DK2615089T3 - Pyrazoloquinolinforbindelser - Google Patents
Pyrazoloquinolinforbindelser Download PDFInfo
- Publication number
- DK2615089T3 DK2615089T3 DK11823618.1T DK11823618T DK2615089T3 DK 2615089 T3 DK2615089 T3 DK 2615089T3 DK 11823618 T DK11823618 T DK 11823618T DK 2615089 T3 DK2615089 T3 DK 2615089T3
- Authority
- DK
- Denmark
- Prior art keywords
- alkyl
- substituted
- alkylene
- group
- aryl
- Prior art date
Links
- 125000000217 alkyl group Chemical group 0.000 claims description 456
- 150000001875 compounds Chemical class 0.000 claims description 229
- -1 C 1-6 alkylene oxygen Chemical compound 0.000 claims description 162
- 150000003839 salts Chemical class 0.000 claims description 112
- 229910052736 halogen Inorganic materials 0.000 claims description 106
- 125000005842 heteroatom Chemical group 0.000 claims description 94
- 125000005843 halogen group Chemical group 0.000 claims description 80
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 71
- 230000004064 dysfunction Effects 0.000 claims description 70
- 229910052757 nitrogen Inorganic materials 0.000 claims description 64
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 62
- 229910052705 radium Inorganic materials 0.000 claims description 52
- 229910052701 rubidium Inorganic materials 0.000 claims description 52
- 125000003118 aryl group Chemical group 0.000 claims description 48
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 40
- 208000004168 Underactive Urinary Bladder Diseases 0.000 claims description 39
- 150000002367 halogens Chemical class 0.000 claims description 39
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 38
- 229910052760 oxygen Inorganic materials 0.000 claims description 29
- 239000001301 oxygen Substances 0.000 claims description 29
- 125000005275 alkylenearyl group Chemical group 0.000 claims description 28
- 125000005936 piperidyl group Chemical group 0.000 claims description 28
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 25
- 125000004193 piperazinyl group Chemical group 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 19
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 239000011593 sulfur Chemical group 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 13
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 230000002265 prevention Effects 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 150000001925 cycloalkenes Chemical class 0.000 claims description 4
- 230000004927 fusion Effects 0.000 claims description 4
- MWRPBVYROYCCKJ-HNNXBMFYSA-N 7-methyl-1-[(3S)-oxolan-3-yl]-8-[4-(3,3,3-trifluoropropyl)piperazine-1-carbonyl]-5H-pyrazolo[4,3-c]quinolin-4-one Chemical compound C1=2C=3C=C(C(=O)N4CCN(CCC(F)(F)F)CC4)C(C)=CC=3NC(=O)C=2C=NN1[C@H]1CCOC1 MWRPBVYROYCCKJ-HNNXBMFYSA-N 0.000 claims description 3
- 150000001924 cycloalkanes Chemical class 0.000 claims description 3
- KKCDHUAUUKENRP-UHFFFAOYSA-N 7-methyl-1-(oxan-4-yl)-8-[4-(3,3,3-trifluoropropyl)piperazine-1-carbonyl]-5H-pyrazolo[4,3-c]quinolin-4-one Chemical compound C1=2C=3C=C(C(=O)N4CCN(CCC(F)(F)F)CC4)C(C)=CC=3NC(=O)C=2C=NN1C1CCOCC1 KKCDHUAUUKENRP-UHFFFAOYSA-N 0.000 claims description 2
- UMIQYRZUIYRXSP-KRWDZBQOSA-N 8-[4-(2-methoxyethyl)piperidine-1-carbonyl]-7-methyl-1-[(3S)-oxolan-3-yl]-5H-pyrazolo[4,3-c]quinolin-4-one Chemical compound C1CC(CCOC)CCN1C(=O)C(C(=C1)C)=CC2=C1NC(=O)C1=C2N([C@@H]2COCC2)N=C1 UMIQYRZUIYRXSP-KRWDZBQOSA-N 0.000 claims description 2
- NRHBSXLQBRXWHB-MRXNPFEDSA-N 8-[4-[(2R)-2-fluoropropoxy]piperidine-1-carbonyl]-7-methyl-1-(oxan-4-yl)-5H-pyrazolo[4,3-c]quinolin-4-one Chemical compound C1CC(OC[C@H](F)C)CCN1C(=O)C(C(=C1)C)=CC2=C1NC(=O)C1=C2N(C2CCOCC2)N=C1 NRHBSXLQBRXWHB-MRXNPFEDSA-N 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims 17
- RUKHCDXJWPFYHK-AWEZNQCLSA-N 7-methyl-1-[(3S)-oxolan-3-yl]-8-[4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl]-5H-pyrazolo[4,3-c]quinolin-4-one Chemical compound C1=2C=3C=C(C(=O)N4CCN(CC(F)(F)F)CC4)C(C)=CC=3NC(=O)C=2C=NN1[C@H]1CCOC1 RUKHCDXJWPFYHK-AWEZNQCLSA-N 0.000 claims 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 2
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 138
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
- 238000002360 preparation method Methods 0.000 description 105
- 239000000243 solution Substances 0.000 description 71
- 239000000203 mixture Substances 0.000 description 64
- 238000000034 method Methods 0.000 description 62
- 238000003756 stirring Methods 0.000 description 62
- 210000003932 urinary bladder Anatomy 0.000 description 62
- 238000006243 chemical reaction Methods 0.000 description 61
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 60
- 230000002829 reductive effect Effects 0.000 description 55
- 239000002904 solvent Substances 0.000 description 55
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- 125000001424 substituent group Chemical group 0.000 description 33
- 210000003708 urethra Anatomy 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 238000010898 silica gel chromatography Methods 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 27
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 25
- 238000001816 cooling Methods 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 239000012295 chemical reaction liquid Substances 0.000 description 24
- 239000003795 chemical substances by application Substances 0.000 description 23
- 239000007788 liquid Substances 0.000 description 22
- 239000000126 substance Substances 0.000 description 21
- PMZDQRJGMBOQBF-UHFFFAOYSA-N 1H-quinolin-4-one Natural products C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 description 20
- VSGPVHSTVTXREH-UHFFFAOYSA-N quinolin-4-one Chemical compound C1=CC=C[C]2C(=O)C=CN=C21 VSGPVHSTVTXREH-UHFFFAOYSA-N 0.000 description 20
- 238000003860 storage Methods 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- 101100407341 Drosophila melanogaster Pde9 gene Proteins 0.000 description 19
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- 238000001914 filtration Methods 0.000 description 18
- 239000000843 powder Substances 0.000 description 18
- 206010071289 Lower urinary tract symptoms Diseases 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 230000009471 action Effects 0.000 description 16
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- 125000006239 protecting group Chemical group 0.000 description 16
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- 229920006395 saturated elastomer Polymers 0.000 description 15
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- 230000002401 inhibitory effect Effects 0.000 description 14
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 14
- 210000005070 sphincter Anatomy 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
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- 125000004430 oxygen atom Chemical group O* 0.000 description 13
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
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- 238000012360 testing method Methods 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- 235000011054 acetic acid Nutrition 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 11
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- 125000004434 sulfur atom Chemical group 0.000 description 11
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 10
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- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 9
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- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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Claims (22)
1. Forbindelse med formlen (I) eller et salt deraf:
(I) hvor R1 er hydrogen, halogeno-Ci-6 alkyl, Ci-β alkyl, eller -O-Ci-6 alkyl, R2 er en gruppe med formlen (II):
(II) R3 er Ci-6 alkylen-(cycloalkyl der kan være substitueret med halogen eller -O-Ci-6 alkyl); Ci-6 alkylen-oxygen-indeholdende mættet heteroring; cycloalkyl der kan være substitueret med halogen eller -O-Ci-6 alkyl; en oxygen-indeholdende mættet heteroring; eller en monocyklisk nitrogen-indeholdende mættet heteroring der kan være substitueret med Ci-6 alkyl, Ci-6 alkylen-aryl, eller -CO-Ci-6 alkylen-O-Ci-6 alkyl, R4, R5 og R5 er hydrogen, Ra og Rb er kombineret med det tilgrænsende nitrogenatom til at danne en monocyklisk nitrogen-indeholdende heteroring, der kan være substitueret med en gruppe valgt fra: -OH; halogeno-Ci-6 alkyl; -O-Ci-6 alkyl der kan være substitueret med 1 til 3 grupper valgt fra gruppen bestående af halogen, halogeno-Ci-6 alkyl og cycloalkyl; aryl der kan være substitueret med en gruppe valgt fra en gruppe Gi; en heteroring der kan være substitueret med en gruppe valgt fra en gruppe G2; Ci-6 alkylen-O-cycloalkyl; -O-cycloalkyl; -O-(heteroring der kan være substitueret med en gruppe valgt fra en gruppe G2); Ci-6 alkyl der kan være substitueret med én eller flere grupper valgt fra gruppen bestående af halogen, halogeno-Ci-6 al kyl, -O-cycloalkyl, -O-Ci-6 alkyl, og -O-halogeno-Ci-6 alkyl; og Ci-6 alkylen-O-Ci-6 alkyl der kan være substitueret med én eller flere grupper valgt fra gruppen bestående af halogen, halogeno-Ci-6 alkyl og cycloalkyl, gruppen Gi består af halogen, Ci-6 alkyl, halogeno-Ci-e alkyl, -OH, -O-Ci-6 alkyl, -O-heteroring, -O-Ci-e alkylen-aryl, -O-Ci-6 alkylen-heteroring, -O-halogeno-Ci-6 alkyl, -N(Ci-6 alkyl)2, Ci-β alkylen-N(Ci-6 alkyl)2, Ci-β alkylen-heteroring, aryl der kan være substitueret med Ci-6 alkyl, en heteroring der kan være substitueret med Ci-6 alkyl, -COOH, -CO-O-C1-6 alkyl, -CO-O-Ci-6 alkylen-O-Ci-6 alkyl, - CO-O-Ci-6 alkylen-aryl, -CO-O-Ci-6 alkylen-O-aryl, -CO-NH2, -CO-NH-C1-6 alkyl, - CO-N(Ci-6 alkyl)2, -CO-N(Ci-5 alkyl)-aryl, -CO-N(Ci-5 alkyl)-heteroring, -CO-N(Ci-e alkyl)-(Ci-5 alkylen-aryl), -CO-NH-Ci-e alkylen-OH, og -CO-NH-heteroring, og gruppen G2 består af halogen, Ci-5 alkyl, halogeno-Ci-5 alkyl, -OH, -O-Ci-e alkyl, -O-C1-6 alkylen-aryl, -O-C1-6 alkylen-heteroring, -O-halogeno- Ci-6 alkyl, cyano, -N(Ci-6 alkyl)2, -NH-CO-Ci-β alkyl, Ci-β alkylen-O-Ci-6 alkyl, C1-6 alkylen-heteroring, aryl, en heteroring der kan være substitueret med Ci-β alkyl, -COOH, -CO-O-Ci-6 alkyl, -CO-O-Ci-6 alkylen-O-Ci-6 alkyl, -CO-O-Ci-s alkylen-aryl, -CO-O-Ci-6 alkylen-O-aryl, -CO-NH2, -CO-NH-Ci-e alkyl, -CO-N(Ci-6 alkyl)2, -CO-N(Ci-6 alkyl)-aryl, -CON(Ci-6 alkyl)-heteroring, -CO-N(Ci-e alkyl)-(Ci-6 alkylen-aryl), -CO-NH-Ci-e alkylen-OH, og -CO-NH-heteroring hvor "aryl" henviser til en Ce-14 monocyklisk til tricyklisk aromatisk hydrocarbonringgruppe og udtrykket "heteroring" henviser til en ringgruppe indeholdende (i) en monocyklisk 3- til 8-leddet ring indeholdende 1 til 4 heteroatomer valgt fra oxygen, svovl og nitrogen, eller (ii) en bi- til tricyklisk ring indeholdende 1 til 5 heteroatomer valgt fra oxygen, svovl og nitrogen, dannet ved ringfusion af en monocyklisk heteroring med én eller to ringe valgt fra gruppen bestående af en monocyklisk heteroring, en benzenring, C5-8 cycloalkan, og C5-8 cycloalken.
2. Forbindelsen eller et salt deraf som angivet i krav 1, hvor den monocykliske nitrogenindeholdende heteroring der kan være substitueret, dannet af Ra og Rb som er kombineret med det tilgrænsende nitrogenatom, er piperidyl eller piperazinyl, der hver kan være substitueret med 1 til 3 grupper valgt fra: -OH; halogeno-Ci-6 alkyl; -O-C1-6 alkyl der kan være substitueret med 1 til 3 grupper valgt fra gruppen bestående af halogen, halogeno-Ci-6 alkyl og cycloalkyl; aryl der kan være substitueret med en gruppe valgt fra en gruppe Gi; en heteroring der kan være substitueret med en gruppe valgt fra en gruppe G2; C1-6 alkylen-O-cycloalkyl; -O-cycloalkyl; -0-(heteroring der kan være substitueret med en gruppe valgt fra en gruppe G2); C1-6 alkyl der kan være substitueret med én eller flere grupper valgt fra gruppen bestående af halogen, halogeno-Ci-6 alkyl, -O-cycloalkyl, -Ο-Ci-ealkyl, og -O-halogeno-Ci-6 alkyl; og C1-6 alkylen-O-Ci-6 alkyl der kan være substitueret med én eller flere grupper valgt fra gruppen bestående af halogen, halogeno-Ci-e al kyl og cycloalkyl, gruppen Gi består af halogen, Ci-β alkyl, halogeno-Ci-6 alkyl, -OH, -O-C1-6 alkyl, -O-heteroring, -O-Ci-β alkylen-aryl, -O-Ci-β alkylen-heteroring, -O-halogeno-Ci-6 alkyl, -N(Ci-6 alkyl)2, Ci-β alkylen-N(Ci-6 alkyl)2, Ci-β alkylen-heteroring, aryl der kan være substitueret med Ci-6 alkyl, en heteroring der kan være substitueret med Ci-β alkyl, -COOH, -CO-O-Ci-6 alkyl, -CO-O-Ci-6 alkylen-O-Ci-6 alkyl, - CO-O-Ci-6 alkylen-aryl, -CO-O-C1-6 alkylen-O-aryl, -CO-NH2, -CO-NH-C1-6 alkyl, - CO-N(Ci-6 alkyl)2, -CO-N(Ci-6 alkyl)-aryl, -CO-N(Ci-e alkyl)-heteroring, -CO-N(Ci-5 alkyl)-(Ci-6 alkylen-aryl), -CO-NH-Ci-e alkylen-OH, og -CO-NH-heteroring, og gruppen G2 består af halogen, Ci-6 alkyl, halogeno-Ci-6 alkyl, -OH, -O-Ci-e alkyl, -O-Ci-6 alkylen-aryl, -0-Ci-6 alkylen-heteroring, -O-halogeno- Ci-6 alkyl, cyano, -N(Ci-6 alkyl)2, -NH-CO-Ci e alkyl, Ci-6 alkylen-O-Ci-6 alkyl, Ci-6 alkylen-heteroring, aryl, en heteroring der kan være substitueret med Ci-β alkyl, -COOH, -CO-O-Ci-6 alkyl, -CO-O-Ci-6 alkylen-O-Ci-6 alkyl, -CO-O-Ci-6 alkylen-aryl, -CO-O-Ci-6 alkylen-O-aryl, -CO-NH2, -CO-NH-Ci-e alkyl, -CO-N(Ci-5 alkyl)2, -CO-N(Ci-6 alkyl)-aryl, -CON(Ci-6 alkyl)-heteroring, -CO-N(Ci-6 alkyl)-(Ci-6 alkylen-aryl), -CO-NH-Ci-s alkylen-OH, og -CO-NH-heteroring.
3. Forbindelsen eller et salt deraf som angivet i krav 2, hvor piperidyl eller piperazinyl, der hver kan være substitueret, dannet af Ra og Rb som er kombineret med det tilgrænsende nitrogenatom, kan være substitueret med 1 til 3 grupper valgt fra gruppen bestående af: - O-Ci-e al kyl der kan være substitueret med 1 til 3 grupper valgt fra halogen og cycloalkyl; Ci-6 alkylen-O-cycloalkyl; -O-cycloalkyl; Ci-6 alkyl der kan være substitueret med én eller flere grupper valgt fra gruppen bestående af halogen, halogeno-Ci-6 alkyl, og -O-Ci-6 alkyl; eller Ci-6 alkylen-O-Ci-6 alkyl.
4. Forbindelsen eller et salt deraf ifølge et hvilket som helst af kravene 1 til 3, hvor R1 er Ci-6 alkyl, og R3 er Ci-6 alkylen-(cycloalkyl), Ci-e alkylen-(cycloalkyl substitueret med to halogenatomer), cycloalkyl, cycloalkyl substitueret med to halogenatomer, en oxygen-indeholdende mættet heteroring, eller en monocyklisk nitrogen-indeholdende mættet heteroring substitueret med Ci-6 alkyl.
5. Forbindelsen eller et salt deraf ifølge et hvilket som helst af kravene 1 til 3, hvor R1 er Ci-6 alkyl, og R3 er cycloalkyl eller en oxygen-indeholdende mættet heteroring.
6. Forbindelsen eller et salt deraf som angivet i krav 1, der er 8-[(4-{[(2S)-2-fluorpropyl]oxy>piperidin-l-yl)carbonyl]-7-methyl-l-(tetrahydro-2H-pyran- 4-yl)-l,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-on, 7- methyl-l-(tetrahydro-2H-pyran-4-yl)-8-{ [4-(3,3,3-trifluorpropyl)piperazin-1-yl]carbonyl}-l,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-on, 8- [(4- {[(2R)-2-fluorpropyl]oxy}piperidin-l-yl)carbonyl]-7-methyl-l-(tetrahydro-2H- pyran-4-yl)-l,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-on, 7- methyl-l-[(3S)-tetrahydrofuran-3-yl]-8-{[4-(3,3,3-trifluorpropyl)piperazin-l-yl]carbonyl>-l,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-on, 8- {[4-(2-methoxyethyl)piperidin-l-yl]carbonyl}-7-nnethyl-l-[(3S)-tetrahydrofuran-3-yl]- 1.5- dihydro-4H-pyrazolo[4,3-c]quinolin-4-on, 7-methyl-l-[(3S)-tetrahydrofuran-3-yl]-8-{[4-(2,2,2-trifluorethyl)piperazin-l- yl]carbonyl}-l,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-on, eller et salt deraf.
7. Forbindelsen eller et salt deraf som angivet i krav 1, der er 7-methyl-l-(tetrahydro-2H-pyran-4-yl)-8-{ [4-(3,3,3-trifluorpropyl)pi perazin-1-yl]carbonyl-l,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-on, 7-methyl-l-[(3S)-tetrahydrofuran-3-yl]-8-{[4-(3,3,3-trifluorpropyl)piperazin-l-yl]carbonyl}-l,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-on, 7- methyl-l-[(3S)-tetrahydrofuran-3-yl]-8-{[4-(2,2,2-trifluorethyl)piperazin-l-yl]carbonyl- 1.5- dihydro-4H-pyrazolo[4,3-c]quinolin-4-on, eller et salt deraf.
8. Forbindelsen eller et salt deraf som angivet i krav 1, der er 8- [(4- {[(2S)-2-fluorpropyl]oxy}piperidin-l-yl)carbonyl]-7-methyl-l-(tetrahydro-2FI-pyran-4-yl)-l,5-dihydro-4FI-pyrazolo[4,3-c]quinolin-4-on, eller et salt deraf.
9. Forbindelsen eller et salt deraf som angivet i krav 1, der er 7- methyl-l-(tetrahydro-2FI-pyran-4-yl)-8-{[4-(3,3,3-trifluorpropyl)piperazin-l-yl]carbonyl}-l,5-dihydro-4FI-pyrazolo[4,3-c]quinolin-4-on, eller et salt deraf.
10. Forbindelsen eller et salt deraf som angivet i krav 1, der er 8- [(4-{[(2R)-2-fluorpropyl]oxy>piperidin-l-yl)carbonyl]-7-methyl-l-(tetrahydro-2FI-pyran-4-yl)-l,5-dihydro-4FI-pyrazolo[4,3-c]quinolin-4-on, eller et salt deraf.
11. Forbindelsen eller et salt deraf som angivet i krav 1, der er 7-methyl-l-[(3S)-tetrahydrofuran-3-yl]-8-{[4-(3,3,3-trifluorpropyl)piperazin-l-yl]carbonyl}-l,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-on, eller et salt deraf.
12. Forbindelsen eller et salt deraf som angivet i krav 1, der er 8-{[4-(2-methoxyethyl)piperidin-l-yl]carbonyl>-7-methyl-l-[(3S)-tetrahydrofuran-3-yl]- l,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-on, eller et salt deraf.
13. Forbindelsen eller et salt deraf som angivet i krav 1, der er 7-methyl-l-[(3S)-tetrahydrofuran-3-yl]-8-{[4-(2,2,2-trifluorethyl)piperazin-l-yl]carbonyl}-l,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-on, eller et salt deraf.
14. Farmaceutisk sammensætning omfattende forbindelsen eller et salt deraf ifølge et hvilket som helst af kravene 1 til 13, og en farmaceutisk acceptabel excipiens.
15. Anvendelse af forbindelsen eller et salt deraf ifølge et hvilket som helst af kravene 1 til 13 til fremstillingen af den farmaceutiske sammensætning til forebyggelse eller behandling af underaktiv blære.
16. Anvendelse af forbindelsen eller et salt deraf ifølge et hvilket som helst af kravene 1 til 13 til fremstillingen af den farmaceutiske sammensætning til forebyggelse eller behandling af dysfunktion af tømning i den underaktive blære.
17. Anvendelse af forbindelsen eller et salt deraf ifølge et hvilket som helst af kravene 1 til 13 til fremstillingen af den farmaceutiske sammensætning til forebyggelse eller behandling af godartet prostatahyperplasi.
18. Anvendelse af forbindelsen eller et salt deraf ifølge et hvilket som helst af kravene 1 til 13 til fremstillingen af den farmaceutiske sammensætning til forebyggelse eller behandling af dysfunktion af tømning ledsagende godartet prostatahyperplasi.
19. Forbindelsen eller et salt deraf ifølge et hvilket som helst af kravene 1 til 13, til anvendelse til forebyggelse eller behandling af underaktiv blære.
20. Forbindelsen eller et salt deraf ifølge et hvilket som helst af kravene 1 til 13, til anvendelse til forebyggelse eller behandling af dysfunktion af tømning i den underaktive blære.
21. Forbindelsen eller et salt deraf ifølge et hvilket som helst af kravene 1 til 13, til anvendelse til forebyggelse eller behandling af godartet prostatahyperplasi.
22. Forbindelsen eller et salt deraf ifølge et hvilket som helst af kravene 1 til 13, til anvendelse til forebyggelse eller behandling af dysfunktion af tømning ledsagende godartet prostatahyperplasi.
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| JP2010200403 | 2010-09-07 | ||
| PCT/JP2011/070410 WO2012033144A1 (ja) | 2010-09-07 | 2011-09-07 | ピラゾロキノリン化合物 |
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| US9169246B2 (en) * | 2011-09-26 | 2015-10-27 | Sanofi | Pyrazoloquinolinone derivatives, preparation thereof and therapeutic use thereof |
| JP6042060B2 (ja) * | 2011-09-26 | 2016-12-14 | サノフイ | ピラゾロキノリノン誘導体、その調製および治療上の使用 |
| PT2573073E (pt) * | 2011-09-26 | 2015-02-05 | Sanofi Sa | Derivados de pirazoloquinolinona, sua preparação e sua utilização terapêutica |
| AR088235A1 (es) * | 2011-10-07 | 2014-05-21 | Eisai R&D Man Co Ltd | Derivados de pirazoloquinolina |
| CN102786525B (zh) | 2012-08-08 | 2014-12-17 | 中山大学 | N-取代吡唑并[3,4-d]嘧啶酮类化合物、其制备方法及其应用 |
| BR112015024075B1 (pt) * | 2013-04-05 | 2022-05-03 | Eisai R&D Management Co., Ltd | Compostos de piridinilpirazoloquinolina |
| ES2645149T3 (es) | 2013-04-05 | 2017-12-04 | Eisai R&D Management Co., Ltd. | Sal de derivado de pirazoloquinolina y cristal de esta |
| WO2016054491A1 (en) | 2014-10-03 | 2016-04-07 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| AR102849A1 (es) * | 2015-03-09 | 2017-03-29 | Astellas Pharma Inc | Compuesto de piridina bicíclica |
| US10919914B2 (en) | 2016-06-08 | 2021-02-16 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| AU2018278422B2 (en) | 2017-06-01 | 2022-03-17 | Eisai R&D Management Co., Ltd. | Lewy body disease therapeutic agent containing pyrazoloquinoline derivative |
| EP3632437B1 (en) | 2017-06-01 | 2024-03-13 | Eisai R&D Management Co., Ltd. | Dementia therapeutic agent combining pyrazoloquinoline derivative and memantine |
| AU2018276565A1 (en) | 2017-06-01 | 2019-11-07 | Eisai R&D Management Co., Ltd. | Dementia therapeutic agent combining pyrazoloquinoline derivative and donepezil |
| KR20200010211A (ko) | 2017-06-01 | 2020-01-30 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | Pde9 저해제를 포함하는 약제학적 조성물 |
| US20240368133A1 (en) * | 2021-07-30 | 2024-11-07 | Confo Therapeutics N.V. | Compounds for the Treatment of Pain, in Particular, Neuropathic Pain, and/or Other Diseases or Disorders that are Associated with AT2R and/or AT2R Mediated Signaling |
| MX2024004444A (es) | 2021-10-14 | 2024-05-08 | Incyte Corp | Compuestos de quinolina como inhibidores de la proteina del virus de sarcoma de rata kirsten (kras). |
| AU2023235233A1 (en) | 2022-03-14 | 2024-09-12 | Slap Pharmaceuticals Llc | Multicyclic compounds |
| WO2025036472A1 (en) * | 2023-08-16 | 2025-02-20 | Pharmaengine, Inc. | Spirocyclic mta-cooperative prmts inhibitor |
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| US5192768A (en) | 1990-09-14 | 1993-03-09 | Kyowa Hakko Kogyo Co., Ltd. | Pyrazoloquinoline derivatives |
| JPH05132484A (ja) * | 1991-04-26 | 1993-05-28 | Otsuka Pharmaceut Factory Inc | ピラゾロキノリン及びピラゾロナフチリジン誘導体 |
| WO2003037432A1 (en) | 2001-11-02 | 2003-05-08 | Pfizer Products Inc. | Treatment of insulin resistance syndrome and type 2 diabetes with pde9 inhibitors |
| HN2002000317A (es) | 2001-11-02 | 2003-05-21 | Pfizer | Inhibidores de pde9 para tratamiento de trastornos cardiovasculares |
| DE10238723A1 (de) | 2002-08-23 | 2004-03-11 | Bayer Ag | Phenyl-substituierte Pyrazolyprimidine |
| RU2328499C2 (ru) | 2003-01-09 | 2008-07-10 | Астеллас Фарма Инк. | Производные пирролопиридазина, фармацевтическая композиция, способ профилактики или лечения заболеваний, применение в качестве ингибитора фосфодиэстеразы iv, и/или продуцирования tnf |
| TW200508233A (en) | 2003-05-29 | 2005-03-01 | Millennium Pharm Inc | Chk-1 inhibitors |
| JP2006045118A (ja) * | 2004-08-04 | 2006-02-16 | Mochida Pharmaceut Co Ltd | 新規ピラゾロキノロン誘導体 |
| AU2006258461B2 (en) | 2005-06-14 | 2011-08-25 | Aska Pharmaceutical Co., Ltd. | Thienopyrimidine derivative |
| WO2007115232A2 (en) | 2006-03-30 | 2007-10-11 | Chemocentryx, Inc. | Cxcr4 modulators |
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| JPWO2008072778A1 (ja) | 2006-12-13 | 2010-04-02 | あすか製薬株式会社 | 尿路系疾患の処置剤 |
| WO2008072779A1 (ja) | 2006-12-13 | 2008-06-19 | Aska Pharmaceutical Co., Ltd. | キノキサリン誘導体 |
| MY147330A (en) | 2007-05-11 | 2012-11-30 | Pfizer | Amino-heterocyclic compounds |
| JP5498392B2 (ja) | 2007-11-30 | 2014-05-21 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 1,5−ジヒドロ−ピラゾロ[3,4−d]ピリミジン−4−オン誘導体及びcns障害の治療のためのpde9aモジュレーターとしてのそれらの使用 |
| UA105362C2 (en) | 2008-04-02 | 2014-05-12 | Бьорингер Ингельхайм Интернациональ Гмбх | 1-heterocyclyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their use as pde9a modulators |
| WO2010026214A1 (en) | 2008-09-08 | 2010-03-11 | Boehringer Ingelheim International Gmbh | Pyrazolopyrimidines and their use for the treatment of cns disorders |
| US9259564B2 (en) | 2009-01-22 | 2016-02-16 | Avent, Inc. | Enteral feeding assembly with lock assembly |
| TWI404721B (zh) | 2009-01-26 | 2013-08-11 | Pfizer | 胺基-雜環化合物 |
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- 2011-09-07 DK DK11823618.1T patent/DK2615089T3/da active
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- 2011-09-07 WO PCT/JP2011/070410 patent/WO2012033144A1/ja not_active Ceased
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- 2011-09-07 MX MX2013002584A patent/MX2013002584A/es active IP Right Grant
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Also Published As
| Publication number | Publication date |
|---|---|
| EA023493B1 (ru) | 2016-06-30 |
| WO2012033144A1 (ja) | 2012-03-15 |
| EA201390353A1 (ru) | 2013-08-30 |
| EP2615089A1 (en) | 2013-07-17 |
| CN103097383A (zh) | 2013-05-08 |
| CY1117547T1 (el) | 2017-04-26 |
| ES2583528T3 (es) | 2016-09-21 |
| KR20130106358A (ko) | 2013-09-27 |
| KR101860583B1 (ko) | 2018-05-23 |
| US8822448B2 (en) | 2014-09-02 |
| HRP20160473T1 (hr) | 2016-07-29 |
| MX2013002584A (es) | 2013-04-29 |
| US20130225553A1 (en) | 2013-08-29 |
| BR112013005444A2 (pt) | 2017-09-19 |
| EP2615089A4 (en) | 2014-01-01 |
| CN103097383B (zh) | 2015-09-16 |
| HUE028038T2 (en) | 2016-11-28 |
| BR112013005444B1 (pt) | 2019-07-09 |
| CA2810696C (en) | 2018-09-18 |
| SI2615089T1 (sl) | 2016-08-31 |
| JP5888237B2 (ja) | 2016-03-16 |
| CA2810696A1 (en) | 2012-03-15 |
| RS54834B1 (sr) | 2016-10-31 |
| JPWO2012033144A1 (ja) | 2014-01-20 |
| EP2615089B1 (en) | 2016-04-27 |
| PL2615089T3 (pl) | 2016-10-31 |
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