DE2855703C2 - 8-Substituierte 3-Fluor-10-piperazino-10,11-dihydrodibenzo[b,f]thiepine, ihre Herstellung und diese enthaltende pharmazeutische Mittel - Google Patents
8-Substituierte 3-Fluor-10-piperazino-10,11-dihydrodibenzo[b,f]thiepine, ihre Herstellung und diese enthaltende pharmazeutische MittelInfo
- Publication number
- DE2855703C2 DE2855703C2 DE2855703A DE2855703A DE2855703C2 DE 2855703 C2 DE2855703 C2 DE 2855703C2 DE 2855703 A DE2855703 A DE 2855703A DE 2855703 A DE2855703 A DE 2855703A DE 2855703 C2 DE2855703 C2 DE 2855703C2
- Authority
- DE
- Germany
- Prior art keywords
- fluoro
- formula
- dihydrodibenzo
- thiepin
- mixture
- 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.)
- Expired
Links
- -1 8-Substituted 3-fluoro-10-piperazino-10,11-dihydrodibenzo[b,f]thiepines Chemical class 0.000 title claims description 25
- 238000002360 preparation method Methods 0.000 title claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 150000002148 esters Chemical class 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 230000009467 reduction Effects 0.000 claims description 13
- 230000008569 process Effects 0.000 claims description 12
- 230000029936 alkylation Effects 0.000 claims description 8
- 238000005804 alkylation reaction Methods 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 5
- 150000001414 amino alcohols Chemical class 0.000 claims description 5
- 150000004885 piperazines Chemical class 0.000 claims description 5
- 150000003335 secondary amines Chemical class 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 150000002081 enamines Chemical class 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 4
- 150000003551 thiepines Chemical class 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 150000001735 carboxylic acids Chemical class 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 229910052987 metal hydride Inorganic materials 0.000 claims description 2
- 150000004681 metal hydrides Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 2
- IHOYNYISJIXRQB-UHFFFAOYSA-N 9-fluoro-5-(4-methylpiperazin-1-yl)-5,6-dihydrobenzo[b][1]benzothiepin-3-ol Chemical compound C1CN(C)CCN1C1C2=CC(O)=CC=C2SC2=CC(F)=CC=C2C1 IHOYNYISJIXRQB-UHFFFAOYSA-N 0.000 claims 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 221
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 173
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 144
- 239000000203 mixture Substances 0.000 description 120
- 239000000243 solution Substances 0.000 description 117
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 97
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 91
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 81
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 52
- 239000002585 base Substances 0.000 description 51
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 50
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 50
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 48
- 238000010992 reflux Methods 0.000 description 47
- 239000000126 substance Substances 0.000 description 46
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 44
- 239000000047 product Substances 0.000 description 43
- 230000000694 effects Effects 0.000 description 41
- 238000001816 cooling Methods 0.000 description 34
- 238000003756 stirring Methods 0.000 description 29
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 26
- 239000011976 maleic acid Substances 0.000 description 26
- 241001465754 Metazoa Species 0.000 description 25
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 25
- 229910000027 potassium carbonate Inorganic materials 0.000 description 25
- 235000011181 potassium carbonates Nutrition 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 24
- 238000002844 melting Methods 0.000 description 23
- 230000008018 melting Effects 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 238000009835 boiling Methods 0.000 description 21
- 238000006386 neutralization reaction Methods 0.000 description 18
- 239000003208 petroleum Substances 0.000 description 18
- 239000002253 acid Substances 0.000 description 16
- 230000006742 locomotor activity Effects 0.000 description 16
- 208000009132 Catalepsy Diseases 0.000 description 15
- 206010047853 Waxy flexibility Diseases 0.000 description 15
- 238000000605 extraction Methods 0.000 description 15
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 14
- 229960004046 apomorphine Drugs 0.000 description 14
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- 230000003354 anti-apomorphinic effect Effects 0.000 description 13
- 239000000155 melt Substances 0.000 description 13
- BISQTCXKVNCDDA-UHFFFAOYSA-N thiepine Chemical compound S1C=CC=CC=C1 BISQTCXKVNCDDA-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 230000035929 gnawing Effects 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 241000700159 Rattus Species 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 11
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 238000013019 agitation Methods 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- KUORKOPHMADFKV-UHFFFAOYSA-N 2-(4-fluoro-2-iodophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(F)C=C1I KUORKOPHMADFKV-UHFFFAOYSA-N 0.000 description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 230000004973 motor coordination Effects 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 231100000419 toxicity Toxicity 0.000 description 9
- 230000001988 toxicity Effects 0.000 description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 206010047700 Vomiting Diseases 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
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- 230000008673 vomiting Effects 0.000 description 7
- 238000010626 work up procedure Methods 0.000 description 7
- 206010003591 Ataxia Diseases 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000008096 xylene Substances 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000006900 dealkylation reaction Methods 0.000 description 5
- QXFLHYYXOQKRBC-UHFFFAOYSA-N ethyl 4-(2-chloroethyl)piperazine-1-carboxylate Chemical compound CCOC(=O)N1CCN(CCCl)CC1 QXFLHYYXOQKRBC-UHFFFAOYSA-N 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
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- 230000002401 inhibitory effect Effects 0.000 description 5
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 4
- OLEPNWSDXKHOLM-UHFFFAOYSA-N 2-[4-fluoro-2-(4-nitrophenyl)sulfanylphenyl]acetic acid Chemical compound OC(=O)CC1=CC=C(F)C=C1SC1=CC=C([N+]([O-])=O)C=C1 OLEPNWSDXKHOLM-UHFFFAOYSA-N 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
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- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 150000001805 chlorine compounds Chemical class 0.000 description 4
- XRYLGRGAWQSVQW-UHFFFAOYSA-N clorotepine Chemical compound C1CN(C)CCN1C1C2=CC(Cl)=CC=C2SC2=CC=CC=C2C1 XRYLGRGAWQSVQW-UHFFFAOYSA-N 0.000 description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
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- AQGYXBXZRINPFW-UHFFFAOYSA-N 1-(9-fluoro-3-propan-2-yl-5,6-dihydrobenzo[b][1]benzothiepin-5-yl)piperazine Chemical compound C12=CC(C(C)C)=CC=C2SC2=CC(F)=CC=C2CC1N1CCNCC1 AQGYXBXZRINPFW-UHFFFAOYSA-N 0.000 description 3
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- SKYZYDSNJIOXRL-BTQNPOSSSA-N (6ar)-6-methyl-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinoline-10,11-diol;hydrochloride Chemical compound Cl.C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 SKYZYDSNJIOXRL-BTQNPOSSSA-N 0.000 description 2
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- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 2
- GDFDQXODRRNHGF-UHFFFAOYSA-N 1-[2-(4-fluorophenyl)sulfanylethyl]-4-(9-fluoro-3-propan-2-yl-5,6-dihydrobenzo[b][1]benzothiepin-5-yl)piperazine Chemical compound C12=CC(C(C)C)=CC=C2SC2=CC(F)=CC=C2CC1N(CC1)CCN1CCSC1=CC=C(F)C=C1 GDFDQXODRRNHGF-UHFFFAOYSA-N 0.000 description 2
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- 238000007171 acid catalysis Methods 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 150000004645 aluminates Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- WPUJEWVVTKLMQI-UHFFFAOYSA-N benzene;ethoxyethane Chemical compound CCOCC.C1=CC=CC=C1 WPUJEWVVTKLMQI-UHFFFAOYSA-N 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- RVIQSSNDHKQZHH-UHFFFAOYSA-N carbonyl diiodide Chemical compound IC(I)=O RVIQSSNDHKQZHH-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003874 central nervous system depressant Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 238000001944 continuous distillation Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- QOCVFCQKMHPXLN-UHFFFAOYSA-N ethyl 4-(2-chloroethyl)piperazine-1-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)N1CCN(CCCl)CC1 QOCVFCQKMHPXLN-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- GEOVEUCEIQCBKH-UHFFFAOYSA-N hypoiodous acid Chemical compound IO GEOVEUCEIQCBKH-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229940126701 oral medication Drugs 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
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940007042 proteus vulgaris Drugs 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940048181 sodium sulfide nonahydrate Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- WMDLZMCDBSJMTM-UHFFFAOYSA-M sodium;sulfanide;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[SH-] WMDLZMCDBSJMTM-UHFFFAOYSA-M 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- WZEOZJQLTRFNCU-UHFFFAOYSA-N trifluoro(trifluoromethoxy)methane Chemical compound FC(F)(F)OC(F)(F)F WZEOZJQLTRFNCU-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
- C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/14—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the side-chain of aromatic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
- C07D337/02—Seven-membered rings
- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D337/14—[b,f]-condensed
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS778728A CS196893B1 (en) | 1977-12-22 | 1977-12-22 | 3-fluor-10-piperazino-8-substituted 10,11-dihydro-dibenzothiepines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE2855703A1 DE2855703A1 (de) | 1979-06-28 |
| DE2855703C2 true DE2855703C2 (de) | 1987-02-26 |
Family
ID=5438253
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2855703A Expired DE2855703C2 (de) | 1977-12-22 | 1978-12-22 | 8-Substituierte 3-Fluor-10-piperazino-10,11-dihydrodibenzo[b,f]thiepine, ihre Herstellung und diese enthaltende pharmazeutische Mittel |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4243805A (pt-PT) |
| JP (1) | JPS5492979A (pt-PT) |
| AT (1) | AT368151B (pt-PT) |
| BE (1) | BE872496A (pt-PT) |
| CA (1) | CA1100134A (pt-PT) |
| CH (1) | CH642077A5 (pt-PT) |
| CS (1) | CS196893B1 (pt-PT) |
| DE (1) | DE2855703C2 (pt-PT) |
| DK (1) | DK521078A (pt-PT) |
| FI (1) | FI66374C (pt-PT) |
| FR (1) | FR2412312A1 (pt-PT) |
| GB (1) | GB2010843B (pt-PT) |
| SE (1) | SE442403B (pt-PT) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3029365A1 (de) * | 1980-08-01 | 1982-03-25 | Bayer Ag, 5090 Leverkusen | Verfahren zur (alpha)-bromierung von gegebenenfalls substituierten fluortoluolen und gemischen von in (alpha)-stellung verschieden hoch bromierten, gegebenenfalls substituierten fluortoluolen |
| CS249455B1 (en) * | 1985-01-24 | 1987-03-12 | Miroslav Protiva | N-substituted 2-chloro-7-fluoro-10-piperazino-10,11-dihydrodibenzo(b,f)thiepines and their salts and method of their preparation |
| US5700445A (en) * | 1994-12-12 | 1997-12-23 | Allelix Biopharmaceuticals, Inc. | N-methyl piperazine compounds having dopamine receptor affinity |
| WO2002018954A2 (en) | 2000-08-30 | 2002-03-07 | Chemocentryx, Inc. | Inhibition of cmv infection and dissemination |
| US20050250767A1 (en) * | 2003-01-23 | 2005-11-10 | Weiner David M | Use of N-desmethylclozapine to treat human neuropsychiatric disease |
| EP1994932A1 (en) * | 2003-01-23 | 2008-11-26 | Arcadia Pharmaceuticals Inc. | Use of N-desmethylclozapine to treat human psychosis |
| US7550454B2 (en) * | 2003-12-22 | 2009-06-23 | Acadia Pharmaceuticals, Inc. | Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders |
| WO2006001866A2 (en) * | 2004-04-01 | 2006-01-05 | Acadia Pharmaceuticals Inc. | Crystalline forms of n-desmethylclozapine |
| GB0415320D0 (en) * | 2004-07-08 | 2004-08-11 | Astrazeneca Ab | Novel compounds |
| DE102004049728A1 (de) * | 2004-10-11 | 2006-04-13 | Merck Patent Gmbh | Verfahren zur Herstellung von monosubstituierten Piperazinderivaten |
| US20070105836A1 (en) * | 2005-10-31 | 2007-05-10 | Lars Pettersson | Prodrugs of muscarinic agonists and methods of treatment of neuropsychiatric disorders |
| US10525376B2 (en) | 2015-07-20 | 2020-01-07 | W. L. Gore & Associates, Inc. | Affinity chromatography devices |
| WO2019092044A1 (en) * | 2017-11-08 | 2019-05-16 | Centre National De La Recherche Scientifique | Dihydrobenzo[b][1]benzothiepin compounds useful in therapy |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2412521A1 (de) * | 1973-03-30 | 1974-10-10 | Hoffmann La Roche | Tricyclische verbindungen |
| DE2412520C2 (de) * | 1973-03-30 | 1982-09-16 | F. Hoffmann-La Roche & Co. AG, 4002 Basel | Tricyclische Verbindungen, Verfahren zu deren Herstellung und diese enthaltende Präparate |
| FI753625A (pt-PT) * | 1975-01-06 | 1976-07-07 | Spofa Vereinigte Pharma Werke | |
| JPS5835449B2 (ja) * | 1979-08-31 | 1983-08-02 | 中興化成工業株式会社 | 表面に波型状凹凸部を有する無機質繊維織布管の製造方法 |
-
1977
- 1977-12-22 CS CS778728A patent/CS196893B1/cs unknown
-
1978
- 1978-11-17 FR FR7832559A patent/FR2412312A1/fr active Granted
- 1978-11-22 DK DK521078A patent/DK521078A/da not_active Application Discontinuation
- 1978-11-24 FI FI783607A patent/FI66374C/fi not_active IP Right Cessation
- 1978-12-04 BE BE192114A patent/BE872496A/xx not_active IP Right Cessation
- 1978-12-14 AT AT0892578A patent/AT368151B/de not_active IP Right Cessation
- 1978-12-14 GB GB7848581A patent/GB2010843B/en not_active Expired
- 1978-12-20 SE SE7813114A patent/SE442403B/sv not_active IP Right Cessation
- 1978-12-21 CH CH1305178A patent/CH642077A5/de not_active IP Right Cessation
- 1978-12-21 CA CA318,360A patent/CA1100134A/en not_active Expired
- 1978-12-22 JP JP15770178A patent/JPS5492979A/ja active Granted
- 1978-12-22 DE DE2855703A patent/DE2855703C2/de not_active Expired
- 1978-12-22 US US05/972,323 patent/US4243805A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| SE442403B (sv) | 1985-12-23 |
| DK521078A (da) | 1979-06-23 |
| JPS638109B2 (pt-PT) | 1988-02-19 |
| BE872496A (fr) | 1979-03-30 |
| CH642077A5 (de) | 1984-03-30 |
| DE2855703A1 (de) | 1979-06-28 |
| AT368151B (de) | 1982-09-27 |
| JPS5492979A (en) | 1979-07-23 |
| SE7813114L (sv) | 1979-06-23 |
| CS196893B1 (en) | 1980-04-30 |
| US4243805A (en) | 1981-01-06 |
| FI66374B (fi) | 1984-06-29 |
| GB2010843A (en) | 1979-07-04 |
| CA1100134A (en) | 1981-04-28 |
| GB2010843B (en) | 1982-08-18 |
| FI66374C (fi) | 1984-10-10 |
| FR2412312B1 (pt-PT) | 1982-10-29 |
| FR2412312A1 (fr) | 1979-07-20 |
| FI783607A (fi) | 1979-06-23 |
| ATA892578A (de) | 1982-01-15 |
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