HRP20220059T1 - Inhibitori kalikreina humane plazme - Google Patents
Inhibitori kalikreina humane plazme Download PDFInfo
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- HRP20220059T1 HRP20220059T1 HRP20220059TT HRP20220059T HRP20220059T1 HR P20220059 T1 HRP20220059 T1 HR P20220059T1 HR P20220059T T HRP20220059T T HR P20220059TT HR P20220059 T HRP20220059 T HR P20220059T HR P20220059 T1 HRP20220059 T1 HR P20220059T1
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- Prior art keywords
- alkyl
- aryl
- halo
- nhc
- heteroaryl
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- 101001091365 Homo sapiens Plasma kallikrein Proteins 0.000 title 1
- 229940127379 Kallikrein Inhibitors Drugs 0.000 title 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 48
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 23
- 150000001875 compounds Chemical class 0.000 claims 22
- 125000005843 halogen group Chemical group 0.000 claims 21
- 125000001072 heteroaryl group Chemical group 0.000 claims 19
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims 8
- 125000001424 substituent group Chemical group 0.000 claims 7
- 125000000623 heterocyclic group Chemical group 0.000 claims 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 6
- -1 -C(O)NH2 Chemical group 0.000 claims 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 5
- 230000000694 effects Effects 0.000 claims 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 4
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 3
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 3
- 102000003827 Plasma Kallikrein Human genes 0.000 claims 3
- 108090000113 Plasma Kallikrein Proteins 0.000 claims 3
- 125000000304 alkynyl group Chemical group 0.000 claims 3
- 229910052799 carbon Inorganic materials 0.000 claims 3
- 201000010099 disease Diseases 0.000 claims 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 3
- 150000003839 salts Chemical class 0.000 claims 3
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- 206010019860 Hereditary angioedema Diseases 0.000 claims 2
- 229910003827 NRaRb Inorganic materials 0.000 claims 2
- 229910006074 SO2NH2 Inorganic materials 0.000 claims 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 2
- 125000004429 atom Chemical group 0.000 claims 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 2
- 125000002619 bicyclic group Chemical group 0.000 claims 2
- 125000002837 carbocyclic group Chemical group 0.000 claims 2
- 206010012601 diabetes mellitus Diseases 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 125000005842 heteroatom Chemical group 0.000 claims 2
- 125000002950 monocyclic group Chemical group 0.000 claims 2
- 229910052757 nitrogen Inorganic materials 0.000 claims 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 2
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 239000001301 oxygen Chemical group 0.000 claims 2
- 229910052717 sulfur Chemical group 0.000 claims 2
- 239000011593 sulfur Chemical group 0.000 claims 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims 1
- 102000009027 Albumins Human genes 0.000 claims 1
- 108010088751 Albumins Proteins 0.000 claims 1
- 206010002383 Angina Pectoris Diseases 0.000 claims 1
- 208000028185 Angioedema Diseases 0.000 claims 1
- 206010048962 Brain oedema Diseases 0.000 claims 1
- 206010051055 Deep vein thrombosis Diseases 0.000 claims 1
- 206010012688 Diabetic retinal oedema Diseases 0.000 claims 1
- 206010012689 Diabetic retinopathy Diseases 0.000 claims 1
- 208000032843 Hemorrhage Diseases 0.000 claims 1
- 101001081555 Homo sapiens Plasma protease C1 inhibitor Proteins 0.000 claims 1
- 206010061218 Inflammation Diseases 0.000 claims 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims 1
- 102000001399 Kallikrein Human genes 0.000 claims 1
- 108060005987 Kallikrein Proteins 0.000 claims 1
- 208000001344 Macular Edema Diseases 0.000 claims 1
- 206010025415 Macular oedema Diseases 0.000 claims 1
- KBHCPIJKJQNHPN-UHFFFAOYSA-N N=NP(O)=O Chemical compound N=NP(O)=O KBHCPIJKJQNHPN-UHFFFAOYSA-N 0.000 claims 1
- 206010030113 Oedema Diseases 0.000 claims 1
- 102100027637 Plasma protease C1 inhibitor Human genes 0.000 claims 1
- 206010063837 Reperfusion injury Diseases 0.000 claims 1
- 208000017442 Retinal disease Diseases 0.000 claims 1
- 206010038923 Retinopathy Diseases 0.000 claims 1
- WBTCZXYOKNRFQX-UHFFFAOYSA-N S1(=O)(=O)NC1=O Chemical compound S1(=O)(=O)NC1=O WBTCZXYOKNRFQX-UHFFFAOYSA-N 0.000 claims 1
- 208000006011 Stroke Diseases 0.000 claims 1
- 206010047249 Venous thrombosis Diseases 0.000 claims 1
- 206010000891 acute myocardial infarction Diseases 0.000 claims 1
- 125000004414 alkyl thio group Chemical group 0.000 claims 1
- 206010003246 arthritis Diseases 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 125000004104 aryloxy group Chemical group 0.000 claims 1
- 150000001540 azides Chemical group 0.000 claims 1
- 208000034158 bleeding Diseases 0.000 claims 1
- 230000000740 bleeding effect Effects 0.000 claims 1
- 239000008280 blood Substances 0.000 claims 1
- 210000004369 blood Anatomy 0.000 claims 1
- 208000006752 brain edema Diseases 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 230000002612 cardiopulmonary effect Effects 0.000 claims 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 1
- 201000011190 diabetic macular edema Diseases 0.000 claims 1
- 230000006806 disease prevention Effects 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 230000029142 excretion Effects 0.000 claims 1
- 239000003527 fibrinolytic agent Substances 0.000 claims 1
- 230000003480 fibrinolytic effect Effects 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 230000004054 inflammatory process Effects 0.000 claims 1
- 208000017169 kidney disease Diseases 0.000 claims 1
- 208000002780 macular degeneration Diseases 0.000 claims 1
- 201000010230 macular retinal edema Diseases 0.000 claims 1
- 125000006574 non-aromatic ring group Chemical group 0.000 claims 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 claims 1
- 125000003367 polycyclic group Chemical group 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- 230000001172 regenerating effect Effects 0.000 claims 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
Classifications
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- 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
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
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- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- 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]
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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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
- A61P7/02—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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P9/00—Drugs for disorders of the cardiovascular 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
- 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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- 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
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
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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
- C07D401/02—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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- 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
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- C07D405/02—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
- 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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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Ophthalmology & Optometry (AREA)
- Biomedical Technology (AREA)
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- Neurology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pyrrole Compounds (AREA)
- Pyridine Compounds (AREA)
Claims (22)
1. Spoj predstavljen formulom (I), ili njegova farmaceutski prihvatljiva sol:
[image]
pri čemu, neovisno za svaku pojavu:
R1 predstavlja -OH, -ORc, -NH2, -NHRc, -NRcRd, (C1-C10)alkil, (C6-C10)aril, (C6-C10)aril(C1-C10)alkil, heteroaril, heteroaril(C1-C10)alkil, halo, halo(C1-C10)alkil, (C3-C12)cikloalkil, ((C3-C12)cikloalkil)(C1-C10)alkil, -C(O)Rc, -C(O)OH, -C(O)ORc, -OC(O)Rc, -C(O)NH2, -C(O)NHRc,-C(O)NRcRd, -NHC(O)Rc, ili -NRcC(O)Rd; ili dvije geminalne pojave R1 zajedno s ugljikom na koji su vezani predstavljaju -C(O)-; ili dvije vicinalne ili geminalne pojave R1 zajedno tvore opcijski supstituirani kondenzirani ili spirociklički (C3-C12)karbociklički ili heterociklički prsten;
W je -C(O)NH- ili -C(O)N(Rc);
R2 predstavlja opcionalno supstituirani (C6-C10)aril ili heteroaril;
V predstavlja opcionalno supstituirani (C6-C10)aril ili heteroaril;
Z je odsutan ili predstavlja jedan ili više supstituenata neovisno odabranih iz skupine koju čine halo, halo(C1-C10)alkil, -NO2, -CN, -C(O)Rc, -C(O)OH, -C(O)ORc, -OC(O)Rc, -C(O)NH2, -C(O)NHRc, -C(O)NRcRd, -NHC(O)Rc, -N(Rc)C(O)Rd, -OS(O)p(Rc), -NHS(O)p(Rc), i -NRcS(O)p(Rc);
X predstavlja -C(NH2)-, -C(NH(Rc))-, -C(NRcRd)-, -C(NHS(O)pRc)-, -C(NHC(O)Rc)-, -C(NHC(O)NH2)-, -C(NHC(O)NHRc)-, -C(NHC(O)NRcRd)-, -C(OH)-, -C(O((C1-C10)alkil))-, -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-C10)alkil), -C(((C3-C12)cikloalkil)(C1-C10)alkil), -C((C2-C10)alkenil)-, -C((C2-C10)alkinil)-, ili -C((C6-C10)aril(C1-C10)alkil)-;
R3 predstavlja opcionalno supstituirani (C6-C10)aril, heteroaril, (C3-C12)cikloalkil, ili heterocikloalkil;
R3a je odsutan ili predstavlja jedan ili više supstituenata neovisno odabranih iz skupine koju čine halo, hidroksi, (C1-C10)alkil, -CF3, -OCF3, (C1-C10)alkoksi, (C6-C10)aril, heteroaril, (C6-C10)ariloksi, amino, amino(C1-C10)alkil, -C(O)NH2, cijano, -NHC(O)(C1-C10)alkil, -SO2(C1-C10)alkil, -SO2NH2, (C3-C12)cikloalkil, -(CH2)rORa, -NO2, -(CH2)rNRaRb, -(CH2)rC(O)Ra, -NRaC(O)Rb, -C(O)NRcRd, -NRaC(O)NRcRd, -C(=NRa)NRcRd, -NHC(=NRa)NRcRd, -NRaRb, -SO2NRcRd, -NRaSO2NRcRd, -NRaSO2(C1-C10)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;
Y predstavlja vezu; ili -Y-R4 predstavlja opcionalno supstituirani -(C1-C10)alkilen-R4, -CH2C(O)-R4, -CH2NH-R4, -CH2N((C1-C10)alkil)-R4, -CRaRb-R4, -NH-R4, -NHCH2-R4, -NHC(O)-R4, -N((C1-C10)alkil)-R4, -N((C1-C10)alkil)CH2-R4, -N((CH2)2OH)-R4, -N(((C3-C12)cikloalkil)(C1-C10)alkil)R4, -heterociklil-R4, -OR4, -OCH2-R4, -OC(O)-R4, -OC(O)NRaRb, -SCH2R4, ili -SR4;
R4 predstavlja hidrogen, hidroksi, opcionalno supstituirani (C1-C10)alkil, (C3-C12)cikloalkil, (heterocikloalkil)(C1-C10)alkil, ((C3-C12)cikloalkil)(C1-C10)alkil, -CH2OH, -CH((C1-C10)alkil)OH, -CH(NH2)CH((C1-C10)alkil)2, (C6-C10)aril, (C6-C10)aril(C1-C10)alkil, heteroaril, heteroaril(C1-C10)alkil, -CH2S((C1-C10)alkil), amino, ili cijano; ili -(CRaRb)r(CRaRb)p- spojen na 4-poziciju prstena koji nosi Z kako bi se formiralo 5- do 7-člani heterociklični prsten s opcionalnim supstituentima; ili,
kada je svaki R3 fenil, R4 može predstavljati -NRa- spojen s pozicijom ili okomito na X na taj fenil;
Ra i Rb je neovisno H, (C1-C10)alkil, (C2-C10)alkenil, (C2-C10)alkinil, (C6-C10)aril(C1-C10)alkil, ((C3-C12)cikloalkil)(C1-C10)alkil, -C(=O)Rc, -C(=O)ORc, -C(=O)NRcRd, -C(=O)SRc, -S(O)Rc, -S(O)2Rc, -S(O)(ORc), ili -SO2NRcRd;
Rc i Rd predstavlja, neovisno za svaku pojavnost, opcionalno supstituirani (C1-C10)alkil, (C2-C10)alkenil, (C2-C10)alkinil, halo(C1-C10)alkil, (C6-C10)aril, (C6-C10)aril(C1-C10)alkil, heteroaril, heteroaril(C1-C10)alkil, (C3-C12)cikloalkil, ((C3-C12)cikloalkil)(C1-C10)alkil, heterocikloalkil, (heterocikloalkil)(C1-C10)alkil, -C(O)(C1-C10)alkil, ili -S(O)p((C1-C10)alkil); ili Rc i Rd može zajedno formirati opcionalno supstituirani heterociklični prsten;
r je 0, 1, 2, ili 3;
n je cijeli broj od 0 do 6; i
p je 0,1, ili 2;
nadalje:
"heteroaril" predstavlja monociklični, biciklični, ili policiklični aromatski prsten koji ima 3-12 ukupno atoma i najmanje jedan heteroatom odabran iz skupine koju čine dušik, kisik i sumpor;
"heterociklični," "heterocikloalkil," i "heterociklil" predstavljaju monociklični, biciklični, ili triciklični ne-aromatski prsten koji ima 3-12 ukupno atoma i najmanje jedan heteroatom odabran iz skupine koju čine dušik, kisik i sumpor; i
"opcionalno supstituirani" predstavlja nesupstituirani ili supstituiran jednim ili više supstituenata svaki neovisno odabran iz skupine koja se sastoji od halogena, azida, (C1-C10)alkil, (C6-C10)aril(C1-C10)alkil, (C2-C10)alkenil, (C2-C10)alkinil, (C3-C12)cikloalkil, hidroksil, (C1-C10)alkoksi, amino (npr., -NH2, -NH((C1-C6)alkil), - N((C1-C6)alkil)2), nitro, sulfhidril, imino, amido, fosfonat, fosfinat, karbonil, karboksil, silil, eter, (C1-C10)alkiltio, sulfonil, sulfonamido, keton, aldehid, ester, heterociklil, (C6-C10)aril, heteroaril, fluoro(C1-C10)alkil, cijano, -C(O)O(C1-C6)alkil, -C(O)NH2, -C(O)NH(C1-C6)alkil, -C(O)N((C1-C6)alkil)2, i (C1-C6)haloalkil.
2. Spoj prema zahtjevu 1, pri čemu R1 predstavlja -OH, -ORc, -NH2, -NHRc, -NRcRd, (C1-C10)alkil, (C6-C10)aril, heteroaril, halo, halo(C1-C10)alkil, (C3-C12)cikloalkil, -OC(O)Rc, -NHC(O)Rc, ili -NRcC(O)Rd; ili dvije geminalne pojave R1 zajedno s ugljikom na koji su vezani predstavljaju -C(O)-; ili dvije vicinalne ili geminalne pojave R1 zajedno tvore opcijski supstituirani kondenzirani ili spirociklički (C3-C12)karbociklički ili heterociklički prsten.
3. Spoj prema zahtjevu 2, pri čemu R1 predstavlja-OH, -ORc, -NH2, (C1-C10)alkil, (C6-C10)aril, halo, halo(C1-C10)alkil, (C3-C12)cikloalkil, ili -OC(O)Rc; i pri čemu n je 1 ili n je 2.
4. Spoj prema zahtjevu 3, pri čemu n je 1; i pri čemu
R1 predstavlja-OH, -O((C1-C6)alkil), -OC(O)((C1-C6)alkil), -NH2, ili (C1-C6)alkil.
5. Spoj prema zahtjevu 3, pri čemu n je 2; i pri čemu
dvije pojavnosti R1 are geminal.
6. Spoj prema zahtjevu 5, pri čemu:
(a) jedna pojavnost R1 predstavlja -OH ili -ORc; i druga pojavnost R1 predstavlja (C6-C10)aril ili heteroaril;
(b) jedna pojavnost R1 predstavlja -OH ili -ORc; i druga pojavnost R1 predstavlja halo(C1-C10)alkil; ili
(c) obje pojavnosti R1 su halo.
7. Spoj prema zahtjevu 2, pri čemu dvije geminalne pojavnosti R1 zajedno s ugljikom na koji su vezani predstavljaju -C(O)-.
8. Spoj prema zahtjevu 3, pri čemu n je 2; i pri čemu dvije pojavnosti R1 su vicinalne; i dvije vicinalne pojavnosti R1 zajedno formiraju opcionalno supstituirani spojeni (C3-C12)karbociklični prsten.
9. Spoj prema zahtjevu 1, pri čemu R2 predstavlja (C6-C10)aril ili heteroaril, supstituiran jednim ili više supstituenata odabranih iz skupine koja se sastoji od -OH, halo, -NH2, -NH((C1-C6)alkil), -N((C1-C6)alkil)2, -CN, -NO2, (C1-C6)alkil, (C1-C6)haloalkil, (C1-C6)alkoksi, -C(O)OH, -C(O)O(C1-C6)alkil, -C(O)NH2, - C(O)NH(C1-C6)alkil, i -C(O)N((C1-C6)alkil)2; preferabli pri čemu R2 predstavlja (halo)(C6-C10)aril ili (halo)heteroaril.
10. Spoj prema bilo kojem od zahtjeva 1-9, pri čemu V predstavlja opcionalno supstituirani (C6-C10)aril.
11. Spoj prema bilo kojem od zahtjeva 1-10, pri čemu Z je odsutan, ili pri čemu Z predstavlja jedan ili više supstituenata neovisno odabranih iz skupine koju čine halo, halo(C1-C10)alkil, -NO2, i -CN.
12. Spoj prema zahtjevu 11, pri čemu Z predstavlja jednu instancu halo; ili pri čemu Z predstavlja jednu instancu fluoro.
13. Spoj prema bilo kojem od zahtjeva 1-12, pri čemu X predstavlja -C(NH2)-, -C(NH(Rc))-, -C(NRcRd)-, -C(NHS(O)pRc)-, -C(NHC(O)Rc)-, -C(NHC(O)NH2)-, -C(NHC(O)NHRc)-, ili -C(NHC(O)NRcRd)-.
14. Spoj prema zahtjevu 13 pri čemu X predstavlja -C(NH2)-; -C(NH((C3-C12)cikloalkil)-(C1-C10)alkil)-; -C(NH(C1-C6)alkil)-; -C(NHS(O)p(C1-C6)alkil)-, pri čemu p je 1 ili 2; opcionalno supstituirani -C(NHC(O)NH((C6-C10)aril))-; opcionalno supstituirani C(NHC(O)NH(heteroaril))-; ili -C(NHC(O)((C1-C6)alkil))-.
15. Spoj prema bilo kojem od zahtjeva 1-14, pri čemu R3 predstavlja opcionalno supstituirani ((C6-C10)aril ili opcionalno supstituirani heteroaril, preferabli pri čemu R3 predstavlja fenil, opcionalno supstituirani jednim ili više supstituenata odabranih iz skupine koja se sastoji od -CN, halo, -NO2, (C1-C6)alkil, i (C1-C6)haloalkil; ili pri čemu R3 predstavlja piridil.
16. Spoj prema bilo kojem od zahtjeva 1-15, pri čemu R3a je odsutan ili predstavlja halo, (C1-C10)alkil, -CF3, -OCF3, (C6-C10)aril, heteroaril, -C(O)NH2, cijano, -NHC(O)(C1-C10)alkil, -SO2(C1-C10)alkil, -SO2NH2, -NO2, -NRaC(O)Rb, -C(O)NRcRd, - NRaC(O)NRcRd, -C(=NRa)NRcRd, -NHC(=NRa)NRcRd, -SO2NRcRd, -NRaSO2NRcRd, -NRaSO2(C1-C10)alkil, -NRaSO2Ra, -S(O)pRa, ili -(CF2)rCF3.
17. Spoj prema bilo kojem od zahtjeva 1-16, pri čemu Y predstavlja vezu i/ili pri čemu R4 predstavlja H, ((C3-C12)cikloalkil) (C1-C10)alkil, ili (ciklopropil)(C1-C6)alkil.
18. Spoj prema zahtjevu 1, odabran iz sljedeće tabele:
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19. Farmaceutski pripravak, naznačen time što sadrži spoj prema jednom od zahtjeva 1-18, ili njegovu farmaceutski prihvatljivu sol; i farmaceutski prihvatljiv nosač, izborno pri čemu je farmaceutski pripravak formuliran za parenteralnu primjenu ili oralnu primjenu.
20. Spoj prema bilo kojem od zahtjeva 1-18, ili njegova farmaceutski prihvatljiva sol, za uporabu u liječenju ili prevenciji bolesti ili stanja koja su naznačena neželjenom aktivnošću kalikreina u plazmi; pri čemu je bolest ili stanje naznačeno neželjenom aktivnošću kalikreina u plazmi odabrano iz skupine koja se sastoji od moždanog udara, upale, reperfuzijske ozljede, akutnog infarkta miokarda, duboke venske tromboze, stanja nakon fibrinolitičkog liječenja, angine, edema, angioedema, hereditarne angioedeze, artritisa, krvarenja, gubitka krvi tijekom kardiopulmonarne prijenosnice, inflamatorne bolesti crijeva, dijabetes melitusa, retinopatije, dijabetičke retinopatije, dijabetičkog makularnog edema, dijabetičke makularne degeneracije, makularnog edema povezanog s dobi, hiperpatije povezane sa starošću, makularne hiperpatije, regenerativne makularne hiperpatije, edema mozga, povećanog izlučivanja albumina, makroalbuminurije, i nefropatije.
21. Spoj za uporabu prema zahtjevu 20, pri čemu je bolest ili stanje naznačeno neželjenom aktivnošću kalikreina u plazmi angioedem.
22. Spoj za uporabu prema zahtjevu 20, pri čemu je bolest ili stanje naznačeno neželjenom aktivnošću kalikreina u plazmi hereditarni angioedem.
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