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NZ733574B2 - Dihydroindolizinone derivative - Google Patents
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NZ733574B2 - Dihydroindolizinone derivative - Google Patents

Dihydroindolizinone derivative Download PDF

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Publication number
NZ733574B2
NZ733574B2 NZ733574A NZ73357415A NZ733574B2 NZ 733574 B2 NZ733574 B2 NZ 733574B2 NZ 733574 A NZ733574 A NZ 733574A NZ 73357415 A NZ73357415 A NZ 73357415A NZ 733574 B2 NZ733574 B2 NZ 733574B2
Authority
NZ
New Zealand
Prior art keywords
solvate
salt
disease
oxide
compound according
Prior art date
Application number
NZ733574A
Other versions
NZ733574A (en
Inventor
Atsushi Hiramatsu
Yasuo Hirooka
Tomoyuki Koda
Takashi Kondo
Sho Kouyama
Taihei Nishiyama
Motoyuki Tanaka
Original Assignee
Ono Pharmaceutical Co Ltd
Filing date
Publication date
Application filed by Ono Pharmaceutical Co Ltd filed Critical Ono Pharmaceutical Co Ltd
Priority claimed from PCT/JP2015/084573 external-priority patent/WO2016093285A1/en
Publication of NZ733574A publication Critical patent/NZ733574A/en
Publication of NZ733574B2 publication Critical patent/NZ733574B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • 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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A—HUMAN NECESSITIES
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D487/04—Ortho-condensed systems

Abstract

compound represented by general formula (I) (wherein all symbols are as defined in the description) or a salt, solvate, N-oxide form or prodrug thereof is a potent FXIa inhibitor, has excellent oral absorption properties and kinetics in blood, can exert a potent anti-coagulation activity over a long period of time after being administered orally, and has a discrepancy between the anti-coagulation activity thereof and the CYP-inhibiting activity thereof. Therefore, the compound or the salt, solvate, N-oxide form or prodrug thereof can be used as an efficient prophylactic and/or therapeutic agent for vascular occlusive diseases.

Claims (17)

1. A compound represented by general formula (I): [wherein, represents: represents: and X represents CH or N]; a salt thereof, a solvate thereof, or an N-oxide thereof.
2. The compound according to claim 1, wherein the compound represented by general formula (I) is (3S)[5- (6-aminofluoropyridinyl)fluoro-1H-imidazol 5 yl][5-chloro(1H-tetrazolyl)phenyl]-2,3-dihydro- 5(1H)-indolizinone, a salt thereof, a solvate thereof, or an N-oxide thereof.
3. The compound according to claim 1, wherein the compound represented by general formula (I) is (3S)[2- 10 (6-aminofluoropyridinyl)fluoro-1H-imidazol yl][5-chloro(1H-tetrazolyl)phenyl]-2,3-dihydro- 5(1H)-indolizinone, a salt thereof, a solvate thereof, or an N-oxide thereof.
4. The compound according to claim 1, wherein the 15 compound represented by general formula (I) is (6S)[2- (6-aminofluoropyridinyl)fluoro-1H-imidazol yl][5-chloro(1H-tetrazolyl)phenyl]-7,8- dihydropyrrolo[1,2-a]pyrimidin-4(6H)-one, a salt thereof, a solvate thereof, or an N-oxide thereof. 20
5. The compound according to claim 1, wherein the compound represented by general formula (I) is 1-(2- {(3S)[5-(4-aminophenyl)fluoro-1H-imidazolyl] oxo-1,2,3,5-tetrahydroindolizinyl}chlorophenyl)-1H- 1,2,3-triazolecarbonitrile, a salt thereof, a solvate 25 thereof, or an N-oxide thereof.
6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5, a salt thereof, a solvate thereof, or an N-oxide thereof as an active ingredient. 30
7. An FXIa inhibitor comprising the compound according to any one of claims 1 to 5, a salt thereof, a solvate thereof, or an N-oxide thereof as an active ingredient.
8. Use of the compound according to any one of 35 claims 1 to 5, a salt thereof, a solvate thereof, or an N-oxide thereof in the manufacture of a medicament for preventing and/or treating thromboembolic disease.
9. Use according to claim 8, wherein the thromboembolic disease is arterial cardiovascular thromboembolic disorder, venous cardiovascular thromboembolic disorder, arterial cerebrovascular 5 thromboembolic disorder, venous cerebrovascular thromboembolic disorder or thromboembolic disorder in the heart chamber or in the peripheral circulation.
10. Use according to claim 8 or 9, wherein the thromboembolic disease is coronary artery disease, 10 unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, cerebral stroke, peripheral arterial disease, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, venous 15 thromboembolism, deep venous thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, portal vein thrombosis, pulmonary embolism, pulmonary infarction, liver embolism, 20 hepatic veno-occlusive disease/sinusoidal obstruction syndrome, thrombotic microangiopathy, disseminated intravascular coagulation, sepsis, acute respiratory distress syndrome, acute lung injury, antiphospholipid antibody syndrome, thrombosis resulting from coronary 25 artery bypass graft surgery or thrombosis induced by treatment in which blood is exposed to an artificial surface which promotes thrombus formation.
11. The use according to any one of claims 8 to 10, wherein the thromboembolic disease is venous 30 thromboembolism, ischemic stroke, thromboembolic disease induced by treatment in which blood is exposed to an artificial surface which promotes thrombus formation, acute coronary syndrome, coronary artery disease or peripheral arterial disease. 35
12. The compound according to any one of claims 1 to 5, a salt thereof, a solvate thereof, or an N-oxide thereof for preventing and/or treating thromboembolic disease.
13. A compound according to any one of claims 1 to 5, substantially as herein described with reference to any example thereof and with or without reference to the 5 accompanying figures.
14. A pharmaceutical composition according to claim 6, substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures. 10
15. An FXIa inhibitor according to claim 7, substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.
16. Use according to any one of claims 8 to 11, 15 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.
17. A compound for use according to claim 12, substantially as herein described with reference to any 20 example thereof and with or without reference to the accompanying figures.
NZ733574A 2015-12-09 Dihydroindolizinone derivative NZ733574B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
JP2014249822 2014-12-10
JP2014263251 2014-12-25
JP2015046150 2015-03-09
JP2015160632 2015-08-17
PCT/JP2015/084573 WO2016093285A1 (en) 2014-12-10 2015-12-09 Dihydroindolizinone derivative

Publications (2)

Publication Number Publication Date
NZ733574A NZ733574A (en) 2024-03-22
NZ733574B2 true NZ733574B2 (en) 2024-06-25

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