HRP20150500T1 - Derivati pirazina kao enac-blokatori - Google Patents
Derivati pirazina kao enac-blokatori Download PDFInfo
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- HRP20150500T1 HRP20150500T1 HRP20150500TT HRP20150500T HRP20150500T1 HR P20150500 T1 HRP20150500 T1 HR P20150500T1 HR P20150500T T HRP20150500T T HR P20150500TT HR P20150500 T HRP20150500 T HR P20150500T HR P20150500 T1 HRP20150500 T1 HR P20150500T1
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- alkyl
- optionally substituted
- membered
- heterocyclic group
- alkoxy
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- 239000002713 epithelial sodium channel blocking agent Substances 0.000 title description 2
- 150000003216 pyrazines Chemical class 0.000 title 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 26
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 21
- 150000001875 compounds Chemical class 0.000 claims 16
- 229910052736 halogen Inorganic materials 0.000 claims 15
- 150000002367 halogens Chemical class 0.000 claims 13
- 229910052760 oxygen Inorganic materials 0.000 claims 13
- 150000003839 salts Chemical class 0.000 claims 13
- 229910052717 sulfur Inorganic materials 0.000 claims 13
- 125000005842 heteroatom Chemical group 0.000 claims 12
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 11
- -1 3-{2-[(Z)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl} -3-oxo-propyl Chemical group 0.000 claims 11
- 125000003118 aryl group Chemical group 0.000 claims 10
- 125000000217 alkyl group Chemical group 0.000 claims 9
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 6
- 229910052799 carbon Inorganic materials 0.000 claims 6
- 125000005843 halogen group Chemical group 0.000 claims 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 5
- 229910052757 nitrogen Inorganic materials 0.000 claims 4
- 125000001424 substituent group Chemical group 0.000 claims 4
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims 3
- 125000004429 atom Chemical group 0.000 claims 3
- 125000004432 carbon atom Chemical group C* 0.000 claims 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 3
- 229910052739 hydrogen Inorganic materials 0.000 claims 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 3
- 125000004043 oxo group Chemical group O=* 0.000 claims 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 2
- 201000010099 disease Diseases 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 229940124597 therapeutic agent Drugs 0.000 claims 2
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims 1
- RNMRTGIATJFFQB-UHFFFAOYSA-N 2-(2-oxopiperidin-1-yl)ethyl 2-[2-chloro-4-[3-[2-[(3,5-diamino-6-chloropyrazine-2-carbonyl)amino]-1,3,8-triazaspiro[4.5]dec-2-en-8-yl]-3-oxopropyl]phenoxy]acetate Chemical compound N1=C(Cl)C(N)=NC(N)=C1C(=O)\N=C/1NC2(CCN(CC2)C(=O)CCC=2C=C(Cl)C(OCC(=O)OCCN3C(CCCC3)=O)=CC=2)CN\1 RNMRTGIATJFFQB-UHFFFAOYSA-N 0.000 claims 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 1
- 101100173726 Arabidopsis thaliana OR23 gene Proteins 0.000 claims 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims 1
- 208000025678 Ciliary Motility disease Diseases 0.000 claims 1
- 201000003883 Cystic fibrosis Diseases 0.000 claims 1
- 102000003837 Epithelial Sodium Channels Human genes 0.000 claims 1
- 108090000140 Epithelial Sodium Channels Proteins 0.000 claims 1
- DSPJHXXYPOAPHP-UHFFFAOYSA-N [2-(dipropylamino)-2-oxoethyl] 2-[2-chloro-4-[3-[2-[(3,5-diamino-6-chloropyrazine-2-carbonyl)amino]-1,3,8-triazaspiro[4.5]dec-2-en-8-yl]-3-oxopropyl]phenoxy]acetate Chemical compound C1=C(Cl)C(OCC(=O)OCC(=O)N(CCC)CCC)=CC=C1CCC(=O)N1CCC2(NC(/NC2)=N/C(=O)C=2C(=NC(N)=C(Cl)N=2)N)CC1 DSPJHXXYPOAPHP-UHFFFAOYSA-N 0.000 claims 1
- VVVHUYKVJYCLQF-UHFFFAOYSA-N [2-(dipropylamino)-2-oxoethyl] 3-[[3-[2-[(3,5-diamino-6-chloropyrazine-2-carbonyl)amino]-1,3,8-triazaspiro[4.5]dec-2-ene-8-carbonyl]phenyl]carbamoylamino]propanoate Chemical compound CCCN(CCC)C(=O)COC(=O)CCNC(=O)NC1=CC=CC(C(=O)N2CCC3(NC(/NC3)=N/C(=O)C=3C(=NC(N)=C(Cl)N=3)N)CC2)=C1 VVVHUYKVJYCLQF-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003120 macrolide antibiotic agent Substances 0.000 claims 1
- 230000001404 mediated effect Effects 0.000 claims 1
- 239000003607 modifier Substances 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 239000008177 pharmaceutical agent Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 201000009266 primary ciliary dyskinesia Diseases 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 150000003890 succinate salts Chemical class 0.000 claims 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical class C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4747—Quinolines; Isoquinolines spiro-condensed
-
- 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
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- 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
-
- 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
- A61P11/06—Antiasthmatics
-
- 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
- A61P11/10—Expectorants
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
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- Animal Behavior & Ethology (AREA)
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- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
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Description
DERIVATI PIRAZINA KAO ENAC-BLOKATORI
Claims (17)
1. Spoj, naznačen time, da ima formulu Ia:
[image]
ili njegova farmaceutski prihvatljiva sol, pri čemu R10 je predstavljen putem formule 2:
-(C0-C3alkilen)-B-X-(CR11aR12a)m-(CR11bR12b)n-(CR11cR12c)p-C(O)OR13,
gdje su alkilen-skupine po želji supstituirane s jednom ili više Z-skupina;
B je aril koji je po želji supstituiran s jednom ili više Z-skupina;
X je odabrana od sljedećih: veza, -NR15(SO2)-, -(SO2)NR15-, -(SO2)-, -NR15C(O)-, -C(O)NR15-, -NR15C(O)NR17-, -NR15C(O)O-, -NR15-, C(O)O, OC(O), C(O), O i S;
svaka od R11a, R11b, R11c, R12a, R12b i R12c je neovisno odabrana od H i C1-C6 alkila; ili
R11a i R12a zajedno s atomom ugljika na kojega su priključene, tvore 3-članu do 8-članu cikloalkil-skupinu; ili
R11b i R12b zajedno s atomom ugljika na kojega su priključene, tvore 3-članu do 8-članu cikloalkil-skupinu; ili
R11c i R12c zajedno s atomom ugljika na kojega su priključene, tvore 3-članu do 8-članu cikloalkil-skupinu;
R13 je odabrana od sljedećih: (C1-C3 alkil)-C(O)NR22R23;
(C1-C3 alkil)-C(O)OR23; i (C1-C3 alkil)-NR23C(O)R22;
svaka od R15 i R17 je neovisno odabrana od H i C1-C6 alkila;
Z je neovisno odabrana od sljedećih: -OH, aril, -O-aril, C7-C14 aralkil, -O-C7-C14 aralkil, C1-C6 alkil, C1-C6 alkoksi, -NR19(SO2)R21, -(SO2)NR19R21, -(SO2)R20, -NR19C(O)R20, -C(O)NR19R20, -NR19C(O)NR20R18, -NR19C(O)OR20, -NR19R21, C(O)OR19, -C(O)R19, SR19, -OR19, okso, CN, NO2, i halogen, gdje je svaka od skupina aril, alkil, alkoksi, aralkil i aril po želji supstituirana s jednim ili više supstituenata odabranih od sljedećih: OH, halogen, C1-C4 haloalkil i C1-C4 alkoksi;
svaka od R18, R20 i R22 je neovisno odabrana od H i C1-C6 alkila;
svaka od R19, R21 i R23 je neovisno odabrana od sljedećih: H; C1-C8 alkil;
C3-C8 cikloalkil; C1-C4 alkoksi-C1-C4 alkil; (C0-C4 alkil)-aril po želji supstituirana s jednom ili više skupina odabranih od C1-C6 alkila, C1-C6 alkoksi i halogena; (C0-C4 alkil)-3-člana do 14-člana heterociklička skupina, gdje heterociklička skupina uključuje jedan ili više heteroatoma odabranih od N, O i S, po želji supstituirana s jednom ili više skupina odabranih od sljedećih: halogen, okso, C1-C6 alkil i -C(O)C1-C6 alkil;
-(C0-C4 alkil)-O-aril po želji supstituirana s jednom ili više skupina odabranih od C1-C6 alkila, C1-C6 alkoksi i halogena; i (C0-C4 alkil)-O-3-člana do 14-člana heterociklička skupina, gdje heterociklička skupina uključuje jedan ili više heteroatoma odabranih od N, O i S, po želji supstituirana s jednom ili više skupina odabranih od halogena, C1-C6 alkila i -C(O)C1-C6 alkila; pri čemu su alkil-skupine po želji supstituirane s jednim ili više atoma halogena, hidroksila, C1-C4 alkoksi, -C(O)NH2, -C(O)NHC1-C6 alkila ili -C(O)N(C1-C6 alkila)2; ili
R19 i R20 zajedno s atomom dušika na kojega su priključene, tvore 5-članu do 10-članu heterocikličku skupinu, gdje heterociklička skupina uključuje jedan ili više dodatnih heteroatoma odabranih od N, O i S, pri čemu je heterociklička skupina po želji supstituirana s jednim ili više supstituenata odabranih od OH; halogen; aril; 5-člana do 10-člana heterociklička skupina uključujući jedan ili više heteroatoma odabranih od N, O i S; -S(O)2-aril; -S(O)2-C1-C6 alkil; C1-C6 alkil po želji supstituirana s jednim ili više atoma halogena; C1-C6 alkoksi po želji supstituirana s jednom ili više OH-skupina ili C1-C4 alkoksi; i C(O)OC1-C6 alkil, gdje su supstitucijske arilne i heterocikličke skupine same po želji supstituirane s C1-C6 alkilom, C1-C6 haloalkilom ili C1-C6 alkoksi; ili
R19 i R21 zajedno s atomom dušika na kojega su priključene, tvore 5-članu do 10-članu heterocikličku skupinu, gdje heterociklička skupina uključuje jedan ili više dodatnih heteroatoma odabranih od N, O i S, pri čemu je heterociklička skupina po želji supstituirana s jednim ili više supstituenata odabranih od OH; halogen; aril; 5-člana do 10-člana heterociklička skupina koja uključuje jedan ili više heteroatoma odabranih od N, O i S; -S(O)2-aril; -S(O)2-C1-C6 alkil; C1-C6 alkil po želji supstituirana s jednim ili više atoma halogena; C1-C6 alkoksi po želji supstituirana s jednom ili više OH-skupina ili C1-C4 alkoksi; i -C(O)OC1-C6 alkil, gdje su supstitucijske arilne i heterocikličke skupine same po želji supstituirane s C1-C6 alkilom, C1-C6 haloalkilom ili C1-C6 alkoksi; ili
R18 i R20 zajedno s atomom dušika na kojega su priključene, tvore 5-članu do 10-članu heterocikličku skupinu, gdje heterociklička skupina uključuje jedan ili više dodatnih heteroatoma odabranih od N, O i S, pri čemu je heterociklička skupina po želji supstituirana s jednim ili više supstituenata odabranih od OH; halogen; aril; 5-člana do 10-člana heterociklička skupina koja uključuje jedan ili više heteroatoma odabranih od N, O i S; -S(O)2-aril; -S(O)-C1-C6 alkil; C1-C6 alkil po želji supstituiran s jednim ili više atoma halogena; C1-C6 alkoksi po želji supstituiran s jednom ili više OH-skupina ili C1-C4 alkoksi; i -C(O)OC1-C6 alkil, gdje su arilne i heterocikličke supstitucijske skupine same po želji supstituirane s C1-C6 alkilom, C1-C6 haloalkilom ili C1-C6 alkoksi; ili
R22 i R23 zajedno s atomom ili atomima na koje su priključene, tvore 5-članu do 10-članu heterocikličku skupinu, gdje heterociklička skupina uključuje jedan ili više dodatnih heteroatoma odabranih od N, O i S, pri čemu je heterociklička skupina po želji supstituirana s jednom ili više Z-skupina;
m je 0, 1, 2 ili 3;
n je 0, 1, 2 ili 3;
p je 0, 1, 2 ili 3;
gdje najmanje jedan od m, n ili p, nije 0.
2. Spoj prema zahtjevu 1, naznačen time, da B je fenil koji je po želji supstituiran s halogenom.
3. Spoj prema zahtjevu 1 ili 2, naznačen time, da X je odabran od sljedećih: -(SO2)NR15-, -NR15C(O)NR17-, i O.
4. Spoj prema bilo kojem od prethodnih zahtjeva, naznačen time, da
R13 je odabrana od sljedećih: (C1-C3 alkil)-C(O)NR22R23 i (C1-C3 alkil)-C(O)OR23; i gdje
R22 je odabrana od H i C1-C3 alkila; R23 je odabrana od H; C1-C8 alkila;
C3-C8 cikloalkila; C1-C4 alkoksi-C1-C4 alkila; (C0-C4 alkil)-aril po želji supstituiran s jednom ili više skupina odabranih od C1-C6 alkila, C1-C6 alkoksi i halogena;
(C0-C4 alkil)-3-člana do 14-člana heterociklička skupina, gdje heterociklička skupina uključuje jedan ili više heteroatoma odabranih od N, O i S, po želji supstituirana s jednom ili više skupina odabranih od halogena, okso, C1-C6 alkila i C(O)C1-C6 alkila; (C0-C4 alkil)-O-aril po želji supstituiran s jednom ili više skupina odabranih od C1-C6 alkila, C1-C6 alkoksi i halogena; i
(C0-C4 alkil)-O-3-člana do 14-člana heterociklička skupina, gdje heterociklička skupina uključuje jedan ili više heteroatoma odabranih od N, O i S, po želji supstituirana s jednom ili više skupina odabranih od halogena, C1-C6 alkila i C(O)C1-C6 alkila; gdje su alkil-skupine po želji supstituirane s jednim ili više atoma halogena, hidroksila, C1-C4 alkoksi, C(O)NH2, C(O)NHC1-C6 alkila ili C(O)N(C1-C6 alkila)2; ili
R22 i R23 zajedno s dušikom na kojega su priključene, tvore 5-članu do 7-članu heterocikloalkil-skupinu, gdje heterocikloalkil-skupina uključuje jedan ili više dodatnih heteroatoma odabranih od N, O i S, pri čemu je heterocikloalkil-skupina po želji supstituirana s jednom ili više Z-skupina.
5. Spoj prema zahtjevu 1, naznačen time, da je odabran od sljedećih:
3-((3-{2-[(E)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dekan-8-karbonil}-benzesulfonilamino)-propionska kiselina- dipropilkarbamoil-metilester;
[4-((3-{2-[(Z)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dek-8-il}-3-okso-propil)-fenoksi]-octena kiselina-[(2-hidroksi-etil)-metil-karbamoil]-metilester;
[4-((3-{2-[(E)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dek-8-il}-3-okso-propil)-fenoksi]-octena kiselina-cikloheksiloksi-karbonil-metilester;
3-((3-{2-[(E)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dekan-8-karbonil}-benzen-sulfonilamino)-propionska kiselina-cikloheksiloksi-karbonil-metilester;
[4-((3-{2-[(E)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dek-8-il}-3-okso-propil)-fenoksi]-octena kiselina-dimetilkarbamoil-metilester;
[4-((3-{2-[(E)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dek-8-il}-3-okso-propil)-fenoksi]-octena kiselina-dipropilkarbamoil-metilester;
[4-((3-{2-[(E)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dek-8-il}-3-okso-propil)-fenoksi]-octena kiselina-tert-butoksikarbonil-metilester;
[4-((3-{2-[(E)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dek-8-il}-3-okso-propil)-fenoksi]-octena kiselina-benziloksikarbonil-metilester;
[4-((3-{2-[(E)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dek-8-il}-3-okso-propil)-fenoksi]-octena kiselina-dietilkarbamoil-metilester;
[4-((3-{2-[(E)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dek-8-il}-3-okso-propil)-fenoksi]-octena kiselina-2-okso-2-piperidin-1-il-etilester;
[2-kloro-4-(3-{2-[(E)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dek-8-il}-3-okso-propil)-fenoksi]-octena kiselina-dipropilkarbamoil-metilester;
3-((3-{2-[(E)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dekan-8-karbonil}-benzensulfonilamino)-propionska kiselina-2-okso-2-(2-trifluorometil-pirolidin-1-il)-etilester;
[2-kloro-4-(3-{2-[(E)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dek-8-il}-3-okso-propil)-fenoksi]-octena kiselina-2-(2-okso-piperidin-1-il)-etilester;
[4-((3-{2-[(E)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dek-8-il}-3-okso-propil)-fenoksi]-octena kiselina-2-morfolin-4-il-2-okso-etilester;
1-[((3-{2-[(E)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dekan-8-karbonil}-benzensulfonilamino)-metil]-ciklobutan-karboksilna kiselina-dipropilkarbamoil-metilester;
3-[3-(3-{2-[(E)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dekan-8-karbonil}-fenil)-ureido]-propionska kiselina-dipropilkarbamoil-metilester; i
1-[((3-{2-[(E)-3,5-diamino-6-kloro-pirazin-2-karbonilimino]-1,3,8-triaza-spiro[4.5]dekan-8-karbonil}-benzensulfonilamino)-metil]-ciklobutan-karboksilna kiselina-2-okso-2-(2-trifluorometil-pirolidin-1-il)-etilester;
ili njegova farmaceutski prihvatljiva sol ili njegov solvat.
6. Spoj ili sol prema zahtjevu 1, naznačen(a) time, da ima sljedeću strukturu:
[image]
ili njegova farmaceutski prihvatljiva sol.
7. Spoj ili sol prema zahtjevu 1, naznačen(a) time, da spoj je sukcinatna sol.
8. Spoj ili sol prema zahtjevu 1, naznačen(a) time, da ima sljedeću strukturu:
[image]
ili njegova farmaceutski prihvatljiva sol.
9. Spoj ili sol prema zahtjevu 1, naznačen(a) time, da ima sljedeću strukturu:
[image]
ili njegova farmaceutski prihvatljiva sol.
10. Spoj ili sol prema zahtjevu 1, naznačen(a) time, da ima sljedeću strukturu:
[image]
ili njegova farmaceutski prihvatljiva sol.
11. Spoj ili sol prema zahtjevu 1, naznačen(a) time, da ima sljedeću strukturu:
[image]
ili njegova farmaceutski prihvatljiva sol.
12. Farmaceutski sastav, naznačen time, da obuhvaća spoj prema bilo kojem od zahtjeva 1 do 11 i jedno ili više farmaceutski prihvatljivih pomoćnih sredstava, razrjeđivača i/ili nosača.
13. Farmaceutski sastav prema zahtjevu 12, naznačen time, da se upotrebljava u kombinaciji s jednim ili više nekih drugih terapeutskih sredstava.
14. Farmaceutski sastav prema zahtjevu 13, naznačen time, da je neko drugo terapeutsko sredstvo odabrano od modifikatora funkcije CFTR i makrolidnih antibiotika.
15. Spoj prema bilo kojem od zahtjeva 1 do 11, naznačen time, da se upotrebljava kao farmaceutsko sredstvo.
16. Spoj prema bilo kojem od zahtjeva 1 do 11, naznačen time, da se upotrebljava u liječenju ili prevenciji bolesti ili stanja posredovanog putem blokade epitelnog natrijskog kanala.
17. Spoj prema zahtjevu 16, naznačen time, da je bolest ili stanje odabrana/o od cistične fibroze, primarne cilijarne diskinezije i kronične opstrukcijske bolesti pluća.
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