HRP20221373T1 - Supstituirani pirazoli kao inhibitori kalikreina u ljudskoj plazmi - Google Patents
Supstituirani pirazoli kao inhibitori kalikreina u ljudskoj plazmi Download PDFInfo
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- HRP20221373T1 HRP20221373T1 HRP20221373TT HRP20221373T HRP20221373T1 HR P20221373 T1 HRP20221373 T1 HR P20221373T1 HR P20221373T T HRP20221373T T HR P20221373TT HR P20221373 T HRP20221373 T HR P20221373T HR P20221373 T1 HRP20221373 T1 HR P20221373T1
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- Prior art keywords
- alkyl
- optionally substituted
- compound according
- amino
- cyano
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- 101001091365 Homo sapiens Plasma kallikrein Proteins 0.000 title 1
- 229940127379 Kallikrein Inhibitors Drugs 0.000 title 1
- 150000003217 pyrazoles Chemical class 0.000 title 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 39
- 150000001875 compounds Chemical class 0.000 claims 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims 12
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 10
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 8
- 125000003107 substituted aryl group Chemical group 0.000 claims 8
- 125000003118 aryl group Chemical group 0.000 claims 7
- 125000005843 halogen group Chemical group 0.000 claims 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 6
- -1 -C(O)NH2 Chemical group 0.000 claims 6
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 6
- 229910003827 NRaRb Inorganic materials 0.000 claims 5
- 201000010099 disease Diseases 0.000 claims 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 5
- 125000001072 heteroaryl group Chemical group 0.000 claims 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 5
- 229910006074 SO2NH2 Inorganic materials 0.000 claims 4
- 125000004104 aryloxy group Chemical group 0.000 claims 4
- 125000004452 carbocyclyl group Chemical group 0.000 claims 4
- 206010012601 diabetes mellitus Diseases 0.000 claims 4
- 125000000623 heterocyclic group Chemical group 0.000 claims 4
- 208000002780 macular degeneration Diseases 0.000 claims 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 4
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims 3
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims 3
- 206010019860 Hereditary angioedema Diseases 0.000 claims 3
- 229910052799 carbon Inorganic materials 0.000 claims 3
- 229910052757 nitrogen Inorganic materials 0.000 claims 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims 3
- 150000003839 salts Chemical class 0.000 claims 3
- 125000001424 substituent group Chemical group 0.000 claims 3
- 102000009027 Albumins Human genes 0.000 claims 2
- 108010088751 Albumins Proteins 0.000 claims 2
- 206010002383 Angina Pectoris Diseases 0.000 claims 2
- 206010048962 Brain oedema Diseases 0.000 claims 2
- 206010051055 Deep vein thrombosis Diseases 0.000 claims 2
- 206010012688 Diabetic retinal oedema Diseases 0.000 claims 2
- 206010012689 Diabetic retinopathy Diseases 0.000 claims 2
- 208000032843 Hemorrhage Diseases 0.000 claims 2
- 101001081555 Homo sapiens Plasma protease C1 inhibitor Proteins 0.000 claims 2
- 206010020772 Hypertension Diseases 0.000 claims 2
- 206010061218 Inflammation Diseases 0.000 claims 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims 2
- 102000001399 Kallikrein Human genes 0.000 claims 2
- 108060005987 Kallikrein Proteins 0.000 claims 2
- 208000001344 Macular Edema Diseases 0.000 claims 2
- 206010025415 Macular oedema Diseases 0.000 claims 2
- 206010030113 Oedema Diseases 0.000 claims 2
- 102100027637 Plasma protease C1 inhibitor Human genes 0.000 claims 2
- 206010063837 Reperfusion injury Diseases 0.000 claims 2
- 208000017442 Retinal disease Diseases 0.000 claims 2
- 206010038923 Retinopathy Diseases 0.000 claims 2
- 206010038934 Retinopathy proliferative Diseases 0.000 claims 2
- 206010040047 Sepsis Diseases 0.000 claims 2
- 208000006011 Stroke Diseases 0.000 claims 2
- 206010047249 Venous thrombosis Diseases 0.000 claims 2
- 206010000891 acute myocardial infarction Diseases 0.000 claims 2
- 125000002252 acyl group Chemical group 0.000 claims 2
- 206010064930 age-related macular degeneration Diseases 0.000 claims 2
- 206010003246 arthritis Diseases 0.000 claims 2
- 208000034158 bleeding Diseases 0.000 claims 2
- 230000000740 bleeding effect Effects 0.000 claims 2
- 239000008280 blood Substances 0.000 claims 2
- 210000004369 blood Anatomy 0.000 claims 2
- 208000006752 brain edema Diseases 0.000 claims 2
- 230000002612 cardiopulmonary effect Effects 0.000 claims 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 2
- 201000011190 diabetic macular edema Diseases 0.000 claims 2
- 230000000694 effects Effects 0.000 claims 2
- 230000029142 excretion Effects 0.000 claims 2
- 230000003480 fibrinolytic effect Effects 0.000 claims 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims 2
- 125000005842 heteroatom Chemical group 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 230000004054 inflammatory process Effects 0.000 claims 2
- 208000017169 kidney disease Diseases 0.000 claims 2
- 201000010230 macular retinal edema Diseases 0.000 claims 2
- 201000001119 neuropathy Diseases 0.000 claims 2
- 230000007823 neuropathy Effects 0.000 claims 2
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 208000033808 peripheral neuropathy Diseases 0.000 claims 2
- 229910052717 sulfur Inorganic materials 0.000 claims 2
- 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 claims 1
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims 1
- 208000028185 Angioedema Diseases 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 229910007161 Si(CH3)3 Inorganic materials 0.000 claims 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 230000006806 disease prevention Effects 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 230000000069 prophylactic effect Effects 0.000 claims 1
- 125000005017 substituted alkenyl group Chemical group 0.000 claims 1
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- 125000004426 substituted alkynyl group Chemical group 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or 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
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/04—Drugs for disorders of the respiratory system for throat disorders
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61P25/00—Drugs for disorders of the nervous system
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- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- A61P7/10—Antioedematous agents; Diuretics
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- 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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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- 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
- C07D401/02—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 two hetero rings
- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
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- 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
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- 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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- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
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- Vascular Medicine (AREA)
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Claims (16)
1. Spoj, ili njegova farmaceutski prihvatljiva sol, predstavljen formulom II:
[image]
naznačen time što:
X predstavlja CH, C(OH), C(O(C1-C6)alkil), -C(NH2), -C(NRaRb), -C(N3), -C(CN), - C(NO2), -C(S(O)nRa), -C[-C(=O)Rc], -C[-C(=O)NRcRd], -C[-C(=O)SRc], -C[-S(O)Rc], -C[-S(O)2Rc], -C[S(O)(ORc)], -C[-S(O)2(ORc)], -C[-SO2NRcRd], - C(halogen), -C[(C1-C8)alkil], -C[(C4-C8)karbociklil], -C[(C1-C8)supstituiran alkil], -C[(C2-C8)alkenil], -C[(C2-C8)supstituiran alkenil], -C[(C2-C8)alkinil], -C[(C2-C8)supstituiran alkinil], -C[aril(C1-C8)alkil], ili N;
-Y-R4 predstavlja -((C1-C6)alkil)-R4, -CH2C(O)-R4, -CH2NH-R4, -CH2N((C1-C6)alkil)-R4, -CRaRb-R4, -NH-R4, -NHCH2-R4, -NHC(O)-R4, -N((C1-C6)alkil)-R4, -N((C1-C6)alkil)CH2-R4, -N((CH2)2OH)-R4, -N[(C3-C8)cikloalkil(C1-C6)alkil]R4, -heterociklil-R4, -OR4, -OCH2-R4, -OC(O)-R4, -SCH2R4, ili -SR4, pri čemu je dio (C1-C6)alkil iz -((C1-C6)alkil)-R4 po izboru supstituiran;
Z je odsutan ili predstavlja jedan ili više supstituenata neovisno odabranih iz skupine koja sadrži halo, hidroksi, (C1-C6)alkil, -CF3, -OCF3, (C1-C6)alkoksi, aril, ariloksi, amino, amino(C1-C6)alkil, -C(O)NH2, cijano, -NHC(O)(C1-C6)alkil, -SO2(C1-C6)alkil, -SO2NH2, (C3-C8)cikloalkil, (CH2)rORa, NO2, (CH2)r NRaRb, (CH2)rC(O)Ra, NRaC(O)Rb, C(O)NRcRd, NRaC(O)NRcRd,-C(=NRa)NRcRd, NHC(=NRa)NRcRd, NRaRb, SO2NRcRd, NRaSO2NRcRd, NRaSO2-(C1-C6)alkil, NRaSO2Ra, S(O)pRa, (CF2)rCF3, NHCH2Ra, OCH2Ra, SCH2Ra, NH(CH2)2(CH2)rRa, O(CH2)2(CH2)rRa, i S(CH2)2(CH2)rRa; ili alternativno Z je 5- ili 6-člani aromatski heterocikl koji sadrži od 1 do 4 heteroatoma odabrana iz skupine koju čine N, O, i S;
R1c predstavlja halo, amino(C1-C6)alkil, (C1-C6)alkoksi, cijano, -C(=NH)NH2, - CONRaRb, -(C1-C6)alkilCONRaRb, -SO2CH3, formil, acil, -NH2, - C(=NH)NH(OH), -C(=NH)NH(C(O)O-(C1-C6)alkil), -C(=NH)NH(C(O)O-(C1-C6)haloalkil), -C(=NH)NH(C(O)S-(C1-C6)alkil), - C(=NH)NH(C(O)(OCH(C1-C6)alkil)OC(O)(C1-C6)alkil), po izboru supstituiran aril, ili po izboru supstituiran heteroaril;
R2 predstavlja halo, (C1-C6)alkil, (C3-C8)cikloalkil, (C1-C6)fluoralkil, -OCH3, - Si(CH3)3, -CONH2, -C(O)OH, cijano, ili fenil;
R3 predstavlja -NH-, -O-, po izboru supstituiran aril, heteroaril, fenil, karbociklil, ili heterociklil;
R3a je odsutan ili predstavlja jedan ili više supstituenata neovisno odabranih iz skupine koja sadrži halo, hidroksi, (C1-C6)alkil, -CF3, -OCF3, (C1-C6)alkoksi, aril, ariloksi, amino, amino(C1-C6)alkil, -C(O)NH2, cijano, -NHC(O)(C1-C6)alkil, -SO2(C1-C6)alkil, -SO2NH2, (C3-C8)cikloalkil, (CH2)rORa, NO2, (CH2)r NRaRb, (CH2)rC(O)Ra, NRaC(O)Rb, C(O)NRcRd, NRaC(O)NRcRd, - C(=NRa)NRcRd, NHC(=NRa)NRcRd, NRaRb, SO2NRcRd, NRaSO2NRcRd, NRaSO2-(C1-C6)alkil, NRaSO2Ra, S(O)pRa, (CF2)rCF3, NHCH2Ra, OCH2Ra, SCH2Ra, NH(CH2)2(CH2)rRa, O(CH2)2(CH2)rRa, ili S(CH2)2(CH2)rRa; ili alternativno R3a je 5- ili 6-člani aromatski heterocikl koji sadrži od 1 do 4 heteroatoma odabrana iz skupine koju čine N, O, i S;
R4 predstavlja vodik, hidroksi, po izboru supstituiran (C1-C6)alkil, po izboru supstituiran (C3-C8)cikloalkil, heterociklil(C1-C6)alkil, (C3-C8)cikloalkil(C1-C6)alkil, -CH2OH, -CH((C1-C6)alkil)OH, -CH(NH2)CH((C1-C6)alkil)2, po izboru supstituiran aril, po izboru supstituiran aril(C1-C6)alkil, heteroaril, po izboru supstituiran heteroaril(C1-C6)alkil, -CH2S(C1-C6)alkil, amino, ili cijano;
svaki Ra i Rb je neovisno H, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, aril(C1-C8)alkil, (C3-C8)karbociklil, -C(=O)Rc, -C(=O)ORc, -C(=O)NRcRd,-C(=O)SRc, -S(O)Rc, -S(O)2Rc, -S(O)(ORc), ili -SO2NRcRd;
svaki Rc i Rdje neovisno H, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C4-C8) karbociklil, po izboru supstituiran aril, po izboru supstituiran heteroaril, -C(=O)(C1-C8)alkil, -S(O)n(C1-C8)alkil, ili aril(C1-C8)alkil; ili kada su Rc i Rd vezani na zajednički atom dušika, tada oni mogu tvoriti 3- do 7-člani heterociklički prsten pri čemu se po izboru ugljikov atom navedenog heterocikličkog prstena može zamijeniti s -O-, -S- ili -NRa-;
n je 2 ili 3;
r je neovisno za svaku pojavu 0, 1, 2, ili 3;
p je neovisno za svaku pojavu 0, 1, ili 2; i
stereokemijska konfiguracija u bilo kojem kiralnom središtu je R, S, ili smjesa R i S.
2. Spoj prema zahtjevu 1, ili njegova farmaceutski prihvatljiva sol naznačen time što:
X predstavlja CH, C(OH), C(O(C1-C6)alkil), C(NH2), ili N;
-Y-R4 predstavlja -((C1-C6)alkil)-R4, -CH2C(O)-R4, -CH2NH-R4, -CH2N((C1-C6)alkil)-R4, -CRaRb-R4, -NH-R4, -NHCH2-R4, -NHC(O)-R4, -N((C1-C6)alkil)-R4, -N((C1-C6)alkil)CH2-R4, -N((CH2)2OH)-R4, -N[(C3-C8)cikloalkil(C1-C6)alkil]R4, -heterociklil-R4, -OR4, -OCH2-R4, -OC(O)-R4, -SCH2R4, ili -SR4, pri čemu je dio (C1-C6)alkil iz -((C1-C6)alkil)-R4 po izboru supstituiran;
Z je odsutan ili predstavlja halo, hidroksi, (C1-C6)alkil, -CF3, -OCF3, (C1-C6)alkoksi, aril, ariloksi, amino, amino(C1-C6)alkil, -C(O)NH2, cijano, -NHC(O)(C1-C6)alkil, -SO2(C1-C6)alkil, -SO2NH2, ili (C3-C8)cikloalkil;
R1c predstavlja halo, amino(C1-C6)alkil, (C1-C6)alkoksi, cijano, -SO2CH3, formil, acil, ili po izboru supstituiran aril;
R3a je odsutan ili predstavlja jedan ili više supstituenata neovisno odabranih iz skupine koja sadrži halo, hidroksi, (C1-C6)alkil, -CF3, -OCF3, (C1-C6)alkoksi, aril, ariloksi, amino, amino(C1-C6)alkil, -C(O)NH2, cijano, -NHC(O)(C1-C6)alkil, -SO2(C1-C6)alkil, i -SO2NH2; i
R4 predstavlja vodik, hidroksi, po izboru supstituiran (C1-C6)alkil, po izboru supstituiran (C3-C8)cikloalkil, heterociklil(C1-C6)alkil, (C3-C8)cikloalkil(C1-C6)alkil, -CH2OH, -CH((C1-C6)alkil)OH, - CH(NH2)CH((C1-C6)alkil)2, po izboru supstituiran aril, po izboru supstituiran aril(C1-C6)alkil, heteroaril, po izboru supstituiran heteroaril(Ci-C6)alkil, -CH2S(C1-C6)alkil, amino, ili cijano.
3. Spoj prema zahtjevu 1 ili 2, naznačen time što X predstavlja CH.
4. Spoj prema zahtjevu 1 ili 2, naznačen time što -X-Y- predstavlja -CHNHCH2- , -C(OH)CH2CH2- ili -CHOCH2-.
5. Spoj prema zahtjevu 1 ili 2, naznačen time što R3 predstavlja fenilen-R3a.
6. Spoj prema zahtjevu 1 ili 2, naznačen time što -R3-R3a predstavlja
[image]
[image]
[image]
[image]
po izboru pri čemu -R3-R3a predstavlja
[image]
, po izboru pri čemu -R3-R3a predstavlja
[image]
[image]
7. Spoj prema zahtjevu 1 ili 2, naznačen time što je R3a odsutan.
8. Spoj prema zahtjevu 1 ili 2, naznačen time što je R4 ciklopropil.
9. Spoj prema zahtjevu 1 ili 2, naznačen time što R3 je fenil, i R3a je orto, meta, ili para -OH, ili pri čemu R3 je fenil, i R3a je orto, meta, ili para -NH2, ili pri čemu R3 je fenil, i R3a je orto, meta, ili para -CN.
10. Spoj prema zahtjevu 1 ili 2, naznačen time što Z je odsutan ili pri čemu Z predstavlja fluor ili klor ili 2-F, 3-F, 5-F, 6-F, 6-Cl, ili 5-(C3-C8)cikloalkil, po izboru pri čemu Z predstavlja 6-F.
11. Spoj prema zahtjevu 1 ili 2, naznačen time što R1c predstavlja aminometil ili cijano ili - SO2CH3.
12. Spoj prema bilo kojem od zahtjeva 1-11, naznačen time što R2 je -CH3, -CF3, tert-butil, ciklopropil, -OCH3, -Si(CH3)3, -CONH2, cijano ili fenil.
13. Farmaceutski pripravak, naznačen time što sadrži spoj prema bilo kojem od zahtjeva 1-12 i farmaceutski prihvatljiv nosač, po izboru pri čemu je farmaceutski pripravak formuliran za parenteralnu primjenu ili oralnu primjenu, po izboru pri čemu je farmaceutski pripravak formuliran za profilaktičku primjenu ili terapijsko liječenje bolesti ili stanja u kojem je poželjno smanjiti aktivnost kalikreina u plazmi;
pri čemu je bolest ili stanje odabrano iz skupine koju čine moždani udar, upala, reperfuzijska ozljeda, akutni infarkt miokarda, duboka venska tromboza, stanje nakon liječenja fibrinolitikom, angina, edem, angioedem, nasljedni angioedem, sepsa, artritis, krvarenje, gubitak krvi tijekom kardiopulmonalne premosnice, upalna bolest crijeva, dijabetes melitus, retinopatija, dijabetička retinopatija, dijabetički makularni edem, dijabetička makularna degeneracija, makularni edem povezan sa starenjem, makularna degeneracija povezana sa starenjem, proliferativna retinopatija, neuropatija, hipertenzija, edem mozga, povećano izlučivanje albumina, makroalbuminurija, i nefropatija.
14. Spoj prema bilo kojem od zahtjeva 1-12, ili njegova farmaceutski prihvatljiva sol, za uporabu u liječenju ili prevenciji bolesti ili stanja u kojima je poželjno smanjiti aktivnost kalikreina u plazmi; pri čemu je bolest ili stanje odabrano iz skupine koju čine moždani udar, upala, reperfuzijska ozljeda, akutni infarkt miokarda, duboka venska tromboza, stanje nakon liječenja fibrinolitikom, angina, edem, angioedem, nasljedni angioedem, sepsa, artritis, krvarenje, gubitak krvi tijekom kardiopulmonalne premosnice, upalna bolest crijeva, dijabetes melitus, retinopatija, dijabetička retinopatija, dijabetički makularni edem, dijabetička makularna degeneracija, makularni edem povezan sa starenjem, makularna degeneracija povezana sa starenjem, proliferativna retinopatija, neuropatija, hipertenzija, edem mozga, povećano izlučivanje albumina, makroalbuminurija i nefropatija.
15. Spoj za uporabu prema zahtjevu 14, naznačen time što je bolest ili stanje angioedem.
16. Spoj za uporabu prema zahtjevu 14, naznačen time što je bolest ili stanje nasljedni angioedem.
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