DE10063885A1 - Drug formulation useful e.g. for treating angina or hypertension contains thieno (2,3-d) pyrimidine derivative phosphodiesterase V inhibitor and antithrombotic agent, calcium antagonist or prostaglandin, - Google Patents
Drug formulation useful e.g. for treating angina or hypertension contains thieno (2,3-d) pyrimidine derivative phosphodiesterase V inhibitor and antithrombotic agent, calcium antagonist or prostaglandin,Info
- Publication number
- DE10063885A1 DE10063885A1 DE2000163885 DE10063885A DE10063885A1 DE 10063885 A1 DE10063885 A1 DE 10063885A1 DE 2000163885 DE2000163885 DE 2000163885 DE 10063885 A DE10063885 A DE 10063885A DE 10063885 A1 DE10063885 A1 DE 10063885A1
- Authority
- DE
- Germany
- Prior art keywords
- pyrimidin
- chloro
- benzothieno
- benzylamino
- methoxy
- 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- Withdrawn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
- 229940127291 Calcium channel antagonist Drugs 0.000 title claims abstract description 40
- 239000000480 calcium channel blocker Substances 0.000 title claims abstract description 22
- 206010002383 Angina Pectoris Diseases 0.000 title claims description 4
- 206010020772 Hypertension Diseases 0.000 title claims description 4
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 title abstract description 4
- 239000003146 anticoagulant agent Substances 0.000 title abstract 3
- 229960004676 antithrombotic agent Drugs 0.000 title abstract 3
- 150000003180 prostaglandins Chemical class 0.000 title abstract 3
- DDWBRNXDKNIQDY-UHFFFAOYSA-N thieno[2,3-d]pyrimidine Chemical class N1=CN=C2SC=CC2=C1 DDWBRNXDKNIQDY-UHFFFAOYSA-N 0.000 title abstract 3
- 239000013583 drug formulation Substances 0.000 title 1
- -1 OCH2CH2 Chemical group 0.000 claims abstract description 88
- 150000002169 ethanolamines Chemical class 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 22
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims abstract description 17
- 239000012453 solvate Substances 0.000 claims abstract description 12
- 206010019280 Heart failures Diseases 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 6
- 208000002815 pulmonary hypertension Diseases 0.000 claims abstract description 4
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 40
- 150000001875 compounds Chemical group 0.000 claims description 37
- 125000004432 carbon atom Chemical group C* 0.000 claims description 32
- PYHXQKPRNCIMHW-UHFFFAOYSA-N 5-[4-[(3-chloro-4-methoxyphenyl)methylamino]-5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-2-yl]pentanoic acid Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(CCCCC(O)=O)=NC2=C1C(CCCC1)=C1S2 PYHXQKPRNCIMHW-UHFFFAOYSA-N 0.000 claims description 7
- IUEZNVXQJJMXHB-UHFFFAOYSA-N 3-[4-[(3-chloro-4-methoxyphenyl)methylamino]-5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-2-yl]propanoic acid Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(CCC(O)=O)=NC2=C1C(CCCC1)=C1S2 IUEZNVXQJJMXHB-UHFFFAOYSA-N 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- 206010039163 Right ventricular failure Diseases 0.000 claims description 4
- 229940085304 dihydropyridine derivative selective calcium channel blockers with mainly vascular effects Drugs 0.000 claims description 4
- 230000002685 pulmonary effect Effects 0.000 claims description 4
- 229940085239 selective calcium channel blockers with direct cardiac effects phenylalkylamine derivative Drugs 0.000 claims description 4
- 201000006306 Cor pulmonale Diseases 0.000 claims description 3
- 206010016654 Fibrosis Diseases 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 208000018262 Peripheral vascular disease Diseases 0.000 claims description 3
- 208000004186 Pulmonary Heart Disease Diseases 0.000 claims description 3
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 3
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- 201000009961 allergic asthma Diseases 0.000 claims description 3
- 201000010105 allergic rhinitis Diseases 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 206010006451 bronchitis Diseases 0.000 claims description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
- 208000023819 chronic asthma Diseases 0.000 claims description 3
- 230000007882 cirrhosis Effects 0.000 claims description 3
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 3
- 230000003247 decreasing effect Effects 0.000 claims description 3
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 3
- 201000006370 kidney failure Diseases 0.000 claims description 3
- 208000012201 sexual and gender identity disease Diseases 0.000 claims description 3
- 208000015891 sexual disease Diseases 0.000 claims description 3
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-UHFFFAOYSA-N 0.000 claims description 2
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 claims description 2
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 claims description 2
- ZBIAKUMOEKILTF-UHFFFAOYSA-N 2-[4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazinyl]-N-(2,6-dimethylphenyl)acetamide Chemical compound CC1=CC=CC(C)=C1NC(=O)CN1CCN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 ZBIAKUMOEKILTF-UHFFFAOYSA-N 0.000 claims description 2
- NMKSAYKQLCHXDK-UHFFFAOYSA-N 3,3-diphenyl-N-(1-phenylethyl)-1-propanamine Chemical compound C=1C=CC=CC=1C(C)NCCC(C=1C=CC=CC=1)C1=CC=CC=C1 NMKSAYKQLCHXDK-UHFFFAOYSA-N 0.000 claims description 2
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 claims description 2
- LYUPWDYILLXCBH-UHFFFAOYSA-N 4-[4-(1,3-benzodioxol-5-ylmethylamino)-5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-2-yl]butanoic acid Chemical compound C1CCCC2=C1C1=C(NCC=3C=C4OCOC4=CC=3)N=C(CCCC(=O)O)N=C1S2 LYUPWDYILLXCBH-UHFFFAOYSA-N 0.000 claims description 2
- MWRPZZKSUQYFQF-UHFFFAOYSA-N 4-[4-(1,3-benzodioxol-5-ylmethylamino)-6-methylthieno[2,3-d]pyrimidin-2-yl]butanoic acid Chemical compound C1=C2OCOC2=CC(CNC2=C3C=C(SC3=NC(CCCC(O)=O)=N2)C)=C1 MWRPZZKSUQYFQF-UHFFFAOYSA-N 0.000 claims description 2
- IAYPBSUFZUDVCB-UHFFFAOYSA-N 4-[4-[(3-chloro-4-methoxyphenyl)methylamino]-6-methylthieno[2,3-d]pyrimidin-2-yl]butanoic acid Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(CCCC(O)=O)=NC2=C1C=C(C)S2 IAYPBSUFZUDVCB-UHFFFAOYSA-N 0.000 claims description 2
- OGJAHBNONYXIQS-UHFFFAOYSA-N 5-[4-(1,3-benzodioxol-5-ylmethylamino)-6-methylthieno[2,3-d]pyrimidin-2-yl]pentanoic acid Chemical compound C1=C2OCOC2=CC(CNC2=C3C=C(SC3=NC(CCCCC(O)=O)=N2)C)=C1 OGJAHBNONYXIQS-UHFFFAOYSA-N 0.000 claims description 2
- IVKAATVWGBPOCV-UHFFFAOYSA-N 5-[4-[(3-chloro-4-methoxyphenyl)methylamino]-6-methylthieno[2,3-d]pyrimidin-2-yl]pentanoic acid Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(CCCCC(O)=O)=NC2=C1C=C(C)S2 IVKAATVWGBPOCV-UHFFFAOYSA-N 0.000 claims description 2
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 claims description 2
- CQPWMZYGLYAPAX-UHFFFAOYSA-N 7-[4-(1,3-benzodioxol-5-ylmethylamino)-5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-2-yl]heptanoic acid Chemical compound C1CCCC2=C1C1=C(NCC=3C=C4OCOC4=CC=3)N=C(CCCCCCC(=O)O)N=C1S2 CQPWMZYGLYAPAX-UHFFFAOYSA-N 0.000 claims description 2
- XQLWNAFCTODIRK-UHFFFAOYSA-N Gallopamil Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC(OC)=C(OC)C(OC)=C1 XQLWNAFCTODIRK-UHFFFAOYSA-N 0.000 claims description 2
- HBNPJJILLOYFJU-VMPREFPWSA-N Mibefradil Chemical compound C1CC2=CC(F)=CC=C2[C@H](C(C)C)[C@@]1(OC(=O)COC)CCN(C)CCCC1=NC2=CC=CC=C2N1 HBNPJJILLOYFJU-VMPREFPWSA-N 0.000 claims description 2
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 claims description 2
- FAIIFDPAEUKBEP-UHFFFAOYSA-N Nilvadipine Chemical compound COC(=O)C1=C(C#N)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 FAIIFDPAEUKBEP-UHFFFAOYSA-N 0.000 claims description 2
- 229960002992 barnidipine Drugs 0.000 claims description 2
- VXMOONUMYLCFJD-DHLKQENFSA-N barnidipine Chemical compound C1([C@@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)O[C@@H]2CN(CC=3C=CC=CC=3)CC2)=CC=CC([N+]([O-])=O)=C1 VXMOONUMYLCFJD-DHLKQENFSA-N 0.000 claims description 2
- 150000007657 benzothiazepines Chemical class 0.000 claims description 2
- 229960003665 bepridil Drugs 0.000 claims description 2
- UIEATEWHFDRYRU-UHFFFAOYSA-N bepridil Chemical compound C1CCCN1C(COCC(C)C)CN(C=1C=CC=CC=1)CC1=CC=CC=C1 UIEATEWHFDRYRU-UHFFFAOYSA-N 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 claims description 2
- 229960004166 diltiazem Drugs 0.000 claims description 2
- 229960003580 felodipine Drugs 0.000 claims description 2
- 229960002602 fendiline Drugs 0.000 claims description 2
- 229960000457 gallopamil Drugs 0.000 claims description 2
- 229960004427 isradipine Drugs 0.000 claims description 2
- 229960004340 lacidipine Drugs 0.000 claims description 2
- GKQPCPXONLDCMU-CCEZHUSRSA-N lacidipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C1=CC=CC=C1\C=C\C(=O)OC(C)(C)C GKQPCPXONLDCMU-CCEZHUSRSA-N 0.000 claims description 2
- 229960004294 lercanidipine Drugs 0.000 claims description 2
- ZDXUKAKRHYTAKV-UHFFFAOYSA-N lercanidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)CN(C)CCC(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZDXUKAKRHYTAKV-UHFFFAOYSA-N 0.000 claims description 2
- 229960001941 lidoflazine Drugs 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 claims description 2
- 229960003963 manidipine Drugs 0.000 claims description 2
- ANEBWFXPVPTEET-UHFFFAOYSA-N manidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ANEBWFXPVPTEET-UHFFFAOYSA-N 0.000 claims description 2
- 229960004438 mibefradil Drugs 0.000 claims description 2
- 229960001783 nicardipine Drugs 0.000 claims description 2
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims description 2
- 229960001597 nifedipine Drugs 0.000 claims description 2
- 229960005366 nilvadipine Drugs 0.000 claims description 2
- 229960000715 nimodipine Drugs 0.000 claims description 2
- 229960005425 nitrendipine Drugs 0.000 claims description 2
- CYXKNKQEMFBLER-UHFFFAOYSA-N perhexiline Chemical compound C1CCCNC1CC(C1CCCCC1)C1CCCCC1 CYXKNKQEMFBLER-UHFFFAOYSA-N 0.000 claims description 2
- 229960000989 perhexiline Drugs 0.000 claims description 2
- 229960001722 verapamil Drugs 0.000 claims description 2
- 125000004925 dihydropyridyl group Chemical class N1(CC=CC=C1)* 0.000 claims 2
- CZUVEOGVLQIXMO-UHFFFAOYSA-N 2-[4-[4-[(3-chloro-4-methoxyphenyl)methylamino]-5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-2-yl]cyclohexylidene]acetic acid Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(C2CCC(CC2)=CC(O)=O)=NC2=C1C(CCCC1)=C1S2 CZUVEOGVLQIXMO-UHFFFAOYSA-N 0.000 claims 1
- 206010003210 Arteriosclerosis Diseases 0.000 claims 1
- 210000004072 lung Anatomy 0.000 claims 1
- 201000004193 respiratory failure Diseases 0.000 claims 1
- 206010007559 Cardiac failure congestive Diseases 0.000 abstract description 7
- WSNHDFQLDMMXBB-UHFFFAOYSA-N 5-[4-[(3-chloro-4-methoxyphenyl)methylamino]-4,5,6,7-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-2-yl]pentanoic acid Chemical compound ClC=1C=C(CNC2C=3C(=NC(=N2)CCCCC(=O)O)SC=2C3CCCC2)C=CC1OC WSNHDFQLDMMXBB-UHFFFAOYSA-N 0.000 abstract 2
- 206010010970 Cor pulmonale chronic Diseases 0.000 abstract 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract 1
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- 125000006237 oxymethylenoxy group Chemical group [H]C([H])([*:1])[*:2] 0.000 abstract 1
- 238000004806 packaging method and process Methods 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 30
- 239000002253 acid Substances 0.000 description 24
- 239000004480 active ingredient Substances 0.000 description 16
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
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- 238000006243 chemical reaction Methods 0.000 description 12
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- 239000002585 base Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
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- 238000007792 addition Methods 0.000 description 6
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- 150000001342 alkaline earth metals Chemical class 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
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- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 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 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- DKYYKIHEIOOWRB-UHFFFAOYSA-N methyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate Chemical compound C1CCCC2=C1SC(N)=C2C(=O)OC DKYYKIHEIOOWRB-UHFFFAOYSA-N 0.000 description 1
- XCCLUBXUFWORLI-UHFFFAOYSA-N methyl 3-(4-chloro-5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-2-yl)propanoate Chemical compound C1CCCC2=C1C1=C(Cl)N=C(CCC(=O)OC)N=C1S2 XCCLUBXUFWORLI-UHFFFAOYSA-N 0.000 description 1
- LROMJHRXOSOPCW-UHFFFAOYSA-N methyl 3-[4-[(3-chloro-4-methoxyphenyl)methylamino]-5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-2-yl]propanoate Chemical compound C=12C=3CCCCC=3SC2=NC(CCC(=O)OC)=NC=1NCC1=CC=C(OC)C(Cl)=C1 LROMJHRXOSOPCW-UHFFFAOYSA-N 0.000 description 1
- FOAVFHLOVVDTQD-UHFFFAOYSA-N methyl 4-(4-chloro-5,6-dimethylthieno[2,3-d]pyrimidin-2-yl)butanoate Chemical compound COC(=O)CCCC1=NC(Cl)=C2C(C)=C(C)SC2=N1 FOAVFHLOVVDTQD-UHFFFAOYSA-N 0.000 description 1
- HYXRWTOYHWGILF-UHFFFAOYSA-N methyl 4-(4-chloro-6-ethylthieno[2,3-d]pyrimidin-2-yl)butanoate methyl 4-[4-[(3-chloro-4-methoxyphenyl)methylamino]-6-ethylthieno[2,3-d]pyrimidin-2-yl]butanoate Chemical compound ClC=1C=C(CNC=2C3=C(N=C(N2)CCCC(=O)OC)SC(=C3)CC)C=CC1OC.ClC=1C3=C(N=C(N1)CCCC(=O)OC)SC(=C3)CC HYXRWTOYHWGILF-UHFFFAOYSA-N 0.000 description 1
- DGABDUQGMPSQQR-UHFFFAOYSA-N methyl 4-(4-chloro-6-methylthieno[2,3-d]pyrimidin-2-yl)butanoate Chemical compound COC(=O)CCCC1=NC(Cl)=C2C=C(C)SC2=N1 DGABDUQGMPSQQR-UHFFFAOYSA-N 0.000 description 1
- LAGQMYRWDCDFQM-UHFFFAOYSA-N methyl 4-[4-(1,3-benzodioxol-5-ylmethylamino)-5,6-dimethylthieno[2,3-d]pyrimidin-2-yl]butanoate methyl 4-(4-chloro-5,6-dimethylthieno[2,3-d]pyrimidin-2-yl)butanoate Chemical compound C1OC=2C=C(CNC=3C4=C(N=C(N3)CCCC(=O)OC)SC(=C4C)C)C=CC2O1.ClC=1C2=C(N=C(N1)CCCC(=O)OC)SC(=C2C)C LAGQMYRWDCDFQM-UHFFFAOYSA-N 0.000 description 1
- WCBZTAIEOBFGMC-UHFFFAOYSA-N methyl 4-[4-(1,3-benzodioxol-5-ylmethylamino)-6-chlorothieno[2,3-d]pyrimidin-2-yl]butanoate methyl 4-(4,6-dichlorothieno[2,3-d]pyrimidin-2-yl)butanoate Chemical compound C1OC=2C=C(CNC=3C4=C(N=C(N3)CCCC(=O)OC)SC(=C4)Cl)C=CC2O1.ClC=1C2=C(N=C(N1)CCCC(=O)OC)SC(=C2)Cl WCBZTAIEOBFGMC-UHFFFAOYSA-N 0.000 description 1
- ILKOIBBRSZNPGH-UHFFFAOYSA-N methyl 4-[4-(1,3-benzodioxol-5-ylmethylamino)-6-ethylthieno[2,3-d]pyrimidin-2-yl]butanoate methyl 4-(4-chloro-6-ethylthieno[2,3-d]pyrimidin-2-yl)butanoate Chemical compound C1OC=2C=C(CNC=3C4=C(N=C(N3)CCCC(=O)OC)SC(=C4)CC)C=CC2O1.ClC=1C2=C(N=C(N1)CCCC(=O)OC)SC(=C2)CC ILKOIBBRSZNPGH-UHFFFAOYSA-N 0.000 description 1
- AEVBMPBKDYBNTN-UHFFFAOYSA-N methyl 4-[4-(1,3-benzodioxol-5-ylmethylamino)-6-methylthieno[2,3-d]pyrimidin-2-yl]butanoate methyl 4-(4-chloro-6-methylthieno[2,3-d]pyrimidin-2-yl)butanoate Chemical compound C1OC=2C=C(CNC=3C4=C(N=C(N3)CCCC(=O)OC)SC(=C4)C)C=CC2O1.ClC=1C2=C(N=C(N1)CCCC(=O)OC)SC(=C2)C AEVBMPBKDYBNTN-UHFFFAOYSA-N 0.000 description 1
- MVBAMFZRCDKPAL-UHFFFAOYSA-N methyl 4-[4-[(3-chloro-4-methoxyphenyl)methylamino]-5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-2-yl]butanoate Chemical compound C=12C=3CCCCC=3SC2=NC(CCCC(=O)OC)=NC=1NCC1=CC=C(OC)C(Cl)=C1 MVBAMFZRCDKPAL-UHFFFAOYSA-N 0.000 description 1
- VZZPZAFCBNZLMQ-UHFFFAOYSA-N methyl 5-(4-chloro-5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-2-yl)pentanoate Chemical compound C1CCCC2=C1C1=C(Cl)N=C(CCCCC(=O)OC)N=C1S2 VZZPZAFCBNZLMQ-UHFFFAOYSA-N 0.000 description 1
- BLHNPKSMMWMNDJ-UHFFFAOYSA-N methyl 5-(4-chloro-6-ethylthieno[2,3-d]pyrimidin-2-yl)pentanoate Chemical compound N1=C(CCCCC(=O)OC)N=C2SC(CC)=CC2=C1Cl BLHNPKSMMWMNDJ-UHFFFAOYSA-N 0.000 description 1
- NGPLCBIPUVHOFO-UHFFFAOYSA-N methyl 5-(4-chloro-6-methylthieno[2,3-d]pyrimidin-2-yl)pentanoate Chemical compound COC(=O)CCCCC1=NC(Cl)=C2C=C(C)SC2=N1 NGPLCBIPUVHOFO-UHFFFAOYSA-N 0.000 description 1
- HKTZVHFFIRMKLG-UHFFFAOYSA-N methyl 5-[4-(1,3-benzodioxol-5-ylmethylamino)-6-chlorothieno[2,3-d]pyrimidin-2-yl]pentanoate;methyl 5-(4,6-dichlorothieno[2,3-d]pyrimidin-2-yl)pentanoate Chemical compound COC(=O)CCCCC1=NC(Cl)=C2C=C(Cl)SC2=N1.C1=C2OCOC2=CC(CNC=2N=C(N=C3SC(Cl)=CC3=2)CCCCC(=O)OC)=C1 HKTZVHFFIRMKLG-UHFFFAOYSA-N 0.000 description 1
- ZINZNVSMOGYBPJ-UHFFFAOYSA-N methyl 5-[4-(1,3-benzodioxol-5-ylmethylamino)-6-ethylthieno[2,3-d]pyrimidin-2-yl]pentanoate methyl 5-(4-chloro-6-ethylthieno[2,3-d]pyrimidin-2-yl)pentanoate Chemical compound CCc1cc2c(Cl)nc(CCCCC(=O)OC)nc2s1.CCc1cc2c(NCc3ccc4OCOc4c3)nc(CCCCC(=O)OC)nc2s1 ZINZNVSMOGYBPJ-UHFFFAOYSA-N 0.000 description 1
- LMMOVDDLRNRAAU-UHFFFAOYSA-N methyl 5-[4-[(3-chloro-4-methoxyphenyl)methylamino]-5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-2-yl]pentanoate Chemical compound C=12C=3CCCCC=3SC2=NC(CCCCC(=O)OC)=NC=1NCC1=CC=C(OC)C(Cl)=C1 LMMOVDDLRNRAAU-UHFFFAOYSA-N 0.000 description 1
- DRQCYVWPEBXARJ-UHFFFAOYSA-N methyl 5-[6-chloro-4-[(3-chloro-4-methoxyphenyl)methylamino]thieno[2,3-d]pyrimidin-2-yl]pentanoate methyl 5-(4,6-dichlorothieno[2,3-d]pyrimidin-2-yl)pentanoate Chemical compound COC(=O)CCCCC1=NC(Cl)=C2C=C(Cl)SC2=N1.C=12C=C(Cl)SC2=NC(CCCCC(=O)OC)=NC=1NCC1=CC=C(OC)C(Cl)=C1 DRQCYVWPEBXARJ-UHFFFAOYSA-N 0.000 description 1
- XUOZGYFMFNNEOX-UHFFFAOYSA-N methyl 7-(4,6-dichlorothieno[2,3-d]pyrimidin-2-yl)heptanoate Chemical compound COC(=O)CCCCCCC1=NC(Cl)=C2C=C(Cl)SC2=N1 XUOZGYFMFNNEOX-UHFFFAOYSA-N 0.000 description 1
- SCLMBZDOVNJPBW-UHFFFAOYSA-N methyl 7-(4-chloro-6-methylthieno[2,3-d]pyrimidin-2-yl)heptanoate Chemical compound COC(=O)CCCCCCC1=NC(Cl)=C2C=C(C)SC2=N1 SCLMBZDOVNJPBW-UHFFFAOYSA-N 0.000 description 1
- FAGHRFBOAJJPKA-UHFFFAOYSA-N methyl 7-[4-(1,3-benzodioxol-5-ylmethylamino)-5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-2-yl]heptanoate Chemical compound C1CCCC2=C1C1=C(NCC=3C=C4OCOC4=CC=3)N=C(CCCCCCC(=O)OC)N=C1S2 FAGHRFBOAJJPKA-UHFFFAOYSA-N 0.000 description 1
- VQAXSGZZZPGFCO-UHFFFAOYSA-N methyl 7-[4-(1,3-benzodioxol-5-ylmethylamino)-5,6-dimethylthieno[2,3-d]pyrimidin-2-yl]heptanoate methyl 7-(4-chloro-5,6-dimethylthieno[2,3-d]pyrimidin-2-yl)heptanoate Chemical compound C1OC=2C=C(CNC=3C4=C(N=C(N3)CCCCCCC(=O)OC)SC(=C4C)C)C=CC2O1.ClC=1C2=C(N=C(N1)CCCCCCC(=O)OC)SC(=C2C)C VQAXSGZZZPGFCO-UHFFFAOYSA-N 0.000 description 1
- RRWKBLBUCIIZJL-UHFFFAOYSA-N methyl 7-[4-(1,3-benzodioxol-5-ylmethylamino)-6-ethylthieno[2,3-d]pyrimidin-2-yl]heptanoate;methyl 7-(4-chloro-6-ethylthieno[2,3-d]pyrimidin-2-yl)heptanoate Chemical compound N1=C(CCCCCCC(=O)OC)N=C2SC(CC)=CC2=C1Cl.C1=C2OCOC2=CC(CNC2=C3C=C(SC3=NC(CCCCCCC(=O)OC)=N2)CC)=C1 RRWKBLBUCIIZJL-UHFFFAOYSA-N 0.000 description 1
- RUDLKVBCNFDYAJ-UHFFFAOYSA-N methyl 7-[4-[(3-chloro-4-methoxyphenyl)methylamino]-5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-2-yl]heptanoate Chemical compound C=12C=3CCCCC=3SC2=NC(CCCCCCC(=O)OC)=NC=1NCC1=CC=C(OC)C(Cl)=C1 RUDLKVBCNFDYAJ-UHFFFAOYSA-N 0.000 description 1
- UGESVNIAFODBKA-UHFFFAOYSA-N methyl 7-[6-chloro-4-[(3-chloro-4-methoxyphenyl)methylamino]thieno[2,3-d]pyrimidin-2-yl]heptanoate methyl 7-(4,6-dichlorothieno[2,3-d]pyrimidin-2-yl)heptanoate Chemical compound ClC=1C=C(CNC=2C3=C(N=C(N2)CCCCCCC(=O)OC)SC(=C3)Cl)C=CC1OC.ClC=1C3=C(N=C(N1)CCCCCCC(=O)OC)SC(=C3)Cl UGESVNIAFODBKA-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000004682 monohydrates Chemical class 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
- 230000000414 obstructive effect Effects 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
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 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
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[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
- 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
- 150000003246 quinazolines Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 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
- 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
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 150000003577 thiophenes Chemical class 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 229940070710 valerate 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
- 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
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Die Erfindung betrifft pharmazeutische Formulierungen enthaltend
mindestens einen Phosphodiesterase V-Hemmer der Formel I
The invention relates to pharmaceutical formulations containing at least one phosphodiesterase V inhibitor of the formula I.
worin
R1, R2 jeweils unabhängig voneinander H, A oder Hal,
wobei einer der Reste R1 oder R2 immer ≠ H ist,
R1 und R2 zusammen auch Alkylen mit 3-5 C-Atomen,
R3, R4 jeweils unabhängig voneinander H, A, OH, OA oder Hal,
R3 und R4 zusammen auch Alkylen mit 3-5 C-Atomen,
-O-CH2-CH2-, -O-CH2-O- oder
-O-CH2-CH2-O-,
X einfach durch R7 substituiertes R5 oder R6,
R5 lineares oder verzweigtes Alkylen mit 1-10 C-Atomen, worin
eine oder zwei CH2-Gruppen durch -CH=CH-Gruppen ersetzt
sein können, oder
-C6H4-(OH2)m-,
R6 Cycloalkylalkylen mit 6-12 C-Atomen,
R7 COOH, COOA, CONH2, CONHA, CON(A)2 oder CN,
A Alkyl mit 1 bis 6 C Atomen,
Hal F, Cl, Br oder I,
m 1 oder 2 und
n 0, 1, 2 oder 3
bedeuten,
und/oder deren physiologisch unbedenklichen Salze und/oder Solvate und
mindestens einen Calcium-Antagonisten.wherein
R 1 , R 2 each independently of one another H, A or Hal, where one of the radicals R 1 or R 2 is always ≠ H,
R 1 and R 2 together also alkylene with 3-5 C atoms,
R 3 , R 4 each independently of one another H, A, OH, OA or Hal,
R 3 and R 4 together also alkylene with 3-5 C atoms, -O-CH 2 -CH 2 -, -O-CH 2 -O- or -O-CH 2 -CH 2 -O-,
X is monosubstituted by R 7 R 5 or R 6,
R 5 linear or branched alkylene with 1-10 C atoms, in which one or two CH 2 groups can be replaced by -CH = CH groups, or -C 6 H 4 - (OH 2 ) m -,
R 6 cycloalkylalkylene with 6-12 C atoms,
R 7 COOH, COOA, CONH 2 , CONHA, CON (A) 2 or CN,
A alkyl with 1 to 6 C atoms,
Hal F, Cl, Br or I,
m 1 or 2 and
n 0, 1, 2 or 3
mean,
and / or their physiologically acceptable salts and / or solvates and at least one calcium antagonist.
Die Erfindung betrifft weiterhin die Verwendung der Formulierung zur Her stellung eines Arzneimittels zur Behandlung von Angina, Bluthochdruck, pulmonalem Hochdruck, congestivem Herzversagen (CHF), chronischer obstruktiver pulmonaler Krankheit (COPD), Cor pulmonale, Rechtsherzin suffizienz, Atherosklerose, Bedingungen verminderter Durchgängigkeit der Herzgefäße, peripheren vaskulären Krankheiten, Schlaganfall, Bronchitis, allergischem Asthma, chronischem Asthma, allergischer Rhinitis, Glau com, Irritable Bowel Syndrome, Tumoren, Niereninsuffizienz, Leberzirrho se und zur Behandlung weiblicher Sexualstörungen.The invention further relates to the use of the formulation for the manufacture provision of a medicine to treat angina, high blood pressure, pulmonary high pressure, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale, right heart sufficiency, atherosclerosis, conditions of decreased patency of the Cardiovascular, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma com, Irritable Bowel Syndrome, tumors, renal failure, cirrhosis se and for the treatment of female sexual disorders.
Pharmazeutische Formulierungen bestehend aus anderen Phosphodi esterase V (PDE V)-Hemmern zusammen mit Calcium-Antagonisten (= Calciumkanalblocker) sind in der WO 00/15639 beschrieben.Pharmaceutical formulations consisting of other phosphodi esterase V (PDE V) inhibitors together with calcium antagonists (= Calcium channel blockers) are described in WO 00/15639.
Der Erfindung lag die Aufgabe zugrunde, neue Arzneimittel in Form von pharmazeutischen Zubereitungen zur Verfügung zu stellen, die bessere Eigenschaften besitzen als bekannte, für die gleichen Zwecke verwend bare Arzneimittel.The invention was based, new pharmaceuticals in the form of the task to provide pharmaceutical preparations, the better Properties as known, used for the same purposes bare drugs.
Diese Aufgabe wurde durch das Auffinden der neuen Zubereitung gelöst.This task was solved by finding the new preparation.
Die Verbindungen der Formel I und ihre Salze zeigen bei guter Verträg lichkeit sehr wertvolle pharmakologische Eigenschaften besitzen. Insbesondere zeigen sie eine spezifische Inhibierung der cGMP-Phospho diesterase (PDE V).The compounds of formula I and their salts show a good contract very valuable pharmacological properties. In particular, they show a specific inhibition of cGMP phospho diesterase (PDE V).
Chinazoline mit cGMP-Phosphodiesterase hemmender Aktivität sind z. B. in J. Med. Chem. 36, 3765 (1993) und ibid. 37, 2106 (1994) beschrieben.Quinazolines with cGMP phosphodiesterase inhibitory activity are e.g. B. in J. Med. Chem. 36, 3765 (1993) and ibid. 37, 2106 (1994).
Die biologische Aktivität der Verbindungen der Formel I kann nach Metho den bestimmt werden, wie sie z. B. in der WO 93/06104 beschrieben sind. The biological activity of the compounds of formula I can according to Metho which are determined as z. B. are described in WO 93/06104.
Die Affinität der erfindungsgemäßen Verbindungen für cGMP- und cAMP- Phosphodiesterase wird durch die Ermittlung ihrer IC50-Werte (Konzentra tion des Inhibitors, die benötigt wird, um eine 50%ige Inhibierung der En zymaktivität zu erreichen) bestimmt.The affinity of the compounds according to the invention for cGMP and cAMP phosphodiesterase is determined by determining their IC 50 values (concentration of the inhibitor which is required in order to achieve a 50% inhibition of the enzyme activity).
Zur Durchführung der Bestimmungen können nach bekannten Methoden isolierte Enzyme verwendet werden (z. B. W. J. Thompson et al., Biochem. 1971, 10, 311). Zur Durchführung der Versuche kann eine modifizierte "batch"-Methode von W. J. Thompson und M. M. Appleman (Biochem. 1979, 18, 5228) angewendet werden.Known methods can be used to carry out the determinations isolated enzymes can be used (e.g. W. J. Thompson et al., Biochem. 1971, 10, 311). A modified can be used to carry out the tests "batch" method by W. J. Thompson and M. M. Appleman (Biochem. 1979, 18, 5228) can be used.
Die Verbindungen eignen sich daher zur Behandlung von Erkrankungen des Herz-Kreislaufsystems, insbesondere der Herzinsuffizienz und zur Be handlung und/oder Therapie von Potenzstörungen (erektile Dysfunktion).The compounds are therefore suitable for the treatment of diseases of the cardiovascular system, especially heart failure and action and / or therapy of erectile dysfunction.
Die Verwendung von substituierten Pyrazolopyrimidinonen zur Behandlung von Impotenz ist z. B. in der WO 94/28902 beschrieben.The use of substituted pyrazolopyrimidinones for treatment of impotence is e.g. B. described in WO 94/28902.
Die Verbindungen sind wirksam als Inhibitoren der Phenylephrin-induzier ten Kontraktionen in Corpus cavernosum-Präparationen von Hasen.The compounds are effective as inhibitors of phenylephrine-induced contractions in corpus cavernosum preparations of rabbits.
Diese biologische Wirkung kann z. B. nach der Methode nachgewiesen werden, die von F. Holmquist et al. in J. Urol., 150, 1310-1315 (1993) be schrieben wird.This biological effect can e.g. B. detected by the method by F. Holmquist et al. in J. Urol., 150, 1310-1315 (1993) be is written.
Die Inhibierung der Kontraktion, zeigt die Wirksamkeit der erfindungsge mäßen Verbindungen zur Therapie und/oder Behandlung von Potenzstö rungen.The inhibition of the contraction shows the effectiveness of the Invention moderate connections for the therapy and / or treatment of erectile dysfunction requirements.
Die Wirksamkeit der erfindungsgemäßen pharmazeutischen Formulierun gen insbesondere zur Behandlung von pulmonalem Hochdruck kann nachgewiesen werden, wie von E. Braunwald beschrieben in Heart Disea se 5th edition, WB Saunders Company, 1997, chapter 6: Cardiac cathete rization 177-200.The efficacy of the pharmaceutical Formulierun invention gen particularly for the treatment of pulmonary hypertension can be demonstrated in Heart Disea se as described by E. Braunwald 5 edition th, WB Saunders Company, 1997, chapter 6: Cardiac cathete rization 177-200.
Die Verbindungen der Formel I können als Arzneimittelwirkstoffe in der Human- und Veterinärmedizin eingesetzt werden. Ferner können sie als Zwischenprodukte zur Herstellung weiterer Arzneimittelwirkstoffe einge setzt werden. The compounds of formula I can be used as active pharmaceutical ingredients in the Human and veterinary medicine are used. They can also be used as Intermediates for the production of other active pharmaceutical ingredients be set.
Die Verbindungen der Formel I nach Anspruch 1 sowie deren Salze wer
den durch ein Verfahren hergestellt, dadurch gekennzeichnet, daß man
The compounds of formula I according to claim 1 and the salts thereof who are produced by a process, characterized in that
-
a) eine Verbindung der Formel II
worin
R1, R2 und X die angegebenen Bedeutungen haben, und L Cl, Br, OH, SCH3 oder eine reaktionsfähige veresterte OH- Gruppe bedeutet,
mit einer Verbindung der Formel III
worin
R3, R4 und n die angegebenen Bedeutungen haben,
umsetzt,
odera) a compound of formula II
wherein
R 1 , R 2 and X have the meanings given and L is Cl, Br, OH, SCH 3 or a reactive esterified OH group,
with a compound of formula III
wherein
R 3 , R 4 and n have the meanings given,
implements,
or -
b) in einer Verbindung der Formel I einen Rest X in einen anderen
Rest X umwandelt, indem man z. B. eine Estergruppe zu einer COOH-
Gruppe hydrolysiert oder eine COOH-Gruppe in ein Amid oder in eine Cy
angruppe umwandelt
und/oder daß man eine Verbindung der Formel I in eines ihrer Salze überführt.b) in a compound of formula I converts a radical X into another radical X by z. B. hydrolyses an ester group to a COOH group or converts a COOH group into an amide or into a cy group
and / or converting a compound of formula I into one of its salts.
Unter Solvaten der Verbindungen der Formel I werden Anlagerungen von inerten Lösungsmittelmolekülen an die Verbindungen der Formel I ver standen, die sich aufgrund ihrer gegenseitigen Anziehungskraft ausbilden. Solvate sind z. B. Mono- oder Dihydrate oder Alkoholate.Solvates of the compounds of the formula I include additions of inert solvent molecules to the compounds of formula I ver stood, which develop because of their mutual attraction. Solvates are e.g. B. mono- or dihydrates or alcoholates.
Vor- und nachstehend haben die Reste R1, R2, R3, R4, R5, R6, R7, X, L und n die bei den Formeln I, II und III angegebenen Bedeutungen, sofern nicht ausdrücklich etwas anderes angegeben ist.Above and below, the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, L and n have the meanings given in the formulas I, II and III, unless expressly stated otherwise is specified.
A bedeutet Alkyl mit 1-6 C-Atomen.A means alkyl with 1-6 C atoms.
In den vorstehenden Formeln ist Alkyl vorzugsweise unverzweigt und hat 1, 2, 3, 4, 5 oder 6 C-Atome und bedeutet vorzugsweise Methyl, Ethyl oder Propyl, weiterhin bevorzugt Isopropyl, Butyl, Isobutyl, sek.-Butyl oder tert.- Butyl, aber auch n-Pentyl, Neopentyl, Isopentyl oder Hexyl.In the above formulas, alkyl is preferably unbranched and has 1, 2, 3, 4, 5 or 6 carbon atoms and is preferably methyl, ethyl or Propyl, further preferably isopropyl, butyl, isobutyl, sec-butyl or tert.- Butyl, but also n-pentyl, neopentyl, isopentyl or hexyl.
X bedeutet einen einfach durch R7 substituierten R5 oder R6-Rest.X denotes an R 5 or R 6 radical which is simply substituted by R 7 .
R5 bedeutet einen linearen oder verzweigten Alkylenrest mit 1-10, vor zugsweise 1-8 C-Atomen, wobei der Alkylenrest vorzugsweise z. B. Me thylen, Ethylen, Propylen, Isopropylen, Butylen, Isobutylen, sek.-Butylen, Pentylen, 1-, 2- oder 3-Methylbutylen, 1,1-, 1,2- oder 2,2-Dimethyl propylen, 1-Ethylpropylen, Hexylen, 1-, 2-, 3- oder 4-Methylpentylen, 1,1- 1,2-, 1,3-, 2,2-, 2,3- oder 3,3-Dimethylbutylen, 1- oder 2-Ethylbutylen, 1-Ethyl-1-methylpropylen, 1-Ethyl-2-methylpropylen, 1,1,2-oder 1,2,2-Tri methylpropylen, lineares oder verzweigtes Heptylen, Octylen, Nonylen oder Decylen bedeutet.R 5 represents a linear or branched alkylene radical with 1-10, preferably 1-8 C atoms, the alkylene radical preferably z. B. Me, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, 1-, 2- or 3-methylbutylene, 1,1-, 1,2- or 2,2-dimethyl propylene, 1st -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 decylene.
R5 bedeutet ferner z. B. But-2-en-ylen oder Hex-3-en-ylen.R 5 also means z. B. but-2-en-ylene or hex-3-en-ylene.
R6 bedeutet Cycloalkylalkylen mit 6-12 C-Atomen, vorzugsweise z. B. Cycclopentylmethylen, Cyclohexylmethylen, Cyclohexylethylen, Cyclohe xylpropylen oder Cyclohexylbutylen. R 6 denotes cycloalkylalkylene with 6-12 C atoms, preferably z. B. cycclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohe xylpropylene or cyclohexylbutylene.
Von den Resten R1 und R2 steht einer vorzugsweise für H, während der andere bevorzugt Propyl oder Butyl, besonders bevorzugt aber Ethyl oder Methyl bedeutet. Ferner bedeuten R1 und R2 auch zusammen bevorzugt Propylen, Butylen oder Pentylen.Of the radicals R 1 and R 2 , one is preferably H, while the other is preferably propyl or butyl, but particularly preferably ethyl or methyl. Furthermore, R 1 and R 2 together preferably also mean propylene, butylene or pentylene.
Hal bedeutet vorzugsweise F, Cl oder Br, aber auch I.Hal is preferably F, Cl or Br, but also I.
Die Reste R3 und R4 können gleich oder verschieden sein und stehen vor zugsweise in der 3- oder 4-Position des Phenylrings. Sie bedeuten bei spielsweise jeweils unabhängig voneinander H, OH, Alkyl, F, Cl, Br oder I oder zusammen Alkylen, wie z. B. Propylen, Butylen oder Pentylen, ferner Ethylenoxy, Methylendioxy oder Ethylendioxy. Bevorzugt stehen sie auch jeweils für Alkoxy, wie z. B. für Methoxy, Ethoxy oder Propoxy.The radicals R 3 and R 4 can be the same or different and are preferably in the 3- or 4-position of the phenyl ring. They mean for example each independently of one another H, OH, alkyl, F, Cl, Br or I or together alkylene, such as. As propylene, butylene or pentylene, furthermore ethyleneoxy, methylenedioxy or ethylenedioxy. They are preferably also each alkoxy, such as. B. for methoxy, ethoxy or propoxy.
Der Rest R7 bedeutet vorzugsweise z. B. COOH, COOCH3, COOC2H5, CONH2, CON(CH3)2, CONHCH3 oder CN.The radical R 7 preferably means z. B. COOH, COOCH 3 , COOC 2 H 5 , CONH 2 , CON (CH 3 ) 2 , CONHCH 3 or CN.
Für die gesamte Erfindung gilt, daß sämtliche Reste, die mehrfach auf treten, gleich oder verschieden sein können, d. h. unabhängig voneinander sind.For the entire invention applies that all residues that occur multiple times kick, may be the same or different, d. H. independently of each other are.
Gegenstand der Erfindung sind insbesondere solche pharmazeutischen
Formulierungen enthaltend einen Calcium-Antagonisten und mindestens
eine Verbindung der Formel I, in denen mindestens einer der genannten
Reste eine der vorstehend angegebenen bevorzugten Bedeutungen hat.
Einige bevorzugte Gruppen von Verbindungen können durch die folgenden
Teilformeln Ia bis Ie ausgedrückt werden, die der Formel I entsprechen
und worin die nicht näher bezeichneten Reste die bei der Formel I ange
gebene Bedeutung haben, worin jedoch
in Ia X durch COOH oder COOA substituiertes R5 oder R6
bedeuten;
in Ib R1, R2 jeweils unabhängig voneinander H, A oder Hal,
wobei mindestens einer der Reste R1 oder R2 immer
≠ H ist,
R3 und R4 zusammen Alkylen mit 3-5 C-Atomen, -O-CH2-CH2-,
-O-CH2-O- oder -O-CH2-CH2-O,
X durch COOH oder COOA, substituiertes R5 oder R6
bedeuten;
in Ic R1, R2 jeweils unabhängig voneinander H, A oder Hal,
wobei mindestens einer der Reste R oder R immer
≠ H ist,
R3, R4 jeweils unabhängig voneinander H, A, OA oder Hal,
R3 und R4 zusammen Alkylen mit 3-5 C-Atomen, -O-CH2-CH2-,
-O-CH2-O- oder -O-CH2-CH2-O,
X durch COOH oder COOA substituiertes R5 oder R6,
n 1 oder 2
bedeuten;
in Id R1, R2 jeweils unabhängig voneinander H, A oder Hal,
wobei einer der Reste R1 oder R2 immer ≠ H ist,
R1 und R2 zusammen auch Alkylen mit 3-5 C-Atomen,
R3, R4 jeweils unabhängig voneinander H, A, OA oder
Hal,
R3 und R4 zusammen auch -O-CH2-O-,
X einfach durch R7 substituiertes R5,
R5 lineares oder verzweigtes Alkylen mit 1-10 C-Atomen,
oder
-C6H4-CH2-,
R7 COOH oder COOA,
A Alkyl mit 1 bis 6 C-Atomen,
Hal F, Cl, Br oder I,
m 1 und
n 1 oder 2 bedeuten;
in Ie R1, R2 jeweils unabhängig voneinander H, A oder Hal,
wobei einer der Reste R1 oder R2 immer ≠ H ist,
R1 und R2 zusammen auch Alkylen mit 3-5 C-Atomen,
R3, R4 jeweils unabhängig voneinander H, A, OH, OA oder
Hal,
R3 und R4 zusammen auch -O-CH2-O-,
X einfach durch R7 substituiertes R5,
R5 lineares oder verzweigtes Alkylen mit 1-10 C-Atomen,
oder
-C6H4-CH2-,
R7 COOH oder COOA,
A Alkyl mit 1 bis 6 C-Atomen,
Hal F, Cl, Br oder I,
m 1 und
n 1 oder 2 bedeuten.The invention relates in particular to pharmaceutical formulations containing a calcium antagonist and at least one compound 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 Ie, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
in Ia X is R 5 or R 6 substituted by COOH or COOA;
in Ib R 1 , R 2 each independently of one another H, A or Hal, where at least one of the radicals R 1 or R 2 is always ≠ H,
R 3 and R 4 together alkylene with 3-5 C atoms, -O-CH 2 -CH 2 -, -O-CH 2 -O- or -O-CH 2 -CH 2 -O,
X is R 5 or R 6 substituted by COOH or COOA;
in Ic R 1 , R 2 each independently of one another H, A or Hal, where at least one of the radicals R or R is always ≠ H,
R 3 , R 4 each independently of one another H, A, OA or Hal,
R 3 and R 4 together alkylene with 3-5 C atoms, -O-CH 2 -CH 2 -, -O-CH 2 -O- or -O-CH 2 -CH 2 -O,
X is R 5 or R 6 substituted by COOH or COOA,
n 1 or 2
mean;
in Id R 1 , R 2 each independently of one another H, A or Hal, one of the radicals R 1 or R 2 always being ≠ H,
R 1 and R 2 together also alkylene with 3-5 C atoms,
R 3 , R 4 each independently of one another H, A, OA or Hal,
R 3 and R 4 together also -O-CH 2 -O-,
X is simply substituted by R 7, R 5 ,
R 5 linear or branched alkylene with 1-10 C atoms, or -C 6 H 4 -CH 2 -,
R 7 COOH or COOA,
A alkyl with 1 to 6 carbon atoms,
Hal F, Cl, Br or I,
m 1 and
n represents 1 or 2;
in Ie R 1 , R 2 each independently of one another H, A or Hal, where one of the radicals R 1 or R 2 is always ≠ H,
R 1 and R 2 together also alkylene with 3-5 C atoms,
R 3 , R 4 each independently of one another H, A, OH, OA or Hal,
R 3 and R 4 together also -O-CH 2 -O-,
X is simply substituted by R 7, R 5 ,
R 5 linear or branched alkylene with 1-10 C atoms, or -C 6 H 4 -CH 2 -,
R 7 COOH or COOA,
A alkyl with 1 to 6 carbon atoms,
Hal F, Cl, Br or I,
m 1 and
n is 1 or 2.
Gegenstand der Erfindung ist vorzugsweise eine Formulierung enthaltend 5-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno- [2,3-d]-pyrimidin-2-yl]-valeriansäure sowie dessen physiologisch unbe denklichen Salze und/oder Solvate und mindestens einen Calcium- Antagonisten.The invention preferably relates to a formulation 5- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] valeric acid and its physiologically unbe possible salts and / or solvates and at least one calcium Antagonists.
Bevorzugt ist neben der freien Säure das Ethanolaminsalz.In addition to the free acid, the ethanolamine salt is preferred.
Bevorzugte sind Calcium-Antagonisten ausgewählt aus der Gruppe der selektiven und nicht-selektiven Calcium-Antagonisten.Calcium antagonists are preferably selected from the group of selective and non-selective calcium antagonists.
Bevorzugt sind selektive Calcium-Antagonisten ausgewählt aus der Grup pe der Dihydropyridinderivate, Phenylalkylaminderivate, Benzothiazepinde rivate und anderen selektiven Calcium-Antagonisten.Selective calcium antagonists are preferably selected from the group pe of the dihydropyridine derivatives, phenylalkylamine derivatives, benzothiazepinde derivatives and other selective calcium antagonists.
Dihydropyridinderivate sind vorzugsweise ausgewählt aus der Gruppe Amlodipine, Felodipine, Isradipine, Nicardipine, Nifedipine, Nimodipine, Ni soldipine, Nitrendipine, Lacidipine, Nilvadipine, Manidipine, Barnidipine, Lercanidipine.Dihydropyridine derivatives are preferably selected from the group Amlodipine, Felodipine, Isradipine, Nicardipine, Nifedipine, Nimodipine, Ni soldipine, nitrendipine, lacidipine, nilvadipine, manidipine, barnidipine, Lercanidipine.
Die Phenylalkylaminderivate sind vorzugsweise ausgewählt aus der Grup pe Verapamil, Gallopamil. The phenylalkylamine derivatives are preferably selected from the group pe verapamil, gallopamil.
Die Benzothiazepinderivate bedeuten vorzugsweise Diltiazem.The benzothiazepine derivatives are preferably diltiazem.
Die anderen selektiven Calcium-Antagonisten bedeuten vorzugsweise Mibefradil.The other selective calcium antagonists preferably mean Mibefradil.
Die nicht-selektiven Calcium-Antagonisten sind vorzugsweise ausgewählt aus der Gruppe Fendiline, Bepridil, Lidoflazine, Perhexiline.The non-selective calcium antagonists are preferably selected from the group Fendiline, Bepridil, Lidoflazine, Perhexiline.
Die Verbindungen der Formel I und auch die Ausgangsstoffe zu ihrer Her stellung werden im übrigen nach an sich bekannten Methoden hergestellt, wie sie in der Literatur (z. B. in den Standardwerken wie Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart), be schrieben sind, und zwar unter Reaktionsbedingungen, die für die ge nannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten Varianten Gebrauch machen.The compounds of formula I and also the starting materials for their manufacture position are otherwise produced by methods known per se, as described in literature (e.g. in standard works such as Houben-Weyl, Methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart), be are written, namely under reaction conditions for the ge mentioned implementations are known and suitable. You can also do that use of known variants not mentioned here do.
In den Verbindungen der Formeln II oder III haben R1, R2, R3, R4, X und n die angegebenen Bedeutungen, insbesondere die angegebenen bevor zugten Bedeutungen.In the compounds of the formulas II or III, R 1 , R 2 , R 3 , R 4 , X and n have the meanings given, in particular the meanings given before.
Falls L eine reaktionsfähige veresterte OH-Gruppe bedeutet, so ist diese vorzugsweise Alkylsulfonyloxy mit 1-6 C-Atomen (bevorzugt Methyl sulfonyloxy) oder Arylsulfonyloxy mit 6-10 C-Atomen (bevorzugt Phenyl- oder p-Tolylsulfonyloxy, ferner auch 2-Naphthalinsulfonyloxy).If L is a reactive esterified OH group, this is preferably alkylsulfonyloxy with 1-6 C atoms (preferably methyl sulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy, and also 2-naphthalenesulfonyloxy).
Die Verbindungen der Formel I können vorzugsweise erhalten werden, in dem man Verbindungen der Formel II mit Verbindungen der Formel III um setzt.The compounds of formula I can preferably be obtained in which one around compounds of formula II with compounds of formula III puts.
Die Ausgangsstoffe können, falls erwünscht, auch in situ gebildet werden, so daß man sie aus dem Reaktionsgemisch nicht isoliert, sondern sofort weiter zu den Verbindungen der Formel I umsetzt.If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of formula I.
Andererseits ist es möglich, die Reaktion stufenweise durchzuführen. On the other hand, it is possible to carry out the reaction in stages.
Die Ausgangsverbindungen der Formel II und III sind in der Regel bekannt. Sind sie nicht bekannt, so können sie nach an sich bekannten Methoden hergestellt werden.The starting compounds of the formula II and III are generally known. If they are not known, they can be made using methods known per se getting produced.
Verbindungen der Formel II können z. B. durch Umsetzung mit POCl3 aus Verbindungen erhalten werden, die aus Thiophenderivaten und CN- substituierten Alkylencarbonsäureestern aufgebaut werden (Eur. J. Med. Chem. 23, 453 (1988).Compounds of formula II can, for. B. be obtained by reaction with POCl 3 from compounds which are built up from thiophene derivatives and CN-substituted alkylene carboxylic acid esters (Eur. J. Med. Chem. 23, 453 (1988).
Im einzelnen erfolgt die Umsetzung der Verbindungen der Formel II mit den Verbindungen der Formel III in Gegenwart oder Abwesenheit eines inerten Lösungsmittels bei Temperaturen zwischen etwa -20 und etwa 150°, vorzugsweise zwischen 20 und 100°.In detail, the compounds of the formula II are reacted with the compounds of formula III in the presence or absence of a inert solvent at temperatures between about -20 and about 150 °, preferably between 20 and 100 °.
Der Zusatz eines säurebindenden Mittels, beispielsweise eines Alkali- oder Erdalkalimetall-hydroxids, -carbonats oder -bicarbonats oder eines ande ren Salzes einer schwachen Säure der Alkali- oder Erdalkalimetalle, vor zugsweise des Kaliums, Natriums oder Calciums, oder der Zusatz einer organischen Base wie Triethylamin, Dimethylamin, Pyridin oder Chinolin oder eines Überschusses der Aminkomponente kann günstig sein.The addition of an acid-binding agent, for example an alkali or Alkaline earth metal hydroxides, carbonates or bicarbonates or another salt of a weak acid of the alkali or alkaline earth metals preferably of potassium, sodium or calcium, or the addition of a organic base such as triethylamine, dimethylamine, pyridine or quinoline or an excess of the amine component may be beneficial.
Als inerte Lösungsmittel eignen sich z. B. Kohlenwasserstoffe wie Hexan, Petrolether, Benzol, Toluol oder Xylol; chlorierte Kohlenwassertoffe wie Trichlorethylen, 1,2-Dichlorethan, Tetrachlorkohlenstoff, Chloroform oder Dichlormethan; Alkohole wie Methanol, Ethanol, Isopropanol, n-Propanol, n-Butanol oder tert.-Butanol; Ether wie Diethylether, Diisopropylether, Te trahydrofuran (THF) oder Dioxan; Glykolether wie Ethylenglykolmono methyl- oder -monoethylether (Methylglykol oder Ethylglykol), Ethylen glykoldimethylether (Diglyme); Ketone wie Aceton oder Butanon; Amide wie Acetamid, Dimethylacetamid, N-Methylpyrrolidon oder Dimethylform amid (DMF); Nitrile wie Acetonitril; Sulfoxide wie Dimethylsulfoxid (DMSO); Nitroverbindungen wie Nitromethan oder Nitrobenzol; Ester wie Ethylacetat oder Gemische der genannten Lösungsmittel.Suitable inert solvents are, for. B. 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, Te trahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol mono methyl 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 dimethyl form amide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.
Es ist ferner möglich, in einer Verbindung der Formel I einen Rest X in ei nen anderen Rest X umzuwandeln, z. B. indem man einen Ester oder eine Cyangruppe zu einer COOH-Gruppe hydrolysiert. It is also possible in a compound of the formula I to have a radical X in an egg to convert another X, e.g. B. by using an ester or a Cyan group hydrolyzed to a COOH group.
Estergruppen können z. B. mit NaOH oder KOH in Wasser, Wasser-THF oder Wasser-Dioxan bei Temperaturen zwischen 0 und 100° verseift wer den.Ester groups can e.g. B. with NaOH or KOH in water, water-THF or saponified water-dioxane at temperatures between 0 and 100 ° the.
Carbonsäuren können z. B. mit Thionylchlorid in die entsprechenden Car bonsäurechloride und diese in Carbonsäureamide umgewandelt werden. Durch Wasserabspaltung in bekannter Weise erhält man aus diesen Car bonitrile.Carboxylic acids can e.g. B. with thionyl chloride in the corresponding car acid chlorides and these are converted into carboxamides. By dehydration in a known manner, you get from this car bonitrile.
Eine Säure der Formel I kann mit einer Base in das zugehörige Säure additionssalz übergeführt werden, beispielsweise durch Umsetzung äqui valenter Mengen der Säure und der Base in einem inerten Lösungsmittel wie Ethanol und anschließendes Eindampfen. Für diese Umsetzung kom men insbesondere Basen in Frage, die physiologisch unbedenkliche Salze liefern.An acid of formula I can with a base in the associated acid addition salt can be transferred, for example by reaction equi valent amounts of the acid and the base in an inert solvent such as ethanol and subsequent evaporation. For this implementation Men in particular bases, the physiologically acceptable salts deliver.
So kann die Säure der Formel I mit einer Base (z. B. Natrium- oder Kali umhydroxid oder -carbonat) in das entsprechende Metall-, insbesondere Alkalimetall- oder Erdalkalimetall-, oder in das entsprechende Ammonium salz umgewandelt werden.For example, the acid of formula I can be mixed with a base (e.g. sodium or potassium umhydroxid or carbonate) in the corresponding metal, in particular Alkali metal or alkaline earth metal, or in the corresponding ammonium salt are converted.
Für diese Umsetzung kommen insbesondere auch organische Basen in Frage, die physiologisch unbedenkliche Salze liefern, wie z. B. Ethanol amin.Organic bases are particularly suitable for this implementation Question that provide physiologically acceptable salts, such as. B. ethanol amine.
Eine Säure der Formel I kann mit einer Base in das zugehörige Säure additionssalz übergeführt werden, beispielsweise durch Umsetzung äqui valenter Mengen der Säure und der Base in einem inerten Lösungsmittel wie Ethanol und anschließendes Eindampfen. Für diese Umsetzung kom men insbesondere Basen in Frage, die physiologisch unbedenkliche Salze liefern.An acid of formula I can with a base in the associated acid addition salt can be transferred, for example by reaction equi valent amounts of the acid and the base in an inert solvent such as ethanol and subsequent evaporation. For this implementation Men in particular bases, the physiologically acceptable salts deliver.
So kann die Säure der Formel I mit einer Base (z. B. Natrium- oder Kali umhydroxid oder -carbonat) in das entsprechende Metall-, insbesondere Alkalimetall- oder Erdalkalimetall-, oder in das entsprechende Ammonium salz umgewandelt werden.For example, the acid of formula I can be mixed with a base (e.g. sodium or potassium umhydroxid or carbonate) in the corresponding metal, in particular Alkali metal or alkaline earth metal, or in the corresponding ammonium salt are converted.
Für diese Umsetzung kommen insbesondere auch organische Basen in Frage, die physiologisch unbedenkliche Salze liefern, wie z. B. Ethanol amin. Organic bases are particularly suitable for this implementation Question that provide physiologically acceptable salts, such as. B. ethanol amine.
Andererseits kann eine Base der Formel I mit einer Säure in das zugehö rige Säureadditionssalz übergeführt werden, beispielsweise durch Umset zung äquivalenter Mengen der Base und der Säure in einem inerten Lö sungsmittel wie Ethanol und anschließendes Eindampfen. Für diese Um setzung kommen insbesondere Säuren in Frage, die physiologisch unbe denkliche Salze liefern. So können anorganische Säuren verwendet wer den, z. B. Schwefelsäure, Salpetersäure, Halogenwasserstoffsäuren wie Chlorwasserstoffsäure oder Bromwasserstoffsäure, Phosphorsäuren wie Orthophosphorsäure, Sulfaminsäure, ferner organische Säuren, insbe sondere aliphatische, alicyclische, araliphatische, aromatische oder he terocyclische ein- oder mehrbasige Carbon-, Sulfon- oder Schwefelsäuren, z. B. Ameisensäure, Essigsäure, Propionsäure, Pivalinsäure, Diethylessig säure, Malonsäure, Bernsteinsäure, Pimelinsäure, Fumarsäure, Malein säure, Milchsäure, Weinsäure, Äpfelsäure, Citronensäure, Gluconsäure, Ascorbinsäure, Nicotinsäure, Isonicotinsäure, Methan- oder Ethansulfon säure, Ethandisulfonsäure, 2-Hydroxyethansulfonsäure, Benzolsulfon säure, p-Toluolsulfonsäure, Naphthalin-mono- und -disulfonsäuren, Lauryl schwefelsäure. Salze mit physiologisch nicht unbedenklichen Säuren, z. B. Pikrate, können zur Isolierung und/oder Aufreinigung der Verbindungen der Formel I verwendet werden.On the other hand, a base of formula I with an acid can be added to the acid addition salt are transferred, for example by conversion equivalent amounts of the base and the acid in an inert Lö solvent such as ethanol and subsequent evaporation. For this order Settling in particular acids that are physiologically unintended delivering saline salts. So you can use inorganic acids the, e.g. B. sulfuric acid, nitric acid, hydrohalic acids such as Hydrochloric acid or hydrobromic acid, phosphoric acids such as Orthophosphoric acid, sulfamic acid, also organic acids, esp special aliphatic, alicyclic, araliphatic, aromatic or he terocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, z. B. formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malein acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, Ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfone acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfone acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. B. Picrates, can be used to isolate and / or purify the compounds of formula I can be used.
Gegenstand der Erfindung sind ferner pharmazeutische Formulierungen enthaltend mindestens eine Verbindung der Formel I und/oder eines ihrer physiologisch unbedenklichen Salze und mindestens einen Calcium- Antagonisten sowie enthaltend einen oder mehrere Träger- und/oder Hilfs stoffe.The invention further relates to pharmaceutical formulations containing at least one compound of formula I and / or one of them physiologically acceptable salts and at least one calcium Antagonists and containing one or more carriers and / or auxiliaries substances.
Die Herstellung der pharmazeutischer Zubereitungen geschieht insbeson dere auf nicht-chemischem Wege. Hierbei werden die Wirkstoffe zusam men mit mindestens einem festen, flüssigen und/oder halbflüssigen Trä ger- oder Hilfsstoff in eine geeignete Dosierungsform gebracht werden.The pharmaceutical preparations are manufactured in particular the non-chemical way. The active ingredients are combined men with at least one solid, liquid and / or semi-liquid tear ger- or excipient are brought into a suitable dosage form.
Diese Zubereitungen können als Arzneimittel in der Human- oder Veteri närmedizin verwendet werden. Als Trägerstoffe kommen organische oder anorganische Substanzen in Frage, die sich für die enterale (z. B. orale), parenterale oder topische Applikation eignen und mit den neuen Verbin dungen nicht reagieren, beispielsweise Wasser, pflanzliche Öle, Benzylalkohole, Alkylenglykole, Polyethylenglykole, Glycerintriacetat, Gelatine, Kohlehydrate wie Lactose oder Stärke, Magnesiumstearat, Talk, Vaseline. Zur oralen Anwendung dienen insbesondere Tabletten, Pillen, Dragees, Kapseln, Pulver, Granulate, Sirupe, Säfte oder Tropfen, zur rektalen An wendung Suppositorien, zur parenteralen Anwendung Lösungen, vor zugsweise ölige oder wässrige Lösungen, ferner Suspensionen, Emulsio nen oder Implantate, für die topische Anwendung Salben, Cremes oder Puder. Die neuen Verbindungen können auch lyophilisiert und die erhalte nen Lyophilisate z. B. zur Herstellung von Injektionspräparaten verwendet werden. Die angegebenen Zubereitungen können sterilisiert sein und/oder Hilfsstoffe wie Gleit-, Konservierungs-, Stabilisierungs- und/oder Netzmit tel, Emulgatoren, Salze zur Beeinflussung des osmotischen Druckes, Puffersubstanzen, Farb-, Geschmacks- und /oder mehrere weitere Wirk stoffe enthalten, z. B. ein oder mehrere Vitamine. Sie könne ferner als Na sensprays verabreicht werden.These preparations can be used as medicinal products in human or veteri used in medicine. Organic or inorganic substances in question that are suitable for enteral (e.g. oral), parenteral or topical application and with the new compound not react, e.g. 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, coated tablets, Capsules, powder, granules, syrups, juices or drops, for rectal application suppositories, for parenteral application solutions preferably oily or aqueous solutions, further suspensions, emulsions or implants, for topical application of ointments, creams or Powder. The new compounds can also be lyophilized and obtained NEN lyophilisates e.g. B. used for the preparation of injectables become. The specified preparations can be sterilized and / or Auxiliaries such as lubricants, preservatives, stabilizers and / or Netzmit tel, emulsifiers, salts to influence the osmotic pressure, Buffer substances, color, taste and / or several other active ingredients contain substances, e.g. B. one or more vitamins. You can also as Na sensprays are administered.
Dabei werden die Substanzen in der Regel vorzugsweise in Dosierungen zwischen etwa 1 und 500 mg, insbesondere zwischen 5 und 100 mg pro Dosierungseinheit verabreicht. Die tägliche Dosierung liegt vorzugsweise zwischen etwa 0,02 und 10 mg/kg Körpergewicht. Die spezielle Dosis für jeden Patienten hängt jedoch von den verschiedensten Faktoren ab, bei spielsweise von der Wirksamkeit der eingesetzten speziellen Verbindung, vom Alter, Körpergewicht, allgemeinen Gesundheitszustand, Geschlecht, von der Kost, vom Verabreichungszeitpunkt und -weg, von der Ausschei dungsgeschwindigkeit, Arzneistoffkombination und Schwere der jeweiligen Erkrankung, welcher die Therapie gilt. Die orale Applikation ist bevorzugt.The substances are usually preferably in doses between about 1 and 500 mg, in particular between 5 and 100 mg per Dosage unit administered. The daily dosage is preferably between about 0.02 and 10 mg / kg body weight. The special dose for however, each patient depends on a variety of factors for example on the effectiveness of the special connection used, on age, body weight, general health, gender, of the food, the time and route of administration, the excretion application rate, drug combination and severity of each Disease to which the therapy applies. Oral application is preferred.
Gegenstand der Erfindung ist daher auch die Verwendung der beschrie benen pharmazeutischen Zubereitungen zur Herstellung eines Arznei mittels zur Behandlung von Angina, Bluthochdruck, pulmonalem Hoch druck, congestivem Herzversagen (CHF), chronischer obstruktiver pulmo naler Krankheit (COPD), Cor pulmonale, Rechtsherzinsuffizienz, Athe rosklerose, Bedingungen verminderter Durchgängigkeit der Herzgefäße, peripheren vaskulären Krankheiten, Schlaganfall, Bronchitis, allergischem Asthma, chronischem Asthma, allergischer Rhinitis, Glaucom, Irritable Bowel Syndrome, Tumoren, Niereninsuffizienz, Leberzirrhose und zur Be handlung weiblicher Sexualstörungen.The invention therefore also relates to the use of the described benen pharmaceutical preparations for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, congestive heart failure (CHF), chronic obstructive pulmo nal disease (COPD), cor pulmonale, right heart failure, athe rosclerosis, conditions of decreased patency of the heart vessels, peripheral vascular diseases, stroke, bronchitis, allergic Asthma, Chronic Asthma, Allergic Rhinitis, Glaucoma, Irritable Bowel Syndromes, tumors, renal failure, cirrhosis of the liver and act of female sexual disorders.
Gegenstand der Erfindung ist insbesondere die Verwendung der erfin dungsgemäßen Formulierungen zur Herstellung eines Arzneimittels zur Behandlung von pulmonalem Hochdruck, congestivem Herzversagen (CHF), chronischer obstruktiver pulmonaler Krankheit (COPD), Cor pulmo nale und/oder Rechtsherzinsuffizienz.The invention relates in particular to the use of the invention formulations according to the invention for the manufacture of a medicament for Treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmo nal and / or right heart failure.
Die Bestandteile der neuen pharmazeutischen Zubereitung werden vor zugsweise kombiniert verabreicht. Sie können aber auch einzeln gleichzei tig oder aufeinanderfolgend verabreicht werden.The components of the new pharmaceutical preparation are pre preferably administered in combination. You can also do it individually at the same time dosed or sequentially.
Gegenstand der Erfindung ist auch ein Set (Kit), bestehend aus getrennten
Packungen von
The invention also relates to a set (kit) consisting of separate packs of
- a) einer wirksamen Menge an 5-[4-(3-Chlor-4-methoxy-benzylamino)- 5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]- valeriansäure, Ethanolaminsalza) an effective amount of 5- [4- (3-chloro-4-methoxy-benzylamino) - 5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] - valeric acid, ethanolamine salt
undand
- a) einer wirksamen Menge eines Calcium-Antagonisten.a) an effective amount of a calcium antagonist.
Das Set enthält geeignete Behälter, wie Schachteln oder Kartons, indivi duelle Flaschen, Beutel oder Ampullen. Das Set kann z. B. separate Am pullen enthalten, in denen jeweils eine wirksame Menge an 5-[4-(3-Chlor- 4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]- pyrimidin-2-yl]-valeriansäure, Ethanolaminsalz und des Calcium- Antagonisten gelöst oder in lyophylisierter Form vorliegt.The set contains suitable containers, such as boxes or boxes, individually dual bottles, bags or ampoules. The set can e.g. B. separate Am contain pullen, in each of which an effective amount of 5- [4- (3-chloro 4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] - pyrimidin-2-yl] valeric acid, ethanolamine salt and calcium Antagonists dissolved or in lyophilized form.
Vor- und nachstehend sind alle Temperaturen in °C angegeben. In den
nachfolgenden Beispielen bedeutet "übliche Aufarbeitung": Man gibt, falls
erforderlich, Wasser hinzu, stellt, falls erforderlich, je nach Konstitution des
Endprodukts auf pH-Werte zwischen 2 und 10 ein, extrahiert mit Ethyla
cetat oder Dichlormethan, trennt ab, trocknet die organische Phase über
Natriumsulfat, dampft ein und reinigt durch Chromatographie an Kieselgel
und/oder durch Kristallisation.
Massenspektrometrie (MS):
EI (Elektronenstoß-Ionisation) M+
FAB (Fast Atom Bombardment) (M + H)+ All temperatures above and below are given in ° C. In the following examples, "customary work-up" means: if necessary, water is added, if necessary, depending on the constitution of the end product, to a pH between 2 and 10, extracted with ethyl acetate or dichloromethane, separated, dried the organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.
Mass spectrometry (MS):
EI (electron impact ionization) M +
FAB (Fast Atom Bombardment) (M + H) +
1,9 g 3-(4-Chlor-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)- propionsäuremethylester [erhältlich durch Cyclisierung von 2-Amino- 4,5,6,7-tetrahydrobenzothiophen-3-carbonsäuremethylester mit 3- Cyanpropionsäuremethylester und nachfolgender Chlorierung mit Phos phoroxichlorid/Dimethylamin] und 2,3 g 3-Chlor-4-methoxybenzylamin ("A") in 20 ml N-Methylpyrrolidon werden 5 Stunden bei 110° gerührt. Das Lö sungsmittel wird entfernt und wie üblich aufgearbeitet. Man erhält 2,6 g 3- [4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno- [2,3-d]-pyrimidin-2-yl]-propionsäuremethylester als farbloses Öl.1.9 g 3- (4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl) - methyl propionate [obtainable by cyclization of 2-amino 4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid methyl ester with 3- Methyl cyanopropionate and subsequent chlorination with Phos phoroxichloride / dimethylamine] and 2.3 g of 3-chloro-4-methoxybenzylamine ("A") in 20 ml of N-methylpyrrolidone are stirred at 110 ° for 5 hours. The Lö Solvent is removed and worked up as usual. 2.6 g of 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno Methyl [2,3-d] pyrimidin-2-yl] propionate as a colorless oil.
Analog erhält man durch Umsetzung von "A"
mit 3-(4-Chlor-5,6-cyclopenteno-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
propionsäuremethylester
3-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-cyclopenteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-propionsäuremethylester;
mit 3-(4-Chlor-5,6-cyclohepteno-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
propionsäuremethylester
3-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-cyclohepteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-propionsäuremethylester;
mit 3-(4-Chlor-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-propionsäure
methylester
3-[4-(3-Chlor-4-methoxy-benzylamino)-6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-propionsäuremethylester;
mit 3-(4-Chlor-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-propionsäure
methylester
3-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-dimethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-propionsäuremethylester;
mit 3-(4-Chlor-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-propionsäure
methylester
3-[4-(3-Chlor-4-methoxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-propionsäuremethylester;
mit 3-(4,6-Dichlor-thieno-[2,3-d]-pyrimidin-2-yl)-propionsäuremethylester
3-[4-(3-Chlor-4-methoxy-benzylamino)-6-chlor-thieno-[2,3-d]-
pyrimidin-2-yl]-propionsäuremethylester;
mit 2-(4-Chlor-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
essigsäuremethylester
2-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-essigsäuremethylester.Analogously, by converting "A"
with methyl 3- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) propionate
3- [4- (3-chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] propionic acid methyl ester;
with methyl 3- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) propionate 3- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno - [2,3-d] - pyrimidin-2-yl] propionic acid methyl ester;
with 2- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) methyl acetate
Methyl 2- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno [2,3-d] pyrimidin-2-yl] acetic acid.
Analog erhält man durch Umsetzung von 3,4-Methylendioxybenzylamin
mit 3-(4-Chlor-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
propionsäuremethylester
3-[4-(3,4-Methylendioxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-propionsäuremethylester;
mit 3-(4-Chlor-5,6-cyclopenteno-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
propionsäuremethylester
3-[4-(3,4-Methylendioxy-benzylamino)-5,6-cyclopenteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-propionsäuremethylester;
mit 3-(4-Chlor-5,6-cyclohepteno-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
propionsäuremethylester
3-[4-(3,4-Methylendioxy-benzylamino)-5,6-cyclohepteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-propionsäuremethylester;
mit 3-(4-Chlor-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-propionsäure
methylester
3-[4-(3,4-Methylendioxy-benzylamino)-6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-propionsäuremethylester;
mit 3-(4-Chlor-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-propionsäure
methylester
3-[4-(3,4-Methylendioxy-benzylamino)-5,6-dimethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-propionsäuremethylester;
mit 3-(4-Chlor-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-propionsäure
methylester
3-[4-(3,4-Methylendioxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-propionsäuremethylester;
mit 3-(4,6-Dichlor-thieno-[2,3-d]-pyrimidin-2-yl)-propionsäuremethylester
3-[4-(3,4-Methylendioxy-benzylamino)-6-chlor-thieno-[2,3-d]-
pyrimidin-2-yl]-propionsäuremethylester.Analogously, reaction of 3,4-methylenedioxybenzylamine with 3- (4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl) - propionate
Methyl 3- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl) propionate
3- [4- (3,4-methylenedioxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid methyl ester;
with methyl 3- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) propionate
3- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] propionic acid methyl ester;
with methyl 3- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) propionate 3- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno- [ 2,3-d] - pyrimidin-2-yl] propionic acid methyl ester.
Analog erhält man durch Umsetzung von "A"
mit 4-(4-Chlor-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
buttersäuremethylester
4-[4-(3-Chlor-4-methoxy-benzylamino)-5, 6, 7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-buttersäuremethylester;
mit 4-(4-Chlor-5,6-cyclopenteno-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
buttersäuremethylester
4-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-cyclopenteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-buttersäuremethylester;
mit 4-(4-Chlor-5,6-cyclohepteno-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
buttersäuremethylester
4-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-cyclohepteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-buttersäuremethylester;
mit 4-(4-Chlor-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-buttersäure
methylester
4-[4-(3-Chlor-4-methoxy-benzylamino)-6-methyl-thieno-[2,3-d)-
pyrimidin-2-yl]-buttersäuremethylester;
mit 4-(4-Chlor-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-buttersäure
methylester
4-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-dimethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-buttersäuremethylester;
mit 4-(4-Chlor-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-buttersäuremethylester
4-[4-(3-Chlor-4-methoxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-buttersäuremethylester;
mit 4-(4,6-Chlor-6-chlor-thieno-[2,3-d]-pyrimidin-2-yl)-buttersäure
methylester
4-[4-(3-Chlor-4-methoxy-benzylamino)-6-chlor-thieno-[2,3-d]-
pyrimidin-2-yl]-buttersäuremethylester.Analogously, by converting "A"
with 4- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester
4- [4- (3-Chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl] butyric acid methyl ester;
with 4- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester
Methyl 4- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] butyrate;
with 4- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester
4- [4- (3-Chloro-4-methoxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid methyl ester;
with 4- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester
4- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d) pyrimidin-2-yl] butyric acid methyl ester;
with 4- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester
Methyl 4- [4- (3-chloro-4-methoxy-benzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] butyrate;
with 4- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3-chloro-4-methoxy-benzylamino) -6-ethyl -thieno- [2,3-d] - pyrimidin-2-yl] -butyric acid methyl ester;
with 4- (4,6-chloro-6-chlorothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3-chloro-4-methoxy-benzylamino) - 6-chlorothieno [2,3-d] pyrimidin-2-yl] butyric acid methyl ester.
Analog erhält man durch Umsetzung von 3,4-Methylendioxybenzylamin
mit 4-(4-Chlor-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
buttersäuremethylester
4-[4-(3,4-Methylendioxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-buttersäuremethylester;
mit 4-(4-Chlor-5,6-cyclopenteno-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
buttersäuremethylester
4-[4-(3,4-Methylendioxy-benzylamino)-5,6-cyclopenteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-buttersäuremethylester;
mit 4-(4-Chlor-5,6-cyclohepteno-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
buttersäuremethylester
4-[4-(3,4-Methylendioxy-benzylamino)-5,6-cyclohepteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-buttersäuremethylester;
mit 4-(4-Chlor-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-buttersäure
methylester
4-[4-(3,4-Methylendioxy-benzylamino)-6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-buttersäuremethylester;
mit 4-(4-Chlor-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-buttersäure
methylester
4-[4-(3,4-Methylendioxy-benzylamino)-5,6-dimethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-buttersäuremethylester;
mit 4-(4-Chlor-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-buttersäuremethylester
4-[4-(3,4-Methylendioxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-buttersäuremethylester;
mit 4-(4,6-Dichlor-thieno-[2,3-d]-pyrimidin-2-yl)-buttersäuremethylester
4-[4-(3,4-Methylendioxy-benzylamino)-6-chlor-thieno-[2,3-d]-
pyrimidin-2-yl]-buttersäuremethylester.An analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine
with 4- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester
Methyl 4- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl] butyrate;
with 4- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester
4- [4- (3,4-methylenedioxy-benzylamino) -5,6-cyclopenteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid methyl ester;
with 4- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester
4- [4- (3,4-methylenedioxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid methyl ester;
with 4- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester
4- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid methyl ester;
with 4- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester
4- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] butyric acid methyl ester;
with 4- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno - [2,3-d] - pyrimidin-2-yl] butyric acid methyl ester;
with 4- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno- [ 2,3-d] - pyrimidin-2-yl] butyric acid methyl ester.
Analog erhält man durch Umsetzung von "A"
mit 5-(4-Chlor-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
valeriansäuremethylester
5-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-valeriansäuremethylester;
mit 5-(4-Chlor-5,6-cyclopenteno-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
valeriansäuremethylester
5-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-cyclopenteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-valeriansäuremethylester;
mit 5-(4-Chlor-5,6-cyclohepteno-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
valeriansäuremethylester
5-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-cyclohepteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-valeriansäuremethylester;
mit 5-(4-Chlor-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-valeriansäure
methylester
5-[4-(3-Chlor-4-methoxy-benzylamino)-6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäuremethylester;
mit 5-(4-Chlor-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-valeriansäure
methylester
5-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-dimethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäuremethylester;
mit 5-(4-Chlor-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-valeriansäure
methylester
5-[4-(3-Chlor-4-methoxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäuremethylester;
mit 5-(4,6-Dichlor-thieno-[2,3-d]-pyrimidin-2-yl)-valeriansäuremethylester
5-[4-(3-Chlor-4-methoxy-benzylamino)-6-chlor-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäuremethylester.Analogously, by converting "A"
with 5- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester
5- [4- (3-Chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;
with 5- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester
5- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclopenteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;
with methyl 5- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl)
5- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;
with 5- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester
5- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;
with 5- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester
5- [4- (3-chloro-4-methoxy-benzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;
with 5- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester
5- [4- (3-Chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;
with 5- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester 5- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno - [2,3-d] - pyrimidin-2-yl] valeric acid methyl ester.
Analog erhält man durch Umsetzung von 3,4-Methylendioxybenzylamin
mit 5-(4-Chlor-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
vaieriansäuremethylester
5-[4-(3,4-Methylendioxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-valeriansäuremethylester;
mit 5-(4-Chlor-5,6-cyclopenteno-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
valeriansäuremethylester
5-[4-(3,4-Methylendioxy-benzylamino)-5,6-cyclopenteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-valeriansäuremethylester;
mit 5-(4-Chlor-5,6-cyclohepteno-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
valeriansäuremethylester
5-[4-(3,4-Methylendioxy-benzylamino)-5,6-cyclohepteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-valeriansäuremethylester;
mit 5-(4-Chlor-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-
valeriansäuremethylester
5-[4-(3,4-Methylendioxy-benzylamino)-6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäuremethylester;
mit 5-(4-Chlor-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-
valeriansäuremethylester
5-[4-(3,4-Methylendioxy-benzylamino)-5,6-dimethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäuremethylester;
mit 5-(4-Chlor-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-
valeriansäuremethylester
5-[4-(3,4-Methylendioxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäuremethylester;
mit 5-(4,6-Dichlor-thieno-[2,3-d]-pyrimidin-2-yl)-valeriansäuremethylester
5-[4-(3,4-Methylendioxy-benzylamino)-6-chlor-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäuremethylester.An analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine
with 5- (4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) - vaieric acid methyl ester
Methyl 5- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid;
with 5- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester
Methyl 5- [4- (3,4-methylenedioxy-benzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] valerate;
with methyl 5- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl)
5- [4- (3,4-methylenedioxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;
with 5- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester
Methyl 5- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valerate;
with 5- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester
5- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;
with 5- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester
5- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;
with 5- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester 5- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno- [ 2,3-d] - pyrimidin-2-yl] -valeric acid methyl ester.
Analog erhält man durch Umsetzung von "A"
mit 7-(4-Chlor-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
heptansäuremethylester
7-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-heptansäuremethylester;
mit 7-(4-Chlor-5,6-cyclopenteno-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
heptansäuremethylester
7-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-cyclopenteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-heptansäuremethylester;
mit 7-(4-Chlor-5,6-cyclohepteno-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
heptansäuremethylester
7-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-cyclohepteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-heptansäuremethylester;
mit 7-(4-Chlor-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-heptansäure
methylester
7-[4-(3-Chlor-4-methoxy-benzylamino)-6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-heptansäuremethylester;
mit 7-(4-Chlor-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-heptansäure
methylester
7-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-dimethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-heptansäuremethylester;
mit 7-(4-Chlor-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-heptansäure
methylester
7-[4-(3-Chlor-4-methoxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-heptansäuremethylester;
mit 7-(4-Chlor-6-chlor-thieno-[2,3-d]-pyrimidin-2-yl)-heptansäure
methylester
7-[4-(3-Chlor-4-methoxy-benzylamino)-6-chlor-thieno-[2,3-d]-
pyrimidin-2-yl]-heptansäuremethylester.Analogously, by converting "A"
with 7- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester
7- [4- (3-Chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] heptanoic acid methyl ester;
with 7- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester
7- [4- (3-Chloro-4-methoxy-benzylamino) -5,6-cyclopenteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] heptanoic acid methyl ester;
with 7- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester
7- [4- (3-Chloro-4-methoxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] heptanoic acid methyl ester;
with 7- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester
7- [4- (3-Chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid methyl ester;
with 7- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester
7- [4- (3-Chloro-4-methoxy-benzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid methyl ester;
with 7- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester
7- [4- (3-Chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid methyl ester;
with 7- (4-chloro-6-chlorothieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester
Methyl 7- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] -heptanoate.
Analog erhält man durch Umsetzung von 3,4-Methylendioxybenzylamin
mit 7-(4-Chlor-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
heptansäuremethylester
7-[4-(3,4-Methylendioxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-heptansäuremethylester;
mit 7-(4-Chlor-5,6-cyclopenteno-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
heptansäuremethylester
7-[4-(3,4-Methylendioxy-benzylamino)-5,6-cyclopenteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-heptansäuremethylester;
mit 7-(4-Chlor-5,6-cyclohepteno-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
heptansäuremethylester
7-[4-(3,4-Methylendioxy-benzylamino)-5,6-cyclohepteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-heptansäuremethylester;
mit 7-(4-Chlor-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-
heptansäuremethylester
7-[4-(3,4-Methylendioxy-benzylamino)-6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäuremethylester;
mit 7-(4-Chlor-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-
heptansäuremethylester
7-[4-(3,4-Methylendioxy-benzylamino)-5,6-dimethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-heptansäuremethylester;
mit 7-(4-Chlor-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-
heptansäuremethylester
7-[4-(3,4-Methylendioxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-heptansäuremethylester;
mit 7-(4,6-Dichlor-thieno-[2,3-d]-pyrimidin-2-yl)-heptansäuremethylester
7-[4-(3,4-Methylendioxy-benzylamino)-6-chlor-thieno-[2,3-di]-
pyrimidin-2-yl]-heptansäuremethylester.An analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine
with 7- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester
7- [4- (3,4-Methylenedioxy-benzylamino) -5,6,7,8-tetrahydro- [1] benzothieno- [2,3-d] pyrimidin-2-yl] heptanoic acid methyl ester;
with 7- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester
7- [4- (3,4-Methylenedioxy-benzylamino) -5,6-cyclopenteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] -heptanoic acid methyl ester;
with 7- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester
7- [4- (3,4-Methylenedioxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] heptanoic acid methyl ester;
with 7- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester
7- [4- (3,4-Methylenedioxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;
with 7- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester
7- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid methyl ester;
with 7- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester
7- [4- (3,4-Methylenedioxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid methyl ester;
with 7- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester 7- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno- [ 2,3-di] - pyrimidin-2-yl] heptanoic acid methyl ester.
Analog erhält man durch Umsetzung von "A"
mit 2-[4-(4-Chlor-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
cyclohexyl-1-yl]-essigsäuremethylester
2-{4-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-cyclohexyl-1-yl}-
essigsäuremethylester;
mit 2-[4-(4-Chlor-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-cyclohexyl-1-yl]-es
sigsäuremethylester
2-{4-[4-(3-Chlor-4-methoxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-cyclohexyl-1-yl}-essigsäuremethylester;Analogously, by converting "A"
with 2- [4- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) cyclohexyl-1-yl] acetic acid methyl ester
2- {4- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] -cyclohexyl-1-yl} - methyl acetate;
with 2- [4- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) cyclohexyl-1-yl] es methyl acetate
Methyl 2- {4- [4- (3-chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] cyclohexyl-1-yl} acetic acid;
Analog erhält man durch Umsetzung von 3,4-Methylendioxybenzylamin
mit 2-[4-(4-Chlor-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
cyclohexyl-1-yl]-essigsäuremethylester
2-{4-[4-(3,4-Methyiendioxy-benzyiamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-cyclohexyl-1-yl}-
essigsäuremethylester.
An analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine
with 2- [4- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) cyclohexyl-1-yl] acetic acid methyl ester
2- {4- [4- (3,4-Methienedioxy-benzyiamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl] cyclohexyl -1-yl} - methyl acetate.
Analog erhält man durch Umsetzung von Benzylamin
mit 3-(4-Chlor-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
propionsäuremethylester
3-(4-Benzylamino-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-
pyrimidin-2-yl)-propionsäuremethylester;
mit 4-(4-Chlor-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
buttersäuremethylester
4-(4-Benzylamino-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-
pyrimidin-2-yl)-buttersäuremethylester;
mit 5-(4-Chlor-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-
valeriansäuremethylester
5-(4-Benzylamino-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-
pyrimidin-2-yl)-valeriansäuremethylester;
mit 4-(4-Chlor-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-buttersäure
methylester
4-[4-Benzylamino-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-
buttersäuremethylester;
mit 5-(4-Chlor-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-valeriansäure
methylester
5-[4-Benzylamino-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl]-
valeriansäuremethylester.One obtains analogously by conversion of benzylamine
with methyl 3- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) propionate
3- (4-Benzylamino-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) propionic acid methyl ester;
with 4- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester
4- (4-Benzylamino-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) -butyric acid methyl ester;
with 5- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester
5- (4-Benzylamino-5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] - pyrimidin-2-yl) -valeric acid methyl ester;
with 4- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester
4- [4-benzylamino-6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid methyl ester;
with 5- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester
5- [4-Benzylamino-6-ethylthieno [2,3-d] pyrimidin-2-yl] methyl valerate.
2,2 g 3-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]- benzothieno-[2,3-d]-pyrimidin-2-yl]-propionsäuremethylester wird in 20 ml Ethylenglycolmonomethylether gelöst und nach Zugabe von 10 ml 32%iger NaOH 5 Stunden bei 110° gerührt. Nach Zugabe von 20%iger HCl wird mit Dichlormethan extrahiert. Durch Zugabe von Petrolether erhält man 2,0 g 3-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]- benzothieno-[2,3-d]-pyrimidin-2-yl]-propionsäure, F. 229°. 2.2 g 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid methyl ester is in 20 ml Ethylene glycol monomethyl ether dissolved and after adding 10 ml of 32% NaOH stirred at 110 ° for 5 hours. After adding 20% HCl is extracted with dichloromethane. Obtained by adding petroleum ether 2.0 g of 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno [2,3-d] pyrimidin-2-yl] propionic acid, mp 229 °.
Die ausgefallenen Kristalle werden in 30 ml Isopropanol gelöst und mit 0,5 g Ethanolamin versetzt. Nach Kristallisation erhält man 1,35 g 3-[4-(3- Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]- pyrimidin-2-yl]-propionsäure, Ethanolaminsalz, F. 135°.The precipitated crystals are dissolved in 30 ml of isopropanol and with 0.5 g Ethanolamine added. After crystallization, 1.35 g of 3- [4- (3- Chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] - pyrimidin-2-yl] propionic acid, ethanolamine salt, mp 135 °.
Analog erhält man aus den unter Beispiel 1 aufgeführten Estern die nach
stehenden Carbonsäuren:
3-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-cyclopenteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-propionsäure;
3-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-cyclohepteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-propionsäure;
3-[4-(3-Chlor-4-methoxy-benzylamino)-6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-propionsäure;
3-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-propionsäure;
3-[4-(3-Chlor-4-methoxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-propionsäure;
3-[4-(3-Chlor-4-methoxy-benzylamino)-6-chlor-thieno-[2,3-d]-
pyrimidin-2-yl]-propionsäure;
2-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-essigsäure, Ethanolaminsalz, F.
126°;
3-[4-(3,4-Methylendioxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-propionsäure;
3-[4-(3,4-Methylendioxy-benzylamino)-5,6-cyclopenteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-propionsäure;
3-[4-(3,4-Methylendioxy-benzylamino)-5,6-cyclohepteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-propionsäure;
3-[4-(3,4-Methylendioxy-benzylamino)-6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-propionsäure;
3-[4-(3,4-Methylendioxy-benzylamino)-5,6-dimethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-propionsäure;
3-[4-(3,4-Methylendioxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-propionsäure;
3-[4-(3,4-Methylendioxy-benzylamino)-6-chlor-thieno-[2,3-d]-
pyrimidin-2-yl]-propionsäure;
4-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-buttersäure;
4-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-cyclopenteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-buttersäure;
4-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-cyclohepteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-buttersäure;
4-[4-(3-Chlor-4-methoxy-benzylamino)-6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-buttersäure, Ethanolaminsalz, F. 142°;
4-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-buttersäure;
4-[4-(3-Chlor-4-methoxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-buttersäure, Ethanolaminsalz, F. 170°;
4-[4-(3-Chlor-4-methoxy-benzylamino)-6-chlor-thieno-[2,3-d]-
pyrimidin-2-yl]-buttersäure;
4-[4-(3,4-Methylendioxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-buttersäure, Ethanolaminsalz, F.
114°;
4-[4-(3,4-Methylendioxy-benzylamino)-5,6-cyclopenteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-buttersäure;
4-[4-(3,4-Methylendioxy-benzylamino)-5,6-cyclohepteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-buttersäure;
4-[4-(3,4-Methylendioxy-benzylamino)-6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-buttersäure, Ethanolaminsalz, F. 170°;
4-[4-(3,4-Methylendioxy-benzylamino)-5,6-dimethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-buttersäure;
4-[4-(3,4-Methylendioxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-buttersäure;
4-[4-(3,4-Methylendioxy-benzylamino)-6-chlor-thieno-[2,3-d]-
pyrimidin-2-yl]-buttersäure;
5-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-valeriansäure, F. 165°; Ethanol
aminsalz, F. 112°;
5-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-cyclopenteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-valeriansäure;
5-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-cyclohepteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-valeriansäure;
5-[4-(3-Chlor-4-methoxy-benzylamino)-6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäure, Ethanolaminsalz, F. 156°;
5-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-dimethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäure;
5-[4-(3-Chlor-4-methoxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäure, Ethanolaminsalz, F. 156°;
5-[4-(3-Chlor-4-methoxy-benzylamino)-6-chlor-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäure;
5-[4-(3,4-Methylendioxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-valeriansäure;
5-[4-(3,4-Methylendioxy-benzylamino)-5,6-cyclopenteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-valeriansäure;
5-[4-(3,4-Methylendioxy-benzylamino)-5,6-cyclohepteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-valeriansäure;
5-[4-(3,4-Methylendioxy-benzylamino)-6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäure, Ethanolaminsalz, F. 167°;
5-[4-(3,4-Methylendioxy-benzylamino)-5,6-dimethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäure;
5-[4-(3,4-Methylendioxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäure;
5-[4-(3,4-Methylendioxy-benzylamino)-6-chlor-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäure;
7-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-heptansäure, Ethanolaminsalz, F.
130°;
7-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-cyclopenteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-heptansäure;
7-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-cyclohepteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-heptansäure;
7-[4-(3-Chlor-4-methoxy-benzylamino)-6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-heptansäure;
7-[4-(3-Chlor-4-methoxy-benzylamino)-5,6-dimethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-heptansäure;
7-[4-(3-Chlor-4-methoxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-heptansäure;
7-[4-(3-Chlor-4-methoxy-benzylamino)-6-chlor-thieno-[2,3-d]-
pyrimidin-2-yl]-heptansäure;
7-[4-(3,4-Methylendioxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-heptansäure, Ethanolaminsalz, F.
137°;
7-[4-(3,4-Methylendioxy-benzylamino)-5,6-cyclopenteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-heptansäure;
7-[4-(3,4-Methylendioxy-benzylamino)-5,6-cyclohepteno-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-heptansäure;
7-[4-(3,4-Methylendioxy-benzylamino)-6-methyl-thieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäure;
7-[4-(3,4-Methylendioxy-benzylamino)-5,6-dimethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-heptansäure;
7-[4-(3,4-Methylendioxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-heptansäure;
7-[4-(3,4-Methylendioxy-benzylamino)-6-chlor-thieno-[2,3-d]-
pyrimidin-2-yl]-heptansäure;
2-{4-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-cyclohexyl}-essigsäure;
2-{4-[4-(3-Chlor-4-methoxy-benzylamino)-6-ethyl-thieno-[2,3-d]-
pyrimidin-2-yl]-cyclohexyl}-essigsäure;
2-{4-[4-(3,4-Methylendioxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-cyclohexyl}-essigsäure;
3-(4-Benzylamino-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-
pyrimidin-2-yl)-propionsäure, Ethanolaminsalz, F. 126°;
4-(4-Benzylamino-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-
pyrimidin-2-yl)-buttersäure, Ethanolaminsalz, F. 133°;
5-(4-Benzylamino-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-
pyrimidin-2-yl)-valeriansäure, Ethanolaminsalz, F. 135°;
4-[4-Benzylamino-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-buttersäure,
Ethanolaminsalz, F. 165°;
5-[4-Benzylamino-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl]-valeriansäure,
Ethanolaminsalz, F. 162°.The following carboxylic acids are obtained analogously from the esters listed in Example 1:
3- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] propionic acid;
3- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid;
3- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] propionic acid;
3- [4- (3-chloro-4-methoxy-benzylamino) -5,6-methylthieno [2,3-d] pyrimidin-2-yl] propionic acid;
3- [4- (3-chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] propionic acid;
3- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] propionic acid;
2- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] acetic acid, Ethanolamine salt, mp 126 °;
3- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid;
3- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclopenteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid;
3- [4- (3,4-methylenedioxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid;
3- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] propionic acid;
3- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] propionic acid;
3- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] propionic acid;
3- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] propionic acid;
4- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid;
4- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] butyric acid;
4- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid;
4- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid, ethanolamine salt, mp 142 °;
4- [4- (3-chloro-4-methoxy-benzylamino) -5,6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid;
4- [4- (3-chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] butyric acid, ethanolamine salt, mp 170 °;
4- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] butyric acid;
4- [4- (3,4-methylenedioxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid, ethanolamine salt, F. 114 °;
4- [4- (3,4-methylenedioxy-benzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] butyric acid;
4- [4- (3,4-methylenedioxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid;
4- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid, ethanolamine salt, mp 170 °;
4- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] butyric acid;
4- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] butyric acid;
4- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] butyric acid;
5- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid, F. 165 °; Ethanol amine salt, mp 112 °;
5- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclopenteno [1] benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid;
5- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid;
5- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt, mp 156 °;
5- [4- (3-chloro-4-methoxy-benzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] valeric acid;
5- [4- (3-chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt, mp 156 °;
5- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] valeric acid;
5- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid;
5- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] valeric acid;
5- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid;
5- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt, mp 167 °;
5- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] valeric acid;
5- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] valeric acid;
5- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] valeric acid;
7- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] -heptanoic acid, Ethanolamine salt, mp 130 °;
7- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclopenteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] heptanoic acid;
7- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] heptanoic acid;
7- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
7- [4- (3-chloro-4-methoxy-benzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
7- [4- (3-chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
7- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
7- [4- (3,4-methylenedioxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] -heptanoic acid, ethanolamine salt, Mp 137 °;
7- [4- (3,4-methylenedioxy-benzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
7- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclohepteno- [1] benzothieno- [2,3-d] pyrimidin-2-yl] heptanoic acid;
7- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid;
7- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
7- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
7- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
2- {4- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] -cyclohexyl} -acetic acid;
2- {4- [4- (3-chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] cyclohexyl} acetic acid;
2- {4- [4- (3,4-Methylenedioxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl] cyclohexyl }-acetic acid;
3- (4-Benzylamino-5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl) propionic acid, ethanolamine salt, mp 126 °;
4- (4-benzylamino-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) butyric acid, ethanolamine salt, mp 133 °;
5- (4-benzylamino-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) valeric acid, ethanolamine salt, mp 135 °;
4- [4-benzylamino-6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid, ethanolamine salt, mp 165 °;
5- [4-Benzylamino-6-ethylthieno [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt, mp 162 °.
1 Äquivalent 3-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]- benzothieno-[2,3-d]-pyrimidin-2-yl]-propionsäure und 1,2 Äquivalente Thionylchlorid werden 2 Stunden in Dichlormethan gerührt. Das Lösungs mittel wird entfernt und man erhält 3-[4-(3-Chlor-4-methoxy-benzylamino)- 5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]- propionsäurechlorid. 1 equivalent of 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid and 1.2 equivalents Thionyl chloride is stirred in dichloromethane for 2 hours. The solution medium is removed and 3- [4- (3-chloro-4-methoxy-benzylamino) - 5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] - propionic acid.
Man überführt in wässriges Ammoniak, rührt eine Stunde und erhält nach üblicher Aufarbeitung 3-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8- tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]-propionsäureamid.It is transferred into aqueous ammonia, stirred for one hour and obtained usual work-up 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8- tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] -propionsäureamid.
1 Äquivalent DMF und 1 Äquivalent Oxalylchlorid werden bei 0° in Aceto nitril gelöst. Danach wird 1 Äquivalent 3-[4-(3-Chlor-4-methoxy- benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]- propionsäureamid zugegeben. Es wird eine Stunde nachgerührt. Nach üb licher Aufarbeitung erhält man 3-[4-(3-Chlor-4-methoxy-benzylamino)- 5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]-propionitril.1 equivalent of DMF and 1 equivalent of oxalyl chloride are in Aceto at 0 ° nitrile dissolved. Then 1 equivalent of 3- [4- (3-chloro-4-methoxy- benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] - propionic acid added. It is stirred for an hour. After practice Working up gives 3- [4- (3-chloro-4-methoxy-benzylamino) - 5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] -propionitrile.
Analog zu den Beispielen 1 und 2 werden die nachstehenden Verbindun
gen erhalten
6-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-
[2,3-d]-pyrimidin-2-yl]-hexansäure, F. 165°;
2-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-
[2,3-d]-pyrimidin-2-yl]-propionsäure, Ethanolaminsalz, F. 150°;
4-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-
[2,3-d]-pyrimidin-2-yl]-2,2-dimethyl-buttersäure, Ethanolaminsalz, F. 130°;
4-[4-(3,4-Methylendioxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-
[2,3-d]-pyrimidin-2-yl]-2,2-dimethyl-buttersäure, Ethanolaminsalz, F. 126°;
5-[4-(3-Chlor-4-hydroxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-
[2,3-d]-pyrimidin-2-yl]-valeriansäure, F. 179°;
5-[4-(3,4-Dichlor-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-
pyrimidin-2-yl]-valeriansäure, Ethanolaminsalz F. 136°;
5-[4-(3-Chlor-4-isopropyloxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl]-valeriansäure, Ethanolaminsalz, F.
118°;
2-[4-(4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl)-phenyl]-essigsäure, Ethanolaminsalz,
F. 119°;
2-[4-(4-(3,4-Methylendioxy-benzylamino)-5,6,7,8-tetrahydro-[1]-
benzothieno-[2,3-d]-pyrimidin-2-yl)-phenyl]-essigsäure, F. 214.
Analogously to Examples 1 and 2, the following compounds are obtained
6- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl] hexanoic acid, F. 165 °;
2- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid, Ethanolamine salt, mp 150 °;
4- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl] -2, 2-dimethyl-butyric acid, ethanolamine salt, mp 130 °;
4- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl] -2,2- dimethyl butyric acid, ethanolamine salt, mp 126 °;
5- [4- (3-chloro-4-hydroxy-benzylamino) -5,6,7,8-tetrahydro- [1] benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid, F. 179 °;
5- [4- (3,4-dichlorobenzylamino) -5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt F 136 °;
5- [4- (3-chloro-4-isopropyloxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid, Ethanolamine salt, mp 118 °;
2- [4- (4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl) -phenyl] acetic acid, ethanolamine salt, mp 119 °;
2- [4- (4- (3,4-Methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] benzothieno- [2,3-d] pyrimidin-2-yl) phenyl ] acetic acid, F. 214.
Die nachfolgenden Beispiele betreffen pharmazeutische Zubereitungen:The following examples relate to pharmaceutical preparations:
Eine Lösung von 100 g eines Wirkstoffes der Formel I, 100 g des Calcium-Antagonisten und 5 g Dinatriumhydrogenphosphat wird in 3 l zweifach destilliertem Wasser mit 2 n Salzsäure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, unter sterilen Bedingungen lyo philisiert und steril verschlossen. Jedes Injektionsglas enthält 5 mg jedes Wirkstoffs.A solution of 100 g of an active ingredient of formula I, 100 g of Calcium antagonists and 5 g disodium hydrogenphosphate is in 3 l double-distilled water adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyo under sterile conditions philized and sterile sealed. Each injection jar contains 5 mg each Active ingredient.
Man schmilzt ein Gemisch von 20 g eines Wirkstoffes der Formel I, von 20 g eines Calcium-Antagonisten mit 100 g Sojalecithin und 1400 g Kakao butter, gießt in Formen und läßt erkalten. Jedes Suppositorium enthält 20 mg jedes Wirkstoffs.A mixture of 20 g of an active ingredient of the formula I is melted 20 g of a calcium antagonist with 100 g soy lecithin and 1400 g cocoa butter, pour into molds and let cool. Each suppository contains 20 mg of each active ingredient.
Man bereitet eine Lösung aus 1 g eines Wirkstoffes der Formel I, 1 g eines Calcium-Antagonisten, 9,38 g NaH2PO4.2H2O, 28,48 g Na2HPO4.12H2O und 0,1 g Benzalkoniumchlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 ein, füllt auf 1 l auf und sterilisiert durch Be strahlung. Diese Lösung kann in Form von Augentropfen verwendet wer den.A solution is prepared from 1 g of an active ingredient of the formula I, 1 g of a calcium antagonist, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO 4 .12H 2 O and 0.1 g Benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 l and sterilized by radiation. This solution can be used in the form of eye drops.
Man mischt 500 mg eines Wirkstoffes der Formel I, 500 m g eines Calcium- Antagonisten mit 99,5 g Vaseline unter aseptischen Bedingungen.500 mg of an active ingredient of the formula I, 500 m g of a calcium Antagonists with 99.5 g petroleum jelly under aseptic conditions.
Ein Gemisch von 1 kg Wirkstoff der Formel I, 1 kg eines Calcium- Antagonisten, 4 kg Lactose, 1,2 kg Kartoffelstärke, 0,2 kg Talk und 0,1 kg Magnesiumstearat wird in üblicher Weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg jedes Wirkstoffs enthält.A mixture of 1 kg of active ingredient of formula I, 1 kg of a calcium Antagonists, 4 kg lactose, 1.2 kg potato starch, 0.2 kg talc and 0.1 kg Magnesium stearate is compressed into tablets in the usual way, such that that each tablet contains 10 mg of each active ingredient.
Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.Analogously to Example E, tablets are pressed, which are then made in the usual manner Wise with a coating of sucrose, potato starch, talc, tragacanth and dye are coated.
2 kg Wirkstoff der Formel I und 2 kg eines Calcium-Antagonisten werden in üblicher Weise in Hartgelatinekapseln gefüllt, so daß jede Kapsel 20 mg jedes Wirkstoffs enthält.2 kg of active ingredient of formula I and 2 kg of a calcium antagonist filled in the usual way in hard gelatin capsules, so that each capsule 20 mg contains each active ingredient.
Eine Lösung von 1 kg Wirkstoff der Formel I und 1 kg eines Calcium- Antagonisten in 60 l zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingungen lyophilisiert und steril ver schlossen. Jede Ampulle enthält 10 mg jedes Wirkstoffs.A solution of 1 kg of active ingredient of formula I and 1 kg of a calcium Antagonists in 60 l of double distilled water are sterile filtered, in Filled ampoules, lyophilized under sterile conditions and sterile ver closed. Each ampoule contains 10 mg of each active ingredient.
Man löst 14 g Wirkstoff der Formel I und 14 g eines Calcium-Antagonisten in 10 l isotonischer NaCl-Lösung und füllt die Lösung in handelsübliche Sprühgefäße mit Pump-Mechanismus. Die Lösung kann in Mund oder Na se gesprüht werden. Ein Sprühstoß (etwa 0,1 ml) entspricht einer Dosis von etwa 0,14 mg jedes Wirkstoffs.14 g of active ingredient of the formula I and 14 g of a calcium antagonist are dissolved in 10 l isotonic NaCl solution and fills the solution into commercially available Spray tanks with pump mechanism. The solution can be in mouth or na be sprayed. One spray (about 0.1 ml) corresponds to one dose of about 0.14 mg of each active ingredient.
Claims (19)
worin
R1, R2 jeweils unabhängig voneinander H, A oder Hal, wobei einer der Reste R1 oder R2 immer ≠ H ist,
R1 und R2 zusammen auch Alkylen mit 3-5 C-Atomen,
R3, R4 jeweils unabhängig voneinander H, A, OH, OA oder Hal,
R3 und R4 zusammen auch Alkylen mit 3-5 C-Atomen, -O-CH2-CH2-, -O-CH2-O- oder -O-CH2-CH2-O-,
X einfach durch R7 substituiertes R5 oder R6,
R5 lineares oder verzweigtes Alkylen mit 1-10 C-Atomen, worin eine oder zwei CH2-Gruppen durch -CH=CH- Gruppen ersetzt sein können, oder -C6H4-(CH2)m-,
R6 Cycloalkylalkylen mit 6-12 C-Atomen,
R7 COOH, COOA, CONH2, CONHA, CON(A)2 oder CN,
A Alkyl mit 1 bis 6 C-Atomen,
Hal F, Cl, Br oder I,
m 1 oder 2 und
n 0, 1, 2 oder 3
bedeuten,
und/oder deren physiologisch unbedenklichen Salze und/oder Sol vate und mindestens einen Calcium-Antagonisten. 1. Pharmaceutical formulation containing at least one compound of formula I.
wherein
R 1 , R 2 each independently of one another H, A or Hal, where one of the radicals R 1 or R 2 is always ≠ H,
R 1 and R 2 together also alkylene with 3-5 C atoms,
R 3 , R 4 each independently of one another H, A, OH, OA or Hal,
R 3 and R 4 together also alkylene with 3-5 C atoms, -O-CH 2 -CH 2 -, -O-CH 2 -O- or -O-CH 2 -CH 2 -O-,
X is monosubstituted by R 7 R 5 or R 6,
R 5 linear or branched alkylene with 1-10 C atoms, in which one or two CH 2 groups can be replaced by -CH = CH- groups, or -C 6 H 4 - (CH 2 ) m -,
R 6 cycloalkylalkylene with 6-12 C atoms,
R 7 COOH, COOA, CONH 2 , CONHA, CON (A) 2 or CN,
A alkyl with 1 to 6 carbon atoms,
Hal F, Cl, Br or I,
m 1 or 2 and
n 0, 1, 2 or 3
mean,
and / or their physiologically acceptable salts and / or sol vate and at least one calcium antagonist.
R1, R2 jeweils unabhängig voneinander H, A oder Hal, wobei mindestens einer der Reste R1 oder R2 immer ≠ H ist,
R3 und R4 zusammen Alkylen mit 3-5 C-Atomen, -O-CH2-CH2-, -O-CH2-O- oder -O-CH2-CH2-O,
X durch COOH oder COOA, substituiertes R5 oder R6
bedeuten;
und/oder deren physiologisch unbedenklichen Salze und/oder Sol vate und mindestens einen Calcium-Antagonisten.3. Pharmaceutical formulation according to claim 1, comprising at least one compound of formula I according to claim 1, wherein
R 1 , R 2 each independently of one another H, A or Hal, where at least one of the radicals R 1 or R 2 is always ≠ H,
R 3 and R 4 together alkylene with 3-5 C atoms, -O-CH 2 -CH 2 -, -O-CH 2 -O- or -O-CH 2 -CH 2 -O,
X is substituted by COOH or COOA, R 5 or R 6
mean;
and / or their physiologically acceptable salts and / or sol vate and at least one calcium antagonist.
R1, R2 jeweils unabhängig voneinander H, A oder Hal, wobei mindestens einer der Reste R1 oder R2 immer ≠ H ist,
R3, R4 jeweils unabhängig voneinander H, A, OA oder Hal,
R3 und R4 zusammen Alkylen mit 3-5 C-Atomen, -O-CH2-CH2-, -O-CH2-O- oder -O-CH2-CH2-O,
X durch COOH oder COOA substituiertes R5 oder R6,
n 1 oder 2
bedeuten;
und/oder deren physiologisch unbedenklichen Salze und/oder Sol vate und mindestens einen Calcium-Antagonisten.4. Pharmaceutical formulation according to claim 1, comprising at least one compound of formula I according to claim 1, wherein
R 1 , R 2 each independently of one another H, A or Hal, where at least one of the radicals R 1 or R 2 is always ≠ H,
R 3 , R 4 each independently of one another H, A, OA or Hal,
R 3 and R 4 together alkylene with 3-5 C atoms, -O-CH 2 -CH 2 -, -O-CH 2 -O- or -O-CH 2 -CH 2 -O,
X is R 5 or R 6 substituted by COOH or COOA,
n 1 or 2
mean;
and / or their physiologically acceptable salts and / or sol vate and at least one calcium antagonist.
R1, R2 jeweils unabhängig voneinander H, A oder Hal, wobei einer der Reste R1 oder R2 immer ≠ H ist,
R1 und R2 zusammen auch Alkylen mit 3-5 C-Atomen,
R3, R4 jeweils unabhängig voneinander H, A, OA oder Hal,
R3 und R4 zusammen auch -O-CH2-O-,
X einfach durch R7 substituiertes R5,
R5 lineares oder verzweigtes Alkylen mit 1-10 C-Atomen, oder -C6H4-CH2-,
R7 COOH oder COOA,
A Alkyl mit 1 bis 6 C-Atomen,
Hal F, Cl, Br oder I,
m 1 und
n 1 oder 2
bedeuten;
und/oder deren physiologisch unbedenklichen Salze und/oder Sol vate und mindestens einen Calcium-Antagonisten.5. Pharmaceutical formulation according to claim 1, comprising at least one compound of formula I according to claim 1, wherein
R 1 , R 2 each independently of one another H, A or Hal, where one of the radicals R 1 or R 2 is always ≠ H,
R 1 and R 2 together also alkylene with 3-5 C atoms,
R 3 , R 4 each independently of one another H, A, OA or Hal,
R 3 and R 4 together also -O-CH 2 -O-,
X is simply substituted by R 7, R 5 ,
R 5 linear or branched alkylene with 1-10 C atoms, or -C 6 H 4 -CH 2 -,
R 7 COOH or COOA,
A alkyl with 1 to 6 carbon atoms,
Hal F, Cl, Br or I,
m 1 and
n 1 or 2
mean;
and / or their physiologically acceptable salts and / or sol vate and at least one calcium antagonist.
R1, R2 jeweils unabhängig voneinander H, A oder Hal, wobei einer der Reste R1 oder R2 immer ≠ H ist,
R1 und R2 zusammen auch Alkylen mit 3-5 C-Atomen,
R3, R4 jeweils unabhängig voneinander H, A, OH, OA oder Hal,
R3 und R4 zusammen auch -O-CH2-O-,
X einfach durch R7 substituiertes R5,
R5 lineares oder verzweigtes Alkylen mit 1-10 C-Atomen,
oder -C6H4-OH2-,
R7 COOH oder COOA,
A Alkyl mit 1 bis 6 C-Atomen,
Hal F, Cl, Br oder I,
m 1 und
n 1 oder 2
bedeuten;
und/oder deren physiologisch unbedenklichen Salze und/oder Sol vate und mindestens einen Calcium-Antagonisten.6. Pharmaceutical formulation according to claim 1, comprising at least one compound of formula I according to claim 1, wherein
R 1 , R 2 each independently of one another H, A or Hal, where one of the radicals R 1 or R 2 is always ≠ H,
R 1 and R 2 together also alkylene with 3-5 C atoms,
R 3 , R 4 each independently of one another H, A, OH, OA or Hal,
R 3 and R 4 together also -O-CH 2 -O-,
X is simply substituted by R 7, R 5 ,
R 5 linear or branched alkylene with 1-10 C atoms,
or -C 6 H 4 -OH 2 -,
R 7 COOH or COOA,
A alkyl with 1 to 6 carbon atoms,
Hal F, Cl, Br or I,
m 1 and
n 1 or 2
mean;
and / or their physiologically acceptable salts and / or sol vate and at least one calcium antagonist.
- a) 3-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]- benzothieno-[2,3-d]-pyrimidin-2-yl]-propionsäure;
- b) 4-[4-(3,4-Methylendioxy-benzylamino)-5,6,7,8-tetrahydro-[1]- benzothieno-[2,3-d]-pyrimidin-2-yl]-buttersäure;
- c) 7-[4-(3,4-Methylendioxy-benzylamino)-5,6,7,8-tetrahydro-[1]- benzothieno-[2,3-d]-pyrimidin-2-yl]-heptansäure;
- d) 7-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]- benzothieno-[2,3-d]-pyrimidin-2-yl]-heptansäure;
- e) 5-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]- benzothieno-[2,3-d]-pyrimidin-2-yl]-valeriansäure;
- f) 5-[4-(3-Chlor-4-methoxy-benzylamino)-6-methyl-thieno-[2,3-d]- pyrimidin-2-yl]-valeriansäure;
- g) 4-[4-(3-Chlor-4-methoxy-benzylamino)-6-methyl-thieno-[2,3-d]- pyrimidin-2-yl]-buttersäure;
- h) 4-[4-(3,4-Methylendioxy-benzylamino)-6-methyl-thieno-[2,3-d]- pyrimidin-2-yl]-buttersäure;
- i) 2-{4-[4-(3-Chlor-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]- benzothieno-[2,3-d]-pyrimidin-2-yl]-cyclohexyl-1-yl}-essigsäure;
- j) 5-[4-(3,4-Methylendioxy-benzylamino)-6-methyl-thieno-[2,3-d]- pyrimidin-2-yl]-valeriansäure
- a) 3- [4- (3-Chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] - propionic acid;
- b) 4- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid;
- c) 7- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] heptanoic acid;
- d) 7- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] - heptanoic;
- e) 5- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] - valeric acid;
- f) 5- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid;
- g) 4- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid;
- h) 4- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid;
- i) 2- {4- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidine-2- yl] -cyclohexyl-1-yl} -acetic acid;
- j) 5- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid
- a) einer wirksamen Menge an 5-[4-(3-Chlor-4-methoxy- benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2- yl]-valeriansäure, Ethanolaminsalz und
- b) einer wirksamen Menge eines Calcium-Antagonisten.
- a) an effective amount of 5- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidine-2 - yl] -valeric acid, ethanolamine salt and
- b) an effective amount of a calcium antagonist.
Priority Applications (18)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2000163885 DE10063885A1 (en) | 2000-12-21 | 2000-12-21 | Drug formulation useful e.g. for treating angina or hypertension contains thieno (2,3-d) pyrimidine derivative phosphodiesterase V inhibitor and antithrombotic agent, calcium antagonist or prostaglandin, |
EP01989533A EP1347761A2 (en) | 2000-12-19 | 2001-11-28 | Pharmaceutical formulation containing thienopyrimidines and antithrombotics, calcium antagonists, prostaglandins or prostaglandin derivatives |
AU2002227957A AU2002227957A1 (en) | 2000-12-19 | 2001-11-28 | Pharmaceutical formulation containing thienopyrimidines and antithrombotics, calcium antagonists, prostaglandins or prostaglandin derivatives |
BR0116255-1A BR0116255A (en) | 2000-12-19 | 2001-11-28 | Pharmaceutical formulation comprising thienopyrimidines and antithrombotics, calcium antagonists, prostaglandins and prostaglandin derivatives (1) |
MXPA03005405A MXPA03005405A (en) | 2000-12-19 | 2001-11-28 | Pharmaceutical formulation containing thienopyrimidines and antithrombotics, calcium antagonists, prostaglandins or prostaglandin derivatives. |
CNA018208207A CN1481242A (en) | 2000-12-19 | 2001-11-28 | Pharmaceutical formulation contg thienopyrimidines and antithrombotics, calcium-antagonists, prostaglandins or prostaglandin derivatives |
PL01361805A PL361805A1 (en) | 2000-12-19 | 2001-11-28 | Pharmaceutical formulation containing thienopyrimidines and antithrombotics, calcium antagonists, prostaglandins or prostaglandin derivatives |
JP2002550990A JP2004516269A (en) | 2000-12-19 | 2001-11-28 | Pharmaceutical preparation containing thienopyrimidine and antithrombotic agent, calcium antagonist, prostaglandin or prostaglandin derivative |
SK808-2003A SK8082003A3 (en) | 2000-12-19 | 2001-11-28 | Pharmaceutical formulation containing thienopyrimidines and antithrombotics, calcium antagonists, prostaglandins or prostaglandin derivatives |
HU0303289A HUP0303289A2 (en) | 2000-12-19 | 2001-11-28 | Pharmaceutical compositions comprising thienopyrimidines and antithrombotics, calcium antagonists, prostaglandins or prostaglandin derivatives |
CA002431074A CA2431074A1 (en) | 2000-12-19 | 2001-11-28 | Pharmaceutical formulation comprising thienopyrimidines and antithrombotics, calcium antagonists, prostaglandins or prostaglandin derivatives (1) |
PCT/EP2001/013915 WO2002049650A2 (en) | 2000-12-19 | 2001-11-28 | Pharmaceutical formulation containing thienopyrimidines and antithrombotics, calcium antagonists, prostaglandins or prostaglandin derivatives |
CZ20031754A CZ20031754A3 (en) | 2000-12-19 | 2001-11-28 | Pharmaceutical preparation containing thienopyrimidine derivatives and antithrombotics, calcium antagonists, prostaglandins or prostaglandin derivatives (1) |
RU2003121014/15A RU2003121014A (en) | 2000-12-19 | 2001-11-28 | Pharmaceutical composition containing thienopyrimidines and antithrombotic agents, calcium antagonists, prostaglandins or prostaglandin derivatives (1) |
KR10-2003-7008155A KR20030059351A (en) | 2000-12-19 | 2001-11-28 | Pharmaceutical formulation comprising thienopyrimidines and antithrombotics, calcium antagonists, prostaglandins or prostaglandin derivatives |
US10/451,118 US20040072846A1 (en) | 2000-12-19 | 2001-11-28 | Pharmaceutical formulation containing thienopyrimidines and antithrombotics, calcium antagonists, prostaglandins or prostaglandin derivatives |
ARP010105887A AR032009A1 (en) | 2000-12-19 | 2001-12-19 | PHARMACEUTICAL FORMULATION CONTAINING TIENOPIRIMIDINES AND ANTITROMBOTICS, CALCIUM ANTAGONISTS, PROSTAGLANDINAS OR DERIVATIVES OF PROSTAGLANDINA |
NO20032772A NO20032772L (en) | 2000-12-19 | 2003-06-18 | Pharmaceutical preparation comprising thienopyrimidines and antithrombotics, calcium antagonists, prostaglandins or prostaglandin derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2000163885 DE10063885A1 (en) | 2000-12-21 | 2000-12-21 | Drug formulation useful e.g. for treating angina or hypertension contains thieno (2,3-d) pyrimidine derivative phosphodiesterase V inhibitor and antithrombotic agent, calcium antagonist or prostaglandin, |
Publications (1)
Publication Number | Publication Date |
---|---|
DE10063885A1 true DE10063885A1 (en) | 2002-07-11 |
Family
ID=7668210
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE2000163885 Withdrawn DE10063885A1 (en) | 2000-12-19 | 2000-12-21 | Drug formulation useful e.g. for treating angina or hypertension contains thieno (2,3-d) pyrimidine derivative phosphodiesterase V inhibitor and antithrombotic agent, calcium antagonist or prostaglandin, |
Country Status (1)
Country | Link |
---|---|
DE (1) | DE10063885A1 (en) |
-
2000
- 2000-12-21 DE DE2000163885 patent/DE10063885A1/en not_active Withdrawn
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