RU2016144329A - Агонисты рецептора апелина (apj) и его применение - Google Patents
Агонисты рецептора апелина (apj) и его применение Download PDFInfo
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- RU2016144329A RU2016144329A RU2016144329A RU2016144329A RU2016144329A RU 2016144329 A RU2016144329 A RU 2016144329A RU 2016144329 A RU2016144329 A RU 2016144329A RU 2016144329 A RU2016144329 A RU 2016144329A RU 2016144329 A RU2016144329 A RU 2016144329A
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- 102100030949 Apelin receptor Human genes 0.000 title claims 5
- 108091008803 APLNR Proteins 0.000 title claims 4
- 239000000018 receptor agonist Substances 0.000 title 1
- 229940044601 receptor agonist Drugs 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims 58
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 17
- 125000003118 aryl group Chemical group 0.000 claims 17
- 150000001875 compounds Chemical class 0.000 claims 16
- 125000003545 alkoxy group Chemical group 0.000 claims 11
- 125000001072 heteroaryl group Chemical group 0.000 claims 11
- 208000019423 liver disease Diseases 0.000 claims 10
- 125000004171 alkoxy aryl group Chemical group 0.000 claims 9
- 239000008194 pharmaceutical composition Substances 0.000 claims 9
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 6
- 208000035475 disorder Diseases 0.000 claims 6
- 206010020772 Hypertension Diseases 0.000 claims 4
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims 4
- 230000004770 neurodegeneration Effects 0.000 claims 4
- 230000008085 renal dysfunction Effects 0.000 claims 4
- 201000002282 venous insufficiency Diseases 0.000 claims 4
- 102000016555 Apelin receptors Human genes 0.000 claims 3
- 125000003342 alkenyl group Chemical group 0.000 claims 3
- 125000000304 alkynyl group Chemical group 0.000 claims 3
- 229910052736 halogen Inorganic materials 0.000 claims 3
- 150000002367 halogens Chemical class 0.000 claims 3
- 210000003462 vein Anatomy 0.000 claims 3
- 239000005541 ACE inhibitor Substances 0.000 claims 2
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 claims 2
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 claims 2
- 208000031229 Cardiomyopathies Diseases 0.000 claims 2
- 208000032928 Dyslipidaemia Diseases 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- 206010061218 Inflammation Diseases 0.000 claims 2
- 208000017170 Lipid metabolism disease Diseases 0.000 claims 2
- 208000008589 Obesity Diseases 0.000 claims 2
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims 2
- 206010047249 Venous thrombosis Diseases 0.000 claims 2
- 241000700605 Viruses Species 0.000 claims 2
- 125000003282 alkyl amino group Chemical group 0.000 claims 2
- 125000005012 alkyl thioether group Chemical group 0.000 claims 2
- 150000001356 alkyl thiols Chemical class 0.000 claims 2
- 229940125364 angiotensin receptor blocker Drugs 0.000 claims 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims 2
- 208000006673 asthma Diseases 0.000 claims 2
- 206010012601 diabetes mellitus Diseases 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- 125000005842 heteroatom Chemical group 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 230000004054 inflammatory process Effects 0.000 claims 2
- 208000030159 metabolic disease Diseases 0.000 claims 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims 2
- 235000020824 obesity Nutrition 0.000 claims 2
- 208000030761 polycystic kidney disease Diseases 0.000 claims 2
- 201000011461 pre-eclampsia Diseases 0.000 claims 2
- 239000000651 prodrug Chemical class 0.000 claims 2
- 229940002612 prodrug Drugs 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- 231100000167 toxic agent Toxicity 0.000 claims 2
- 239000003440 toxic substance Substances 0.000 claims 2
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 claims 1
- 108090000312 Calcium Channels Proteins 0.000 claims 1
- 102000003922 Calcium Channels Human genes 0.000 claims 1
- 239000002160 alpha blocker Substances 0.000 claims 1
- 239000002876 beta blocker Substances 0.000 claims 1
- 229940097320 beta blocking agent Drugs 0.000 claims 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims 1
- 230000036772 blood pressure Effects 0.000 claims 1
- 239000002934 diuretic Substances 0.000 claims 1
- 230000001882 diuretic effect Effects 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
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- 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
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- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Claims (112)
1. Соединение, представленное формулой I:
или его фармацевтически приемлемая соль, пролекарство или соль пролекарства,
где
R1 представлен формулой:
каждый А независимо представляет собой C1-8алкил, C1-8алкил(арил), C1-8алкокси, C1-8алкоксиарил, C2-8алкенил, C3-8алкинил, C3-8циклоалкил, -CF3, -(CH2)xNR7R8, -CN, -CONR7R8, -COR7, -CO2(CH2)xNR7R8, -CO2R7, галоген, гидроксил, -N3, -NHCOR7, -NHSO2C1-8алкил, -NHCO2C1-8алкил, -NO2, -NR7R8, -O(CH2)xNR7R8, -O(CH2)xCO2R7, -OCOC1-8алкил, -OCO(CH2)xNR7R8, -SO(1-3)R7 или -SR7;
R7 и R8 независимо представляют собой алкокси, арил, C1-8алкил, C1-8алканол, C1-8алкиламино, C1-8алкиламидо, C1-8алкил(арил), C1-8алкил(C3-8циклоалкил), C1-8алкилгуанидил, C1-8алкилгетероарил, C1-8алкилимидазолил, C1-8алкилиндолил, C1-8алкилтиоэфир, C1-8алкилтиол, C2-8алкенил, C3-8алкинил, C3-8циклоалкил, -(CH2)xCONHR9, -(CH2)xCOR9, -(CH2)xCO2R9, H или гетероарил; или R7 и R8, взятые вместе, образуют 3-8-членное кольцо, которое может быть замещено одним или более гетероатомами;
n равен 0, 1, 2, 3, 4 или 5;
каждый x независимо равен 0-8;
R2 присутствует или отсутствует, и если присутствует, представляет собой C1-8алкил, C1-8алкил(арил), C1-8алкил(C3-8циклоалкил), C3-8циклоалкил или гетероарил;
R3 присутствует или отсутствует, при этом, отсутствует, если R2 присутствует, и если присутствует, представляет собой C1-8алкил, C1-8алкил(арил), C1-8алкил(C3-8циклоалкил) или C3-8циклоалкил;
R4, R5, и R6 независимо представляют собой адамантанил, арил, C1-8алкил, C1-8алканол, C1-8алкиламино, C1-8алкиламидо, C1-8алкил(арил), C1-8алкил(C3-8циклоалкил), C1-8алкил(C3-8циклоалкил)-CO2R7, C1-8алкилгуанидил, C1-8алкилгетероарил, C1-8алкилимидазолил, C1-8алкилиндолил, C1-8алкилтиоэфир, C1-8алкилтиол, C2-8алкенил, C3-8алкинил, C3-8циклоалкил, C3-8циклоалкил-CO2R7, -(CH2)xNR7R8, -(CH2)xOR7, -(CH2)xNHCOR7, -(CH2)xNHCO2R7, -(CH2)xCONR7R8, -(CH2)xCONR7(CH2)yCO2R9, -(CH2)xCONR7(CH2)yCONR7R8, -(CH2)xCONR7(CH2)yR9, -(CH2)xCOR7, -(CH2)xCO2R7, -CHR7COR9, -CHR7CONHCHR8COR9, -CONR7R8, -CONR7(CH2)xCO2R8, -CONR7CHR8CO2R9, -CO2R9, H или -NHCO2R7; или R4 и R5, вместе образуют 4-8-членное кольцо, которое может быть замещено одним или более гетероатомами или выбрано из групп, содержащих R6;
R9 представляет собой арил, C1-8алкокси, C1-8алкил, C1-8алкил(арил), C3-8циклоалкил, H, гетероарил или гидроксил;
каждый y независимо равен 1-8;
и Z представляет собой H2 или =O.
2. Соединение по п.1, где n равен 4; каждый А независимо представляет собой C1-4алкокси, C1-4алкоксиарил или галоген;
R2 представляет собой C1-8алкил или C3-8циклоалкил;
R4 представляет собой C1-8алкил, C1-8алкил(арил), C1-8алкил(C3-8циклоалкил) или -CO2R9;
R5 представляет собой -(CH2)xCNHCOR7, -(CH2)xCNHCO2R7, -(CH2)xCONR7R8, -(CH2)xCONR7(CH2)yCO2R9, -(CH2)xCONR7(CH2)yCONR7R8, -(CH2)xCONR7(CH2)yR9, -(CH2)xCOR7, -(CH2)xCO2R7, -CHR7COR9, -CHR7CONHCHR8COR9, -CONR7R8, -CONR7(CH2)xCO2R8 или -CO2R9;
R6 представляет собой H;
R9 представляет собой C1-8алкил, H или гетероарил, которым является оксазол;
x равен 1-4;
y равен 1-3; and
Z представляет собой =O.
3. Соединение по п.2, где n равен 4; каждый А независимо представляет собой C1алкокси, C1алкоксиарил или галоген;
R2 представляет собой C4алкил или C6циклоалкил;
R4 представляет собой C1-4алкил, C1-8алкил(арил), C1-8алкил(C3-8циклоалкил) или -CO2R9;
R5 представляет собой -(CH2)xCNHCOR7, -(CH2)xCNHCO2R7, -(CH2)xCONR7R8, -(CH2)xCONR7(CH2)yCO2R9, -(CH2)xCONR7(CH2)yCONR7R8, -(CH2)xCONR7(CH2)yR9, -(CH2)xCOR7, -(CH2)xCO2R7, -CHR7COR9, -CHR7CONHCHR8COR9, -CONR7R8, -CONR7(CH2)xCO2R8 или -CO2R9;
R6 представляет собой H;
R8 представляет собой C1-4алкил или H;
R9 представляет собой C1-8алкил, H или гетероарил, которым является оксазол;
x равен 1-4;
y равен 1-3; и
Z представляет собой =O.
4. Соединение по п.3, где n равен 4; каждый А независимо представляет собой C1алкокси, C1алкоксиарил или фтор;
R2 представляет собой C4алкил или C6циклоалкил;
R4 представляет собой C1-4алкил, C1-4алкил(арил), C1-4алкил(C5-8циклоалкил) или -CO2R9;
R5 представляет собой -(CH2)xCNHCOR7, -(CH2)xCNHCO2R7, -(CH2)xCONR7R8, -(CH2)xCONR7(CH2)yCO2R9, -(CH2)xCONR7(CH2)yCONR7R8, -(CH2)xCONR7(CH2)yR9, -(CH2)xCOR7, -(CH2)xCO2R7, -CHR7COR9, -CHR7CONHCHR8COR9, -CONR7R8, -CONR7(CH2)xCO2R8 или -CO2R9;
R6 представляет собой H;
R8 представляет собой C1-4алкил или H;
R9 представляет собой C1-8алкил, H или гетероарил, которым является оксазол;
x равен 1-4; и
y равен 1-3.
5. Соединение по п.4, где n равен 4; каждый А независимо представляет собой C1алкокси, C1алкоксиарил или фтор;
R2 представляет собой C4алкил или C6циклоалкил;
R4 представляет собой C1-4алкил, C1-4алкил(арил), C1-4алкил(C5-8циклоалкил) или -CO2R9;
R5 представляет собой -(CH2)xCNHCOR7, -(CH2)xCNHCO2R7, -(CH2)xCONR7R8, -(CH2)xCONR7(CH2)yCO2R9, -(CH2)xCONR7(CH2)yCONR7R8, -(CH2)xCONR7(CH2)yR9, -(CH2)xCOR7, -(CH2)xCO2R7, -CHR7COR9, -CHR7CONHCHR8COR9, -CONR7R8, -CONR7(CH2)xCO2R8 или -CO2R9;
R6 представляет собой H;
R8 представляет собой H;
R9 представляет собой C1-8алкил, H или гетероарил, которым является оксазол;
x равен 1-4; и
y равен 1-3.
6. Соединение по п.1, где n равен 2; каждый А независимо представляет собой C1-4алкокси, C1-4алкоксиарил;
R2 представляет собой C1-8алкил или C3-8циклоалкил;
R4 представляет собой C1-8алкил, C1-8алкил(арил), C1-8алкил(C3-8циклоалкил) или -CO2R9;
R5 представляет собой -(CH2)xCNHCOR7, -(CH2)xCNHCO2R7, -(CH2)xCONR7R8, -(CH2)xCONR7(CH2)yCO2R9, -(CH2)xCONR7(CH2)yCONR7R8, -(CH2)xCONR7(CH2)yR9, -(CH2)xCOR7, -(CH2)xCO2R7, -CHR7COR9, -CHR7CONHCHR8COR9, -CONR7R8, -CONR7(CH2)xCO2R8 или -CO2R9;
R6 представляет собой H;
R9 представляет собой C1-8алкил, H или гетероарил, которым является оксазол;
x равен 1-4;
y равен 1-3; и
Z представляет собой =O.
7. Соединение по п.6, где n равен 2; каждый А независимо представляет собой C1алкокси, C1алкоксиарил;
R2 представляет собой C4алкил или C6циклоалкил;
R4 представляет собой C1-8алкил, C1-8алкил(арил), C1-8алкил(C3-8циклоалкил) или -CO2R9;
R5 представляет собой -(CH2)xCNHCOR7, -(CH2)xCNHCO2R7, -(CH2)xCONR7R8, -(CH2)xCONR7(CH2)yCO2R9, -(CH2)xCONR7(CH2)yCONR7R8, -(CH2)xCONR7(CH2)yR9, -(CH2)xCOR7, -(CH2)xCO2R7, -CHR7COR9, -CHR7CONHCHR8COR9, -CONR7R8, -CONR7(CH2)xCO2R8 или -CO2R9;
R6 представляет собой H;
R8 представляет собой C1-4алкил или H;
R9 представляет собой C1-8алкил, H или гетероарил, которым является оксазол;
x равен 1-4;
y равен 1-3; и
Z представляет собой =O.
8. Соединение по п.7, где n равен 2; каждый А независимо представляет собой C1алкокси, C1алкоксиарил;
R2 представляет собой C4алкил или C6циклоалкил;
R4 представляет собой C1-4алкил, C1-4алкил(арил), C1-4алкил(C5-8циклоалкил) или -CO2R9;
R5 представляет собой -(CH2)xCNHCOR7, -(CH2)xCNHCO2R7, -(CH2)xCONR7R8, -(CH2)xCONR7(CH2)yCO2R9, -(CH2)xCONR7(CH2)yCONR7R8, -(CH2)xCONR7(CH2)yR9, -(CH2)xCOR7, -(CH2)xCO2R7, -CHR7COR9, -CHR7CONHCHR8COR9, -CONR7R8, -CONR7(CH2)xCO2R8 или -CO2R9;
R6 представляет собой H;
R8 представляет собой C1-4алкил или H;
R9 представляет собой C1-8алкил, H или гетероарил, которым является оксазол;
x равен 1-4;
y равен 1-3; и
Z представляет собой =O.
9. Соединение по п.8, где n равен 2; каждый А независимо представляет собой C1алкокси, C1алкоксиарил;
R2 представляет собой C4алкил или C6циклоалкил;
R4 представляет собой C1-4алкил, C1-4алкил(арил), C1-4алкил(C5-8циклоалкил) или -CO2R9;
R5 представляет собой -(CH2)xCNHCOR7, -(CH2)xCNHCO2R7, -(CH2)xCONR7R8, -(CH2)xCONR7(CH2)yCO2R9, -(CH2)xCONR7(CH2)yCONR7R8, -(CH2)xCONR7(CH2)yR9, -(CH2)xCOR7, -(CH2)xCO2R7, -CHR7COR9, -CHR7CONHCHR8COR9, -CONR7R8, -CONR7(CH2)xCO2R8 или -CO2R9;
R6 представляет собой H;
R8 представляет собой H;
R9 представляет собой C1-8алкил, H или гетероарил, которым является оксазол;
x равен 1-4;
y равен 1-3; и
Z представляет собой =O.
10. Соединение по п.1, где R4, R5 и R6 представляют собой C1-8алкилгетероарил, и C1-8алкилгетероарилом является C1-8алкилтетразол.
11. Соединение по п.1, имеющее структуру любого из соединений 34, 34P, 56, 65, 67, 70, 71, 77, 79, 81, 82, 86, 93, 95, 103, 118, 126, 127, 129, 130, 132, 133, 134, 136, 137, 138, 140, 141, 142, 143, 153, 154, 155, 156, 157, 161, 162, 163, 164, 167, 168, 169, 171, 172, 173, 174, 175, 176, 181, 182, 183, 184, 185, 186, 187, 188, 189, 191, 198, 204, 205, 212, 213, 214, 215, 217, 218, 219, 220, 225, 226, 228, 229, 231, 232, 233, 234, 235, 236, 238, 239, 240, 241, 242, 245, 247, 249, 251, 252, 253, 256, 257, 258, 259, 263 и 265, как представлено в таблице 1.
12. Фармацевтическая композиция, содержащая по меньшей мере один фармацевтически приемлемый эксципиент и терапевтически эффективное количество соединения по п.1.
13. Фармацевтическая композиция по п.12, где терапевтически эффективным количеством является количество, эффективное для снижения кровяного давления.
14. Фармацевтическая композиция по п.12, где терапевтически эффективным количеством является количество, эффективное при лечении астмы, кардиомиопатии, диабета, дислипидемии, гипертензии, воспалении, заболевания печени, метаболических расстройств, нейродегенеративных заболеваний, ожирения, преэклампсии или почечной дисфункции.
15. Фармацевтическая композиция по п.14, где гипертензия представляет собой легочную артериальную гипертензию.
16. Фармацевтическая композиция по п.14, где заболеванием печени является вызванная алкоголем болезнь печени, индуцированная токсическим веществом болезнь печени или индуцированная вирусом болезнь печени.
17. Фармацевтическая композиция по п.14, где дисфункцией почек является поликистозная болезнь почек.
18. Фармацевтическая композиция по п.12, где терапевтически эффективным количеством является количество, эффективное для лечения связанного с венами расстройства.
19. Фармацевтическая композиция по п.18, где терапевтически эффективным количеством является количество, эффективное для лечения ангиомы, венозной недостаточности, стаза или тромбоза.
20. Фармацевтическая композиция по п.12, где терапевтически эффективным количеством является количество, эффективное для снижения вероятности нейродегенерации, связанной с ВИЧ.
21. Соединение по п.1 для применения при лечении связанных с рецептором апелина (APJ) расстройств.
22. Применение по п.21, где связанным с рецептором апелина (APJ) расстройством является астма, кардиомиопатия, сахарный диабет, дислипидемия, гипертензия, воспаление, болезнь печени, метаболические расстройства, нейродегенеративные заболевания, ожирение, преэклампсия или дисфункция почек.
23. Применение по п.22, где гипертензией является легочная артериальная гипертензия.
24. Применение по п.22, где болезнью печени является вызванная алкоголем болезнь печени, индуцированная токсическим веществом болезнь печени или индуцированная вирусом болезнь печени.
25. Применение по п.22, где дисфункцией почек является поликистозная болезнь почек.
26. Применение по п.21, дополнительно включающее α-блокатор, ингибитор ангиотензин преобразующего фермента (ACE), блокатор рецептора ангиотензина (ARB), β-блокатор кальциевых каналов или диуретик для лечения связанного с рецептором апелина (APJ) расстройства.
27. Соединение по п.1 для применения при лечении связанного с венами расстройства.
28. Применение по п.27, где связанным с венами расстройством является ангиома, венозная недостаточность, стаз или тромбоз.
29. Соединение по п.1 для применения в лечении, приводящем к снижению вероятности нейродегенерации, связанной с ВИЧ.
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BR112016028119A2 (pt) | 2017-08-22 |
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AU2015269247B2 (en) | 2019-10-24 |
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US10377718B2 (en) | 2019-08-13 |
WO2015188073A1 (en) | 2015-12-10 |
MA39999A (fr) | 2015-12-10 |
JP2017523126A (ja) | 2017-08-17 |
ZA201607850B (en) | 2018-05-30 |
RU2016144329A3 (ru) | 2018-11-23 |
CN106459004A (zh) | 2017-02-22 |
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