EP1357904A2 - Utilisation de pyrazolo 4,3-d]pyrimidines - Google Patents
Utilisation de pyrazolo 4,3-d]pyrimidinesInfo
- Publication number
- EP1357904A2 EP1357904A2 EP01997300A EP01997300A EP1357904A2 EP 1357904 A2 EP1357904 A2 EP 1357904A2 EP 01997300 A EP01997300 A EP 01997300A EP 01997300 A EP01997300 A EP 01997300A EP 1357904 A2 EP1357904 A2 EP 1357904A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- methyl
- pyrazolo
- pyrimidin
- propyl
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000003230 pyrimidines Chemical class 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 13
- 239000012453 solvate Substances 0.000 claims abstract description 10
- 206010019280 Heart failures Diseases 0.000 claims abstract description 6
- 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 5
- 206010007559 Cardiac failure congestive Diseases 0.000 claims abstract description 5
- 206010016654 Fibrosis Diseases 0.000 claims abstract description 5
- 206010020772 Hypertension Diseases 0.000 claims abstract description 5
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 5
- 208000018262 Peripheral vascular disease Diseases 0.000 claims abstract description 5
- 208000001647 Renal Insufficiency Diseases 0.000 claims abstract description 5
- 206010039085 Rhinitis allergic Diseases 0.000 claims abstract description 5
- 208000006011 Stroke Diseases 0.000 claims abstract description 5
- 201000009961 allergic asthma Diseases 0.000 claims abstract description 5
- 201000010105 allergic rhinitis Diseases 0.000 claims abstract description 5
- 208000006673 asthma Diseases 0.000 claims abstract description 5
- 206010006451 bronchitis Diseases 0.000 claims abstract description 5
- 208000023819 chronic asthma Diseases 0.000 claims abstract description 5
- 230000007882 cirrhosis Effects 0.000 claims abstract description 5
- 208000019425 cirrhosis of liver Diseases 0.000 claims abstract description 5
- 208000002551 irritable bowel syndrome Diseases 0.000 claims abstract description 5
- 201000006370 kidney failure Diseases 0.000 claims abstract description 5
- 208000012201 sexual and gender identity disease Diseases 0.000 claims abstract description 5
- 208000015891 sexual disease Diseases 0.000 claims abstract description 5
- 208000010412 Glaucoma Diseases 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 45
- -1 COOA Chemical group 0.000 claims description 41
- 125000004432 carbon atom Chemical group C* 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 12
- 125000002947 alkylene group Chemical group 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- 241000251730 Chondrichthyes Species 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 230000002685 pulmonary effect Effects 0.000 claims description 6
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- LIFZVJKHTQXNLW-UHFFFAOYSA-N 2-[[7-[(3-chloro-4-methoxyphenyl)methylamino]-1-methyl-3-propylpyrazolo[4,3-d]pyrimidin-5-yl]methoxy]acetic acid Chemical compound N1=C(COCC(O)=O)N=C2C(CCC)=NN(C)C2=C1NCC1=CC=C(OC)C(Cl)=C1 LIFZVJKHTQXNLW-UHFFFAOYSA-N 0.000 claims description 3
- FSROZMKGWKKLCJ-UHFFFAOYSA-N 4-[7-(1,3-benzodioxol-5-ylmethylamino)-1-methyl-3-propylpyrazolo[4,3-d]pyrimidin-5-yl]butanoic acid Chemical compound C1=C2OCOC2=CC(CNC2=C3N(C)N=C(C3=NC(CCCC(O)=O)=N2)CCC)=C1 FSROZMKGWKKLCJ-UHFFFAOYSA-N 0.000 claims description 2
- JGIJIXPDDMRERS-UHFFFAOYSA-N 5-[7-[(3-chloro-4-methoxyphenyl)methylamino]-1-methyl-3-propylpyrazolo[4,3-d]pyrimidin-5-yl]pentanoic acid Chemical compound N1=C(CCCCC(O)=O)N=C2C(CCC)=NN(C)C2=C1NCC1=CC=C(OC)C(Cl)=C1 JGIJIXPDDMRERS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- DRZWRYBYLHEFQV-UHFFFAOYSA-N 4-[7-[(3-chloro-4-methoxyphenyl)methylamino]-1-methyl-3-propylpyrazolo[4,3-d]pyrimidin-5-yl]benzoic acid Chemical compound N1=C(C=2C=CC(=CC=2)C(O)=O)N=C2C(CCC)=NN(C)C2=C1NCC1=CC=C(OC)C(Cl)=C1 DRZWRYBYLHEFQV-UHFFFAOYSA-N 0.000 claims 1
- OTFCTERWNNKKLG-UHFFFAOYSA-N 5-[7-(benzylamino)-1-methyl-3-propylpyrazolo[4,3-d]pyrimidin-5-yl]pentanoic acid Chemical compound N1=C(CCCCC(O)=O)N=C2C(CCC)=NN(C)C2=C1NCC1=CC=CC=C1 OTFCTERWNNKKLG-UHFFFAOYSA-N 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 210000004185 liver Anatomy 0.000 abstract description 3
- APXRHPDHORGIEB-UHFFFAOYSA-N 1H-pyrazolo[4,3-d]pyrimidine Chemical class N1=CN=C2C=NNC2=C1 APXRHPDHORGIEB-UHFFFAOYSA-N 0.000 abstract description 2
- 208000002815 pulmonary hypertension Diseases 0.000 abstract description 2
- 206010003210 Arteriosclerosis Diseases 0.000 abstract 1
- 206010008190 Cerebrovascular accident Diseases 0.000 abstract 1
- 208000011775 arteriosclerosis disease Diseases 0.000 abstract 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 20
- 239000002253 acid Substances 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- ZILSBZLQGRBMOR-UHFFFAOYSA-N 1,3-benzodioxol-5-ylmethanamine Chemical compound NCC1=CC=C2OCOC2=C1 ZILSBZLQGRBMOR-UHFFFAOYSA-N 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 210000000748 cardiovascular system Anatomy 0.000 description 4
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 201000001881 impotence Diseases 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 125000004809 1-methylpropylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])C([H])([H])[*:2] 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000010228 Erectile Dysfunction Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 239000012154 double-distilled water Substances 0.000 description 3
- 150000002169 ethanolamines Chemical class 0.000 description 3
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- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
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- 229940005605 valeric acid Drugs 0.000 description 3
- OCNMSDZALRAYEX-UHFFFAOYSA-N (3-chloro-4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1Cl OCNMSDZALRAYEX-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
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- APPWKPUSFVSTAH-UHFFFAOYSA-N 4-[7-(2,3-dihydro-1,4-benzodioxin-6-ylmethylamino)-1-methyl-3-propylpyrazolo[4,3-d]pyrimidin-5-yl]benzoic acid Chemical compound N1=C2C(CCC)=NN(C)C2=C(NCC=2C=C3OCCOC3=CC=2)N=C1C1=CC=C(C(O)=O)C=C1 APPWKPUSFVSTAH-UHFFFAOYSA-N 0.000 description 2
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 2
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- OHCIWDKMGBZWSS-UHFFFAOYSA-N methyl 5-[7-(1,3-benzodioxol-5-ylmethylamino)-1-methyl-3-propylpyrazolo[4,3-d]pyrimidin-5-yl]pentanoate Chemical compound C1=C2OCOC2=CC(CNC2=C3N(C)N=C(C3=NC(CCCCC(=O)OC)=N2)CCC)=C1 OHCIWDKMGBZWSS-UHFFFAOYSA-N 0.000 description 1
- JMIFCQFTLYNXAG-UHFFFAOYSA-N methyl 5-[7-[(3-chloro-4-methoxyphenyl)methylamino]-1-methyl-3-propylpyrazolo[4,3-d]pyrimidin-5-yl]pentanoate Chemical compound N1=C(CCCCC(=O)OC)N=C2C(CCC)=NN(C)C2=C1NCC1=CC=C(OC)C(Cl)=C1 JMIFCQFTLYNXAG-UHFFFAOYSA-N 0.000 description 1
- HNEYDRHVVZAVRL-UHFFFAOYSA-N methyl 7-(7-chloro-1-methyl-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)heptanoate Chemical compound N1=C(CCCCCCC(=O)OC)N=C2C(CCC)=NN(C)C2=C1Cl HNEYDRHVVZAVRL-UHFFFAOYSA-N 0.000 description 1
- ZKUIMXLHCFLFAT-UHFFFAOYSA-N methyl 7-[7-(1,3-benzodioxol-5-ylmethylamino)-1-methyl-3-propylpyrazolo[4,3-d]pyrimidin-5-yl]heptanoate Chemical compound C1=C2OCOC2=CC(CNC2=C3N(C)N=C(C3=NC(CCCCCCC(=O)OC)=N2)CCC)=C1 ZKUIMXLHCFLFAT-UHFFFAOYSA-N 0.000 description 1
- GELQPJZCUYWXMG-UHFFFAOYSA-N methyl 7-[7-[(3-chloro-4-methoxyphenyl)methylamino]-1-methyl-3-propylpyrazolo[4,3-d]pyrimidin-5-yl]heptanoate Chemical compound N1=C(CCCCCCC(=O)OC)N=C2C(CCC)=NN(C)C2=C1NCC1=CC=C(OC)C(Cl)=C1 GELQPJZCUYWXMG-UHFFFAOYSA-N 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- 229960001802 phenylephrine Drugs 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- DOTPSQVYOBAWPQ-UHFFFAOYSA-N pyrazolo[4,3-d]pyrimidin-3-one Chemical class N1=CN=C2C(=O)N=NC2=C1 DOTPSQVYOBAWPQ-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 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 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
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Definitions
- the invention relates to the use of compounds of the formula
- R 1 , R 2 each independently of one another are H, A, OH, OA or shark,
- R 1 and R 2 together also alkylene with 3-5 C atoms, -0-CH 2 -CH 2 -, -CH 2 -0-CH 2 -, -0-CH 2 -0- or -0-CH 2 -CH 2 -0-,
- R 3 , R 4 each independently of one another H or A,
- X is simply substituted by R 8, R 5 , R 6 or R 7 ,
- R ° linear or branched alkylene with 1-10 C atoms, in which one or two CH 2 groups can be replaced by -CH CH groups, O, S or SO,
- R b cycloalkyl or cycloalkylalkylene with 5-12 C atoms
- R a COOH, COOA, CONH 2 , CONHA, CON (A) 2 or CN,
- a medicament for the treatment of angina high blood pressure, pulmonary high pressure, congestive heart failure, atherosclerosis, conditions of reduced patency of the cardiovascular system, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic Asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal failure, cirrhosis of the liver and for the treatment of female sexual disorders.
- Pyrimidine derivatives are known for example from EP 201 188 or WO 93/06104.
- the use of other PDE V inhibitors is described e.g. in WO 94/28902.
- the invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments.
- the biological activity of the compounds of the formula I can be determined by methods such as are described, for example, in WO 93/06104.
- the affinity of the compounds of the invention for cGMP and cAMP phosphodiesterase is determined by measuring their IC 5 o values (concentration tion of inhibitor required to cause a 50% to achieve inhibition of the enzyme activity) determined.
- Enzymes isolated according to known methods can be used to carry out the determinations (for example WJ Thompson et al., Biochem. 1971, 10, 311).
- a modified "batch" method by WJ Thompson and MM Appleman can be used to carry out the experiments.
- the compounds are therefore suitable for the treatment of diseases of the cardiovascular system, in particular heart failure and for the treatment and / or therapy of erectile dysfunction.
- substituted pyrazolopyrimidinones for the treatment of impotence is e.g. described in WO 94/28902.
- the compounds are effective as inhibitors of phenylephrine-induced contractions in corpus cavernosum preparations from rabbits.
- This biological effect can e.g. can be detected by the method described by F. Holmquist et al. in J. Ural., 150, 1310-1315 (1993).
- the inhibition of the contraction shows the effectiveness of the compounds according to the invention for the therapy and / or treatment of erectile dysfunction.
- the invention relates to the use of the compounds of the formula I and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, congestive heart failure, atherosclerosis, conditions of reduced patency of the cardiovascular system, peripheral vascular diseases, stroke , Bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal failure, cirrhosis of the liver and for the treatment of female sexual disorders.
- the invention relates in particular to the use of the compounds of the formula I and their physiologically acceptable salts and / or solvates for the production of a medicament for the treatment of pulmonary high pressure.
- the invention preferably relates to the use of [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid and its physiologically harmless salts and / or solvates for the manufacture of a medicament for
- Pulmonary hypertension treatment In addition to the free acid, the ethanolamine salt is preferred.
- the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine. They can also be used as intermediates for the production of further active pharmaceutical ingredients.
- the invention accordingly relates to the compounds of the formula I and a process for the preparation of compounds of the formula I as well as their salts,
- R 3 , R 4 and X have the meanings given
- L denotes Cl, Br, OH, SCH 3 or a reactive esterified OH group
- R 1 and R 2 have the meanings given
- Convert rest X by e.g. hydrolyses an ester group to a COOH group or converts a COOH group into an amide or into a cyan group
- Solvates of the compounds of the formula I are understood to mean the addition of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual attraction. Solvates are e.g. Mono- or dihydrates or alcoholates.
- radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X and L have the meanings given in the formulas I, II and III, unless expressly stated otherwise specified.
- A means alkyl with 1-6 C atoms.
- alkyl is preferably unbranched and has 1, 2, 3, 4, 5 or 6 carbon atoms and is preferably methyl, ethyl or propyl, more preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl , but also n-pentyl, neopentyl, isopentyl or hexyl.
- R 5 denotes a linear or branched alkylene radical with 1-10 C atoms, the alkylene radical preferably being, for example, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, 1-, 2- or 3- Methylbutylene, 1, 1-, 1, 2- or 2,2-dimethylpropylene, 1-ethylpropylene, hexylene, 1-, 2-, 3- or 4-methylpentylene, 1, 1-, 1, 2-, 1, 3 -, 2,2-, 2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-1-methylpropylene, 1-ethyl-2-methylpropylene, 1, 1, 2- or 1, 2,2-trimethylpropylene, linear or branched heptylene, octylene, nonylene or de
- R 5 also means, for example, but-2-en-ylene or hex-3-en-ylene.
- a CH 2 group in R 5 can preferably be replaced by oxygen.
- Ethylene, propylene, butylene or CH 2 -0-CH 2 is very particularly preferred.
- R 6 denotes cycloalkylalkylene with 5-12 C atoms, preferably for example cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene.
- R 6 also means cycloalkyl, preferably having 5-7 carbon atoms.
- Cycloalkyl means, for example, cyclopentyl, cyclohexyl or cycloheptyl.
- the radicals R 1 and R 2 can be the same or different and are preferably in the 3- or 4-position of the phenyl ring. They each mean, for example, independently of one another H, alkyl, OH, F, Cl, Br or I or together alkylene, such as, for example, propylene, butylene or pentylene, furthermore ethyleneoxy, methylenedioxy or ethylenedioxy. They are also preferably each alkoxy, such as methoxy, ethoxy or propoxy.
- the radical R 8 is preferably, for example, COOH, COOA such as COOCH 3 or COOC2H5, CONH2, CON (CH 3 ) 2) CONHCH3 or CN, but in particular COOH or COOA.
- radicals which occur more than once can be the same or different, ie are independent of one another. Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
- Some preferred groups of compounds can be expressed by the following sub-formulas Ia to If, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
- R 5 phenyl or phenylmethyl substituted by COOH, COOA, CONH 2 , CONA 2 , CONHA or CN;
- R 1 and R 2 together alkylene with 3-5 C atoms, -0-CH 2 -CH 2 -,
- CN is substituted R 5 , phenyl or phenylmethyl
- R 1 , R 2 each independently of one another H, A, OH, OA or shark,
- R 1 and R 2 together also alkylene with 3-5 C atoms
- CN is substituted R 5 , phenyl or phenylmethyl
- R 1 , R 2 each independently of one another H, A, OH, OA or
- R 1 and R 2 together also alkylene with 3-5 carbon atoms, -0-CH 2 -CH 2 -, -O-CH2-O- or
- Atoms cyclohexyl, phenyl or phenylmethyl, R 3 alkyl with 1-6 C atoms, R 4 alkyl with 1-6 C atoms,
- R 8 COOH or COOA, A alkyl with 1 to 6 carbon atoms,
- R 1 , R 2 each independently of one another H, A, OH, OA or shark,
- R 1 and R 2 together also alkylene with 3-5 C atoms, -O-CH2-CH 2 -, -O-CH2-O- or -0-CH 2 -CH 2 -0-, R 3 alkyl with 1 -6 C atoms, R 4 alkyl with 1-6 C atoms,
- R 1 and R 2 together also alkylene with 3-5 C atoms
- R 3 alkyl with 1-6 C atoms
- RR 44 alkyl with 1-6 C atoms
- L is a reactive esterified OH group, this is preferably alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy, further also 2- naphthalenesulfonyloxy).
- the compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
- the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.
- the starting compounds of the formula II and III are generally known. If they are not known, they can be produced by methods known per se.
- the compounds of the formula II are reacted with the compounds of the formula III in the presence or absence of an inert solvent at temperatures between about -20 and about 150 °, preferably between 20 and 100 °.
- an acid-binding agent for example an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium or calcium, or the addition of an organic base such as triethylamine, Dimethylamine, pyridine or quinoline or an excess of the amine component may be beneficial.
- an acid-binding agent for example an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium or calcium
- an organic base such as triethylamine, Dimethylamine, pyridine or quinoline or an excess of the amine component
- Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone or
- radical X it is also possible to convert one radical X into another radical X in a compound of formula I, e.g. by hydrolyzing an ester or a cyano group to a COOH group.
- Ester groups can e.g. are saponified with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
- Carboxylic acids can e.g. with thionyl chloride in the corresponding carboxylic acid chlorides and these are converted into carboxamides. By splitting off water in a known manner, carbonitriles are obtained from these.
- An acid of the formula I can be converted with a base into the associated acid addition salt, for example by reacting equivalent amounts of the acid and the base in an inert solvent such as ethanol and then evaporating.
- Bases that provide physiologically acceptable salts are particularly suitable for this implementation.
- the acid of formula I can be converted with a base (eg sodium or potassium hydroxide or carbonate) into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salt.
- a base eg sodium or potassium hydroxide or carbonate
- Organic bases which provide physiologically acceptable salts, such as ethanolamine, are particularly suitable for this reaction.
- a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
- acids which provide physiologically harmless salts are suitable for this implementation.
- So inorganic acids can be used, e.g. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g.
- Formic acid acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane acid or ethanesulfonic acid, ethanesulfonic acid , Benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.
- Picrates can be used for the isolation and / or purification of the compounds of the formula I.
- the invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route.
- they can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and optionally in combination with one or more further active ingredients.
- the invention also relates to medicaments of the formula I and their physiologically acceptable salts as phosphodiesterase V inhibitors.
- the invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.
- Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin .
- Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions for parenteral use, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical application ointments, creams or powder.
- the new compounds can also be lyophilized and the resulting lyophilisates e.g. can be used for the production of injectables.
- the specified preparations can be sterilized and / or contain auxiliaries such as lubricants, concentrators, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, eg one or more vitamins.
- auxiliaries such as lubricants, concentrators, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, eg one or more vitamins.
- the compounds of the formula I and their physiologically acceptable salts can be used in combating diseases in which an increase in the cGMP (cyclo-guanosine monophosphate) level leads to inhibition or prevention of inflammation and muscle relaxation.
- the compounds according to the invention can be used particularly in the treatment of diseases of the cardiovascular system and for the treatment and / or therapy of erectile dysfunction.
- the substances are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit.
- the daily dosage is preferably between about 0.02 and 10 mg / kg body weight.
- the specific dose for each patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination, combination of drugs and severity the respective disease to which the therapy applies. Oral application is preferred.
- customary work-up means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, separated, dried organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.
- connection is obtained analogously 4- [7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid, glucamine salt, m.p. 114 ° and 4- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid.
- Example A Injection glasses
- a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection glass contains 5 mg of active ingredient.
- a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
- a solution of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g Na 2 HP0 4 • 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
- Example D ointment
- 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
- Example F coated tablets
- Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
- Example G capsules
- each capsule contains 20 mg of the active ingredient.
- a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Pulmonology (AREA)
- Heart & Thoracic Surgery (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Epidemiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Ophthalmology & Optometry (AREA)
- Gastroenterology & Hepatology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Immunology (AREA)
- Gynecology & Obstetrics (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10058662 | 2000-11-25 | ||
DE10058662A DE10058662A1 (de) | 2000-11-25 | 2000-11-25 | Verwendung von Pyrazolo[4,3-d]pyrimidinen |
PCT/EP2001/012493 WO2002041880A2 (fr) | 2000-11-25 | 2001-10-29 | Utilisation de pyrazolo[4,3-d]pyrimidines |
Publications (1)
Publication Number | Publication Date |
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EP1357904A2 true EP1357904A2 (fr) | 2003-11-05 |
Family
ID=7664710
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01997300A Withdrawn EP1357904A2 (fr) | 2000-11-25 | 2001-10-29 | Utilisation de pyrazolo 4,3-d]pyrimidines |
Country Status (18)
Country | Link |
---|---|
US (1) | US20040023990A1 (fr) |
EP (1) | EP1357904A2 (fr) |
JP (1) | JP2004513963A (fr) |
KR (1) | KR20030051870A (fr) |
CN (1) | CN1665508A (fr) |
AR (1) | AR035373A1 (fr) |
AU (1) | AU2002215979A1 (fr) |
BR (1) | BR0115187A (fr) |
CA (1) | CA2429645A1 (fr) |
CZ (1) | CZ20031668A3 (fr) |
DE (1) | DE10058662A1 (fr) |
HU (1) | HUP0302720A2 (fr) |
MX (1) | MXPA03004498A (fr) |
PL (1) | PL363077A1 (fr) |
RU (1) | RU2003117477A (fr) |
SK (1) | SK7592003A3 (fr) |
WO (1) | WO2002041880A2 (fr) |
ZA (1) | ZA200304908B (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8756899B2 (en) | 2009-09-04 | 2014-06-24 | Valinge Innovation Ab | Resilient floor |
US11725395B2 (en) | 2009-09-04 | 2023-08-15 | Välinge Innovation AB | Resilient floor |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19942474A1 (de) * | 1999-09-06 | 2001-03-15 | Merck Patent Gmbh | Pyrazolo[4,3-d]pyrimidine |
WO2002049651A1 (fr) * | 2000-12-19 | 2002-06-27 | Merck Patent Gmbh | Formulation pharmaceutique contenant des pyrazolo[4,3-d]pyrimidines et des antithrombotiques, des antagonistes de calcium, des prostaglandines ou des derives de prostaglandine |
RS20050810A (en) | 2003-04-29 | 2007-08-03 | Pfizer Inc., | 5,7-diaminopyrazolo(4,3-d)pyrimidines useful in the treatment of hypertension |
US7572799B2 (en) * | 2003-11-24 | 2009-08-11 | Pfizer Inc | Pyrazolo[4,3-d]pyrimidines as Phosphodiesterase Inhibitors |
GB0327323D0 (en) * | 2003-11-24 | 2003-12-31 | Pfizer Ltd | Novel pharmaceuticals |
DK1742950T3 (da) * | 2004-04-07 | 2009-03-16 | Pfizer Ltd | Pyrazolo-[4,3-D]-pyrimidiner |
WO2018064135A1 (fr) * | 2016-09-30 | 2018-04-05 | Asana Biosciences, Llc | Composés p2x3 et/ou p2x2/3 et méthodes associées |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2657760B2 (ja) * | 1992-07-15 | 1997-09-24 | 小野薬品工業株式会社 | 4−アミノキナゾリン誘導体およびそれを含有する医薬品 |
GB9423911D0 (en) * | 1994-11-26 | 1995-01-11 | Pfizer Ltd | Therapeutic agents |
US5869486A (en) * | 1995-02-24 | 1999-02-09 | Ono Pharmaceutical Co., Ltd. | Fused pyrimidines and pyriazines as pharmaceutical compounds |
DE19942474A1 (de) * | 1999-09-06 | 2001-03-15 | Merck Patent Gmbh | Pyrazolo[4,3-d]pyrimidine |
DE10031584A1 (de) * | 2000-06-29 | 2002-01-10 | Merck Patent Gmbh | 5-Aminoalkyl-pyrazolo[4,3-d]pyrimidine |
-
2000
- 2000-11-25 DE DE10058662A patent/DE10058662A1/de not_active Withdrawn
-
2001
- 2001-10-29 CA CA002429645A patent/CA2429645A1/fr not_active Abandoned
- 2001-10-29 EP EP01997300A patent/EP1357904A2/fr not_active Withdrawn
- 2001-10-29 WO PCT/EP2001/012493 patent/WO2002041880A2/fr not_active Application Discontinuation
- 2001-10-29 CZ CZ20031668A patent/CZ20031668A3/cs unknown
- 2001-10-29 PL PL01363077A patent/PL363077A1/xx unknown
- 2001-10-29 SK SK759-2003A patent/SK7592003A3/sk unknown
- 2001-10-29 RU RU2003117477/15A patent/RU2003117477A/ru not_active Application Discontinuation
- 2001-10-29 CN CN018194281A patent/CN1665508A/zh active Pending
- 2001-10-29 US US10/432,772 patent/US20040023990A1/en not_active Abandoned
- 2001-10-29 HU HU0302720A patent/HUP0302720A2/hu unknown
- 2001-10-29 MX MXPA03004498A patent/MXPA03004498A/es unknown
- 2001-10-29 BR BR0115187-8A patent/BR0115187A/pt not_active Application Discontinuation
- 2001-10-29 AU AU2002215979A patent/AU2002215979A1/en not_active Abandoned
- 2001-10-29 JP JP2002544059A patent/JP2004513963A/ja active Pending
- 2001-10-29 KR KR10-2003-7006947A patent/KR20030051870A/ko not_active Application Discontinuation
- 2001-11-23 AR ARP010105461A patent/AR035373A1/es unknown
-
2003
- 2003-06-24 ZA ZA200304908A patent/ZA200304908B/en unknown
Non-Patent Citations (1)
Title |
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See references of WO0241880A2 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8756899B2 (en) | 2009-09-04 | 2014-06-24 | Valinge Innovation Ab | Resilient floor |
US11725395B2 (en) | 2009-09-04 | 2023-08-15 | Välinge Innovation AB | Resilient floor |
Also Published As
Publication number | Publication date |
---|---|
BR0115187A (pt) | 2004-01-20 |
PL363077A1 (en) | 2004-11-15 |
RU2003117477A (ru) | 2004-11-27 |
KR20030051870A (ko) | 2003-06-25 |
CZ20031668A3 (cs) | 2003-10-15 |
US20040023990A1 (en) | 2004-02-05 |
CA2429645A1 (fr) | 2002-05-30 |
WO2002041880A2 (fr) | 2002-05-30 |
SK7592003A3 (en) | 2003-11-04 |
JP2004513963A (ja) | 2004-05-13 |
WO2002041880A3 (fr) | 2003-08-28 |
HUP0302720A2 (hu) | 2003-11-28 |
MXPA03004498A (es) | 2003-09-05 |
AU2002215979A1 (en) | 2002-06-03 |
ZA200304908B (en) | 2004-07-28 |
DE10058662A1 (de) | 2002-05-29 |
CN1665508A (zh) | 2005-09-07 |
AR035373A1 (es) | 2004-05-12 |
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