koju čine: N, O ili S; gdje je svaki prsten opcijski supstituiran s jednim, dva ili tri supstituenta neovisno odabrana iz skupine koju čine sljedeći: halogen, O2N, NC, H2N, HO, R1.1, R1.1O-, R1.2, R1.3S, R1.3(O)S i R1.3(O)2S;
R1.1 je neovisno odabran iz skupine koju čine sljedeći: C16alkil, C36cikloalkil, C16haloalkil i C36halocikloalkil;
R1.2 je HOC16alkil ili R1.1OC16alkil;
R1.3je neovisno odabran iz skupine koju čine: H, HO-, R1.1 i R1.2;
R2 je fenil ili peteročlani ili šesteročlani heteroaril, gdje su jedan ili dva elementa zamijenjena jednim elementom neovisno odabranim iz skupine koju čine: N, O ili S; dok je svaki prsten opcijski supstituiran sa supstituentom koji je neovisno odabran iz skupine koju čine: halogen, C14alkil, C14haloalkil i C14alkilO-;
R3 je ostatak neovisno odabran iz skupine koju čine sljedeći:
• R3.1;
• R3.2(O)C;
• R3.2O(O)C-;
• R3.2O(O)CA-;
• R3.2S; R3.2(O)S; R3.2(O)2S;
• (R3.2)2N(O)C i
• (R3.2)2N(O)CA;
R3.1 je neovisno odabran iz skupine koju čine sljedeći: H, R3.3, R3.4, C16alkilC36cikloalkil i C36cikloalkilC16alkil, gdje je svaki opcijski supstituiran s jednim ili dva supstituenta neovisno odabrana od R3.1.1;
R3.1.1 je odabran iz skupine koju čine: HO, halogen, NC-, R3.3O-, R3.5, R3.6i R3.7 ili
R3.1.1 označava prsten neovisno odabran od fenila i četveročlanog heterocikličkog prstena koji sadrži jedan element neovisno odabran između N, O, S, S(O) i S(O)2;
R3.1.1 označava peteročlani ili šesteročlani heterociklički ili heteroarilni prsten koji se sastoji od jednog, dva ili tri elementa neovisno odabrana između sljedećih: N, O, S, S(O) i S(O)2;dok je svaki od prstena opcijski supstituiran s jednim ili dva supstituenta neovisno odabrana između sljedećih: HO, O=, halogen, NC-, R3.3, R3.3O-, R3.3-(O)C-, R3.4, R3.5, R3.6 i R3.7 ili su dva supstituenta zajedno R3.8;
R3.2 je neovisno odabran između R3.1, fenila i peteročlanog ili šesteročlanog heterocikličkog ili heteroarilnog prstena koji se sastoji od jednog, dva ili tri elementa neovisno odabrana između: N, O, S, S(O) i S(O)2; dok je svaki prsten opcijski supstituiran s jednim ili dva supstituenta neovisno odabrana između sljedećih: HO, O=, NC-, halogen, R3.3, R3.3O-, R3.3-(O)C-, R3.4, R3.5, R3.6 i R3.7 ili dva supstituenta zajedno su R3.8;
ili su dva R3.2 zajedno tročlani, četveročlani, peteročlani ili šesteročlani monociklički ili šesteročlani, sedmeročlani, osmeročlani, deveteročlani ili deseteročlani biciklički heterociklički ili heteroarilni prsten koji opcijski dodatno uz dušik, obuhvaća jedan ili dva elementa neovisno odabrana između sljedećih: N, O, S, S(O) i S(O)2; dok je opcijski supstituiran s jednim ili dva supstituenta, neovisno odabrana između sljedećih: HO, F, O=, NC-, R3.3, R3.3O-, R3.3-(O)C-, R3.4, R3.5, R3.6, R3.7, fenil i peteročlani ili šesteročlani heterociklički ili heteroarilni prsten koji se sastoji od jednog, dva ili tri elementa neovisno odabrana između sljedećih: N, O, S, S(O) i S(O)2; ili dva supstituenta zajedno su R3.8;
R3.3 je neovisno odabran iz skupine koju čine: C16alkil, C36cikloalkil, C16haloalkil i C36halocikloalkil;
R3.4 je HOC16alkil ili R3.3OC16alkil;
R3.5 je neovisno odabran iz skupine koju čine sljedeći: H2N, R3.3-HN-, (R3.3)2N-, R3.3-(O)C-HN- i R3.3-(O)C-(R3.3)N-;
R3.6 je neovisno odabran iz skupine koju čine sljedeći: R3.3-(O)S-,
R3.3-(O)2S-, R3.3(HN)S, R3.3(HN)(O)S, R3.3(R3.3N)S,
R3.3(R3.3N)(O)S-, R3.3(R3.4N)S, R3.3(R3.4N)(O)S; R3.3(NC-N)S i R3.3(NCN)(O)S;
R3.7 je neovisno odabran iz skupine koju čine sljedeći: HO(O)C, H2N(O)C-, R3.3-O-(O)C-, R3.3-NH-(O)C- i (R3.3)2N-(O)C-;
R3.8 je neovisno odabran iz skupine koju čine sljedeći: C16alkilen i C16haloalkilen, gdje su opcijski jedna ili dvije CH2skupine zamijenjene sa sljedećima: HN, (R3.3)N, (R3.4)N, (R3.3(O)C)N, (R3.4(O)C)N, O, S, S(O) ili S(O)2;
A je -CH2-, -CH2-CH2- ili -CH2-CH2-CH2-; dok je opcijski supstituiran s jednim ili dva supstituenta neovisno odabrana iz skupine koju čine sljedeći: halogen, R3.3, R3.3O- i R3.4 ili dva supstituenta zajedno su R3.8;
R4je neovisno odabran iz skupine koju čine sljedeći: halogen, C16alkil, C36cikloalkil, C16haloalkil i C36halocikloalkil; ili su dva R4zajedno sljedeći: C16alkilen ili C16haloalkilen;
m je 0, 1 ili 2;
ili njegova sol.
2. Spoj formule 1, prema zahtjevu 1, naznačen time, da R1 je R1.c i R1.c je fenil ili piridinil; gdje je svaki prsten opcijski supstituiran s jednim, dva ili tri ostatka neovisno odabrana iz skupine koju čine sljedeći: F, Cl, Br-, NC, R1.1, R1.3(O)S i R1.3(O)2S;
R1.1 je neovisno odabran iz skupine koju čine sljedeći: C16alkil, C36cikloalkil, C16haloalkil i C36halocikloalkil;
R1.2 je HOC16alkil ili R1.1OC16alkil;
R1.3je neovisno odabran iz skupine koju čine: H, HO-, R1.1 i R1.2;
ili njegova sol.
3. Spoj formule 1, prema zahtjevu 1, naznačen time, da R1 je R1.e i R1.e je fenil ili piridinil; dok je svaki prsten opcijski supstituiran s jednim ili dva ostatka neovisno odabrana iz skupine koju čine sljedeći: NC, Me(O)S, Me(O)2S i Et(O)2S; ili njegova sol.
4. Spoj formule 1, prema jednom od zahtjeva 1 do 3, naznačen time, da R2 je R2.b i R2.b je fenil ili šesteročlani heteroaril; gdje su jedan ili dva elementa zamijenjeni s N; dok je svaki prsten opcijski supstituiran sa supstituentom neovisno odabranim iz skupine koju čine sljedeći: halogen, C14alkil i C14haloalkil; ili njegova sol.
5. Spoj formule 1, prema jednom od zahtjeva 1 do 3, naznačen time, da R2 je R2.f i R2.f je piridinil, opcijski supstituiran sa supstituentom neovisno odabranim iz skupine koju čine: F3C i F2HC, ili njegova sol.
6. Spoj formule 1, prema jednom od zahtjeva 1 do 5, naznačen time, da A je Ab i Ab je -CH2-, opcijski supstituiran s jednim ili dva supstituenta neovisno odabrana iz skupine koju čine sljedeći: F, Me, Et, i-Pr, MeO, EtO, HOCH2O- i MeOCH2-; ili njegova sol.
7. Spoj formule 1, prema jednom od zahtjeva 1 do 6, naznačen time, da R4 je R4.a i R4.a je odabran iz skupine koju čine sljedeći: halogen, C16alkil, C36cikloalkil, C16haloalkil i C36halocikloalkil; ili njegova sol.
8. Spoj formule 1, prema jednom od zahtjeva 1 do 7, naznačen time, da R3 je ostatak neovisno odabran iz skupine koju čine sljedeći:
• R3.1;
• R3.2O(O)C ili R3.2O(O)CCH2-;
• R3.2(O)2S i
• (R3.2)2N(O)C ili (R3.2)2N(O)CCH2;
R3.1 je neovisno odabran iz skupine koju čine sljedeći: H, R3.3, R3.4, C16alkilC36cikloalkil i C36cikloalkilC16alkil, dok je svaki opcijski supstituiran s jednim ili dva supstituenta neovisno odabrana od R3.1.1;
R3.1.1 je odabran iz skupine koju čine sljedeći: HO, halogen, NC-,
R3.3O-, R3.5, R3.6 i R3.7 ili
R3.1.1je odabran iz skupine koju čini prsten neovisno odabran od fenila i četveročlanog heterocikličkog prstena koji se sastoji od jednog elementa neovisno odabranog između: N, O, S, S(O) i S(O)2; ili
R3.1.1označava peteročlani ili šesteročlani heterociklički ili heteroarilni prsten koji se sastoji od jednog, dva ili tri elementa neovisno odabrana između sljedećih: N, O, S, S(O) i S(O)2; gdje je svaki od prstena opcijski supstituiran s jednim ili dva supstituenta neovisno odabrana između sljedećih: HO, O=, halogen, R3.3, R3.3O-, R3.3-(O)C-, R3.4, R3.5, R3.6 i R3.7 ili dva supstituenta zajedno su R3.8;
R3.2 je neovisno odabran od sljedećih: R3.1, fenil ili peteročlani ili šesteročlani heterociklički ili heteroarilni prsten koji se sastoji od jednog, dva ili tri elementa neovisno odabrana između sljedećih: N, O, S, S(O) i S(O)2; dok je svaki prsten opcijski supstituiran s jednim ili dva supstituenta neovisno odabrana od sljedećih: HO, O=, NC-, halogen, R3.3, R3.3O-,
R3.3-(O)C-, R3.4, R3.5, R3.6 i R3.7 ili dva supstituenta zajedno su R3.8;
ili su dva R3.2 zajedno peteročlani ili šesteročlani monociklički ili osmeročlani, deveteročlani ili deseteročlani biciklički heterociklički ili heteroarilni prsten koji opcijski dodatno uz dušik, obuhvaća jedan ili dva elementa neovisno odabrana između sljedećih: N, O, S, S(O) i S(O)2; te opcijski supstituirani s jednim ili dva supstituenta, neovisno odabrana od sljedećih: HO, F, O=, R3.3, R3.3O-, R3.3-(O)C-, R3.4, R3.5, R3.7 i R3.6 ili dva supstituenta zajedno su R3.8;
R3.3 je neovisno odabran iz skupine koju čine sljedeći: C16alkil, C36cikloalkil, C16haloalkil i C36halocikloalkil;
R3.4 je HOC16alkil ili R3.3OC16alkil;
R3.5 je neovisno odabran iz skupine koju čine sljedeći: H2N, R3.3-HN-, (R3.3)2N- i R3.3-(O)C-HN-;
R3.6 je neovisno odabran iz skupine koju čine sljedeći: R3.3-(O)S-, R3.3-(O)2S-, R3.3(HN)S, R3.3(HN)(O)S, R3.3(R3.3N)S, R3.3(R3.3N)(O)S, R3.3(R3.4N)S i R3.3(R3.4N)(O)S;
R3.7 je neovisno odabran iz skupine koju čine sljedeći: HO(O)C, H2N(O)C-, R3.3-O-(O)C-, R3.3-NH-(O)C- i (R3.3)2N-(O)C-;
R3.8 je neovisno odabran iz skupine koju čine sljedeći: C16alkilen ili C16haloalkilen, gdje su opcijski jedna ili dvije CH2skupine zamijenjene sa sljedećima:
HN, (R3.3)N, (R3.4)N, (R3.3(O)C)N, (R3.4(O)C)N, O, S, S(O) i
S(O)2;
ili njegova sol.
9. Spoj formule 1, prema jednom od zahtjeva 1 do 7, naznačen time, da R3 je neovisno odabran iz skupine koju čine sljedeći: HO(O)C-H2C,
MeO(O)C-H2C, H2N(O)C-H2C, MeHN(O)C-H2C, Me2N(O)C-H2C, morfolinil-(O)C-H2C, azetidinil-(O)C-H2C, pirolidinil-(O)C-H2C, MeHN(O)C-, EtHN(O)C-, HO(CH2)2HN(O)C-, HO(CMe2)(CH2)HN(O)C-, HO(CH2)3HN(O)C-, Me(O)S(CH2)2HN(O)C-, Me(O)2S(CH2)2HN(O)C-, Et(O)2S i Me(O)2S; ili njegova sol.
10. Spoj prema zahtjevu 1, naznačen time, da ima sljedeće formule od I.a do I.s:
[image]
[image]
[image]
ili njegova sol.
11. Spoj prema jednom od zahtjeva 1 do 10, naznačen time, da konfiguracija formule 1 predstavlja sljedeću formulu 1':
[image]
1'
ili njegova sol.
12. Spoj formule 1 prema bilo kojem od zahtjeva 1 do 11, naznačen time, da se upotrebljava kao lijek.
13. Spoj formule 1 prema bilo kojem od zahtjeva 1 do 11, naznačen time, da se upotrebljava kao lijek za liječenje astme i alergijskih bolesti, gastrointestinalnih upalnih bolesti, eozinofilijskih bolesti, kronične opstrukcijske plućne bolesti, alfa-1-antitripsin-deficijencije, infekcije patogenim mikrobima i reumatoidnog artritisa.
14. Farmaceutski sastav, naznačen time, da on obuhvaća jedan ili više spojeva formule 1, prema bilo kojem od zahtjeva 1 do 11, ili njegovu farmaceutski djelotvornu sol.
15. Farmaceutski sastav, naznačen time, da on dodatno uz spoj formule 1, prema bilo kojem od zahtjeva 1 do 11, obuhvaća farmaceutski djelotvoran spoj odabran iz skupine koju čine sljedeći: betamimetici, antikolinergici, kortikosteroidi, PDE4-inhibitori, LTD4-antagonisti, EGFR-inhibitori, inhibitori katepsina C, CRTH2-inhibitori, 5-LO-inhibitori, antagonisti receptora histamina i SYK-inhibitori, ali također i kombinacije od dvije ili tri djelatne tvari.
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| EP13154256 | 2013-02-06 | ||
| PCT/EP2014/052217 WO2014122160A1 (en) | 2013-02-06 | 2014-02-05 | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
| EP14705723.6A EP2953943B1 (en) | 2013-02-06 | 2014-02-05 | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
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-
2014
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