HRP20211396T1 - 7-supstituirani 1-aril-naftiridin-3-karboksamidi i njihova upotreba - Google Patents
7-supstituirani 1-aril-naftiridin-3-karboksamidi i njihova upotreba Download PDFInfo
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- HRP20211396T1 HRP20211396T1 HRP20211396TT HRP20211396T HRP20211396T1 HR P20211396 T1 HRP20211396 T1 HR P20211396T1 HR P20211396T T HRP20211396T T HR P20211396TT HR P20211396 T HRP20211396 T HR P20211396T HR P20211396 T1 HRP20211396 T1 HR P20211396T1
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- 150000001875 compounds Chemical class 0.000 claims 47
- 229910052731 fluorine Inorganic materials 0.000 claims 34
- 239000011737 fluorine Substances 0.000 claims 34
- 125000001153 fluoro group Chemical group F* 0.000 claims 24
- 229910052739 hydrogen Inorganic materials 0.000 claims 24
- 239000001257 hydrogen Substances 0.000 claims 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 22
- 229910052757 nitrogen Inorganic materials 0.000 claims 21
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 19
- -1 methoxy, difluoromethoxy Chemical group 0.000 claims 15
- 150000003839 salts Chemical group 0.000 claims 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 14
- 229910052801 chlorine Inorganic materials 0.000 claims 14
- 239000000460 chlorine Substances 0.000 claims 14
- 239000012453 solvate Chemical group 0.000 claims 13
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 10
- 125000000623 heterocyclic group Chemical group 0.000 claims 9
- 125000001424 substituent group Chemical group 0.000 claims 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims 6
- 150000001408 amides Chemical group 0.000 claims 6
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 6
- 125000002950 monocyclic group Chemical group 0.000 claims 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 4
- 125000002619 bicyclic group Chemical group 0.000 claims 4
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 4
- 229910052794 bromium Chemical group 0.000 claims 4
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 3
- 150000001204 N-oxides Chemical group 0.000 claims 3
- 229910052799 carbon Inorganic materials 0.000 claims 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims 3
- 229940079593 drug Drugs 0.000 claims 3
- 239000003814 drug Substances 0.000 claims 3
- 125000005842 heteroatom Chemical group 0.000 claims 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 3
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims 3
- 238000011321 prophylaxis Methods 0.000 claims 3
- 238000011282 treatment Methods 0.000 claims 3
- YSZSLPRWNYBWRS-LSFNHRITSA-N (2S,9S,12R)-2-cyclohexyl-12-[2-(3,4-dimethoxyphenyl)ethyl]-24,27-dimethoxy-11,18,22-trioxa-4-azatetracyclo[21.2.2.113,17.04,9]octacosa-1(25),13(28),14,16,23,26-hexaene-3,10-dione Chemical group COC1=C(C=C(C=C1)CC[C@@H]2C3=CC(=CC=C3)OCCCOC4=C(C=C(C=C4OC)[C@@H](C(=O)N5CCCC[C@H]5C(=O)O2)C6CCCCC6)OC)OC YSZSLPRWNYBWRS-LSFNHRITSA-N 0.000 claims 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 2
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims 2
- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 claims 2
- 206010003130 Arrhythmia supraventricular Diseases 0.000 claims 2
- 102220473072 Chemerin-like receptor 2_R14Q_mutation Human genes 0.000 claims 2
- 206010019280 Heart failures Diseases 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 208000001647 Renal Insufficiency Diseases 0.000 claims 2
- 206010047281 Ventricular arrhythmia Diseases 0.000 claims 2
- 230000001746 atrial effect Effects 0.000 claims 2
- VNWKTOKETHGBQD-AKLPVKDBSA-N carbane Chemical compound [15CH4] VNWKTOKETHGBQD-AKLPVKDBSA-N 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- 229910002092 carbon dioxide Inorganic materials 0.000 claims 2
- 239000001569 carbon dioxide Substances 0.000 claims 2
- 150000003857 carboxamides Chemical class 0.000 claims 2
- 208000029078 coronary artery disease Diseases 0.000 claims 2
- 239000004615 ingredient Substances 0.000 claims 2
- 208000017169 kidney disease Diseases 0.000 claims 2
- 201000006370 kidney failure Diseases 0.000 claims 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 2
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims 2
- 125000004043 oxo group Chemical group O=* 0.000 claims 2
- 238000002953 preparative HPLC Methods 0.000 claims 2
- 229920006395 saturated elastomer Polymers 0.000 claims 2
- 125000000165 tricyclic carbocycle group Chemical group 0.000 claims 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 2
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims 1
- OBYVIVUJQDGTKI-RIUYPTKQSA-N 2-[[(2R,3S,4S,5R,6R)-3,5-dihydroxy-2-(hydroxymethyl)-6-methoxyoxan-4-yl]oxymethyl]quinoline-7-carboxylic acid Chemical group CO[C@H]1[C@@H]([C@H]([C@H]([C@H](O1)CO)O)OCC2=NC3=C(C=CC(=C3)C(=O)O)C=C2)O OBYVIVUJQDGTKI-RIUYPTKQSA-N 0.000 claims 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 1
- 101100296726 Caenorhabditis elegans pde-5 gene Proteins 0.000 claims 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 claims 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 claims 1
- 208000001953 Hypotension Diseases 0.000 claims 1
- 102000007205 Muscarinic M2 Receptor Human genes 0.000 claims 1
- 108010008407 Muscarinic M2 Receptor Proteins 0.000 claims 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 150000007513 acids Chemical class 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 230000003288 anthiarrhythmic effect Effects 0.000 claims 1
- 239000003416 antiarrhythmic agent Substances 0.000 claims 1
- 229940127218 antiplatelet drug Drugs 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical group 0.000 claims 1
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims 1
- 208000021822 hypotensive Diseases 0.000 claims 1
- 230000001077 hypotensive effect Effects 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 claims 1
- 229940126027 positive allosteric modulator Drugs 0.000 claims 1
- 229940125526 sGC activator Drugs 0.000 claims 1
- 229940127296 soluble guanylate cyclase stimulator Drugs 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 239000002536 vasopressin receptor antagonist Substances 0.000 claims 1
Classifications
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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
- C07D471/02—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
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pyridine Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Claims (28)
1. Spoj s formulom (I)
[image]
naznačen time što
X predstavlja halogen,
R1 predstavlja vodik,
ili
predstavlja -NR4R5,
u kojoj
R4 predstavlja vodik, metil, (C2-C4) -alkil ili (C3-C6)-cikloalkil,
gdje (C2-C4)-alkil može biti supstituiran s hidroksilom ili do trostruko supstituiran s fluorom i
R5 predstavlja (C1-C6) -alkil, (C3-C6) -cikloalkil, 3- do 6-člani zasićeni heterociklil ili (C1-C4)-alkilsulfonil,
gdje (C1-C6) -alkil, (C3-C6) -cikloalkil i 3- do 6-člani zasićeni heterociklil mogu biti do trostruko supstituirani, identično ili različito, s metilom, difluorometilom, trifluorometilom, hidroksilom, hidroksikarbonilom, okso, metoksi, difluorometoksi, trifluorometoksi i cijano, i dodatno do četverostruko supstituiran s fluorom,
ili
R4 i R5 zajedno s atomom dušika na koji su oni vezani tvore zasićeni ili djelomično nezasićeni, 3- do 6-člani monociklički ili 6- do 10-člani biciklički heterocikal koji mogu sadržavati kao članove prstena jedan ili dva daljnja, identična ili različita heteroatoma iz skupine N, O, S, SO i/ili SO2,
gdje 3- do 6-člani monociklički i 6- do 10-člani biciklički heterocikal može svaki biti supstituiran s 1 do 5 supstituenata koji su neovisno odabrani iz skupine koja sadrži (C1-C4)-alkil, difluorometil, trifluorometil, hidroksi, hidroksikarbonil, okso, (C1-C3)-alkoksi, difluorometoksi, trifluorometoksi, cijano, (C1-C3)-alkoksikarbonil, aminokarbonil, mono-(C1-C3)-alkilaminokarboniloksi,-NHC(=O)R14A, -CH2NHC(=O)R14B, -OC(=O)R15, i dodatno do četverostruko supstituiran s fluorom,
u kojoj (C1-C4)-alkil može biti mono- ili disupstituiran, identično ili različito s hidroksilom i (C1-C3)-alkoksi, i do četverostruko supstituiran s fluorom,
R14A i R14B međusobno neovisno predstavljaju (C1-C3)-alkil ili ciklopropil, i u kojoj
R15 predstavlja (C1-C4)-alkil,
R2 predstavlja skupinu s formulom
[image]
u kojoj
* označava točku vezanja za atom dušika u amidnom dijelu,
R6A predstavlja vodik ili (C1-C4)-alkil,
R6B predstavlja vodik, (C1-C4)-alkil, ciklopropil, monofluorometil, difluorometil, trifluorometil, metoksimetil ili trifluorometoksimetil,
R7 predstavlja (C1-C6) -alkil ili (C3-C5) -cikloalkil koji je do četverostruko supstituiran s fluorom,
gdje (C1-C6)-alkil može biti supstituiran s amino, hidroksi, (C1-C6) -alkoksi i do peterostruko supstituiran s fluorom,
gdje (C1-C6)-alkoksi može biti do peterostruko supstituiran s fluorom,
L1 predstavlja vezu ili skupinu s formulom -C(R8AR8B)-(C(R9AR9B))m-,
u kojoj
m predstavlja 0 ili 1,
R8A predstavlja vodik ili metil,
R8B predstavlja vodik, metil, trifluorometil, pentafluoroetil ili trifluorometoksimetil,
R9A i R9B svaki neovisno jedan od drugoga predstavljaju vodik ili metil,
Ar2 predstavlja fenil,
gdje fenil može biti jednostruko do trostruko supstituiran, identično ili različito, s fluorom, klorom, (C1-C3) -alkilom, difluorometoksimetilom, trifluorometoksimetilom i/ili trifluorometilom,
ili
predstavlja 5- do 10-člani monociklički, biciklički ili triciklički karbocikal ili heterocikal koji može sadržavati jedan ili dva daljnja, identična ili različita heteroatoma iz skupine koja sadrži N i/ili O kao članove prstena,
gdje 5- do 10-člani monociklički, biciklički ili triciklički karbocikal ili heterocikal može biti do trostruko supstituiran s identičnim ili različitim supstituentima iz skupine koju čine (C1-C3) -alkil, trifluorometil i (C1-C4)-alkoksikarbonil i nadalje do četverostruko supstituiran s fluorom,
Ar1 predstavlja skupinu s formulom
[image]
u kojoj
*** označava točku vezanja za atom dušika,
R3A predstavlja fluor, klor, trifluorometil ili metil,
R3B predstavlja vodik ili fluor
i
R3C predstavlja vodik, fluor, klor ili metil,
ili
predstavlja piridinski prsten koji je vezan preko ugljikovog atoma u prstenu,
gdje piridinski prsten može biti mono- ili disupstituiran s fluorom, klorom, cijano, metilom ili trifluorometilom,
i N-oksidi, soli, solvati, soli N-oksida i solvati N -oksida i njihove soli
2. Spoj s formulom (I) prema patentnom zahtjevu 1, naznačen time što
X predstavlja fluor, klor ili brom,
R1 predstavlja vodik,
ili
predstavlja NR4R5,
u kojoj
R4 predstavlja vodik, metil ili etil, i
R5 predstavlja (C1-C3) -alkil koji je do četverostruko supstituiran s fluorom,
gdje (C1-C3)-alkil može biti supstituiran s hidroksi,
ili
R4 i R5 zajedno s atomom dušika na koji su oni spojeni tvore zasićeni 4- do 6-člani monociklički ili 6- do 9-člani biciklički heterocikal koji može sadržavati kao članove prstena jedan ili dva daljnja identična ili različita heteroatoma iz skupine koja se sastoji od N i O,
gdje 4- do 6-člani monociklički i 6- do 9-člani biciklički heterocikal može svaki biti supstituiran s 1 do 4 supstituenata koji su neovisno jedni od drugih odabrani iz skupine koju čine (C1-C4)-alkil, difluorometil, trifluorometil, hidroksi, okso, (C1-C3) -alkoksi, difluorometoksi, trifluorometoksi, (C1-C3)-alkoksikarbonil, (C1-C3) -alkilaminokarboniloksi i -OC(=O)R15 i nadalje do četverostruko supstituiran s fluorom,
gdje (C1-C4)-alkil može biti mono- ili disupstituiran s identičnim ili različitim supstituentima iz skupine koju čine hidroksi i (C1-C3) -alkoksi, i do četverostruko supstituiran s fluorom, i gdje
R15 predstavlja (C1-C4)-alkil,
R2 predstavlja skupinu s formulom
[image]
u kojoj
* označava točku vezanja za atom dušika u amidnom dijelu,
R6A predstavlja vodik ili (C1-C4)-alkil,
R6B predstavlja metil, etil, izopropil, ciklopropil, monofluorometil, difluorometil ili trifluorometil, i
R7 predstavlja (C1-C4)-alkil koji je do peterostruko supstituiran s fluorom, (C3-C5) - cikloalkil koji je do četverostruko supstituiran s fluorom, metoksimetil ili trifluorometoksimetil,
L1 predstavlja vezu ili skupinu s formulom -CR8AR8B-,
u kojoj
R8A predstavlja vodik,
R8B predstavlja vodik, metil, trifluorometil, pentafluoroetil ili trifluorometoksimetil,
Ar2 predstavlja fenil,
gdje fenil može biti mono- do trostruko supstituiran s identičnim ili različitim supstituentima iz skupine koju čine fluor i klor,
ili
predstavlja 5- do 7-člani biciklički karbocikal ili 5- ili 6-člani monociklički heterocikal koji sadrži jedan atom dušika kao član prstena,
gdje 5- do 7-člani biciklički karbocikal ili 5- ili 6-člani monociklički heterocikal može u svakom slučaju biti supstituiran s (C1-C4)-alkoksikarbonilom i dodatno do četverostruko supstituiran s fluorom,
Ar1 predstavlja skupinu s formulom
[image]
u kojoj
*** označava točku vezanja za atom dušika,
R3A predstavlja fluor, klor, trifluorometil ili metil,
R3B predstavlja vodik ili fluor
i
R3C predstavlja vodik, fluor, klor ili metil,
ili
predstavlja piridinski prsten koji je vezan preko ugljikovog atoma u prstenu,
gdje piridinski prsten može biti mono- ili disupstituiran s fluorom, klorom ili cijano, i njihove soli, solvati i solvati njihovih soli.
3. Spoj s formulom (I) prema patentnom zahtjevu 1 ili 2, naznačen time što
X predstavlja fluor, klor ili brom,
R1 predstavlja NR4R5,
u kojoj
R4 predstavlja metil ili etil, i
R5 predstavlja metil, 2-hidroksietil ili 2-hidroksipropil,
ili
predstavlja heterocikal, vezan preko atoma dušika, s formulom
[image]
[image]
u kojoj
**označava mjesto vezivanja za ostatak molekule,
R10 predstavlja fluor, metil, hidroksi, hidroksimetil, metoksikarbonil ili acetiloksi,
p predstavlja broj 0, 1 ili 2, gdje, u slučaju da se supstituenti R10 javljaju više od jednom, njihova značenja mogu u svakom slučaju biti identična ili različita,
Y1 predstavlja -NH-, -N(CH3)- ili -O-,
R2 predstavlja skupinu s formulom
[image]
[image]
u kojoj
* označava točku vezanja za atom dušika u amidnom dijelu,
R6A predstavlja vodik, metil ili etil,
R6B predstavlja metil, etil, trifluorometil, izopropil ili ciklopropil, i
R7 predstavlja metil, etil, difluorometil, trifluorometil, 2,2,2-trifluoroetil, pentafluoroetil, izopropil, izobutil, metoksimetil, trifluorometoksimetil ili ciklopropil,
R11 predstavlja vodik,
R12 predstavlja metoksikarbonil,
R13 predstavlja vodik ili tert-butoksikarbonil,
L1 predstavlja vezu ili skupinu s formulom -CR8AR8B-,
u kojoj
R8A predstavlja vodik,
R8B predstavlja vodik, metil ili trifluorometil,
Ar2 predstavlja fenil,
gdje fenil može biti mono- do disupstituiran s identičnim ili različitim supstituentima iz skupine koja se sastoji od fluora i klora,
Ar1 predstavlja skupinu s formulom
[image]
u kojoj
*** označava točku vezanja za atom dušika,
R3A predstavlja fluor ili klor,
i
R3C predstavlja vodik ili fluor,
i njihove soli, solvati i solvati njihovih soli.
4. Spoj s formulom (I) prema bilo kojem od patentnih zahtjeva 1 do 3,
naznačen time što
X predstavlja fluor,
R1 predstavlja heterocikal, vezan preko atoma dušika, s formulom
[image]
u kojoj
**označava mjesto vezivanja za ostatak molekule,
R2 predstavlja skupinu s formulom
[image]
[image]
u kojoj
* označava točku vezanja za atom dušika u amidnom dijelu,
Ar1 predstavlja skupinu s formulom
[image]
u kojoj
*** označava točku vezanja za atom dušika,
i njihove soli, solvati i solvati njihovih soli.
5. Spoj s formulom (I) prema patentnom zahtjevu 1 ili 2, naznačen time što
X predstavlja fluor,
R1 predstavlja heterocikal, vezan preko atoma dušika, s formulom
[image]
ili
[image]
u kojoj
** označava mjesto vezivanja za ostatak molekule,
R2 predstavlja skupinu s formulom
[image]
u kojoj
* označava točku vezanja za atom dušika u amidnom dijelu,
Ar1 predstavlja skupinu s formulom
[image]
u kojoj
*** označava točku vezanja za atom dušika,
i njihove soli, solvati i solvati njihovih soli.
6. Spoj s formulom (I) prema patentnom zahtjevu 1 ili 2, naznačen time što
X predstavlja fluor,
R1 predstavlja heterocikal, vezan preko atoma dušika, s formulom
[image]
u kojoj
** označava mjesto vezivanja za ostatak molekule,
R2 predstavlja skupinu s formulom
[image]
u kojoj
* označava točku vezanja za atom dušika u amidnom dijelu,
Ar1 predstavlja skupinu s formulom
[image]
u kojoj
*** označava točku vezanja za atom dušika,
i njihove soli, solvati i solvati njihovih soli.
7. Spoj s formulom (I) prema bilo kojem od patentnih zahtjeva 1 do 3, naznačen time što
R1 predstavlja heterocikal, vezan preko atoma dušika, s formulom
[image]
u kojoj
** označava mjesto vezivanja za ostatak molekule.
8. Spoj prema patentnom zahtjevu 1, naznačen time što spoj s formulom (I) ima donju strukturu
[image]
9. Spoj prema patentnom zahtjevu 1, naznačen time što spoj s formulom (I) ima donju strukturu
[image]
10. Spoj prema patentnom zahtjevu 1, naznačen time što spoj s formulom (I) ima donju strukturu
[image]
11. Spoj prema patentnom zahtjevu 1, naznačen time što spoj s formulom (I) ima donju strukturu
[image]
12. Spoj prema patentnom zahtjevu 1, naznačen time što spoj s formulom (I) ima donju strukturu
[image]
13. Spoj prema patentnom zahtjevu 1, naznačen time što spoj s formulom (I) ima donju strukturu
[image]
14. Spoj prema patentnom zahtjevu 1, naznačen time što spoj s formulom (I) ima donju strukturu
[image]
15. Spoj prema patentnom zahtjevu 1, naznačen time što spoj s formulom (I) ima donju strukturu
[image]
16. Spoj prema patentnom zahtjevu 1, naznačen time što spoj s formulom (I) ima donju strukturu
[image]
17. Spoj prema patentnom zahtjevu 10, naznačen time što je dijastereomer 1 koji se može dobiti preparativnom SFC na Daicel Chiralpak AD, 5 µm, 250 × 30 mm s mobilnom fazom 85% ugljikovog dioksida/15% izopropanol na temperaturi od 38°C i brzinom protoka od 130 ml/min pri tlaku od 140 bara iz racemata i, u tim uvjetima, eluira nakon 3.23 min.
18. Spoj prema patentnom zahtjevu 10, naznačen time što je dijastereomer 2 koji se može dobiti preparativnom SFC na Daicel Chiralpak AD, 5 µm, 250 × 30 mm s mobilnom fazom 85% ugljikovog dioksida/15% izopropanol na temperaturi od 38°C i brzinom protoka od 130 ml/min pri tlaku od 140 bara iz racemata i, u tim uvjetima, eluira nakon 4.79 min.
19. Spoj prema patentnom zahtjevu 16, naznačen time što je dijastereomer 1 koji se može dobiti preparativnom HPLC na Daicel Chiralcel OX-H, 5 µm, 250 × 30 mm s mobilnom fazom 80% n-heptan/20% etanol na temperaturi od 25°C i brzinom protoka od 40 ml/min iz racemata i, u tim uvjetima, eluira nakon 6.40 min.
20. Spoj prema patentnom zahtjevu 16, naznačen time što je dijastereomer 2 koji se može dobiti preparativnom HPLC na Daicel Chiralcel OX-H, 5 µm, 250 × 30 mm s mobilnom fazom 80% n-heptan/20% etanol na temperaturi od 25°C i brzinom protoka od 40 ml/min iz racemata i, u tim uvjetima, eluira nakon 8.57 min.
21. Postupak za pripravu spojeva s formulom (I) kako je definirano u bilo kojem od patentnih zahtjeva 1 do 20, naznačen time što
[A] spoj s formulom (II)
[image]
u kojoj X, R2 i Ar1 imaju značenja dana u zahtjevima 1 do 20 za spojeve s formulom (I)
i
Hal predstavlja fluor, klor, brom ili jod,
reagira sa spojem s formulom (III)
R1-H (III),
u kojoj R1 ima značenje navedeno u zahtjevima 1 do 20 za spojeve s formulom (I) i gdje R1 ne predstavlja vodik,
da se dobije karboksamid s formulom (I-A)
[image]
u kojoj X, R1, R2 i Ar1 imaju značenja dana u zahtjevima 1 do 20 za spojeve s formulom (I) i gdje R1 na predstavlja vodik,
ili
[B] spoj s formulom (IV)
[image]
u kojoj X, R1 i Ar1 imaju značenja dana u zahtjevima 1 do 20 za spojeve s formulom (I)
reagira sa spojem s formulom (V)
R2-NH2 (V),
u kojoj R2 ima značenje navedeno u zahtjevima 1 do 20 za spojeve s formulom (I),
da se dobije karboksamid s formulom (I)
[image]
u kojoj R1, R2 i Ar1 imaju značenja dana u zahtjevima 1 do 20 za spojeve s formulom (I),
i dobiveni spojevi formule (I) se po izboru razdvajaju u njihove enantiomere i/ili dijastereomere i/ili se pretvaraju s odgovarajućim (i) otapalima i/ili (ii) bazama ili kiselinama u njihove solvate, soli i/ili solvate soli.
22. Spoj s formulom (II)
[image]
u kojoj X, R2 i Ar1 imaju značenja dana u zahtjevima 1 do 20 za spojeve s formulom (I),
i
Hal predstavlja fluor, klor, brom ili jod.
23. Spoj, kako je definiran u bilo kojem od patentnih zahtjeva 1 do 20, naznačen time što se koristi u liječenju i/ili profilaksi bolesti.
24. Spoj s formulom (I), kako je definiran u bilo kojem od patentnih zahtjeva 1 do 20, naznačen time što je za uporabu u postupku liječenja i/ili profilaksi zatajenja srca, koronarne bolesti srca, atrijalnih i ventrikularnih aritmija, zatajenja bubrega i nefropatija.
25. Lijek, naznačen time što sadrži spoj kako je definiran u bilo kojem od patentnih zahtjeva 1 do 20 u kombinaciji s jednim ili više daljnjih aktivnih sastojaka odabranih iz skupine koja se sastoji od aktivnih hipotenzivnih sastojaka, aktivnih antiaritmičkih sastojaka, antagonista receptora vazopresina, inhibitora PDE 5, inhibitora agregacije trombocita, sGC aktivatora i sGC stimulatora.
26. Lijek, naznačen time što sadrži spoj kako je definiran u bilo kojem od patentnih zahtjeva 1 do 20 u kombinaciji s inertnim, netoksičnim, farmaceutski prikladnim pomoćnim sredstvom.
27. Lijek prema patentnom zahtjevu 25 ili 26 naznačen time što se koristi u liječenju i/ili profilaksi zatajenja srca, koronarne bolesti srca, atrijalnih i ventrikularnih aritmija, zatajenja bubrega i nefropatija.
28. Pozitivni alosterični modulator muskarinergičnog M2 receptora s formulom (I) prema bilo kojem od patentnih zahtjeva 1 do 20.
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| EP16202509 | 2016-12-06 | ||
| PCT/EP2017/072339 WO2018050510A1 (de) | 2016-09-14 | 2017-09-06 | 7-substituierte 1-aryl-naphthyridin-3-carbonsäureamide und ihre verwendung |
| EP17772322.8A EP3512849B1 (de) | 2016-09-14 | 2017-09-06 | 7-substituierte 1-aryl-naphthyridin-3-carbonsäureamide und ihre verwendung |
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| CN103183676B (zh) | 2013-03-12 | 2015-04-08 | 中国医学科学院医药生物技术研究所 | 一组1-取代-1,8萘啶甲酰胺衍生物及制备和应用 |
| GB201409044D0 (en) | 2014-05-21 | 2014-07-02 | Ucl Business Plc | New compounds |
| UY36383A (es) | 2014-11-03 | 2016-06-01 | Bayer Pharma AG | Derivados de feniltriazol sustituido con hidroxialquilo y sus usos |
| JP2017538689A (ja) | 2014-11-17 | 2017-12-28 | ニーロジョン セラピューティクス インコーポレイテッドＮｉｒｏｇｙｏｎｅ Ｔｈｅｒａｐｅｕｔｉｃｓ， Ｉｎｃ． | モノカルボン酸輸送修飾薬およびその使用 |
| TWI726888B (zh) | 2015-06-09 | 2021-05-11 | 美商艾伯維有限公司 | 核受體調節劑 |
| PT3312177T (pt) | 2015-06-09 | 2021-05-17 | Onconic Therapeutics Inc | Composto derivado tricíclico, método para preparar o mesmo e composição farmacêutica compreendendo o mesmo |
| JP6908536B2 (ja) | 2015-06-09 | 2021-07-28 | バイエル・ファルマ・アクティエンゲゼルシャフト | ムスカリンｍ２受容体の正のアロステリックモジュレーター |
| CA3030204A1 (en) | 2016-07-11 | 2018-01-18 | Bayer Pharma Aktiengesellschaft | 7-substituted 1-pyridyl-naphthyridine-3-carboxylic acid amides and use thereof |
| JOP20190045A1 (ar) | 2016-09-14 | 2019-03-14 | Bayer Ag | مركبات أميد حمض 1- أريل-نفثيريدين-3-كربوكسيليك مستبدلة في الموضع 7 واستخدامها. |
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