HRP20211683T1 - Modulator transmembranskog regulatora provodljivosti cistične fibroze, farmaceutski pripravci, postupci liječenja, i postupak za pripravu modulatora - Google Patents
Modulator transmembranskog regulatora provodljivosti cistične fibroze, farmaceutski pripravci, postupci liječenja, i postupak za pripravu modulatora Download PDFInfo
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- HRP20211683T1 HRP20211683T1 HRP20211683TT HRP20211683T HRP20211683T1 HR P20211683 T1 HRP20211683 T1 HR P20211683T1 HR P20211683T T HRP20211683T T HR P20211683TT HR P20211683 T HRP20211683 T HR P20211683T HR P20211683 T1 HRP20211683 T1 HR P20211683T1
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- 238000000034 method Methods 0.000 title claims 19
- 102000012605 Cystic Fibrosis Transmembrane Conductance Regulator Human genes 0.000 title 1
- 108010079245 Cystic Fibrosis Transmembrane Conductance Regulator Proteins 0.000 title 1
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims 79
- 150000001875 compounds Chemical class 0.000 claims 78
- 125000000217 alkyl group Chemical group 0.000 claims 49
- 229910052736 halogen Inorganic materials 0.000 claims 35
- 150000002367 halogens Chemical class 0.000 claims 28
- 239000000825 pharmaceutical preparation Substances 0.000 claims 13
- 125000001424 substituent group Chemical group 0.000 claims 13
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims 11
- 201000003883 Cystic fibrosis Diseases 0.000 claims 11
- 238000006243 chemical reaction Methods 0.000 claims 10
- 125000003545 alkoxy group Chemical group 0.000 claims 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims 7
- 125000005843 halogen group Chemical group 0.000 claims 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 4
- 230000007062 hydrolysis Effects 0.000 claims 4
- 238000006460 hydrolysis reaction Methods 0.000 claims 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 3
- 150000001602 bicycloalkyls Chemical group 0.000 claims 2
- 239000003153 chemical reaction reagent Substances 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 150000003840 hydrochlorides Chemical class 0.000 claims 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 125000004434 sulfur atom Chemical group 0.000 claims 1
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- 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
- C07D401/14—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 three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/12—Mucolytics
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- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Claims (50)
1. Spoj, naznačen time, da je predstavljen Formulom I:
[image]
njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih, gdje:
- jedan od Y1 i Y2 je N i preostali je CH;
- X se bira od O, NH i N(C1-C4 alkil) skupina;
- R1 se bira od –(CR2)k-O-(CR2)m(CR)n(Prsten A)n+1 skupina,
pri čemu se svaki Prsten A neovisno bira od C3-C10 cikloalkil skupina opcionalno supstituiranih s jednim ili više supstituenata od kojih se svaki neovisno bira od C1-C2 alkil skupina, halogeniranih C1-C2 alkil skupina, i halogena, i
pri čemu se svaki R neovisno bira od H, OH i C1-C2 alkil skupina koje su opcionalno supstituirane s jednim ili više halogena;
- svaki R2 se neovisno bira od C1-C2 alkil skupina, OH, C1-C2 alkoksi skupina, halogena i cijano;
- svaki R3 se neovisno bira od C1-C2 alkil skupina koje su opcionalno supstituirane s jednom ili više OH skupina;
- svaki R4 se neovisno bira od halogena;
- k je 0 ili 1;
- r je 0 ili 1;
- m je 0, 1, 2 ili 3;
- n je 0 ili 1;
- p je 0, 1, 2, 3, 4 ili 5; i
- q je 0, 1, 2, 3, 4, 5, 6, 7 ili 8.
2. Spoj prema patentnom zahtjevu 1, naznačen time, da je predstavljen Formulom II:
[image]
njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih, gdje:
- X se bira od O, NH, i N(C1-C4 alkil) skupina;
- R1 se bira od –(CR2)k-O-(CR2)m(CR)n(Prsten A)n+1 skupina,
pri čemu se svaki Prsten A neovisno bira od C3-C10 cikloalkil skupina opcionalno supstituiranih s jednim ili više supstituenata od kojih se svaki neovisno bira od C1-C2 alkil skupina, halogeniranih C1-C2 alkil skupina, i halogena, i
pri čemu se svaki R neovisno bira od H, OH i C1-C2 alkil skupina koje su opcionalno supstituirane s jednim ili više halogena;
- svaki R2 se neovisno bira od C1-C2 alkil skupina, OH, C1-C2 alkoksi skupina, halogena i cijano;
- svaki R3 se neovisno bira od C1-C2 alkil skupina koje su opcionalno supstituirane s jednom ili više OH skupina;
- svaki R4 se neovisno bira od halogena;
- k je 0 ili 1;
- r je 0 ili 1;
- m je 0, 1, 2 ili 3;
- n je 0 ili 1;
- p je 0, 1, 2, 3, 4 ili 5; i
- q je 0, 1, 2, 3, 4, 5, 6, 7 ili 8.
3. Spoj prema patentnom zahtjevu 1, naznačen time, da je predstavljen Formulom III:
[image]
njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojega od gorespomenutih, gdje:
- R1 se bira od –(CR2)k-O-(CR2)m(CR)n(Prsten A)n+1 skupina,
pri čemu se svaki Prsten A neovisno bira od C3-C10 cikloalkil skupina opcionalno supstituiranih s jednim ili više supstituenata od kojih se svaki neovisno bira od C1-C2 alkil skupina, halogeniranih C1-C2 alkil skupina, i halogena, i
pri čemu se svaki R neovisno bira od H, OH i C1-C2 alkil skupina koje su opcionalno supstituirane s jednim ili više halogena;
- svaki R2 se neovisno bira od C1-C2 alkil skupina, OH, C1-C2 alkoksi skupina, halogena i cijano;
- svaki R3 se neovisno bira od C1-C2 alkil skupina koje su opcionalno supstituirane s jednom ili više OH skupina;
- svaki R4 se neovisno bira od halogena;
- k je 0 ili 1;
- r je 0 ili 1;
- m je 0, 1, 2 ili 3;
- n je 0 ili 1;
- p je 0, 1, 2, 3, 4 ili 5; i
- q je 0, 1, 2, 3, 4, 5, 6, 7 ili 8.
4. Spoj prema bilo kojem od patentnih zahtjeva 1 do 3, njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih, naznačen time, da R2 je cijano, tada je spomenuti R2 meta ili para u odnosu na atom sumpora.
5. Spoj prema bilo kojem od patentnih zahtjeva 1 do 3, njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih, naznačen time, da:
- svaki Prsten A se neovisno bira od C3-C10 cikloalkil skupina opcionalno supstituiranih s jednim ili više supstituenata od kojih se svaki neovisno bira od C1-C2 alkil skupina, halogeniranih C1-C2 alkil skupina, i halogena; i
- svaki R se neovisno bira od H i OH;
- svaki R2 se neovisno bira od C1-C2 alkil skupina, OH, C1-C2 alkoksi skupina, i halogena;
- R4 je F;
- k je 0;
- p je 0, 1 ili 2;
- q je 0, 1, 2, 3 ili 4;
- r je 0; i
pri čemu m i n nisu istovremeno 0.
6. Spoj prema patentnom zahtjevu 5, njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih, naznačen time, da:
- R1 se bira od -O(CR2)m-Prsten A skupina;
- pri čemu se Prsten A bira od C3-C10 cikloalkil skupina opcionalno supstituiranih s jednim ili više supstituenata od kojih se svaki neovisno bira od C1-C2 alkil skupina, halogeniranih C1-C2 alkil skupina, i halogena; i
- m je 1 ili 2.
7. Spoj prema patentnom zahtjevu 6, njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih, naznačen time, da svaki R3 je metilna skupina i q je 3 ili 4.
8. Spoj prema patentnom zahtjevu 7, naznačen time, da ima Formulu IV:
[image]
njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih, pri čemu:
- Prsten A se neovisno bira od C3-C10 cikloalkil skupina opcionalno supstituiranih s jednim ili više supstituenata od kojih se svaki neovisno bira od C1-C2 alkil skupina, halogeniranih C1-C2 alkil skupina, i halogena; i
- svaki R2 se neovisno bira od C1-C2 alkil skupina, OH, F, Cl, i C1-C2 alkoksi skupina;
- m je 1 ili 2; i
- p je 0, 1 ili 2.
9. Spoj prema patentnom zahtjevu 8, naznačen time, da:
(a) p je 0 ili 1; ili
(b) p je 0.
10. Spoj prema patentnom zahtjevu 8, naznačen time, da ima Formulu V:
[image]
njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih, pri čemu:
- Prsten A se bira od C3-C10 cikloalkil skupina opcionalno supstituiranih s jednim ili više supstituenata od kojih se svaki neovisno bira od C1-C2 alkil skupina, halogeniranih C1-C2 alkil skupina, i halogena; i
- svaki R2 se neovisno bira od C1-C2 alkil skupina, OH, F, Cl, i C1-C2 alkoksi skupina;
- m je 1 ili 2; i
- p je 0, 1 ili 2.
11. Spoj prema bilo kojem od patentnih zahtjeva 1 do 10, njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih, naznačen time, da se svaki R2 neovisno bira od CH3, OH, F i OCH3.
12. Spoj prema patentnom zahtjevu 11, njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih, naznačen time, da:
(a) p je 0 ili 1; ili
(b) p je 0.
13. Spoj prema patentnom zahtjevu 10, njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih, naznačen time, da:
(a) Prsten A je ciklopropil skupina koja je supstituirana s halogeniranom C1 alkil skupinom ili halogeniranom C2 alkil skupinom; ili
(b) Prsten A je ciklopropil skupina koja je supstituirana sa CF3 skupinom; ili
(c) m je 1, Prsten A je ciklopropil skupina koja je supstituirana sa CF3 skupinom, p je 0 ili 1, i ako postoji, R2 je metilna skupina, hidroksi skupina, ili metoksi skupina; ili
(d) m je 2, Prsten A je C3 cikloalkil skupina koja je supstituirana sa CF3 skupinom, p je 0 ili 1, i ako postoji, R2 je metilna skupina, hidroksi skupina, ili metoksi skupina; ili
(e) m je 2, Prsten A je ciklopropil skupina koja je supstituirana sa CF3 skupinom, i p je 0; ili
(f) Prsten A se bira od C5bicikloalkil skupina koje su opcionalno supstituirane s jednim ili više supstituenata od kojih se svaki neovisno bira od od C1-C2 alkil skupina, halogeniranih C1-C2 alkil skupina, i halogena; ili
(g) Prsten A je C5 bicikloalkil skupina koja je opcionalno supstituirana s halogenom; ili
(h) Prsten A se bira od C7 bicikloalkil skupina i C7 tricikloalkil skupina koje su opcionalno supstituirane s jednim ili više supstituenata od kojih se svaki neovisno bira od od C1-C2 alkil skupina, halogeniranih C1-C2 alkil skupina, i halogena; ili
(i) Prsten A je nesupstituirana C7 tricikloalkil skupina.
14. Spoj prema patentnom zahtjevu 1, naznačen time, da ima formulu koja se bira od bilo koje od dolje prikazanih formula:
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njihova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih.
15. Spoj prema patentnom zahtjevu 1, naznačen time, da ima sljedeću formulu:
[image]
njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih.
16. Spoj prema patentnom zahtjevu 15, naznačen time, da ima sljedeću formulu:
[image]
u obliku farmaceutski prihvatljive soli.
17. Spoj prema patentnom zahtjevu 15, naznačen time, da ima sljedeću formulu:
[image]
18. Spoj prema patentnom zahtjevu 1, naznačen time, da ima:
(a) sljedeću formulu:
[image]
njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih; ili
(b) sljedeću formulu:
[image]
njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih; ili
(c) sljedeću formulu:
[image]
njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih; ili
(d) sljedeću formulu:
[image]
njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih; ili
(e) sljedeću formulu:
[image]
ili njegova farmaceutski prihvatljiva sol;
(f) sljedeću formulu:
[image]
ili njegova farmaceutski prihvatljiva sol; ili
(g) sljedeću formulu:
[image]
ili njegova farmaceutski prihvatljiva sol.
19. Farmaceutski pripravak, naznačen time, da sadrži spoj, njegovu farmaceutski prihvatljivu sol, ili deuterirani derivat bilo kojeg od gorespomenutih, u skladu s definicijom u patentnom zahtjevu 15.
20. Farmaceutski pripravak, naznačen time, da sadrži farmaceutski prihvatljivu sol prema patentnom zahtjevu 16.
21. Farmaceutski pripravak, naznačen time, da sadrži spoj prema patentnom zahtjevu 17.
22. Farmaceutski pripravak, naznačen time, da sadrži najmanje jedan spoj koji se bira od spojeva prema bilo kojem od patentnih zahtjeva 1 do 18, njegovu farmaceutski prihvatljivu sol, ili deuterirani derivat bilo kojeg od gorespomenutih, i opcionalno jedan ili više od:
(a) Spoja II:
[image]
njegove farmaceutski prihvatljive soli, ili deuteriranog derivata bilo kojeg od gorespomenutih;
(b) Spoja III:
[image]
njegove farmaceutski prihvatljive soli, ili deuteriranog derivata bilo kojeg od gorespomenutih; i
(c) farmaceutski prihvatljivog nosača.
23. Farmaceutski pripravak prema patentnom zahtjevu 22, naznačen time, da sadrži spoj prema patentnom zahtjevu 15, ili njegovu farmaceutski prihvatljivu sol, i opcionalno jedan ili više od:
(a) Spoja II:
[image]
ili njegove farmaceutski prihvatljive soli;
(b) Spoja III:
[image]
ili njegove farmaceutski prihvatljive soli; i
(c) farmaceutski prihvatljivog nosača.
24. Farmaceutski pripravak prema patentnom zahtjevu 23, naznačen time, da spoj koji ima formulu:
[image]
nalazi se u obliku farmaceutski prihvatljive soli.
25. Farmaceutski pripravak prema patentnom zahtjevu 22, naznačen time, da je za uporabu u postupku liječenja cistične fibroze.
26. Spoj, njegova farmaceutski prihvatljiva sol, ili deuterirani derivat od bilo kojega navedenog, u skladu s patentnim zahtjevom 15, naznačeni time, da su za uporabu u postupku liječenja cistične fibroze.
27. Farmaceutski prihvatljiva sol u skladu s patentnim zahtjevom 16, naznačena time, da je za uporabu u postupku liječenja cistične fibroze.
28. Spoj u skladu s patentnim zahtjevom 17, naznačen time, da je za uporabu u postupku liječenja cistične fibroze.
29. Farmaceutski pripravak u skladu s patentnim zahtjevom 19, naznačen time, da je za uporabu u postupku liječenja cistične fibroze.
30. Farmaceutski pripravak u skladu s patentnim zahtjevom 20, naznačen time, da je za uporabu u postupku liječenja cistične fibroze.
31. Farmaceutski pripravak u skladu s patentnim zahtjevom 21, naznačen time, da je za uporabu u postupku liječenja cistične fibroze.
32. Farmaceutski pripravak u skladu s patentnim zahtjevom 22, naznačen time, da je za uporabu u postupku liječenja cistične fibroze.
33. Farmaceutski pripravak u skladu s patentnim zahtjevom 23, naznačen time, da je za uporabu u postupku liječenja cistične fibroze.
34. Farmaceutski pripravak u skladu s patentnim zahtjevom 24, naznačen time, da je za uporabu u postupku liječenja cistične fibroze.
35. Postupak za pripravljanje spoja Formule (IIIa):
[image]
njegove farmaceutski prihvatljive soli, ili deuteriranog derivata bilo kojeg od gorespomenutih, naznačen time, da obuhvaća reakciju spoja Formule (F) ili njegove soli sa spojem Formule (G) ili njegovom soli, kako bi se proizveo navedeni spoj Formule (IIIa) ili njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih:
[image]
pri čemu u svakoj od navedenih formula:
- jedan od Y1 i Y2 je N i preostali je CH;
- svaki R1 se neovisno bira od –(CR2)k-O-(CR2)m(CR)n(Prsten A)n+1 skupina,
pri čemu se svaki Prsten A neovisno bira od C3-C10 cikloalkil skupina opcionalno supstituiranih s jednim ili više supstituenata od kojih se svaki neovisno bira od C1-C2 alkil skupina, halogeniranih C1-C2 alkil skupina, i halogena, i
pri čemu se svaki R neovisno bira od H, OH i C1-C2 alkil skupina koje su opcionalno supstituirane s jednim ili više halogena;
- svaki R2 se neovisno bira od C1-C2 alkil skupina, OH, C1-C2 alkoksi skupina, halogena i cijano;
- svaki R3 se neovisno bira od C1-C2 alkil skupina koje su opcionalno supstituirane s jednom ili više OH skupina;
- svaki R4 se neovisno bira od halogena;
- Xa se bira od F ili Cl;
- svaki k je neovisno 0 ili 1;
- svaki r je neovisno 0 ili 1;
- svaki m je neovisno 0, 1, 2 ili 3;
- svaki n je neovisno 0 ili 1;
- svaki p je neovisno 0, 1, 2, 3, 4 ili 5; i
- svaki q je neovisno 0, 1, 2, 3, 4, 5, 6, 7 ili 8; dok opcionalno pritom, svaki Y2 je neovisno N; i svaki Y1 je neovisno CH.
36. Postupak prema patentnom zahtjevu 35, naznačen time, da se spomenuta reakcija spoja Formule (F) ili njegove soli sa spojem Formule (G) ili njegovom soli, izvodi u prisutnosti baze.
37. Postupak prema patentnim zahtjevima 35 ili 36, naznačen time, da se iskorištava sol Formule (G); dok opcionalno pritom, navedena sol spoja Formule (G) je HCl sol spoja Formule (G).
38. Postupak za pripravljanje spoja Formule (F) ili njegove soli:
[image]
ili deuteriranog derivata bilo kojeg od gorespomenutih, naznačen time, da obuhvaća reakciju spoja Formule (D) ili njegove soli sa spojem Formule (E) ili njegovom soli, kako bi se proizveo spoj Formule (F) ili njegova sol:
[image]
pri čemu u svakoj od navedenih formula:
- jedan od Y1 i Y2 je neovisno N i preostali je neovisno CH;
- svaki R1 se neovisno bira od –(CR2)k-O-(CR2)m(CR)n(Prsten A)n+1 skupina,
pri čemu se svaki Prsten A neovisno bira od C3-C10 cikloalkil skupina opcionalno supstituiranih s jednim ili više supstituenata od kojih se svaki neovisno bira od C1-C2 alkil skupina, halogeniranih C1-C2 alkil skupina, i halogena, i
pri čemu se svaki R neovisno bira od H, OH i C1-C2 alkil skupina koje su opcionalno supstituirane s jednim ili više halogena;
- svaki R2 se neovisno bira od C1-C2 alkil skupina, OH, C1-C2 alkoksi skupina, halogena i cijano;
- svaki R4 se neovisno bira od halogena;
- Xa se bira od F ili Cl;
- svaki k je neovisno 0 ili 1;
- svaki r je neovisno 0 ili 1;
- svaki m je neovisno 0, 1, 2 ili 3;
- svaki n je neovisno 0 ili 1; i
- svaki p je neovisno 0, 1, 2, 3, 4 ili 5; dok opcionalno pritom, svaki Y2 je neovisno N; i svaki Y1 je neovisno CH.
39. Postupak prema patentnom zahtjevu 38, naznačen time, da se spomenuta reakcija spoja Formule (D) ili njegove soli sa spojem Formule (E) ili njegovom soli, izvodi u prisutnosti baze; ili obuhvaća reakciju spoja Formule (D-1) s veznim reagensom i uzastopno sa spojem Formule (E-1) u prisutnosti baze.
40. Postupak prema patentnom zahtjevu 35, naznačen time, da je to postupak za pripravljanje spoja sljedeće formule:
[image]
ili njegove farmaceutski prihvatljive soli, ili deuteriranog derivata od bilo kojega navedenog, pri čemu on obuhvaća reakciju spoja Formule (F-1) ili njegove soli, gdje se Xa bira od F ili Cl, sa spojem Formule (G-1) ili njegovom soli, kako bi se proizveo navedeni spoj ili njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih:
[image]
dok se opcionalno pritom, spomenuta reakcija spoja Formule (F-1) ili njegove soli sa spojem Formule (G-1) ili njegovom soli, izvodi u prisutnosti baze.
41. Postupak prema patentnom zahtjevu 40, naznačen time, da se iskorištava sol Formule (G-1); dok opcionalno pritom, navedena sol spoja Formule (G-1) je HCl sol spoja Formule (G-1).
42. Postupak prema patentnom zahtjevu 38, naznačen time, da je to postupak za pripravljanje spoja Formule (F-1) ili njegove soli:
[image]
ili deuteriranog derivata bilo kojeg od navedenog, pri čemu on obuhvaća reakciju spoja Formule (D-1) i spoja Formule (E-1), kako bi se proizveo spoj Formule (F-1) ili njegova sol:
[image]
gdje se svaki Xa neovisno bira od F ili Cl.
43. Postupak prema patentnom zahtjevu 42, naznačen time, da se spomenuta reakcija spoja Formule (D-1) ili njegove soli sa spojem Formule (E-1) ili njegovom soli, izvodi u prisutnosti baze; ili obuhvaća reakciju spoja Formule (D-1) s veznim reagensom i uzastopno sa spojem Formule (E-1) u prisutnosti baze.
44. Postupak za pripravljanje spoja Formule (D) ili njegove soli:
[image]
ili deuteriranog derivata bilo kojeg od navedenog, naznačen time, da obuhvaća:
(i) reakciju spoja Formule (A) ili njegove soli sa spojem Formule (B) ili njegovom soli, kako bi se proizveo spoj Formule (C) ili njegova sol:
[image]
i
(ii) hidrolizu -C(O)ORa skupine spoja Formule (C), kako bi se proizveo spoj Formule (D) ili njegova sol, pri čemu u svakoj od navedenih formula:
- jedan od Y1 i Y2 je neovisno N i preostali je neovisno CH;
- svaki R1 se neovisno bira od –(CR2)k-O-(CR2)m(CR)n(Prsten A)n+1 skupina,
pri čemu se svaki Prsten A neovisno bira od C3-C10 cikloalkil skupina opcionalno supstituiranih s jednim ili više supstituenata od kojih se svaki neovisno bira od C1-C2 alkil skupina, halogeniranih C1-C2 alkil skupina, i halogena, i
pri čemu se svaki R neovisno bira od H, OH i C1-C2 alkil skupina koje su opcionalno supstituirane s jednim ili više halogena;
- svaki R4 se neovisno bira od halogena;
- svaki Ra se neovisno bira od C1-C4 alkila;
- svaki Xa se neovisno bira od F ili Cl;
- svaki k je neovisno 0 ili 1;
- svaki r je neovisno 0 ili 1;
- svaki m je neovisno 0, 1, 2 ili 3; i
- svaki n je neovisno 0 ili 1;
dok opcionalno pritom, svaki Y2 je neovisno N; i svaki Y1 je neovisno CH.
45. Postupak prema patentnom zahtjevu 44, naznačen time, da se hidroliza -C(O)ORa skupine izvodi u prisutnosti baze; gdje se opcionalno pritom spomenuta reakcija spoja Formule (A) ili njegove soli sa spojem Formule (B) ili njegovom soli, izvodi u prisutnosti baze.
46. Postupak prema bilo kojem od patentnih zahtjeva 44 ili 45, naznačen time, da Ra je etil ili t-butil.
47. Postupak prema patentnom zahtjevu 44, naznačen time, da je to postupak za pripravljanje spoja Formule (D-1) ili njegove soli:
[image]
ili deuteriranog derivata bilo kojega od gorespomenutih, naznačen time, da obuhvaća:
(i) reakciju spoja Formule (A-1) ili njegove soli i spoja Formule (B-1) ili njegove soli, kako bi se proizveo spoj Formule (C-1) ili njegova sol:
[image]
i
(ii) hidrolizu -C(O)ORa skupine spoja Formule (C-1) ili njegove soli, kako bi se proizveo spoj Formule (D-1) ili njegova sol,
pri čemu se svaki Ra neovisno bira od C1-C4 alkila; i svaki -Xa se neovisno bira od F ili Cl; dok se opcionalno pritom, hidroliza -C(O)ORa skupine izvodi u prisutnosti baze.
48. Postupak prema patentnom zahtjevu 47, naznačen time, da se navedena reakcija spoja Formule (A-1) ili njegove soli i spoja Formule (B-1) ili njegove soli, izvodi u prisutnosti baze; gdje opcionalno, Ra je etil ili t-butil.
49. Postupak za pripravljanje spoja Formule (I) ili njegove farmaceutski prihvatljive soli, ili deuteriranog derivata od bilo kojega navedenog, naznačen time, da obuhvaća reakciju spoja Formule (L) ili njegove soli sa NR*3:
[image]
pri čemu u svakoj od navedenih formula:
- X je NH ili N(C1-C4 alkil);
- jedan od Y1 i Y2 je neovisno N i preostali je neovisno CH;
- svaki R1 se neovisno bira od –(CR2)k-O-(CR2)m(CR)n(Prsten A)n+1 skupina,
pri čemu se svaki Prsten A neovisno bira od C3-C10 cikloalkil skupina opcionalno supstituiranih s jednim ili više supstituenata od kojih se svaki neovisno bira od C1-C2 alkil skupina, halogeniranih C1-C2 alkil skupina, i halogena, i
pri čemu se svaki R neovisno bira od H, OH i C1-C2 alkil skupina koje su opcionalno supstituirane s jednim ili više halogena;
- svaki R2 se neovisno bira od C1-C2 alkil skupina, OH, C1-C2 alkoksi skupina, halogena i cijano;
- svaki R3 se neovisno bira od C1-C2 alkil skupina koje su opcionalno supstituirane s jednom ili više OH skupina;
- svaki R4 se neovisno bira od halogena;
- R*je H ili C1-C4 alkil;
- Xa se bira od F ili Cl;
- svaki k je neovisno 0 ili 1;
- svaki r je neovisno 0 ili 1;
- svaki m je neovisno 0, 1, 2 ili 3;
- svaki n je neovisno 0 ili 1;
- svaki p je neovisno 0, 1, 2, 3, 4 ili 5; i
- svaki q je neovisno 0, 1, 2, 3, 4, 5, 6, 7 ili 8.
50. Najmanje jedan spoj odabran od spojeva prema bilo kojem od patentnih zahtjeva 1 do 18, njegova farmaceutski prihvatljiva sol, ili deuterirani derivat bilo kojeg od gorespomenutih, i opcionalno jedan ili više od:
(a) Spoja II:
[image]
njegove farmaceutski prihvatljive soli, ili deuteriranog derivata od bilo kojega navedenog; i
(b) Spoja III:
[image]
njegove farmaceutski prihvatljive soli, ili deuteriranog derivata od bilo kojega navedenog;
naznačeni time, da su za uporabu u liječenju cistične fibroze.
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