NO300271B1 - Pyrazolopyridin-forbindelser og farmasoytiske preparater inneholdende disse - Google Patents
Pyrazolopyridin-forbindelser og farmasoytiske preparater inneholdende disse Download PDFInfo
- Publication number
- NO300271B1 NO300271B1 NO19921413A NO921413A NO300271B1 NO 300271 B1 NO300271 B1 NO 300271B1 NO 19921413 A NO19921413 A NO 19921413A NO 921413 A NO921413 A NO 921413A NO 300271 B1 NO300271 B1 NO 300271B1
- Authority
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- Norway
- Prior art keywords
- alkyl
- acid
- compound
- pharmaceutically acceptable
- salt
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title abstract 2
- 150000005229 pyrazolopyridines Chemical class 0.000 title description 6
- -1 pyrazolopyridine compound Chemical class 0.000 claims abstract description 57
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 30
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 4
- 239000003937 drug carrier Substances 0.000 claims abstract description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 43
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 claims description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- UWTYIJJJSYDUQM-GOSISDBHSA-N 2-[(2r)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)prop-2-enoyl]piperidin-2-yl]acetic acid Chemical group OC(=O)C[C@H]1CCCCN1C(=O)C=CC1=C2C=CC=CN2N=C1C1=CC=CC=C1 UWTYIJJJSYDUQM-GOSISDBHSA-N 0.000 claims description 8
- 206010030113 Oedema Diseases 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 5
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 5
- 201000006370 kidney failure Diseases 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- UWTYIJJJSYDUQM-UHFFFAOYSA-N 2-[1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)prop-2-enoyl]piperidin-2-yl]acetic acid Chemical group OC(=O)CC1CCCCN1C(=O)C=CC1=C2C=CC=CN2N=C1C1=CC=CC=C1 UWTYIJJJSYDUQM-UHFFFAOYSA-N 0.000 claims description 3
- 206010002383 Angina Pectoris Diseases 0.000 claims description 3
- 208000000575 Arteriosclerosis Obliterans Diseases 0.000 claims description 3
- 201000005569 Gout Diseases 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 206010020772 Hypertension Diseases 0.000 claims description 3
- 201000001431 Hyperuricemia Diseases 0.000 claims description 3
- 206010062016 Immunosuppression Diseases 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 3
- 206010042440 Sudden infant death syndrome Diseases 0.000 claims description 3
- 208000007536 Thrombosis Diseases 0.000 claims description 3
- 208000032109 Transient ischaemic attack Diseases 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 206010008118 cerebral infarction Diseases 0.000 claims description 3
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 3
- 230000001506 immunosuppresive effect Effects 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 201000005060 thrombophlebitis Diseases 0.000 claims description 3
- 201000010875 transient cerebral ischemia Diseases 0.000 claims description 3
- 206010029164 Nephrotic syndrome Diseases 0.000 claims description 2
- 206010061876 Obstruction Diseases 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 201000008383 nephritis Diseases 0.000 claims description 2
- 208000009928 nephrosis Diseases 0.000 claims description 2
- 231100001027 nephrosis Toxicity 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 231100000572 poisoning Toxicity 0.000 claims description 2
- 230000000607 poisoning effect Effects 0.000 claims description 2
- 208000020401 Depressive disease Diseases 0.000 claims 1
- 208000005374 Poisoning Diseases 0.000 claims 1
- 208000024714 major depressive disease Diseases 0.000 claims 1
- 201000003995 melancholia Diseases 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 7
- 230000008569 process Effects 0.000 abstract description 5
- 239000004480 active ingredient Substances 0.000 abstract description 3
- 125000002252 acyl group Chemical group 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 230000004526 pharmaceutical effect Effects 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 3
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- KEWMAYAFCUFZJQ-GOSISDBHSA-N 2-[(2r)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)prop-2-enoyl]piperidin-2-yl]acetamide Chemical compound NC(=O)C[C@H]1CCCCN1C(=O)C=CC1=C2C=CC=CN2N=C1C1=CC=CC=C1 KEWMAYAFCUFZJQ-GOSISDBHSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- FATAVLOOLIRUNA-UHFFFAOYSA-N formylmethyl Chemical group [CH2]C=O FATAVLOOLIRUNA-UHFFFAOYSA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 230000003907 kidney function Effects 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- OPESRHNSVRRBIS-LJQANCHMSA-N methyl 2-[(2r)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)prop-2-enoyl]piperidin-2-yl]acetate Chemical compound COC(=O)C[C@H]1CCCCN1C(=O)C=CC1=C2C=CC=CN2N=C1C1=CC=CC=C1 OPESRHNSVRRBIS-LJQANCHMSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- KQOWFRJXZCUGGX-JOCHJYFZSA-N n,n-diethyl-2-[(2r)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)prop-2-enoyl]piperidin-2-yl]acetamide Chemical compound CCN(CC)C(=O)C[C@H]1CCCCN1C(=O)C=CC1=C2C=CC=CN2N=C1C1=CC=CC=C1 KQOWFRJXZCUGGX-JOCHJYFZSA-N 0.000 description 2
- 231100000417 nephrotoxicity Toxicity 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 150000003016 phosphoric acids Chemical class 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 239000000296 purinergic P1 receptor antagonist Substances 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000007306 turnover Effects 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- MASDFXZJIDNRTR-UHFFFAOYSA-N 1,3-bis(trimethylsilyl)urea Chemical compound C[Si](C)(C)NC(=O)N[Si](C)(C)C MASDFXZJIDNRTR-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OPLOPFHUHFGKMJ-LJQANCHMSA-N 1-[(2r)-2-(2-hydroxyethyl)piperidin-1-yl]-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)prop-2-en-1-one Chemical compound OCC[C@H]1CCCCN1C(=O)C=CC1=C2C=CC=CN2N=C1C1=CC=CC=C1 OPLOPFHUHFGKMJ-LJQANCHMSA-N 0.000 description 1
- SNUSZUYTMHKCPM-UHFFFAOYSA-N 1-hydroxypyridin-2-one Chemical compound ON1C=CC=CC1=O SNUSZUYTMHKCPM-UHFFFAOYSA-N 0.000 description 1
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical compound C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- HQAQSIPPSXSEMX-LJQANCHMSA-N 2-[(2r)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)prop-2-enoyl]piperidin-2-yl]acetaldehyde Chemical compound O=CC[C@H]1CCCCN1C(=O)C=CC1=C2C=CC=CN2N=C1C1=CC=CC=C1 HQAQSIPPSXSEMX-LJQANCHMSA-N 0.000 description 1
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 1
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- MDQHTWMXYBVSHU-UHFFFAOYSA-N 2-trimethylsilylacetamide Chemical compound C[Si](C)(C)CC(N)=O MDQHTWMXYBVSHU-UHFFFAOYSA-N 0.000 description 1
- SDXAWLJRERMRKF-UHFFFAOYSA-N 3,5-dimethyl-1h-pyrazole Chemical compound CC=1C=C(C)NN=1 SDXAWLJRERMRKF-UHFFFAOYSA-N 0.000 description 1
- ILYHNAKZOPJBHB-UHFFFAOYSA-N 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)prop-2-enoic acid Chemical compound N=1N2C=CC=CC2=C(C=CC(=O)O)C=1C1=CC=CC=C1 ILYHNAKZOPJBHB-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- 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
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Description
Foreliggende oppfinnelse angår nye pyrazolopyridin-forbindelser og farmasøytisk akseptable salter derav.
Mer spesielt angår den nye pyrazolopyridin-forbindelser og farmasøytisk akseptable salter derav, som er adenosin-antagonister og har forskjellige farmasøytiske virkninger, så som en kognitivitets-forbedrende virkning, analgetisk virkning, lokomotorisk virkning, antidepressiv virkning, cerebral vasodilaterende virkning, diuretisk virkning, kardioton virkning, vasodilaterende virkning, økende virkning på den renale blodstrøm, renal profylaktisk effekt, forbedrende effekt på nyrefunksjon, forbedret lipolyse-virkning, hemmende anafylaktisk bronkokonstriktiv virkning, akselererende virkning på insulinfrigjøringen, og er således egnet som psykostimulantia, analgetika, antidepressiva, midler til forbedring av det cerebrale kretsløp, midler ved hjertesvikt, kardiotone midler, antihypertensive midler, medikamenter ved nyreinsuffisiens (nyresvikt), medikamenter ved nyreforgiftning, renalprofylaktiske midler, midler for forbedring av nyrefunksjon, diuretika, midler mot ødem, midler mot fedme, antastmatika, bronkodilaterende midler, midler mot apné, midler mot urinsyregikt, mot hyperurikemi, mot SIDS (sudden infant death syndrome), midler til forbedring av immunsuppresjon av adenosin, antidiabetika eller lignende, og er dessuten hemmer av blodplate-aggregasjon og således egnet som medikamenter ved trombose, ved myokardinfarkt, ved obstruksjon, midler ved arteriosclerosis obliterans, medikamenter ved tromboflebitt, ved cerebralt infarkt, ved transiente ischemiske attakker, ved angina pectoris eller lignende. Oppfinnelsen angår også farmasøytiske preparater som omfatter de ovenfor omtalte pyrazolopyridinforbindelser og som kan benyttes terapeutisk hos mennesker og dyr for å forebygge og/eller behandle melankoli, hjertesvikt, hypertensjon (f.eks. essensiell -hypertensjon, nefrogen hypertensjon, etc), nyreinsuffisiens (nyresvikt) (f.eks. akutt nyresvikt), nyreforgiftning [f.eks. nyreforgiftning forårsaket av medikamenter som cisplatin, gentamicin, FR-900506
(beskrevet i EP-0184162), cyklosporiner (f.eks.
cyklosporin A) eller lignende; glyserol; etc], nefrose, nefritt, ødem (f.eks. kardielt ødem, nefrotisk ødem, hepatisk ødem, idiopatisk ødem, medikamentødem, akutt angioneurotisk ødem, arvelig angioneurotisk ødem, karsinomatøs ascites, ødem ved graviditet), fedme, bronkial astma, urinsyregikt, hyperurikemi, SIDS, immunsuppresjon, diabetes, myokardinfarkt nfarktasjon, trombose (f.eks. arteriell trombose, cerebral trombose, etc.), obstruksjon, arteriosclerosis obliterans, tromboflebitt, cerebralt infarkt, transiente ischemiske attakker, angina pectoris eller lignende.
Et.formål ved foreliggende oppfinnelse er således å tilveiebringe de nye pyrazolopyridin-forbindelsene og farmasøytisk akseptable salter derav, som er anvendelige til de angitte formål.
Et annet formål ved foreliggende oppfinnelse er å tilveiebringe farmasøytiske preparater som inneholder den nevnte pyrazolopyridin-forbindelse eller et farmasøytisk akseptabelt salt derav som virkestoff.
De nye pyrazolopyridin-forbindelsene ifølge oppfinnelsen, har følgende formel (I)
hvor R"*" er fenyl,
R 2er formyl(lavere)alkyl,
karboksy(lavere)alkyl,
- -lavere alkoksykarbonyl (lavere) alkyl, karbamoyl(lavere)alkyl,
N-lavere-alkylkarbamoyl(lavere)alkyl eller N,N-di(lavere)alkylkarbamoyl(lavere)alkyl, og A er lavere alkenylen, og et farmasøytisk akseptabelt salt derav.
Forbindelsen (I) eller salter derav,
kan fremstilles etter følgende reaksjonsskjemaer.
eller dets reaktive eller dets reaktive eller et salt derivat ved derivat ved derav karboksygruppen aminogruppen eller
eller et salt derav et salt derav
(Ib) <Id>
eller dets reaktive eller et salt derav derivat ved karboksy-
gruppen eller et salt derav
hvor R 1 , R 2og A er som defxnert ovenfor,
R a<2>er beskyttet karboksy(lavere) alkyl,
Rk<2>er karboksy(lavere)alkyl,
Rc<2>er formyl(lavere)alkyl eller karboksy(lavere)alkyl,
R^ 2er amidert karboksy(lavere)alkyl, og
R 3 er hydroksy(lavere)alkyl.
Det skal bemerkes at forbindelsen (I) kan innbefatte geometriske isomerer som følge av dobbeltbinding(er) og/eller stereoisomerer som følge av asymmetriske karbonatomer. I så fall kan én isomer omdannes til den andre etter en konvensjonell fremgangsmåte innen feltet.
Egnede farmasøytisk akseptable salter av forbindelsen (I) er de konvensjonelle og innbefatter et metallsalt, så som et alkalimetallsalt (f.eks. natriumsalt, kaliumsalt, etc), og et jordalkalimetallsalt (f.eks. kalsiumsalt, magnesiumsalt, etc), et ammoniumsalt, et organisk basesalt (f.eks. trimetyl-aminsalt, trietylaminsalt, pyridinsalt, pikolinsalt, dicyklo-heksylaminsalt, N,N'-dibenzyletylendiaminsalt, etc), salt av en organisk syre (f.eks. acetat, trifluoracetat, maleat, tartrat, fumarat, metansulfonat, benzensulfonat, formiat, toluensulfonat, etc), salt av en uorganisk syre (f.eks. hydroklorid, hydrobromid, hydrojodid, sulfat, fosfat, etc), et salt med en aminosyre (f.eks. arginin, asparaginsyre, glutaminsyre, etc.) og lignende.
Ovenfor og i den følgende beskrivelse er egnede eksempler og illustrasjoner på de forskjellige definisjoner som faller inn under oppfinnelsens ramme, mer utførlig angitt.
Betegnelsen "lavere" står her for 1 til 6 karbonatomer om intet annet er angitt.
Betegnelsen "lavere alkyl" kan innbefatte rette eller forgrenede alkylgrupper, så som metyl, etyl, propyl, isopropyl-, butyl, t-butyl, pentyl, heksyl, eller lignende, hvorav (c1_c4)alkyl og særlig metyl og etyl foretrekkes.
Betegnelsen "lavere alkoksykarbonyl" kan innbefatte metoksykarbonyl, etoksykarbonyl, propoksykarbonyl, butoksykarbonyl, t-butoksykarbonyl, pentyloksykarbonyl, heksyloksy-karbonyl, etc og særlig (C1~C4)alkoksykarbonyl og helst metoksykarbonyl.
Konkrete eksempler på amidert karboksy kan være karbamoyl; N-(lavere)alkylkarbamoyl (f.eks. N-metylkarbamoyl, N-etylkarbamoyl, N-isopropylkarbamoyl, N-butylkarbamoyl, N-pentylkarbamoyl, N-heksylkarbamoyl, etc.); N,N-di(lavere)alkylkarbamoyl [f.eks. N,N-dimetyl-karbamoyl, N,N-dietylkarbamoyl, N-metyl-N-etylkarbamoyl, N,N-dipropylkarbamoyl, N,N-di(t-butyl)karbamoyl, N-pentyl-N-heksylkarbamoyl, etc.];
Betegnelsen "karboksy(lavere)alkyl" kan f.eks. være karboksy{ C^- C^)alkyl, helst karboksymetyl;
Betegnelsen "beskyttet karboksy(lavere)alkyl" kan være forestret karboksy(lavere)alkyl og amidert karboksy-(lavere)alkyl.
Betegnelsen "hydroksy(lavere)alkyl" står for forbindelser med 2 til 7 karbonatomer og som har hydroksy på det terminale karbonatom, så som 2-hydroksyetyl, 1-(hydroksymetyl)etyl, 2-(hydroksymetyl)propyl, 1-(2-hydroksyetyl)etyl, 5-hydroksy-pentyl, 3-(hydroksymetyl)pentyl, 2-karboksymetyl)heksyl, eller lignende, fortrinnsvis hydroksy(C2-C^)alkyl og helst 2-hydroksyetyl.
Betegnelsen "formyl(lavere)alkyl" kan innbefatte formylmetyl, 1-formyletyl, 2-formylpropyl, 4-formylbutyl, 3-formyl-pentyl, 1-(formylmetyl)etyl, 2-formylheksyl og lignende, fortrinnsvis f ormyl (C^-C^) alkyl og helst formylmetyl.
Betegnelsen "lavere alkenylen" kan innbefatte vinylen, propenylen, 2-butenylen, 3-metyl-l-propenylen, 3-pentenylen, 1-heksenylen og lignende, fortrinnsvis (C2-C^) alkenyle^n og helst vinylen.
Fremgangsmåter for fremstilling av forbindelsene (I) i henhold til oppfinnelsen, er mer utførlig omtalt i det følgende..
Prosess 1
Den ønskede forbindelse (I) eller et salt derav, kan fremstilles ved å omsette forbindelse (II) eller et reaktivt derivat ved karboksygruppen, eller et salt derav, med forbindelse (III) eller et reaktivt derivat ved aminogruppen, eller et_salt derav.
Egnede salter av forbindelsene (II) og (III) er slike som er angitt for forbindelse (I).
Passende reaktive derivater ved karboksygruppen av forbindelse (II) kan være et syrehalogenid, et syreanhydrid, et aktivert amid, en aktivert ester og lignende. Passende eksempler på reaktive derivater kan være et syreklorid; et syreazid, et blandet syreanhydrid med en syre, så som substituert fosforsyre [f.eks. dialkylfosforsyre, fenylfosfor-syre, difenylfosforsyre, dibenzylfosforsyre, halogenert fosforsyre, etc], dialkylfosfonsyre, svovelsyrling, tiosvovelsyre, svovelsyre, sulfonsyre [f.eks. metansulfon-syre ] , alifatiske karboksylsyrer [f.eks. eddiksyre, propionsyre, smørsyre, isosmørsyre, pivalinsyre, pentansyre, isopentansyre, 2-etylsmørsyre, trikloreddiksyre] eller en aromatisk karboksylsyre [f.eks. benzosyre]; et symmetrisk syreanhydrid; et aktivert amid med imidazol, 4-substituert imidazol, dimetylpyrazol, triazol, tetrazol eller 1-hydroksy-lH-benzotriazol; eller en aktivert ester [f.eks. cyanometyl-ester, metoksymetylester, dimetyliminometyl [ ( CB.^) ^ N=CE-]-ester, vinylester, propargylester, p-nitrofenylester, 2,4-dinitrofenylester, triklorfenylester, pentaklorfenylester, mesylfenylester, fenylazofenylester, fenyltioester, p-nitro-fenyltioester, p-kresyltioester, karboksymetyltioester, pyranylester, pyridylester, piperidylester, 8-kinolyltioester] eller en ester med en N-hydroksyforbindelse [f.eks. N,N-dimetylhydroksylamin, l-hydroksy-2-(1H)-pyridon, N-hydroksy-succinimid, N-hydroksyftalimid, 1-hydroksy-lH-benzotriazol, etc] og lignende. Disse reaktive derivatene velges ut fra typen av forbindelse (If) som de skal benyttes sammen med.
Passende reaktive derivater ved aminogruppen av forbindelse (III) innbefatter iminoforbindelser av typen Schiffske baser eller deres tautomere enaminisomerer dannet ved omsetning av forbindelse (III) med en karbonylforbindelse som f.eks. aldehyd eller keton; et silylderivat dannet ved omsetning av forbindelse (III) med en silylforbindelse, så som bis(trimetylsilyl)acetamid, mono(trimetylsilyl)acetamid, bis(trimetylsilyl)urea eller lignende; et derivat dannet ved omsetning av forbindelse (III) med fosfortriklorid eller fosgen og lignende.
Reaksjonen utføres vanligvis i et konvensjonelt opp-løsningsmiddel som vann, alkohol [f.eks. metanol, etanol], aceton, dioksan, acetonitril, kloroform, metylenklorid, etylenklorid, tetrahydrofuran, etylacetat, N,N-dimetyl-formamid, pyridin eller et annet organisk oppløsningsmiddel som ikke ugunstig påvirker omsetningen. Disse konvensjonelle oppløsningsmidlene kan også benyttes i blanding med vann.
Når forbindelsene (II) benyttes i fri syreform eller som salt, foretas reaksjonen fortrinnsvis i nærvær av et konvensjonelt kondensasjonsmiddel, så som N,N-dicykloheksylkarbodiimid eller lignende.
Reaksjonen kan også foretas i nærvær av en uorganisk eller organisk base, så som et alkalimetallkarbonat, alkali-metallbikarbonat, tri(lavere)alkylamin (f.eks. trietylamin), pyridin, N(lavere)alkylmorfolin, N,N-di(lavere)alkylbenzylamin eller lignende.
Reaksjonstemperaturen er ikke av avgjørende betydning og reaksjonen kan foretas under avkjøling eller under oppvarming.
Prosess 2
Den ønskede forbindelse (Ib) eller et salt derav, kan fremstilles ved å fjerne den karboksy-beskyttende gruppe fra en forbindelse med formel (Ia) eller et salt derav.
Egnede salter av forbindelse (Ia) er slike syreaddisjons-salter som er eksemplifisert for forbindelse (I).
Egnede salter av forbindelse (Ib) er slike som er eksemplifisert for forbindelse (I).
Denne omsetning foretas etter konvensjonelle metoder, så som hydrolyse eller lignende.
Hydrolysen utføres fortrinnsvis i nærvær av en base eller en syre, inkludert Lewis-syrer. En passende base kan være en uorganisk eller organisk base, så som et alkalimetall [f.eks. natrium, kalium, etc], et jordalkalimetall [f.eks. magnesium, kalsium, etc], hydroksydet eller karbonatet eller bi-karbonate^fe derav, trialkylamin [f.eks. trimetylamin, trietylamin, etc], pikolin, 1, 5-diazabicyklo [4 . 3 . 0] non-5-en, 1,4-diazabicyklo[2.2.2]oktan, 1,8-diazabicyklo[5.4.0]undek-7-en, eller lignende.
En passende syre kan være en organisk syre [f.eks. maur-syre, eddiksyre, propionsyre, trikloreddiksyre, trifluoreddiksyre] eller en uorganisk syre [f.eks. saltsyre, hydrogen-bromidsyre, svovelsyre, hydrogenklorid, hydrogenbromid].
Fjerning ved bruk av en Lewis-syre, så som trihalogen-eddiksyre [f.eks. trikloreddiksyre, trifluoreddiksyre, etc] eller lignende, utføres fortrinnsvis i nærvær av midler som oppfanger kationer [f.eks. anisol eller fenol].
Reaksjonen utføres vanligvis i et oppløsningsmiddel, så som vann, en alkohol [f.eks. metanol, etanol, etc], metylenklorid, tetrahydrofuran, en blanding derav eller et hvilket som helst annet oppløsningsmiddel som ikke ugunstig påvirker reaksjonen. En flytende base eller syre kan også benyttes som oppløsningsmiddel.
Reaksjonstemperaturen er ikke av avgjørende betydning, og omsetningen kan utføres under avkjøling eller under oppvarming.
Prosess 3
Den ønskede forbindelse (Ic) eller et salt derav, kan fremstilles ved oksydasjon av (IV) eller et salt derav.
Oksydasjonen kan foretas ved å omsette forbindelse (IV) eller et salt derav, med et oksydasjonsmiddel som vanligvis benyttes for oksydasjon av hydroksygruppen.
Passende eksempler på slike oksydasjonsmidler kan være kromsyre, Jones' reagens, mangandioksyd, dimetylsulfoksyd aktivert med dicykloheksylkarbodiimid, syreanhydrid (f.eks. eddiksyreanhydrid, etc.) eller syrehalogenid (f.eks. acetyl-klorid, oksalyldiklorid, etc); eller lignende.
Reaksjonen utføres vanligvis i et passende oppløsnings-middel, så som aceton, kloroform, metylenklorid, pyridin eller et annet oppløsningsmiddel som ikke ugunstig påvirker omsetningen. Oppløsningsmidlet velges med henblikk på de aktuelle -reaksjonsbetingelser.
Reaksjonstemperaturen er ikke av avgjørende betydning, og omsetningen kan utføres under avkjøling, ved romtemperatur eller under oppvarming.
Prosess 4
Den ønskede forbindelse (Id) eller et salt derav, kan fremstilles ved at forbindelsen (Ib) eller et reaktivt derivat ved karboksygruppen, eller et salt derav, underkastes en amideringsreaksj on.
Denne amideringsreaksjonen kan foretas ved å omsette forbindelse (Ib) eller et reaktivt derivat ved karboksygruppen, eller et salt derav, med den aminforbindelse som ønskes innført eller et reaktivt derivat ved aminogruppen, eller et salt derav.
Passende eksempler på slike aminforbindelser har formelen:
[hvor er amino, N-lavere alkylamino, N-høyere alkylamino, N,N-di(lavere)alkylamino eller N-lavere alkyl-N-ar(lavere)-alkylamino], eller lignende.
Reaksjonsbetingelsene for denne prosess (f.eks. salt, reaktivt derivat, oppløsningsmiddel, reaksjonstemperatur, etc.) tilsvarer de som er angitt under Prosess 1.
Forbindelsen (I) i henhold til oppfinnelsen er en adenosinantagonist og har de forskjellige tidligere angitte farmasøytiske virkninger.
For å vise forbindelsens anvendelighet, er resultatet av farmakologiske undersøkelser av en representativ forbindelse ifølge oppfinnelsen, vist i det følgende.
Test 1. Diuretisk aktivitet
[I] Testmetode
Hannrotter av JCL:SD-stamme med en alder på 9 uker og en vekt på 1-70-220 g ble benyttet etter at de var fastet i 18 timer. Umiddelbart etter peroral administrasjon av testforbindelse suspendert i 0,5% metylcellulose (0,5% MC) ble dyrene peroralt gitt 20 ml/kg fysiologisk saltvann. Rottene ble anbragt i grupper på 3 i metaboliseringsbur. Urinen ble oppsamlet i 6 timer og urinvolumet målt med en målesylinder.
[II] Testforbindelse
(2R)-1-[3-(2-fenylpyrazolo [1,5-a]pyridin-3-yl)akryloyl]-2-(karboksymetyl)piperidin (trans-isomer)
[III] Testresultat
Utskilt urin (kontroll = 100)
De farmasøytiske forbindelsene i henhold til oppfinnelsen, kan benyttes i form av et farmasøytisk preparat, f.eks. i fast, halvfast eller flytende form, som inneholder pyrazolopyridin (I) eller et farmasøytisk akseptabelt salt derav, som virkestoff, i blanding med et organisk eller uorganisk bære- eller hjelpestoff egnet for rektal, pulmonal (nasal eller buccal inhalasjon), nasal, okulær, ekstern (lokal), oral eller parenteral (innbefattet subkutan, intravenøs og intramuskulær) administrasjon eller innblåsning. Virkestoffet kan tilberedes for eksempel med de vanlige ugiftige, farmasøytisk akseptable bæremidler for tabletter, pellets, pastiller, kapsler, suppositorier, kremer, salver, aerosoler, pulvere for innblåsning, oppløsninger, emulsjoner, suspensjoner og andre egnede former. Om nødvendig kan det ytterligere benyttes stabiliserende midler, fortykningsmidler og farvestoffer og parfymer. Pyrazolopyridin-forbindelsen (I) eller et farmasøytisk akseptabelt salt derav, inngår herunder i de farmasøytiske preparater i en mengde som er tilstrekkelig til å frembringe den ønskede farmasøytiske effekt.
Ved.administrasjon av preparatet til mennesker eller dyr foretrekkes intravenøs, intramuskulær, pulmonal eller peroral administrasjon eller innblåsning. Doseringen av den terapeutisk effektive mengde av pyrazolopyridin-forbindelsen (I) varierer og avhenger av pasientens alder og tilstand. Ved intravenøs administrasjon vil det i alminnelighet blir gitt en døgndose på 0,01-100 mg av pyrazolopyridin-forbindelsen (I) per kg legemsvekt, og ved intramuskulær administrasjon en døgndose på 0,1-100 mg av pyrazolopyridin-forbindelsen (I) per kg legemsvekt og ved peroral administrasjon en døgndose på 0,5-100 mg pyrazolopyridin-forbindelse (I) per kg legemsvekt.
De etterfølgende eksempler er angitt som ytterligere illustrasjon av foreliggende oppfinnelse.
Eksempel 1
Tienylklorid (14 5 mg) ble dråpevis tilsatt til en omrørt blanding av 3-(2-fenylpyrazolo[1, 5-a]pyridin-3-yl)akrylsyre (trans-isomer) (270 mg) og N,N-dimetylformamid (1 dråpe) i metylenklorid (1,5 ml) under isavkjøling. Etter omrøring ved romtemperatur i 2 timer og 50 minutter, ble oppløsningsmidlet fordampet i vakuum for å gi syreklorid-derivatet. Syrekloridet ble porsjonsvis tilsatt til en omrørt blanding av (R)-2-(metoksykarbonylmetyl)-piperidin-hydroklorid (237 mg) og trietylamin (340 /il) i metylenklorid (1,5 ml) ved -10°C.
Reaksjonsblandingen ble omrørt ved romtemperatur over natten og deretter helt over i isvann (10 ml). Blandingen ble ekstrahert med metylenklorid (20 ml x 2). De kombinerte ekstraktene ble vasket med 0,1N HCl (10 ml), 10% vandig K2C03 (10 ml) og saltvann (10 ml), tørket over natriumsulfat og inndampet i vakuum for å gi et råmateriale som ble renset ved kolonnekromatografi på silikagel (10 g) med en blanding av etylacetat og metylenklorid (1:10) som eluent for å gi (2R)-1-[3-(2-fenylpyrazolo[1,5-a]pyridin-3-yl)akryloyl]-2-(metoksy-karbonylmetyl)piperidin (trans-isomer) (330 mg) som en olje.
[a]D<19> = +65,11° (Ol, 8, MeOH)
IR (film): 1730, 1635, 1590, 1515 crrf<1>
NMR (CDC13, 6): 1,33-1,77 (7H, m), 2,61 (1H, dd, J=14,7 og 7-,1-Hz), 2,76 (1H, bred s) , 3,66 (3H, s) , 4,76 (1H, bred s), 6,90 (1H, td, J=6,9 og 1,2Hz), 7,35 (1H, t, J=7,4Hz), 7,43-7,55 (3H, m), 7,72 (1H, dd, J=7,7 og 1,7Hz), 7,95 (1H, d, J=15,5Hz), 8,53 (1H, d, J=6,9Hz) MS: m/e 403 (M<+>)
Eksempel 2
(2RS)-1-[3-(2-fenylpyrazolo[1,5-a]pyridin-3-yl)-akryloyl]-2-(metoksykarbonylmetyl)piperidin (trans-isomer) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 1.
IR (film): 1730, 1635, 1590, 1510 cm<-1>
NMR spekteret var det samme som for forbindelsen i Eksempel 1.
Eksempel 3
En blanding av (2R)-1-[3-(2-fenylpyrazolo[1,5-a]-pyridin-3-yl)akryloyl]-2-(metoksykarbonylmetyl)piperidin (trans-isomer) (210 mg) og IN natriumhydroksyd-oppløsning (0,573 ml) 1 metanol (2,0 ml) ble kokt under tilbakeløpskjøling i 2 timer. Metanolen ble fordampet i vakuum og residuet tilsatt vann (2 0 ml). Oppløsningen ble surgjort med IN saltsyre og ekstrahert med metylenklorid (10 ml x 2). De kombinerte ekstraktene ble vasket med saltvann (10 ml), tørket over natriumsulfat og inndampet i vakuum. Råkrystallene ble om-krystallisert fra en blanding av etylacetat og dietyleter for å gi farveløse krystaller av (2R)-1-[3-(2-fenylpyrazolo[1,5-a]-pyridin-3-yl)akryloyl]-2-(karboksymetyl)piperidin (trans-isomer) (152,7 mg).
Smp.: 165-166°C
[a]D<18>=+72,75° (C=l,09, MeOH)
IR (Nujol): 1715, 1625, 1570, 1510 cm"<1>
NMR (CDC13, 6): 1,36-1,82 (7H, m) , 2,57 (1H, dd, J=15,l og 6,4Hz), 2,67-3,25 (2H, m) , 4,69 (1H, bred s) , 6,40-7,34 (2H, m), 7,37-7,51 (4H, m), 7,65-7,77 (3H, m), 7,89 (1H, d, J=15,5Hz), 8,44 (1H, bred s), 10,40 (1H, bred s) Analyse beregnet for <C>23H23<N>303: C, 70,93, H, 5,95, N, 10,79
Funnet: C, 70,81, H, 5,97, N, 10,66
Eksempel 4
(2RS)-1-[3-(2-fenylpyrazolo[1,5-a]pyridin-3-yl)-akryloyl]-2-(karboksymetyl)piperidin (trans-isomer) ble oppnådd på lignende måte som i Eksempel 3.
Smp.: 132-134°C
IR (Nujol): 1705, 1625, 1560, 1505 cm"<1>
NMR-spekteret var et samme som for forbindelsen i Eksempel 3.
Eksempel 5
En.oppløsning av dimetylsulfoksyd (202 mg) i metylenklorid (1,0 ml) ble dråpevis tilsatt til en oppløsning av oksalyldiklorid (247 mg) i metylenklorid (10 ml) i løpet av 5 minutter ved -78°C. Etter 10 minutter, ble en oppløsning av (2R)-1-[3-(2-fenylpyrazolo[1,5-a]pyridin-3-yl)akryloyl] -2- (2-hydroksyetyl)piperidin (trans-isomer) (364 mg) i metylenklorid (3,4 mg) tilsatt dråpevis ved -78°C i løpet av 10 minutter. Oppløsningen ble omrørt ved -78°C i 20 minutter og ved -45°C i 1 time. Trietylamin (986 jil) ble tilsatt og blandingen omrørt ved -20° ~ 0°C i 20 minutter. Mettet ammoniumklorid-oppløsning (20 ml) ble tilsatt og reaksjonsblandingen ekstrahert med metylenklorid (10 ml x 2). De kombinerte ekstraktene ble vasket med saltvann (10 ml), tørket over magnesiumsulfat og inndampet i vakuum. Råmaterialet ble renset ved kolonnekromatografi på silikagel (10 g) med en blanding av metylenklorid og etylacetat (10:1) som eluent for å gi (2R)-1-[3-(2-fenylpyrazolo[1,5-a] pyridin-3-yl)akryloyl]-2-formylmetyl)-piperidin (trans-isomer) (139,0 mg) som en olje.
[a]D<17> = +35,41° (C=l,44, MeOH)
IR (film): 1720, 1640, 1590, 1520 cm"<1>
NMR (CDCl3, 6): 1,05-2,10 (8H, m), 2,22-3,12 (3H, m), 6,50-6,93 (2H, m) , 7,05-7,54 (4H, m) , 7,67-7,81 (3H, m) , 7,93. (1H, d, J=15,4Hz), 8,45-8,53 (1H, m) , 9,68-9,75 (1H, ni)
Eksempel 6
Tionylklorid (0,2 ml) ble dråpevis tilsatt til en opp-løsning av metylenklorid (tørr, 40 ml) og N,N-dimetylformamid (0,2 ml) ved 0°C og omrørt i 3 0 minutter. Til denne avkjølte oppløsningen ble det tilsatt (2R)-1-[3-(2-fenylpyrazolo [1,5-a]pyridin-3-yl)akryloyl]-2-(karboksymetyl)piperidin (trans-isomer) (1,0 g) og blandingen omrørt i 1,5 timer. Til denne oppløsningen ble det tilsatt en oppløsning av 28% vandig ammoniakk (20 ml), hvorpå omrøringen ble fortsatt i ytterligere 2 timer. De vandige og organiske faser ble separert og det organiske lag inndampet. Det oljeaktige residuum ble underkastet kolonnekromatografi (silikagel, 60 mesh) ved bruk av etylacetat som eluent. Fordampning av oppløsningsmidlet førte til (2R)-1-[3-(2-fenylpyrazolo[1,5-a]pyridin-3-yl)akryloyl]-2-(karbamoylmetyl)piperidin (trans-isomer)
(405 mg) som et hvitt granulært faststoff.
Smp.: 195-197°C
IR (Nujol): 3440, 3160, 1675, 1645 cm"<1>
NMR (CDC13, 6): 1,6-1,7 (7H, m), 2,47 (1H, dd, J=5,l og J=15,9Hz), 2,7 (1H, bred d), 3,15 (0,25H, bred t), 3,75 (0,3H, bred s), 5,31 (1H, bred d), 6,69 (0,5H, d, J=15,43Hz), 6,92 (1H, t, J=5,63Hz), 7,5 (5H, m), 7,68 (2H, dd, J=l,87 og J=7,6Hz), 7,94 (1H, d, J=15,43Hz), 8,53 (1H, d, J=6,9Hz)
MS: m/e 388 (M<+>), 329, 247, 219, 218, 217, 141
Analyse beregnet for C23H24N4°2 388'468
C, 71,1, H, 6,2, N, 14,4
Funnet: C, 70,6, H, 6,4, N, 14,3
De følgende forbindelser (Eksempel 7 og 8) ble oppnådd på lignende måte som beskrevet i Eksempel 6.
Eksempel 7
(2R)-1-[3-(2-fenylpyrazolo[1,5-a]pyridin-3-yl)-akryloyl]-2-(N-etylkarbamoylmetyl)piperidin (trans-isomer)
Smp.: 142-143°C
IR (Nujol): 3500, 3450, 3300, 1655, 1640 cm"<1>
NMR (CDC13, 5): 1,09 (3H, t, J=7,27Hz), 1,5 (1H, bred s), 1,64 (1H, s), 1,7 (6H, m), 2,45 (1H, dd, J=5,0 og J=15,17Hz), 2,75 (0,6H, breds), 3,25 (2H, m), 4,76 (0,25H, bredd), 5,15 (0,25H, bredd), 6,66 (0,3H, d, J=15,3Hz), 6,91 (1H, t, J=6,25Hz), 7,28-7,68 (8H, m), 7,8 (1H, d, J=15,30Hz), 8,52 (1H, d, J=6,91Hz)
MS: m/e 416 (M<+>), 329, 245, 219, 169
Analyse beregnet for <CocH>„<o>N.0o x l/2H„0
C, 70,56, H, 6,87, N, 13,16
Funnet: C, 70,23 H, 6,99, N, 13,03
Eksempel 8
(2R)-1-[3-(2-fenylpyrazolo[1,5-a]pyridin-3-yl)-akryloyl]-2-(N,N-dietylkarbamoylmetyl)piperidin (trans-isomer)
IR (CHC13): 3700, 3500, 1643, 1600 cm"<1>
NMR (CDC13, 6): 1,08 (3H, t, J=7,lHz), 1,18 (3H, t, J=7,lHz), 1,72 (7H, m), 2,6 (2H, m), 3,33 (4H, m), 5,10 (1H, bred s), 6,90 (1H, t, J=5,58Hz), 7,46 (4H, m), 7,69 (2H, dd, J=6,23 og 7,7Hz), 7,91 (1H, d, J=15,3Hz), 8,2 (0,25H, bred s), 8,52 (1H, d, J=6,92Hz)
MS: m/e 444 (M<+>), 325, 247, 219, 197
Eksempel 9
En oppløsning av (2R)-1-[3-(2-fenylpyrazolo[1,5-a]-pyridin-3-yl)akryloyl]-2-(karboksymetyl)piperidin (trans-isomer) (5,73 g) i metanol (287 ml) ble solbelyst i 32 timer. De gule krystallene ble fraskilt ved filtrering, vasket med metanol -og tørket under vakuum for å gi 4,97 g av cis-isomeren. En suspensjon av denne cis-isomer (4,88 g) i metanol (350 ml) ble oppvarmet til kokepunktet og avkjølt til romtemperatur. Bunnfallet ble oppsamlet ved filtrering, vasket med metanol og tørket under vakuum for å gi gule prismer av
(2R)-1- [3-(2-fenylpyrazolo[1,5-a]pyridin-3-yl)akryloyl]-2-(karboksymetyl)piperidin (cis-isomer) (4,20 g).
Smp.: 195-196°C
IR (Nujol): 1715, 1625, 1570, 1525 cm"<1>
NMR (DMSO-d^6, 5): 0,40-1,60 (6H, m), 2,07 (0,5H, dd, J=15,l og J=5,lHz), 2,90 (0,5H, t, J=12,5Hz), 3,34 (1H, bred s), 3,74 (0,5H, bred d, J=13,3Hz), 4,23 (0,5H, bred d, J=13,3Hz), 4,42-4,59 (0,5H, m), 4,70-4,90 (0,5H, m), 6,20 (0,5H, d, J=12,0Hz), 6,22 (0,5H, d, H=12,0Hz), 6,75 (0,5Hz, d, J=12,0Hz), 6,81 (0,5H, d, J=12,0Hz), 6,97 (1H, t,-J=6,6Hz), 7,31 (1H, t, J=7,9Hz), 7,41-7,55 (4H, m), 7,76-7,79 (2H, m), 8,74 (1H, d, J=6,9Hz), 12,29 (1H, bred s)
Analyse beregnet for C23H23<N>3C>3:
C, 70,93, H, 5,95, N, 10,79 Funnet: C, 70,74, H, 6,05, N, 10,76
De følgende forbindelser (Eksempel 10 til 16) ble frem-stillet på lignende måte som beskrevet i Eksempel 1.
Eksempel 10
(2R)-1- [3-(2-fenylpyrazolo[1,5-a] pyridin-3-yl)-akryloyl]-2-(karboksymetyl)piperidin (trans-isomer)
Smp.: 165-166°C
[a]D<18> = +72,75° (C=l,09, MeOH)
IR (Nujol): 1715, 1625, 1570, 1510 cm"<1>
Eksempel 11
(2RS)-1-[3-(2-fenylpyrazolo[1,5-a]pyridin-3-yl)-akryloyl]-2-(karboksymetyl)piperidin (trans-isomer)
Smp.: 132-134°C
IR (Nujol): 1705, 1625, 1560, 1505 cm"<1>
Eksempel 12
(2R)-1-[3-(2-fenylpyrazolo[1,5-a]pyridin-3-yl)-akryloyl]-2-(formylmetyl)piperidin (trans-isomer)
[a]D<17> = +35,41° (C=l,44, MeOH)
IR (film): 1720, 1640, 1590, 1520 cm"<1>
Eksempel 13
(2R)-1- [3-(2-fenylpyrazolo[1,5-a]pyridin-3-yl)-akryloyl]-2-(karbamoylmetyl)piperidin (trans-isomer)
Smp.: 195-197°C
IR.(Nujol): 3440, 3160, 1675, 1645 cm"<1>
Eksempel 14
(2R)-1-[3-(2-fenylpyrazolo[1,5-a]pyridin-3-yl)-akryloyl]-2-(N-etylkarbamoylmetyl)piperidin (trans-isomer)
Smp.: 142-143°C
IR (Nujol): 3500, 3450, 3300, 1655, 1640 cm"<1>
Eksempel 15
(2R)-1-[3-(2-fenylpyrazolo[1,5-a]pyridin-3-yl)-akryloyl]-2-(N,N-dietylkarbamoylmetyl)piperidin (trans-isomer)
IR (CHC13): 3700, 3500, 1643, 1600 cm"<1>
Eksempel 16
(2R)-1-[3-(2-fenylpyrazolo[1,5-a]pyridin-3-yl)-akryloyl]-2-(karboksymetyl)piperidin (cis-isomer)
Smp.: 195-196°C
IR (Nujol): 1715, 1625, 1570, 1525 cm"<1>
Claims (7)
1. Pyrazolopyridin-forbindelse, karakterisert ved at den har formelen
hvor R er fenyl,
R 2er formyl(lavere)alkyl,
karboksy(lavere)alkyl,
lavere alkoksykarbonyl(lavere)alkyl, karbamoyl(lavere)alkyl, N-lavere-alkylkarbamoyl(lavere)alkyl eller N,N-di(lavere)alkylkarbamoyl(lavere)alkyl, og
A er lavere alkenylen,
og et farmasøytisk akseptabelt salt derav.
2. Forbindelse ifølge krav 1, karakterisert ved at
R 2 er karboksy(lavere)alkyl.
3. Forbindelse ifølge krav 2, karakterisert ved at den er
1-[3-(2-fenylpyrazolo[1,5-a]pyridin-3-yl)akryloyl]-2-(karboksymetyl)piperidin.
4. Forbindelse ifølge krav 3, karakterisert ved at den er
(2R)-1-[3-(2-fenylpyrazolo[1,5-a]pyridin-3-yl)akryloyl]-2-(karboksymetyl)piperidin (trans-isomer).
5. Farmasøytisk preparat
karakterisert ved at virkestoffet utgjøres av en forbindelse ifølge krav 1, eller et farmasøytisk akseptabelt salt derav, i blanding med farmasøytisk akseptable bære- eller hjelpestoffer.
6. Forbindelse til bruk som medikament, karakterisert ved at den har den i krav 1 angitte formel.
7. Anvendelse av en forbindelse ifølge krav 1, eller et farmasøytisk akseptabelt salt derav, for fremstilling av et medikament for behandling av melankoli, hjertesvikt, hypertensjon, nyreinsuffisiens, nyreforgiftning, nefrose, nefritt, ødem, fedme, bronkial astma, urinsyregikt, hyperurikemi, SIDS (sudden infant death syndrome), immunsuppresjon, diabetes, myokardinfarkt, trombose, obstruksjon, arteriosclerosis obliterans, tromboflebitt, cerebralt infarkt, transiente ischemiske attakker eller angina pectoris.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB919107513A GB9107513D0 (en) | 1991-04-10 | 1991-04-10 | Pyrazolopyridine compound and processes for preparation thereof |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO921413D0 NO921413D0 (no) | 1992-04-09 |
| NO921413L NO921413L (no) | 1992-10-12 |
| NO300271B1 true NO300271B1 (no) | 1997-05-05 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| NO19921413A NO300271B1 (no) | 1991-04-10 | 1992-04-09 | Pyrazolopyridin-forbindelser og farmasoytiske preparater inneholdende disse |
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| Country | Link |
|---|---|
| US (1) | US5234930A (no) |
| EP (1) | EP0516941B1 (no) |
| JP (2) | JP2546470B2 (no) |
| KR (1) | KR100248700B1 (no) |
| CN (2) | CN1041203C (no) |
| AT (1) | ATE146473T1 (no) |
| AU (1) | AU653007B2 (no) |
| CA (1) | CA2065644C (no) |
| DE (1) | DE69215965T2 (no) |
| DK (1) | DK0516941T3 (no) |
| ES (1) | ES2095976T3 (no) |
| FI (1) | FI100969B (no) |
| GB (1) | GB9107513D0 (no) |
| GR (1) | GR3022113T3 (no) |
| HU (2) | HU214871B (no) |
| IE (1) | IE921086A1 (no) |
| IL (1) | IL101544A (no) |
| MX (1) | MX9201672A (no) |
| NO (1) | NO300271B1 (no) |
| RU (1) | RU2069662C1 (no) |
| SG (1) | SG43917A1 (no) |
| TW (1) | TW205550B (no) |
| UA (1) | UA27252C2 (no) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5541213A (en) * | 1993-06-24 | 1996-07-30 | Eisai Co., Ltd. | Propenoic acid derivatives diazole propenoic acid compounds which have useful pharmaceutical utility |
| AU694157B2 (en) * | 1993-12-29 | 1998-07-16 | Fujisawa Pharmaceutical Co., Ltd. | Pyrazolopyridine adenosine antagonists |
| AU2405697A (en) * | 1996-04-25 | 1997-11-12 | Fujisawa Pharmaceutical Co., Ltd. | Preventives and remedies for ischemic intestinal lesion and ileus |
| AUPO111096A0 (en) * | 1996-07-18 | 1996-08-08 | Fujisawa Pharmaceutical Co., Ltd. | New compound |
| US6303624B1 (en) | 1997-03-18 | 2001-10-16 | Fujisawa Pharmaceutical Co., Ltd. | Preventives and remedies for hyperphosphatemia |
| CA2333947C (en) * | 1998-06-01 | 2010-09-21 | Fujisawa Pharmaceutical Co., Ltd. | Pyrazolopyridine compounds as adenosine a1 antagonist for male sterility |
| US20040152659A1 (en) * | 1999-05-12 | 2004-08-05 | Fujisawa Pharmaceutical Co. Ltd. | Method for the treatment of parkinson's disease comprising administering an A1A2a receptor dual antagonist |
| PE20020506A1 (es) * | 2000-08-22 | 2002-07-09 | Glaxo Group Ltd | Derivados de pirazol fusionados como inhibidores de la proteina cinasa |
| US6919352B2 (en) | 2000-12-15 | 2005-07-19 | Smithkline Beecham Corporation | Pyrazolopyridinyl pyridine and pyrimidine therapeutic compounds |
| ES2243579T3 (es) * | 2000-12-15 | 2005-12-01 | Glaxo Group Ltd | Derivados de pirazolopirideno. |
| DE60201074T2 (de) * | 2001-03-08 | 2005-09-15 | Smithkline Beecham Corp. | Pyrazolopyridinderivate |
| EP1372642A1 (en) * | 2001-03-30 | 2004-01-02 | SmithKline Beecham Corporation | Use of pyrazolopyridines as therapeutic compounds |
| JP4237497B2 (ja) | 2001-03-30 | 2009-03-11 | スミスクライン ビーチャム コーポレーション | ピラゾロピリジン類、その調製方法及びその治療用化合物としての使用 |
| WO2002083672A1 (en) | 2001-04-10 | 2002-10-24 | Smithkline Beecham Corporation | Antiviral pyrazolopyridine compounds |
| WO2002088124A2 (en) * | 2001-04-27 | 2002-11-07 | Smithkline Beecham Corporation | Pyrazolo'1,5-a!pyridine derivatives |
| AUPR548601A0 (en) * | 2001-06-06 | 2001-06-28 | Fujisawa Pharmaceutical Co., Ltd. | Pyrazolopyrazinecompound and pharmaceutical use thereof |
| HUP0400266A2 (hu) * | 2001-06-21 | 2004-08-30 | Smithkline Beecham Corp. | Imidazo[1,2-a]piridin-származékok, ezeket tartalmazó gyógyszerkészítmények és alkalmazásuk herpeszvírus-fertőzések megelőzésére vagy kezelésére |
| JP2005507878A (ja) * | 2001-09-07 | 2005-03-24 | スミスクライン ビーチャム コーポレーション | ヘルペス感染症を治療するためのピラゾロ−ピリジン類 |
| WO2003031446A1 (en) * | 2001-10-05 | 2003-04-17 | Smithkline Beecham Corporation | Imidazo-pyridine derivatives for use in the treatment of herpes viral infection |
| DE60222465T2 (de) * | 2001-12-11 | 2008-06-05 | Smithkline Beecham Corp. | Pyrazolopyridin-derivate als antiherpesmittel |
| EP1546148A1 (en) * | 2002-10-03 | 2005-06-29 | SmithKline Beecham Corporation | Therapeutic compounds based on pyrazolopyridine derivatives |
| RU2008152776A (ru) * | 2006-06-06 | 2010-07-20 | Эвиджен Инк. (Us) | СОЕДИНЕНИЯ ЗАМЕЩЕННОГО ПИРАЗОЛО[1,5-a]ПИРИДИНА И СПОСОБЫ ИХ ПРИМЕНЕНИЯ |
| US9572528B1 (en) | 2012-08-06 | 2017-02-21 | Los Angeles Biomedical Research Insitute at Harbor-UCLA Medical Center | Monitor for SIDS research and prevention |
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| US4925849A (en) * | 1987-06-15 | 1990-05-15 | Fujisawa Pharmaceutical Company, Ltd. | Pharmaceutically useful pyrazolopyridines |
| GB8901423D0 (en) * | 1989-01-23 | 1989-03-15 | Fujisawa Pharmaceutical Co | Pyrazolopyridine compound and processes for preparation thereof |
-
1991
- 1991-04-10 GB GB919107513A patent/GB9107513D0/en active Pending
-
1992
- 1992-04-02 AU AU13988/92A patent/AU653007B2/en not_active Expired
- 1992-04-02 TW TW081102547A patent/TW205550B/zh active
- 1992-04-03 IE IE108692A patent/IE921086A1/en not_active IP Right Cessation
- 1992-04-07 FI FI921522A patent/FI100969B/fi not_active IP Right Cessation
- 1992-04-08 SG SG1996005302A patent/SG43917A1/en unknown
- 1992-04-08 DE DE69215965T patent/DE69215965T2/de not_active Expired - Lifetime
- 1992-04-08 DK DK92106028.1T patent/DK0516941T3/da active
- 1992-04-08 AT AT92106028T patent/ATE146473T1/de active
- 1992-04-08 EP EP92106028A patent/EP0516941B1/en not_active Expired - Lifetime
- 1992-04-08 ES ES92106028T patent/ES2095976T3/es not_active Expired - Lifetime
- 1992-04-09 NO NO19921413A patent/NO300271B1/no not_active IP Right Cessation
- 1992-04-09 JP JP4088735A patent/JP2546470B2/ja not_active Expired - Lifetime
- 1992-04-09 CA CA002065644A patent/CA2065644C/en not_active Expired - Lifetime
- 1992-04-09 CN CN92103372A patent/CN1041203C/zh not_active Expired - Lifetime
- 1992-04-09 RU SU5011507/04A patent/RU2069662C1/ru active
- 1992-04-09 IL IL10154492A patent/IL101544A/en not_active IP Right Cessation
- 1992-04-09 US US07/866,215 patent/US5234930A/en not_active Expired - Lifetime
- 1992-04-09 HU HU9201213A patent/HU214871B/hu unknown
- 1992-04-09 CN CNB971253781A patent/CN100508975C/zh not_active Expired - Lifetime
- 1992-04-09 KR KR1019920005893A patent/KR100248700B1/ko not_active IP Right Cessation
- 1992-04-10 MX MX9201672A patent/MX9201672A/es unknown
-
1993
- 1993-06-18 UA UA93002532A patent/UA27252C2/uk unknown
-
1995
- 1995-06-22 HU HU95P/P00354P patent/HU211680A9/hu unknown
- 1995-11-16 JP JP7298193A patent/JP2903040B2/ja not_active Expired - Fee Related
-
1996
- 1996-12-19 GR GR960403475T patent/GR3022113T3/el unknown
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Representative=s name: PLOUGMANN 6 VINGTOFT POSTBOKS 1003 SENTRUM OSLO, 0 |
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| MK1K | Patent expired |