DE2345422A1 - N-Substd.-4,4-dimethyl-isoquinolin-1,3-diones - as hypotensive agents also showing bradycardisant, antiarythmic and sedative effects - Google Patents
N-Substd.-4,4-dimethyl-isoquinolin-1,3-diones - as hypotensive agents also showing bradycardisant, antiarythmic and sedative effectsInfo
- Publication number
- DE2345422A1 DE2345422A1 DE19732345422 DE2345422A DE2345422A1 DE 2345422 A1 DE2345422 A1 DE 2345422A1 DE 19732345422 DE19732345422 DE 19732345422 DE 2345422 A DE2345422 A DE 2345422A DE 2345422 A1 DE2345422 A1 DE 2345422A1
- Authority
- DE
- Germany
- Prior art keywords
- dimethyl
- acid addition
- isoquinolin
- dioxo
- addition salts
- 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.)
- Granted
Links
- 230000001624 sedative effect Effects 0.000 title abstract description 3
- 239000002220 antihypertensive agent Substances 0.000 title abstract 2
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 239000002253 acid Substances 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- AKHSBAVQPIRVAG-UHFFFAOYSA-N 4h-isochromene-1,3-dione Chemical compound C1=CC=C2C(=O)OC(=O)CC2=C1 AKHSBAVQPIRVAG-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000011737 fluorine Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 150000003949 imides Chemical class 0.000 claims description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000001294 propane Substances 0.000 claims 5
- 239000003960 organic solvent Substances 0.000 claims 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- LRDIEHDJWYRVPT-UHFFFAOYSA-N 4-amino-5-hydroxynaphthalene-1-sulfonic acid Chemical compound C1=CC(O)=C2C(N)=CC=C(S(O)(=O)=O)C2=C1 LRDIEHDJWYRVPT-UHFFFAOYSA-N 0.000 claims 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims 1
- 150000001447 alkali salts Chemical class 0.000 claims 1
- 239000002775 capsule Substances 0.000 claims 1
- 239000012876 carrier material Substances 0.000 claims 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N dimethylmethane Natural products CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims 1
- 150000004885 piperazines Chemical class 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 239000000375 suspending agent Substances 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 abstract description 2
- 150000002537 isoquinolines Chemical class 0.000 abstract 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 238000002844 melting Methods 0.000 description 20
- 230000008018 melting Effects 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 12
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 10
- -1 alkali metal salt Chemical class 0.000 description 10
- 238000000354 decomposition reaction Methods 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 4
- CVVIJWRCGSYCMB-UHFFFAOYSA-N hydron;piperazine;dichloride Chemical compound Cl.Cl.C1CNCCN1 CVVIJWRCGSYCMB-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 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
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- KKIMDKMETPPURN-UHFFFAOYSA-N 1-(3-(trifluoromethyl)phenyl)piperazine Chemical compound FC(F)(F)C1=CC=CC(N2CCNCC2)=C1 KKIMDKMETPPURN-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229910000000 metal hydroxide Inorganic materials 0.000 description 2
- 150000004692 metal hydroxides Chemical class 0.000 description 2
- 229910044991 metal oxide Inorganic materials 0.000 description 2
- 150000004706 metal oxides Chemical class 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-dimethylbenzene Natural products CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- KPMUKDJNQIJUND-UHFFFAOYSA-N 1-(1-methoxycyclohexa-2,4-dien-1-yl)piperazine Chemical compound C1CNCCN1C1(OC)CC=CC=C1 KPMUKDJNQIJUND-UHFFFAOYSA-N 0.000 description 1
- LMQFWBCKQMNEEH-UHFFFAOYSA-N 1-(2-ethylphenyl)piperazine Chemical compound CCC1=CC=CC=C1N1CCNCC1 LMQFWBCKQMNEEH-UHFFFAOYSA-N 0.000 description 1
- ZTXXGFXIJMMZOP-UHFFFAOYSA-N 1-chloropropane;hydrochloride Chemical compound Cl.CCCCl ZTXXGFXIJMMZOP-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QGNQEODJYRGEJX-UHFFFAOYSA-N 4h-isoquinoline-1,3-dione Chemical compound C1=CC=C2C(=O)NC(=O)CC2=C1 QGNQEODJYRGEJX-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- MXWRJMIKMODSCY-UHFFFAOYSA-N ethane;dihydrochloride Chemical compound Cl.Cl.CC MXWRJMIKMODSCY-UHFFFAOYSA-N 0.000 description 1
- NARWYSCMDPLCIQ-UHFFFAOYSA-N ethane;hydrochloride Chemical compound Cl.CC NARWYSCMDPLCIQ-UHFFFAOYSA-N 0.000 description 1
- GATNOFPXSDHULC-UHFFFAOYSA-N ethylphosphonic acid Chemical compound CCP(O)(O)=O GATNOFPXSDHULC-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMSVPCYSAUKCAZ-UHFFFAOYSA-N propane;hydrochloride Chemical compound Cl.CCC UMSVPCYSAUKCAZ-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Case 5/610
Dr.Cr./Kp.Case 5/610
Dr.Cr./Kp.
DR. KARL THOMAE GMBH., BIBERACH AN DER RISSDR. KARL THOMAE GMBH., BIBERACH AN DER RISS
Neue substituierte Ary!.piperazine, deren Säureadditionssalze, diese enthaltende Arzneimittel sowie Verfahren zu deren Herstellung New substituted Ary! .Piperazine, their acid addition salts, standing pharmaceutical compositions containing them, and methods for Her
Gegenstand der Erfindung sind neue substituierte Arylpiperazine der allgemeinen Formel I,The invention relates to new substituted arylpiperazines general formula I,
(CH2)n -(CH 2 ) n -
(D(D
R1 ein Wasserstoff-, Fluor-, Chloratom oder eine Methoxygruppe, Rp ein Wasserstoffatom oder eine Methoxygruppe, R, ein Wasserstoffatom oder eine Methylgruppe,R 1 is a hydrogen, fluorine, chlorine atom or a methoxy group, Rp is a hydrogen atom or a methoxy group, R is a hydrogen atom or a methyl group,
Rk einen gegebenenfalls durch eine Methylgruppe substituierten Pyridyl-Rest oder einen unsubstituierten oder durch ein Chloratom eine Trifluormethylgruppe, eine oder zwei Methyl-, Äthyloder Methoxygruppen substituierten Phenylrest bedeutet undRk is an optionally substituted by a methyl group Pyridyl radical or an unsubstituted or a chlorine atom trifluoromethyl group, one or two methyl, ethyl or Methoxy groups substituted phenyl means and
η die Zahl 2 oder 3 darstellt und deren Säureadditionssalze mit wertvollen pharmakologischen Eigenschaften.η represents the number 2 or 3 and its acid addition salts with valuable pharmacological properties.
509812/1071509812/1071
L· \J -t ^ 'τ i- t- L · \ J -t ^ 'τ i- t-
Die Erfindung betrifft ferner Verbindungen der Formel I und deren Säureadditionssalze -enthaltende Arzneimittel sov/ie Verfahren zu deren Herstellung.The invention further relates to compounds of the formula I and their acid addition salts -containing medicaments and processes their manufacture.
Die neuen Verbindungen der Formel I lassen sich nach folgenden Verfahren herstellen:The new compounds of the formula I can be prepared by the following processes produce:
a) Umsetzung eines Homophthalsä.ureanhydrids oder -imids der allgemeinen Formel II,a) Implementation of a Homophthalsä.ureanhydrids or imids of the general Formula II,
(H)(H)
worinwherein
R. und R_ die obengenannte Bedeutung besitzen und A ein Sauerstoffatom oder eine gegebenenfalls substituierte Iminogruppe darstellt oder einer Dicarbonsäure der Formel Ha5 R. and R_ have the abovementioned meaning and A represents an oxygen atom or an optionally substituted imino group or a dicarboxylic acid of the formula Ha 5
C(CH J2-COOHC (CH J 2 -COOH
COOHCOOH
(Ha)(Ha)
in derin the
R1 und Rp wie eingangs definiert sind, mit einem substituiertenR 1 and Rp are as defined at the outset, with a substituted one
Aminoalkylpiperazin der allgemeinen Formel III,Aminoalkylpiperazine of the general formula III,
H2N-(CH2)n - N N-R4 (III)H 2 N- (CH 2 ) n - N NR 4 (III)
5 0 9 812/10715 0 9 812/1071
oRieiiJAL inspectedoRieiiJAL inspected
worinwherein
R-, R^ und η die obengenannte Bedeutung besitzen, oder dessen Säureadditionssalz.R-, R ^ and η have the meaning given above, or its Acid addition salt.
Die Umsetzung wird vorzugsweise in einem Lösungsmittel., z.B. Glykol, oder in der Schmelze bei Temperaturen von etwa 50 bis 25O°C durchgeführt. Vorteilhaft ist der Zusatz einer Base wie Kalium-tert.-butylat, insbesondere wenn die Verbindung der Formel III als Säureadditionssalz eingesetzt wird.The reaction is preferably carried out in a solvent, e.g. Glycol, or in the melt at temperatures of about 50 to 250 ° C. The addition of a base such as Potassium tert-butoxide, especially when the compound of the formula III is used as an acid addition salt.
b) Umsetzung eines N-Alkyl-isochinolin-dions der allgemeinen Formel IV,b) Implementation of an N-alkyl-isoquinoline-dione of the general formula IV,
(IV)(IV)
in derin the
R , Rp und η wie oben angegeben definiert sind und Z eine nucleophil leicht austauschbare Gruppe bevorzugt ein Chlor-, Brom- oder Jodatom oder eine Arylsulfonyloxy- oder Alkylsulfonyloxygruppe bedeutet, mit einem substituierten Piperazin der Formel V,R, Rp and η are defined as indicated above and Z is a nucleophilically easily exchangeable group, preferably a chlorine, bromine or iodine atom or an arylsulfonyloxy or Alkylsulfonyloxy means with a substituted Formula V piperazine,
in derin the
R_ und R1. die oben genannte Bedeutung besitzen.R_ and R 1 . have the meaning given above.
Die Umsetzung wird gegebenenfalls in einem Lösungsmittel, z.B. in Methanol, Äther, Tetrahydrofuran, Dimethylformamid, Dimethylsulfoxid oder Benzol und zweckmäMgerweise je nach der Reaktionsfähigkeit des Restes Z bei Temperaturen zwischen -50 und 25O°C durchgeführt. 509812/1071The reaction is optionally carried out in a solvent, e.g. in methanol, ether, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or benzene and conveniently depending on the reactivity of the remainder Z carried out at temperatures between -50 and 25O ° C. 509812/1071
Vorteilhaft ist die Gegenwart eines säurebindenden Mittels wie zum Beispiel eines Alkoholats, eines Metallhydroxides, -oxids oder -!carbonate.The presence of an acid-binding agent such as an alcoholate or a metal hydroxide or oxide is advantageous or -! carbonate.
c) Umsetzung eines Homophthalimids der Formel VI,c) implementation of a homophthalimide of the formula VI,
(VI)(VI)
in derin the
R1 und Rp die obengenannte Bedeutung haben oder dessen Metallsalzes, bevorzugt des Alkalisalzes, mit einem substituierten Alkylpiperazin der Formel VII,R 1 and Rp have the abovementioned meaning or its metal salt, preferably the alkali metal salt, with a substituted alkylpiperazine of the formula VII,
\_l7\ _l7
N * R4 N * R 4
R3 R 3
worinwherein
R.,, L, η sowie Z die obengenannte Bedeutung besitzen.R. ,, L, η and Z have the abovementioned meaning.
Die Umsetzung wird bevorzugt in Gegenwart eines säurebindenden Mittels, wie eines Alkoholats, eines Metalloxids, -hydroxids, -karbonats, zweckmäßigerweise in einem Lösungsmittel, z.B. Methanol, Isopropanol, Dimethylformamid oder Dimethylsulfoxid bei Temperaturen zwischen 0° und der Siedetemperatur des verwendeten Lösungsmittels durchgeführt.The reaction is preferably carried out in the presence of an acid-binding agent, such as an alcoholate, a metal oxide, metal hydroxide, carbonate, expediently in a solvent, e.g. methanol, Isopropanol, dimethylformamide or dimethyl sulfoxide Temperatures between 0 ° and the boiling point of the used Solvent carried out.
Die Umsetzung kann auch in der !-'eise durchgeführt werden, daß direkt ein Alkalimetallsalz des Imids der allgemeinen Formel VI eingesetzt wird.The implementation can also be carried out in such a way that directly an alkali metal salt of the imide of the general formula VI is used.
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23A542223A5422
Die als Ausgangsstoffe verwendeten Verbindungen der allgemeinen Formeln II bis VII sind zum größten Teil literaturbekannt, bzw. lassen sich nach literaturbekannten Verfahren herstellen.The compounds of the general formulas II to VII used as starting materials are for the most part known from the literature, or can be produced by processes known from the literature.
Die Verbindungen der allgemeinen Formel I sind Basen und bilden mit Säuren Additionssalze. Zur Salzbildung geeignete Säuren sind beispielsweise Mineralsäuren, wie Salzsäure, Bromwasserstoffsäure, Jodwasserstoffsäure, Fluorwasserstoffsäure, Salpetersäure, Schwefelsäure, Phosphorsäure oder organische Säuren wie Essigsäure, Propionsäure, Buttersäure, Malonsäure, Bernsteinsäure, Maleinsäure, Fumarsäure, Äpfelsäure, Weinsäure, Zitronensäure, Benzoesäure, p-Hydroxybenzoesäure, p-Aminobenzoesäure, Salicylsäure, Acetylsalicy!säure, Phthalsäure, Terephthalsäure, Ascorbinsäure, Methansulfonsäure, Äthanphosphonsäure,The compounds of general formula I are bases and form addition salts with acids. Suitable acids for salt formation are for example mineral acids such as hydrochloric acid, hydrobromic acid, Hydriodic acid, hydrofluoric acid, nitric acid, sulfuric acid, Phosphoric acid or organic acids such as acetic acid, propionic acid, butyric acid, malonic acid, succinic acid, maleic acid, Fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, salicylic acid, acetylsalicic acid, Phthalic acid, terephthalic acid, ascorbic acid, methanesulfonic acid, ethanephosphonic acid,
Die neuen Verbindungen der Formel I sowie deren Säureadditionssalze zeichnen sich durch eine therapeutisch nutzbare Wirkung aus»und sie besitzen insbesondere eine blutdrucksenkende, bradykardierende und sedierende Wirkung und können daher zur Behandlung der Hypertonie, der Tachycardie und von Erregungszuständen eingesetzt werden. Die erfindungsgemäßen Verbindungen der Formel I sowie deren Säureadditionssalze können auch mit andersartigen Wirkstoffen z.B. Tranquilizern, Muskelrelaxantien und Diuretika zum Einsatz gelangen. Die erfindungsgemäßen Verbindungen sind in Einzeldosen von etwa 20 bis 300 mg, vorzugsweise zwischen 20 und 200 mg für die orale Anwendung geeignet.The new compounds of the formula I and their acid addition salts are characterized by a therapeutically useful effect »and in particular they have a blood pressure lowering, bradycarding effect and sedative effect and can therefore be used for the treatment of hypertension, tachycardia and agitation. The compounds of the formula I according to the invention and their acid addition salts can also be used with other types of active ingredients, e.g. tranquilizers, muscle relaxants and diuretics. The compounds according to the invention are available in single doses of about 20 to 300 mg, preferably between 20 and 200 mg for the oral Application suitable.
Für die galenische Verarbeitung werden die erfindungsgemäßen Verbindungen der Formel I sowie deren Gäureadditionssalze mit üblichen galenischen Hilfs-, Träger-, Schmier-, Sprengmitteln oder Suspensionshilfsmitteln zu üblichen Tabletten, Dragees, Pulver, Emulsionen, Suspensionen, Lösungen verarbeitet; die Herstellung pharmazeutischer Anwendungsformen erfolgt nach den üblichen galenischen Fertigungsmethoden.The compounds according to the invention are used for pharmaceutical processing of formula I and their acid addition salts with customary pharmaceutical auxiliaries, carriers, lubricants, disintegrants or suspension auxiliaries processed into common tablets, coated tablets, powders, emulsions, suspensions, solutions; the manufacture of pharmaceutical Forms of application take place according to the usual pharmaceutical manufacturing methods.
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Die nachfolgenden Beispiele erläutern die Erfindung in nicht beschränkender Weise:The following examples illustrate the invention in a non-limiting manner Way:
l-£j, 1-Dimethy 1-1,3-dioxo- (2H, 4H) piperazin-l-yl)-äthan-dihydrochlorid 1-1,3-dioxo- (2H, 4H) piperazin-l-yl) ethane dihydrochloride
19 g 1,2,3,^-Tetrahydro-1!,JJ-dimethyl-isochroman-dion-Cl,3) und
20,5 g 2-(il-Phenyl-piperazin-l-yl)-äthylamin werden am Was3erabscheider
in 150 ml Xylol 12 Stunden unter Rückfluß gekocht. Anschließend wird das Lösungsmittel entfernt, der Rückstand in
Äther aufgenommen und das Dihydrochlorid mit ätherischer Salzsäure
gefällt.
Umkristallisiert aus Äthanol: Schmelzpunkt: 193-2O5°C (Zersetzung)19 g 1,2,3, ^ - Tetrahydro- 1 !, JJ-dimethyl-isochroman-dione-Cl, 3) and
20.5 g of 2- ( i l-phenyl-piperazin-l-yl) -ethylamine are refluxed for 12 hours in 150 ml of xylene on a water separator. The solvent is then removed, the residue in
Ether absorbed and the dihydrochloride precipitated with ethereal hydrochloric acid.
Recrystallized from ethanol: Melting point: 193-2O5 ° C (decomposition)
1-^i,!»,-Dimethyl-T-chlor-l,3-dioxo-(2H,UH)-isochinolin-2-yl7-2-Ciphenyl-piperazin-1-y1)-äthan-hydrochlorid 1- ^ i,! », - Dimethyl-T-chloro-1,3-dioxo- (2H, UH) -isoquinolin-2-yl7-2-Ci phenyl-piperazin-1-y1) -ethane hydrochloride
Hergestellt analog Beispiel 1, ausgehend von 1,2,3,^-Tetrahydro-?- chlor-il,i<-dimethyl-isochroman-dion-(l,3) und 2-(1J-Phenyl-piperazinl-yl)-äthylamin. Prepared analogously to Example 1, starting from 1,2,3, ^ - tetrahydro -? - chloro-l i, i <-dimethyl-isochroman-dione (l, 3) and 2- (1 J-Phenyl-piperazinl-yl ) ethylamine.
Umkristallisiert aus Isopropanol: Schmelzpunkt: 231-232 C.Recrystallized from isopropanol: Melting point: 231-232 C.
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(ty-phenyl-piperazin-l-yl)-Mthan-hydrochlorid(ty-phenyl-piperazin-1-yl) -thane hydrochloride
Hergestellt analog Beispiel 1, aus l,2,3,^-Tetrahydro-7-niethoxy· Η,4-dimethy l-isochroman-dion- (1,3) und 2-(iJ-Pheny 1-piperazin-lyl)-äthylamin, jedoch in aiykol als Lösungsmittel. Umkristallisiert aus Isopropanol: Schmelzpunkt« 215-2180CPrepared analogously to Example 1, from l, 2,3, ^ - tetrahydro-7-niethoxy · Η, 4-dimethy l-isochroman-dione- (1,3) and 2- (iJ-pheny 1-piperazin-lyl) - ethylamine, but in aiykol as a solvent. Recrystallized from isopropanol: melting point, "215 to 218 0 C
l-^,4-Dimethyl-7-fluor-l,3-diQXo-(2H,HH)-isochinolin~2-y ]J-2-phenyl-piperazin-l-yl)-äthan-hydrochlorid 1- ^, 4-Dimethyl-7-fluoro-1,3-diQXo- (2H, HH) -isoquinoline ~ 2-y] J-2- phenyl-piperazin-1-yl) -ethane hydrochloride
Hergestellt analog Beispiel 3, aus 1,2,3,4-Tetrahydro-7-fluordimethyl-isochroman-dion-(l,3) und 2-(ll-Phenyl-piperazin-l-yl) äthylamin.Prepared analogously to Example 3, from 1,2,3,4-tetrahydro-7-fluordimethyl-isochroman-dione (l, 3) and 2- (l l-phenyl-piperazin-l-yl) ethylamine.
Umkristallisiert aus Isopropanol: Schmelzpunkt: 200 - 203 C.Recrystallized from isopropanol: Melting point: 200 - 203 C.
l-Z5,I*-Diniethyl-6,7-dimethoxy-l,3-dioxo-(2H,'4H)-isochinolin-2-yr7 2-ffi-(2-methoxy-phenyl)-piperazin-l-y;L7-äthan-hydrochlorid 1- Z5, I * -Diniethyl-6,7-dimethoxy-1,3-dioxo- (2H, '4H) -isoquinolin-2-yr7 2-ffi- (2-methoxyphenyl) -piperazin-ly; L7 -ethane hydrochloride
Hergestellt analog Beispiel 1, aus !^^,'' k,4-dimethy1-isochroman-dion-(1,3) und 2-^I-(2-Methoxyphenyl)-piperazin-l-yl7-äthylamin. Prepared analogously to Example 1, from! ^^, '' k , 4-dimethy1-isochroman-dione- (1,3) and 2- ^ I- (2-methoxyphenyl) -piperazin-1-yl7-ethylamine.
Umkristallisiert aus Äthanol: Schmelzpunkt: 26Ί-265°0.Recrystallized from ethanol: melting point: 26-265 ° 0.
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l-Z^-Dimethyl-l,3-dioxo-(2H,ilH)-isochinolin~2-y:i7-3-£J-(pyridyl-(g))-piperazin-l-yl7-propan-dihydrochlorid lZ ^ -Dimethyl-1,3-dioxo- (2H, ilH) -isoquinoline ~ 2-y: 17-3- £ J- (pyridyl- (g)) -piperazin-1-yl7-propane dihydrochloride
Hergestellt analog Beispiel 1 aus 1 J2,3,'i-Tetrahydro-i4,il -dimethylisochroman-dion(l,3) und 3-£?*~ (Pyridyl-(2))-piperazin-l-yX7-propylamin als Ausgangsmaterial.Prepared analogously to Example 1 from 1J 2,3, 'i-tetrahydro- i 4, i l -dimethylisochroman-dione (1,3) and 3-£? * ~ (Pyridyl- (2)) -piperazin-1-yX7 -propylamine as the starting material.
Gefällt aus Toluol mit ätherischer Salzsäure und mit Aceton kristallisiert.Crystallized from toluene with ethereal hydrochloric acid and with acetone.
Dihydrochlorid: Schmelzpunkt 176-178°C.Dihydrochloride: melting point 176-178 ° C.
phenyl)-piperazin-l-yl7-äthan-dihydrochloridphenyl) piperazin-1-yl7-ethane dihydrochloride
Hergestellt analog Beispiel 1, aus l,2,3,1<-Tetrahydro-4,ii-dim isochroman-dion- (1,3) und 2-/Ji- (2-Methoxypheny 1)-piperazin- 1-yl7-äthylamin als Ausgangsmaterial.Prepared analogously to Example 1 from l, 2,3, 1 <-tetrahydro-4, ii-dim isochroman-dione (1.3) and 2- / Ji (2-methoxyphenyl 1) -piperazine-1 yl7- ethylamine as the starting material.
Das Dihydrochlorid wird direkt aus der Toluol-Lösung mit ätherischer Salzsäure gefällt.The dihydrochloride is extracted directly from the toluene solution with ethereal Hydrochloric acid precipitated.
Schmelzpunkt: 215-217°CMelting point: 215-217 ° C
l-$,4-Dimethyl-l,3-dioxo-(2H,liH)-isochinoU^ phenyp-piperazin-l-yu^-athan-dihydrochlorid 1- $, 4-Dimethyl-1,3-dioxo- (2H, liH) -isoquinoU ^ phenyp-piperazin-1-yu ^ -athane dihydrochloride
5 g 2-(2-Chloräthyl)-1<,4-dimethyl-l,2J3,1l — tetrahydro-isochinolindion-(l,3) und 5,3 g l-(2-Hethoxyphenyl)-piperazin-dihydrochlorid werden in 50 ml Glykol zusammen mit ^,75 g Kalium-tert.-butylat 4 Stunden auf 18O C gehalten. Anschließend wird abgekühlt, mit Wasser verdünnt und mit Chloroform extrahiert, die Chloroformphase5 g 2- (2-chloroethyl) - 1 <, 4-dimethyl-l, 2 J 3, 1 l - tetrahydro-isoquinolinedione- (l, 3) and 5.3 g l- (2-methoxyphenyl) -piperazine- dihydrochloride are kept at 18O C for 4 hours in 50 ml of glycol together with ^, 75 g of potassium tert-butoxide. It is then cooled, diluted with water and extracted with chloroform, the chloroform phase
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mit Wasser gewaschen, getrocknet und eingeengt1, Der verbleibende
Rückstand wird über eine Kieselgelsäule mit Chloroform/Methanol 95:5 gereinigt. Die Hauptfraktion wird isoliert, eingeengt, der
Rückstand in Isopropanol gelöst; und mit ätherischer Salzsäure das
Dihydrochlorid ausgefällt.
Umkristallisiert aus Isopropanol: Schmelzpunkt 215-217°Cwashed with water, dried and concentrated 1. The residue that remains is purified on a silica gel column with chloroform / methanol 95: 5. The main fraction is isolated and concentrated, and the residue is dissolved in isopropanol; and the dihydrochloride is precipitated with ethereal hydrochloric acid.
Recrystallized from isopropanol: melting point 215-217 ° C
1-ß ,4-Dimethyl-7-methoxy-l,3-dioxo-(2H, /ffi-(2-Methoxyphenyl)-piperazin-l-y3j-äthan-dihydrochlorid 1-ß , 4-Dimethyl-7-methoxy-1,3-dioxo- (2H, / ffi- (2-methoxyphenyl) -piperazine-1-y3j -ethane dihydrochloride
Hergestellt analog Beispiel 8 aus 2-(2-Chloräthyl)-1l,4-dimethyl-7-methoxy-1,2,3,Jf-tetrahydro-isochinolin-dion-(1,3)
und 1- (2-Methoxypheny1)-piperazin-dihydrochlorid,
Umkristallisiert aus Isopropanol: Schmelzpunkt 211-213°CPrepared analogously to Example 8 from 2- (2-chloroethyl) -1 l, 4-dimethyl-7-methoxy-1,2,3, Jf-tetrahydro-isoquinoline-dione (1,3) and 1- (2-methoxypheny1 ) piperazine dihydrochloride,
Recrystallized from isopropanol: melting point 211-213 ° C
l?-(2-methoxyphenyl)-piperazin-l-yl7-propan-dihydrochloridl? - (2-methoxyphenyl) -piperazin-l-yl7-propane dihydrochloride
Hergestellt analog Beispiel 8 aus 2-(3-Chlorpropyl)-4,4-dimethyl-7-methoxy-l,2,3,'i-tetrahydro-isochinolin-dion-(1,3)
und 1-(2-MethoxyphenyD-piperazin-dihydrochlorid.
Umkristallisiert aus Äthanol: Schmelzpunkt 195-200 CPrepared analogously to Example 8 from 2- (3-chloropropyl) -4,4-dimethyl-7-methoxy-1,2,3, 'i-tetrahydroisoquinoline-dione- (1,3) and 1- (2-methoxyphenyD -piperazine dihydrochloride.
Recrystallized from ethanol: melting point 195-200 ° C
l-^},i|-Dimethy 1-1,3-dioxo-(2H,i}H)-isochinolin-2-y 17-2-(4-phenyl-3-methyl-piperazin-l-yl)-äthan-dihydrochloric. l - ^}, i | -Dimethy 1-1,3-dioxo- (2H, i} H) -isoquinolin-2-y 17-2- (4-phenyl- 3-methyl-piperazin-l-yl) - ethane dihydrochloric.
Hergestellt analog Beispiel 8 aus 2-(2-Chlor£thyl)~1J,i!-dimethyl-Prepared analogously to Example 8 from 2- (2-chloroethyl) ~ 1 J, i ! -Dimethyl-
509812/1071509812/1071
- ίο -- ίο -
-Cl^) und l-Phenyl-2-methylpiperazin
ohne Kalium-tert.-butylat.
Umkristallisation aus Isopropanol! Schmelzpunkt 1960C (Zersetzung)-Cl ^) and l-phenyl-2-methylpiperazine without potassium tert-butoxide.
Recrystallization from isopropanol! Melting point 196 0 C (decomposition)
phenyl)-piperazin-l-y17-äthan-dihydrochloridphenyl) piperazin-1-y17-ethane dihydrochloride
Hergestellt analog Beispiel 8, aus 2-(2-Chloräthyl)-iJ,iJ-dimethyl-I»2»3,1i-tetrahydro-isochinolin-dion-(l,3)
und l-(i-Methoxyphenyl) piperazin ohne Kalium-tert,-butylat,
Umkristallisiert aus Isopropanol: Zersetzung ab 2280CPrepared analogously to Example 8, from 2- (2-chloroethyl) - i J, iJ-dimethyl-I » 2 » 3, 1 i-tetrahydroisoquinolin-dione- (1,3) and 1- (i-methoxyphenyl) piperazine without potassium tert-butoxide,
Recrystallized from isopropanol: decomposition from 228 ° C.
1-ß, 4-Dimethy 1-1,3-dioxo-(2H,
phenyl)-piperazin-l-yl7-athan-dihydrochlorid 1-ß, 4-dimethyl 1-1,3-dioxo- (2H,
phenyl) piperazin-1-yl7-ethane dihydrochloride
Hergestellt analog Beispiel 8, aus 2-(2-Chloräthyl)-il ,4-dimethyl
1,2,3,i-tetrahydro-isochinolin-dion-(1,3) und 1-(1-Chlorpheny1)-piperazin-dihydrochlorid.
Umkristallisiert aus Isopropanol: Zersetzung ab 135°C.Prepared analogously to Example 8, from 2- (2-chloroethyl) - i l, 4-dimethyl 1,2,3, i-tetrahydro-isoquinoline-dione- (1,3) and 1- (1-chloropheny1) -piperazine- dihydrochloride.
Recrystallized from isopropanol: decomposition from 135 ° C.
l-/T,4-Dimethyl-l,3-dioxo-(2H,ilH)-isochinolin-2-yl7-2-Jt-(3-trifluormethyl-phenyl)-piperazin-l-yl7-äthan-hydrochlorid 1- / T, 4-Dimethyl-1,3-dioxo- (2H, IIIH) -isoquinolin-2-yl7-2-Jt- (3- trifluoromethyl-phenyl) -piperazin-l-yl7-ethane hydrochloride
Hergestellt analog Beispiel 8, aus 2-(2-Chloräthyl)-1J,^-di 1,2,3,1-tetrahydro-isochinolin-dion-(1,3) und 1-(3-Trifluormethy1 phenyl)-piperazin mit 1 Äquivalent Kalium-terc.-butylat. Umkristallisiert aus Isopropanol: Schmelzpunkt 23O°C.Prepared analogously to Example 8, from 2- (2-chloroethyl) -1 J, ^ - di 1,2,3,1-tetrahydroisoquinolin-dione- (1,3) and 1- (3-trifluoromethylphenyl) piperazine with 1 equivalent of potassium tert-butoxide. Recrystallized from isopropanol: melting point 230 ° C.
509812/1071509812/1071
- ii -- ii -
dimethyl-phenyl)-piperazin-l-y3j-äthan-hydrochloriddimethyl-phenyl) -piperazine-1-y3j-ethane hydrochloride
Hergestellt analog Beispiel 8 aus 2-(2-Chloräthyl)-i),lJ-dimethyl l»2,3,1'-tetrahydro-isochinolin-dion-(l,3) und l-(2,6-Dimethylphenyl)-piperazin mit 1 Äquivalent Kalium-tert.-butylat. Umkristallisiert aus Isopropanol/Äther: Zersetzung ab 23O0CPrepared analogously to Example 8 from 2- (2-chloroethyl) - i), l l J-dimethyl "2,3, 1 '-tetrahydro-isoquinoline-dione (l, 3) and l- (2,6-dimethylphenyl) -piperazine with 1 equivalent of potassium tert-butoxide. Recrystallized from isopropanol / ether: decomposition from 23O 0 C
l-$,4-Dimethyl-l,3-dioxo-(2H,4H)-isochinolin-2-y]J-2-£M2-chlorphenyl )-piperazin-l-yl7~äthan-hydrochlorid . . . 1- $, 4-Dimethyl-1,3-dioxo- (2H, 4H) -isoquinolin-2-y] J-2- £ M2- chlorophenyl) piperazin-1-yl7 ~ ethane hydrochloride . . .
Hergestellt analog Beispiel 8 aus 2-(2-Chloräthyl)-i»,4-dimethyl-1»2»3,Ί-tetrahydro-isochinolin-dion-(1,3) und 1-(2-Chlorpheny1)-piperazin-hydrochlorid-hydrat mit 2 Äquivalenten Kalium-tert.-butyPrepared analogously to Example 8 from 2- (2-chloroethyl) -i », 4-dimethyl-1» 2 »3, Ί-tetrahydroisoquinoline-dione (1,3) and 1- (2-chloropheny1) -piperazine- hydrochloride hydrate with 2 equivalents of potassium tert-buty
Umkristallisiert aus Isopropanol/Äther: Schmelzpunkt 228°CRecrystallized from isopropanol / ether: melting point 228 ° C
l-Z5,1»-Dimethyl-l,3-dioxo-(2H,iiH)-isochinolin-2-yi7-3-£?i-(3-trif1uormethyl-phenyl)~piperazin-l-yl7-propan-hydrochlorid l-Z5, 1 '-dimethyl-l, 3-dioxo- (2H, IIh) -isoquinoline-2-yi7-3- £? i- (3-tri f1uormethyl-phenyl) ~ piperazin-l-yl7-propane hydrochloride
Hergestellt analog Beispiel 8 aus 2-(3-ChIOrPrOPyI)-1I,^-dimethyl-1»2»3»4-tetrahydro-isochinolin-dion-(1,3) und 1-(3-Trifluormethy1-phenyl)-piperazin mit 1 Äquivalent Kalium-tert.-butylat. Kristallisiert aus Methanol/ätherischer Salzsäure: Schmelzpunkt 215-220°C.Prepared analogously to Example 8 from 2- (3-ChIOrPrOPyI) - 1 I, ^ - dimethyl-1 »2» 3 »4-tetrahydro-isoquinoline-dione (1,3) and 1- (3-trifluoromethyl-phenyl) - piperazine with 1 equivalent of potassium tert-butoxide. Crystallized from methanol / ethereal hydrochloric acid: melting point 215-220 ° C.
509812/1071509812/1071
methoxy-phenyl)-piperazineIrylj-äthan-dihydrochloridmethoxy-phenyl) -piperazineIrylj-ethane dihydrochloride
Hergestellt analog Beispiel 8 aus 2-(2-Chloräthyl)-1J,1J-dimethyl l,2,3,i'-tetrahydro-isochinolin"dion-(l,3) und l-(3f1-DimethoxyphenyD-piperazin mit 1 Äquivalent Kalium-tert,-butylat. Kristallisiert aus Methanol/ätherische Salzsäure: ZersetzungPrepared analogously to Example 8 from 2- (2-chloroethyl) - 1 J, 1 J-dimethyl l, 2,3, i '-tetrahydro-isoquinoline "dione (l, 3) and l- (3-f 1 DimethoxyphenyD- piperazine with 1 equivalent of potassium tert-butoxide.Crystallized from methanol / ethereal hydrochloric acid: decomposition
ab 1580Cfrom 158 0 C
!-^,M-Dimethyl-l^-dioxo-(2H,4H)-isochinolin-2-y 17-2-/1-(2-methylphenyl^piperazin-l-yLZ-äthan-hydrochlorid ! - ^, M-Dimethyl-1 ^ -dioxo- (2H, 4H) -isoquinolin-2-y 17-2- / 1- (2-methyl phenyl ^ piperazin-1-yLZ-ethane hydrochloride
Hergestellt analog Beispiel 8 aus 2-(2-Chloräthyl)-1J,iJ-dimethyl-1,2,3, !J-tetrahydro-isochinolin-dion- (1,3) und 1- (2-Me thy lpheny 1) piperazin-dihydrochlorid Prepared analogously to Example 8 from 2- (2-chloroethyl) - 1 J, IJ-dimethyl-1,2,3 J-tetrahydro-isoquinoline-dione (1,3) and 1- (2-Me thy lpheny 1! ) piperazine dihydrochloride
Umkristallisiert aus Isopropanol/Äther: Zersetzung abRecrystallized from isopropanol / ether: decomposition
l-^l,i|-Dimethyl-l,3-dioxo-(2HiilH)-isochinolin-2-yl7-2-/Ti-(2-äthylphenyl)-piperazin-l-y3^-äthan-dihydrochlorid l- ^ l, i | -Dimethyl-l, 3-dioxo- (2H i ilH) -isoquinolin-2-yl7-2- / Ti (2-ethylphenyl ) -piperazine-l-y3 ^ -ethane dihydrochloride
Hergestellt analog Beispiel 8 aus 2-(2-ChIOrS^yI)-M,ii-dimethyl-112,3,^-tetrahydro-isochinolin-dion-(1,3) und 1-(2-Äthylpheny1)-piperazin mit 1 Äquivalent Kalium-tert.-butylat. Umkristallisiert aus Methanol/Äther: Schmelzpunkt 188-192°CPrepared analogously to Example 8 from 2- (2-ChIOrS ^ yI) -M, ii-dimethyl-112,3, ^ - tetrahydro-isoquinoline-dione- (1,3) and 1- (2-ethylphenyl) piperazine with 1 equivalent of potassium tert-butoxide. Recrystallized from methanol / ether: melting point 188-192 ° C
509812/1071509812/1071
23Α5Λ2223-5-22
yl7-3-ffi-(2-methoxyphenyl)-piperazin-l-yl7-propan-hydrochlüridyl7-3-ffi- (2-methoxyphenyl) piperazin-1-yl7-propane hydrochloride
Hergestellt analog Beispiel 8 aus 2-(3-Chlorpropyl)-1l,1l-dimethyl 6,7-dimethoxy-1,2,3,^-tetrahydro-isochinolin-dion-(1,3) und 1-(2 Methoxypheny1)-piperazin-dihydrochlorid.Prepared analogously to Example 8 from 2- (3-chloropropyl) - 1 l, 1 l-dimethyl 6,7-dimethoxy-1,2,3, ^ - tetrahydro-isoquinoline-dione- (1,3) and 1- (2 Methoxypheny1) piperazine dihydrochloride.
Umkristallisiert aus Methanol/Ätherί Schmelzpunkt 198-2020CRecrystallized from methanol / etherί melting point 198-202 0 C
(Zersetzung)(Decomposition)
phenyl)-piperazin-l-y17-propan-hydrochloridphenyl) piperazine-1-y17-propane hydrochloride
Hergestellt analog Beispiel 8 aus 2-(3-Chlorpropyl)-'t,1-dimethyl-' 1,2,3,M-tetrahydro-isochinolin-dion-(1,3) und 1-(2-Methoxypheny1) piperazin-dihydrochlorid.Prepared analogously to Example 8 from 2- (3-chloropropyl) - 't, 1-dimethyl-' 1,2,3, M-tetrahydro-isoquinoline-dione- (1,3) and 1- (2-methoxypheny1) piperazine dihydrochloride.
Umkristallisiert aus Äthanol: Schmelzpunkt 235-237°CRecrystallized from ethanol: melting point 235-237 ° C
1-/1,4-Dimethy1-7-methoxy-ls3-dioxo-(2H,4H)-isochinoli^1- / 1,4-Dimethy1-7-methoxy-1 s 3-dioxo- (2H, 4H) -isoquinoli ^
^J-(pyridyl-(2))-piperazin-l-yi7-propan-dihydrochlorid^ J- (pyridyl- (2)) -piperazin-l-yi7-propane-dihydrochloride
Hergestellt analog Beispiel 8 aus 2-(3-Chlorpropyl)-4,l|-dimethyl· 7-methoxy-l,2,3,il-tetrahydro-isochinolin-dion-(l,3) und 1-^pyridyl-(2)J-piperazin mit 1 Äquivalent Kalium-tert.-butylat. Gefällt mit ätherischer Salzsäure: Schmelzpunkt 193-1P6°CPrepared analogously to Example 8 from 2- (3-chloropropyl) -4, l | -dimethyl 7-methoxy-l, 2,3, i l-tetrahydro-isoquinoline-dione (l, 3) and 1- ^ pyridyl- (2) J-piperazine with 1 equivalent of potassium tert-butoxide. Like with essential hydrochloric acid: Melting point 193-1P6 ° C
509812/1071509812/1071
-IU--IU-
^3-(6-methyl-pyridyl-(2))-piperazin-l-yL7-propan-dihydrochlorid^ 3- (6-methyl-pyridyl- (2)) -piperazin-l-yL7-propane dihydrochloride
Hergestellt analog Beispiel 8 aus 2-(3-ChIOrPrOPyI)-*! , ^-dimethyl-7~methoxy-l,2,3»i<-tetrahydro-isochinolin-dion-(l,3) und l-ß>-Methyl-pyridyl-(2j7-piperazin mit 1 Äquivalent Kalium-tert,-buty·Manufactured analogously to Example 8 from 2- (3-ChIOrPrOPyI) - *! , ^ -dimethyl-7 ~ methoxy-l, 2,3 » i <-tetrahydro-isoquinoline-dione- (1,3) and l-ß> - methyl-pyridyl- (2j7-piperazine with 1 equivalent of potassium tert, -buty
Umkristallisiert aus Äthanol/Äther: Schmelzpunkt 172-17^°C.Recrystallized from ethanol / ether: melting point 172-17 ^ ° C.
l-/?,4-Dimethy 1-1,3-dioxo-(2H, 4H)-isoc^l - / ?, 4-Dimethy 1-1,3-dioxo- (2H, 4H) -isoc ^
pyridyl- ( 2) ) -piperazin-1-yiJ-propan-hydrochloridpyridyl (2)) piperazin-1-yiJ-propane hydrochloride
Hergestellt analog Beispiel 8 aus 2-(3-ChIOrPrOPyI)-^5U-dimethyll,2,3,it-tetrahydro-isochinolin-dion-(l,3) und l-/6-methyl-pyridyl-(2l7-piperazin mit 1 Äquivalent Kalium-tert.-butylat. Kristallisiert aus Methanol/ätherische Salzsäure: Zersetzung abPrepared analogously to Example 8 from 2- (3-ChIOrPrOPyI) - ^ 5 U-dimethyll, 2,3, i t-tetrahydroisoquinoline-dione- (1,3) and 1- / 6-methyl-pyridyl- (2l7- piperazine with 1 equivalent of potassium tert-butoxide.Crystallized from methanol / ethereal hydrochloric acid: decomposition
88°c88 ° c
l-/ii,1<-Dimethyl-i,3-dioxo-(2H, ^H) -isochinolin-2-y Γ7-3- (U-phenylpiperazin-l-yl)-propan-hydrochlorid l- / i i, 1 <-Dimethyl-i, 3-dioxo- (2H, ^ H) -isoquinolin-2-y 7-3- (U-phenyl piperazin-l-yl) propane hydrochloride
**»9 g 3-(il-Phenyl-piperazin-l-yl)-propylchlorid-hydrochlorid werden in möglichst wenig Wasser vorgelöst und mit einem Gemisch von 100 ml gesättigter Kaliumcarbonat-Lösung und 100 ml Toluol kräftig geschüttelt und die abgetrennte Toluolphase 'Iber Magnesiumsulfat getrocknet. Die nach Abfiltrieren erhaltene Toluollösung wird zu einer Lösung von 3,8 g !^,Sj^-Tetrahydro-^j^ ** »9 g of 3- ( i l-phenyl-piperazin-l-yl) propyl chloride hydrochloride are pre-dissolved in as little water as possible and vigorously shaken with a mixture of 100 ml of saturated potassium carbonate solution and 100 ml of toluene and the separated toluene phase Dried over magnesium sulphate. The toluene solution obtained after filtering off becomes a solution of 3.8 g! ^, Sj ^ -Tetrahydro- ^ j ^
509812/1071509812/1071
(2H,i4H)-isochinolin und 2,6 g Kalium-tert.-butylat in 100 ml Dimethylformamid bei 70°G während einer Stunde zugetropft. Anschließend wird noch 2 Stunden bei dieser Temperatur gerührt. Nach Entfernen des Lösungsmittels wird der obige Rückstand mit Wasser versetzt, mehrmals mit Äther extrahiert und, nach dem Trocknen über wasserfreiem Calciumchlorid und Filtrieren, mit ätherischer Salzsäure versetzt, und der ausgefallene Niederschlag aus Isopropanol utnkristallieiert Schmelzpunkt: 235-2380C (Zersetzung).(2H, i4H) -isoquinoline and 2.6 g of potassium tert-butoxide in 100 ml of dimethylformamide were added dropwise at 70 ° G over the course of one hour. The mixture is then stirred for a further 2 hours at this temperature. After removal of the solvent, the above residue is treated with water, extracted several times with ether and, after drying over anhydrous calcium chloride and filtered, treated with ethereal hydrochloric acid, and the precipitate from isopropanol utnkristallieiert Melting point: 235-238 0 C (decomposition).
Tabletten zu 100 mg l-(Jt iJ-Dimethy 1-1,3~dioxo-(2H,*lH)-isochinolin-2_yi7-2-/Tr-phenylpiperazin-l-yl7-äthan-hydrochlorid Tablets of 100 mg l- (J t iJ-Dimethy 1-1,3 ~ dioxo- (2H, * lH) -isoquinolin-2_yi7-2- / Tr-phenylpiperazin-l-yl7-ethane hydrochloride
Zusammensetzung:Composition:
Wirksubstanz Milchzucker Polyvinylpyrrolidon Carboxymethylcellulose MagnesiumstearatActive ingredient milk sugar polyvinylpyrrolidone carboxymethyl cellulose Magnesium stearate
Der Wirkstoff und der Milchzucker werden gleichmäßig mit einer wäßrigen Lösung des Polyvinylpyrrolidons befeuchtet und granuliert, Nach dem Trocknen wird das Granulat mit den restlichen Wirkstoffen vermischt und die Mischung in üblicher Weise zu Tabletten verpreßt,The active ingredient and the milk sugar are moistened evenly with an aqueous solution of polyvinylpyrrolidone and granulated, After drying, the granules are mixed with the remaining active ingredients and the mixture is pressed into tablets in the usual way,
509812/1071509812/1071
234^22234 ^ 22
2-yl7-2-/J-(2-chlorphenyl )-piperazin-l-yX7-r >Jtlmn-hydrochlorid2-yl7-2- / J- (2-chlorophenyl) -piperazin-1-yX7- r > Jtlmn-hydrochloride
80,0 mg Herstellungsverfahren; 80.0 mg manufacturing process;
Das Gemisch wird wie in Beispiel 27 beschrieben zu Drageekernen verarbeitet, die dann mit Zucker und Gummi-Arabikum dragiert werden,The mixture is processed into tablet cores as described in Example 27, which are then coated with sugar and gum arabic,
Suppositorien zu 150 mg !-/^,^-Dimethyl-l,3-dioxo-(2H,üH)-isochinolin-2-ylV-3-/J1-(6-methyl-pyridy 1- (2 ) )-pipernzin-l-yl7-propanhydrochlorid Suppositories of 150 mg! - / ^, ^ - Dimethyl-1,3-dioxo- (2H, üH) -isoquinolin-2-ylV-3- / J1- (6-methyl-pyridy 1- (2)) -pipernzin -l-yl7-propane hydrochloride
Zusammensetzung:Composition:
Wirkstoff 150,0 ngActive ingredient 150.0 ng
Suppositorienmar.ise 1 550,0 ^g Suppository mar.ise 1 550.0 ^ g
1 700,0 me1,700.0 me
Herstellungsverfahren: Manufacturing process :
Der Wirkstoff wird in die geschmolzene Sunnositoriennasse gleichmäßig eingerührt un-1 suspendiert und di3 flüssige Gemisch in m~ kühlte Suppositori^iiformen ausgegossen.The active ingredient is stirred uniformly in the molten Sunnositoriennasse un-1 suspended and poured di3 liquid mixture in m ~ cooled Suppositori ^ iiformen.
5 0 9 8 1 2 / 10 7 1 ^AD CWGiKAL 5 0 9 8 1 2/10 7 1 ^ AD CWGiKAL
- X f -- X f -
Suspension mit 250 mg l-Z7t,i<-Dimethyl-l,3-dioxo-(2H,4H)-isochinolin-2-yl7-2-^-(2-methylphenyl)-piperazin-l-yl7-fithan-hydrochlorid Suspension with 250 mg of l-Z7t, i <-Dimethyl-1,3-dioxo- (2H, 4H) -isoquinolin-2-yl7-2 - ^ - (2-methylphenyl) -piperazin-l-yl7-fithane hydrochloride
pro 5 mlper 5 ml
100 ml Suspension enthalten: Wirksubstanz
Carboxymethylcellulose p-Hydroxybenzoesäuremethylester
ρ-Hydroxybenzoes&urepropylester
Zucker
Glycerin100 ml suspension contain: active substance
Carboxymethyl cellulose p-hydroxybenzoic acid methyl ester ρ-hydroxybenzoic & urepropyl ester sugar
Glycerin
Sorbitlösung 70 %
Aroma
destilliertes Wasser adSorbitol solution 70 %
Aroma
distilled water ad
In dem auf 70° erhitzten destillierten Wasser wird unter Rühren
p-Hydroxybenzoesäure und -propylester sowie Glycerin und Carboxymethylcellulose gelöst. Die Lösung wird auf Raumtemperatur abgekühlt
und unter Rühren der Wirkstoff zugegeben und homogen dispergiert. Nach Zugabe und Lösen des Zuckers, der Sorbitlösung und
des Aromas wird die Suspension zur Entlüftung unter Rühren evakuiert. In the distilled water heated to 70 ° is stirred while stirring
Dissolved p-hydroxybenzoic acid and propyl ester as well as glycerol and carboxymethyl cellulose. The solution is cooled to room temperature and the active ingredient is added with stirring and dispersed homogeneously. After the sugar, the sorbitol solution and the aroma have been added and dissolved, the suspension is evacuated while stirring for deaeration.
5 ml Suspension enthalten l-/5,4-Dimethyl-l,3-dioxo-(2H,iIH)-isochinolin-2-y17-2-/5-(2-methylphenyl)-piperazin-l-y17-äthan-hydrochlorid 5 ml of suspension contain l- / 5,4-dimethyl-l, 3-dioxo- (2H, i IH) -isoquinolin-2-y17-2- / 5- (2-methylphenyl) -piperazine-l-y17-ethane hydrochloride
5098 12/10715098 12/1071
ORIGINAL INSPECTEDORIGINAL INSPECTED
Claims (1)
R^ undin the
R ^ and
Priority Applications (42)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2345422A DE2345422C2 (en) | 1973-09-08 | 1973-09-08 | Substituted isoquinolyl-arylpiperazines containing these drugs and processes for their preparation |
| AT651474A AT330777B (en) | 1973-09-08 | 1974-08-08 | PROCESS FOR THE PREPARATION OF NEW ISOCHINOLINE DERIVATIVES AND THEIR SALTS |
| FI742465A FI52219C (en) | 1973-09-08 | 1974-08-21 | Process for the preparation of antihypertensive, antiarrhythmic and sedative 4,4-dimethyl-1,3-dioxo- (2H, 4H) -isoquinolin-2-yl derivatives. |
| ES429473A ES429473A1 (en) | 1973-09-08 | 1974-08-23 | 1,3-Dioxo-2-aminoalkyl-4,4-dimethyl-isoquinolines and salts thereof |
| SU2057995A SU528035A3 (en) | 1973-09-08 | 1974-09-04 | The method of obtaining derivatives of isoquinoline or their salts |
| BG028726A BG26195A4 (en) | 1973-09-08 | 1974-09-04 | METHOD FOR OBTAINING ISOQUINOLINE DERIVATIVES |
| BG027624A BG22390A3 (en) | 1973-09-08 | 1974-09-04 | METHOD FOR OBTAINING ISOQUINOLINE DERIVATIVES |
| US05/503,072 US3948898A (en) | 1973-09-08 | 1974-09-04 | 1,3-Dioxo-2-aminoalkyl-4,4-dimethyl-isoquinolines and salts thereof |
| IE1838/74A IE40742B1 (en) | 1973-09-08 | 1974-09-04 | 1,3-diketo-1,2,3,4-tetrahydroisoquinolines |
| YU2391/74A YU39928B (en) | 1973-09-08 | 1974-09-05 | Process for preparing new isoquinoline derivatives |
| AU73023/74A AU489660B2 (en) | 1974-09-05 | N-SUBSTITUTED-l, 3-DIOXO-ISOQUINOLINES | |
| MX559474U MX4054E (en) | 1973-09-08 | 1974-09-06 | PROCEDURE FOR THE PREPARATION OF ISOQUINOLEIN DERIVATIVES |
| NO743220A NO140978C (en) | 1973-09-08 | 1974-09-06 | ANALOGICAL PROCEDURE FOR PREPARATION OF THERAPEUTICALLY ACTIVE ISOKINOLINE DERIVATIVES |
| CH1218974A CH605778A5 (en) | 1973-09-08 | 1974-09-06 | |
| DK472774A DK137124C (en) | 1973-09-08 | 1974-09-06 | R ANALOGICAL PROCEDURE FOR THE PREPARATION OF ISOQUINOLINE DERIVATIVES |
| GB3908374A GB1446791A (en) | 1973-09-08 | 1974-09-06 | 1,3-diketo-1,2,3,4-tetrahydroisoquinolines |
| CH1601477A CH605779A5 (en) | 1973-09-08 | 1974-09-06 | |
| IL45609A IL45609A (en) | 1973-09-08 | 1974-09-06 | Substituted isoquinoline 1,3-dione derivatives their preparation and pharmaceutical compositions containing them |
| FR7430387A FR2242979B1 (en) | 1973-09-08 | 1974-09-06 | |
| JP49102862A JPS596868B2 (en) | 1973-09-08 | 1974-09-06 | Method for producing new isoquinoline derivatives |
| RO7400079932A RO63655A (en) | 1973-09-08 | 1974-09-06 | PROCESS FOR THE PREPARATION OF ISOQUINOLINE DERIVATIVES |
| PH16248A PH12918A (en) | 1973-09-08 | 1974-09-06 | 1,3-dioxo-2-aminoalkyl-4,4-dimethyl-isoquinolines and salts thereof |
| NLAANVRAGE7411843,A NL176363C (en) | 1973-09-08 | 1974-09-06 | METHOD FOR PREPARING C.Q. MANUFACTURE OF A PHARMACEUTICAL PREPARATION WITH AN ANTI-BLOOD PRESSURE EFFECT AND METHOD FOR PREPARING IT AS AN ACTIVE SUBSTANCE 1- (4,4-DIMETHYL-1,3-DIOXO- (2H, 4H) -ISOCHINOLIN-2-YL) -2- OR -3- (4-SUBSTITUTED PIPERAZIN-1-YL) ETHANE OR PROPANE DERIVATIVES. |
| ZA00745688A ZA745688B (en) | 1973-09-08 | 1974-09-06 | Improvements relating to isoquinoline derivatives |
| CS7400006150A CS185660B2 (en) | 1973-09-08 | 1974-09-06 | Process for preparing new 2-substituted 4,4-dimethyl-1,3-dioxo/2h,4h/isochinolines |
| CA208,607A CA1025869A (en) | 1973-09-08 | 1974-09-06 | Isoquinoline derivatives |
| DD180966A DD115122A5 (en) | 1973-09-08 | 1974-09-06 | |
| BE148302A BE819651A (en) | 1973-09-08 | 1974-09-06 | NEW DERIVATIVES OF ISOQUINOLEINE |
| SE7411312A SE424863B (en) | 1973-09-08 | 1974-09-06 | ANALOGY PROCEDURE FOR PREPARING NEW ISOQINOLINE DERIVATIVES |
| HUTO980A HU167869B (en) | 1973-09-08 | 1974-09-06 | |
| PL1974190437A PL96297B1 (en) | 1973-09-08 | 1974-09-07 | METHOD OF MAKING NEW DERIVATIVES OF ISOCHINOLINE |
| PL1974173958A PL91712B1 (en) | 1973-09-08 | 1974-09-07 | |
| PL1974190438A PL96298B1 (en) | 1973-09-08 | 1974-09-07 | METHOD OF MAKING NEW DERIVATIVES OF ISOCHINOLINE |
| ES433959A ES433959A1 (en) | 1973-09-08 | 1975-01-20 | PROCEDURE FOR THE PREPARATION OF NEW DERIVATIVES OF ISOQUINOLEIN. |
| ES433958A ES433958A1 (en) | 1973-09-08 | 1975-01-20 | 1,3-Dioxo-2-aminoalkyl-4,4-dimethyl-isoquinolines and salts thereof |
| SU2145942A SU538664A3 (en) | 1973-09-08 | 1975-06-20 | The method of obtaining derivatives of isoquinoline or their salts |
| SU2145935A SU545256A3 (en) | 1973-09-08 | 1975-06-20 | The method of obtaining derivatives of isoquinoline or their salts |
| AT560675A AT334374B (en) | 1973-09-08 | 1975-07-21 | PROCESS FOR THE PREPARATION OF NEW ISOCHINOLINE DERIVATIVES AND THEIR SALTS |
| AT560775A AT334375B (en) | 1973-09-08 | 1975-07-21 | PROCESS FOR THE PREPARATION OF NEW ISOCHINOLINE DERIVATIVES AND THEIR SALTS |
| US05/651,568 US4021558A (en) | 1973-09-08 | 1976-01-22 | 1,3-Dioxo-2-[(methoxyphenethyl-amino)-alkyl]-4,4-dimethyl-isoquinolines and salts thereof useful as hypotensive agents |
| HK41/80A HK4180A (en) | 1973-09-08 | 1980-01-31 | 1,3-diketo-1,2,3,4-tetrahydroisoquinolines |
| MY330/81A MY8100330A (en) | 1973-09-08 | 1981-12-30 | 1,3-diketo-1,2,3,4-tetrahydrosoquinolines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2345422A DE2345422C2 (en) | 1973-09-08 | 1973-09-08 | Substituted isoquinolyl-arylpiperazines containing these drugs and processes for their preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE2345422A1 true DE2345422A1 (en) | 1975-03-20 |
| DE2345422C2 DE2345422C2 (en) | 1983-12-22 |
Family
ID=5892058
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2345422A Expired DE2345422C2 (en) | 1973-09-08 | 1973-09-08 | Substituted isoquinolyl-arylpiperazines containing these drugs and processes for their preparation |
Country Status (5)
| Country | Link |
|---|---|
| BE (1) | BE819651A (en) |
| DE (1) | DE2345422C2 (en) |
| PL (2) | PL96297B1 (en) |
| SU (1) | SU528035A3 (en) |
| ZA (1) | ZA745688B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005037260A3 (en) * | 2003-10-14 | 2007-08-16 | Wyeth Corp | Use of adrenergic alphaze antagonists for the treatment of vasomotor symptoms |
| WO2007100852A1 (en) * | 2006-02-28 | 2007-09-07 | Helicon Therapeutics, Inc. | Therapeutic piperazines as pde4 inhibitors |
| US8927546B2 (en) | 2006-02-28 | 2015-01-06 | Dart Neuroscience (Cayman) Ltd. | Therapeutic piperazines |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5552412A (en) * | 1995-01-09 | 1996-09-03 | Pfizer Inc | 5-substitued-6-cyclic-5,6,7,8-tetrahydronaphthalen2-ol compounds which are useful for treating osteoporosis |
| SI0850235T1 (en) * | 1995-09-15 | 2000-04-30 | Sanofi-Synthelabo | Quinolein-2(1h)-one derivatives as serotonin antagonists |
-
1973
- 1973-09-08 DE DE2345422A patent/DE2345422C2/en not_active Expired
-
1974
- 1974-09-04 SU SU2057995A patent/SU528035A3/en active
- 1974-09-06 ZA ZA00745688A patent/ZA745688B/en unknown
- 1974-09-06 BE BE148302A patent/BE819651A/en not_active IP Right Cessation
- 1974-09-07 PL PL1974190437A patent/PL96297B1/en unknown
- 1974-09-07 PL PL1974190438A patent/PL96298B1/en unknown
Non-Patent Citations (1)
| Title |
|---|
| Elderfield, Heterocyclic Compounds, 4, 374, 1952 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005037260A3 (en) * | 2003-10-14 | 2007-08-16 | Wyeth Corp | Use of adrenergic alphaze antagonists for the treatment of vasomotor symptoms |
| WO2007100852A1 (en) * | 2006-02-28 | 2007-09-07 | Helicon Therapeutics, Inc. | Therapeutic piperazines as pde4 inhibitors |
| US7829713B2 (en) | 2006-02-28 | 2010-11-09 | Helicon Therapeutics, Inc. | Therapeutic piperazines |
| US8338405B2 (en) | 2006-02-28 | 2012-12-25 | Dart Neuroscience Llc | Therapeutic piperazines |
| US8501745B2 (en) | 2006-02-28 | 2013-08-06 | Dart Neuroscience (Cayman) Ltd. | Piperazine PDE4 inhibitors and uses thereof |
| US8927546B2 (en) | 2006-02-28 | 2015-01-06 | Dart Neuroscience (Cayman) Ltd. | Therapeutic piperazines |
| US9624200B2 (en) | 2006-02-28 | 2017-04-18 | Dart Neuroscience (Cayman) Ltd. | Therapeutic piperazines |
Also Published As
| Publication number | Publication date |
|---|---|
| PL96298B1 (en) | 1977-12-31 |
| BE819651A (en) | 1975-03-06 |
| ZA745688B (en) | 1976-05-26 |
| DE2345422C2 (en) | 1983-12-22 |
| SU528035A3 (en) | 1976-09-05 |
| PL96297B1 (en) | 1977-12-31 |
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| 8364 | No opposition during term of opposition | ||
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