CS225569B1 - Preparation of 10,11-dihydrodibenzo/b,f/ thiepine-10-carboxylic acids - Google Patents
Preparation of 10,11-dihydrodibenzo/b,f/ thiepine-10-carboxylic acids Download PDFInfo
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- CS225569B1 CS225569B1 CS700982A CS700982A CS225569B1 CS 225569 B1 CS225569 B1 CS 225569B1 CS 700982 A CS700982 A CS 700982A CS 700982 A CS700982 A CS 700982A CS 225569 B1 CS225569 B1 CS 225569B1
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- dihydrodibenzo
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- 238000002360 preparation method Methods 0.000 title claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 229910052801 chlorine Chemical group 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- DBQYUWWOBWTUPV-UHFFFAOYSA-N 5,6-dihydrobenzo[b][1]benzothiepine Chemical compound C1CC2=CC=CC=C2SC2=CC=CC=C12 DBQYUWWOBWTUPV-UHFFFAOYSA-N 0.000 claims 1
- 238000005903 acid hydrolysis reaction Methods 0.000 claims 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 150000002825 nitriles Chemical class 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 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
- 241000699670 Mus sp. Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 231100000518 lethal Toxicity 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- BISQTCXKVNCDDA-UHFFFAOYSA-N thiepine Chemical compound S1C=CC=CC=C1 BISQTCXKVNCDDA-UHFFFAOYSA-N 0.000 description 2
- LUOMABZEDNHRGY-UHFFFAOYSA-N 5,6-dihydrobenzo[b][1]benzothiepine-5-carboxylic acid Chemical compound OC(=O)C1CC2=CC=CC=C2SC2=CC=CC=C12 LUOMABZEDNHRGY-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Description
Vynález se týká způsobu přípravy kyselinThe invention relates to a process for the preparation of acids
10,11-dihydrodibenzo (b,f) thiepin-10-karboxylových obecného vzorce I,10,11-dihydrodibenzo (b, f) thiepine-10-carboxylic acids of formula I,
COOH ve kterém R značí atom vodíku nebo atom chlóru.COOH in which R represents a hydrogen atom or a chlorine atom.
Látky vzorce I jsou jednak meziprodukty synthesy dalších farmakologicky účinných látek, jednak mají samy o sobě therapeuticky použitelnou protizánětlivou účinnost. Tak kyselina 10,11-dihydrodibenzo (b,f j thiepin-10-karboxylová (I, R = H) v dávce 200 mg/kg orálně vykazuje statisticky signifikantní inbiční účinnost vůči adjuvantnímu zánětu u krys. Současně je tato látka relativně málo toxická; orální dávka 1 g/kg je letální pro 80 % myší. Kyselina 2-chlor-10,ll-dihydrodibenzo(b,f)thiepin-10-karboxylová (I, R — — Cl) v orální dávce 200 mg/kg statisticky signifikantně inhibuje jak kaolinový, tak i adjuvantní zánět u krys. Je ještě méně toxická než látka předešlá, protože orální dávka 1 g/kg je letální pouze pro 60 % myší.The compounds of formula I are on the one hand intermediates in the synthesis of other pharmacologically active substances and, on the other hand, have therapeutically useful anti-inflammatory activity. Thus, 10,11-dihydrodibenzo [b, f] thiepine-10-carboxylic acid (I, R = H) at a dose of 200 mg / kg orally shows statistically significant inhibition of adjuvant inflammation in rats. dose of 1 g / kg is lethal for 80% of mice 2-chloro-10,11-dihydrodibenzo (b, f) thiepine-10-carboxylic acid (I, R - Cl) at an oral dose of 200 mg / kg statistically significantly inhibits Both kaolin and adjuvant inflammation in rats are even less toxic than the previous ones, as an oral dose of 1 g / kg is lethal only to 60% of mice.
Způsob přípravy látek vzorce I podle tohoto vynálezu spočívá v úplné hydrolyse nitrilů obecného vzorce II,The process for the preparation of the compounds of the formula I according to the invention consists in complete hydrolysis of the nitriles of the formula II,
ve kterém R značí totéž jako ve vzorci 1. Tuto hydrolysu lze provést buď alkalicky, za použití 50% roztoku hydroxidu draselného v ethanolu při teplotě varu reakční směsi, nebo kysele, za použití 30 áž 70% vroucí kyseliny sírové.wherein R is the same as in Formula 1. This hydrolysis can be carried out either alkaline, using a 50% solution of potassium hydroxide in ethanol at the boiling point of the reaction mixture, or acidically, using 30 to 70% boiling sulfuric acid.
Látky podle vynálezu jsou látky nové, v literatuře dosud nepopsané. Jsou to látky krystalické s charakteristickými teplotami tání, jejichž identita byla zajištěna analysami a běžnými spektry. Rovněž výchozí nitrily obecného vzorce II jsou látky nové a jejich příprava je popsána v příkladech provedení.The substances according to the invention are novel substances not previously described in the literature. They are crystalline substances with characteristic melting points, whose identity was assured by analyzes and common spectra. The starting nitriles of formula (II) are also novel and their preparation is described in the Examples.
Příklad 1Example 1
10,11-Dihydrodibenzo (b,f) thlepin-10-karboxylová kyselina (I, R = H). Směs 34 g10,11-Dihydrodibenzo (b, f) thlepin-10-carboxylic acid (I, R = H). Mixture 34 g
10,11-dihydrodibenzo (b,f) thiepín-10-karbonltrilu, 50 g hydroxidu draselného a 50 ml ethanolu se vaří 5 h za míchání pod zpětným chladičem v lázni o teplotě 135 °C. Po ochlazení se zředí 500 ml vody, roztok se promyje chloroformem a okyselí se kyselinou solnou. Vyloučená kyselina se isoluje extrakcí chloroformem. Roztok se vysuší síranem sodným, chloroform se odpaří a zbylá surová kyselina se přečistí krystalisací z benzenu. Získá se ve výtěžku 17,3 g a taje při 126 až 128 °C. Poměrně nízký výtěžek je zaviněn tím, že ; část výchozího nitrilu podléhá jen parciální hydrolyse na amid, který se jako neutrální látka odstraní při vymytí alkalického roztoku chloroformem.10,11-dihydrodibenzo (b, f) thiepine-10-carbonltril, 50 g of potassium hydroxide and 50 ml of ethanol are heated under reflux in a 135 ° C bath for 5 hours. After cooling, it is diluted with 500 ml of water, the solution is washed with chloroform and acidified with hydrochloric acid. The precipitated acid is isolated by extraction with chloroform. The solution was dried over sodium sulfate, the chloroform was evaporated and the residual crude acid was purified by crystallization from benzene. It is obtained in a yield of 17.3 g and melts at 126 to 128 ° C. A relatively low yield is due to ; some of the starting nitrile undergoes only partial hydrolysis to the amide, which is removed as a neutral substance by washing the alkaline solution with chloroform.
Použitý výchozí 10,ll-dihydrodlbenzo(b,f Jthiepin-lO-karbonitril (II, R = H) je látkou novou, kterou lze připravit ze známého 10-bromdibenzo(b,f Jthiepinu (J. O. Jílek a spol., Collect. Czech. Chem. Commun. 32, 3186, 1967] tímto postupem:The starting 10,11-dihydrodibenzo (b, f Jthiepine-10-carbonitrile (II, R = H) used) is a novel substance which can be prepared from the known 10-bromodibenzo (b, f Jthiepine (JO Jílek et al., Collect.) Chem. Commun., 32, 3186 (1967)] as follows:
Směs 14,8 g 10-bromdibenzo(b,f Jthiepinu, 9,0 g kyanidu měďného a 75 ml dimethylformamidu se míchá a vaří 5 h pod zpětným chladičem. Potom se vlije do 300 ml vychlazeného konc. vodného amoniaku. Produkt se extrahuje dichlormethaneiň, extrakt se promyje 2M—HC1 a vodou, vysuší se síranem hořečnatým a odpaří. Krystalický zbytek se překrystaluje z 25 ml benzenu. Filtrací a zpracováním matečného louhu se získá 10,0 g (83 %) dibenzo-(b,f]thiepin-10-karbO'nitrilu tajícího při 133 až 137 °C, který je dostatečně čistý pro další zpracování. Zcela čistá látka se získá krystalisací, z benzenu a taje při 136 až 137 °C.A mixture of 14.8 g of 10-bromodibenzo (b, f) thiepine, 9.0 g of copper (I) cyanide and 75 ml of dimethylformamide is stirred and refluxed for 5 hours, then poured into 300 ml of cold concentrated aqueous ammonia. The extract was washed with 2M HCl and water, dried (MgSO4) and evaporated, the crystalline residue was recrystallized from 25 ml of benzene to give 10.0 g (83%) of dibenzo- (b, f) thiepine-). 10-carbonitrile, m.p. 133 DEG-137 DEG C., which is pure enough for further work-up, is obtained by crystallization from benzene and melts at 136 DEG-137 DEG C.
K míchanému roztoku 102 g dibenzo(b,f )thiepin-10-karbonitrilu ve 2,8 1 ethanolu se přikape roztok 49,1 g borohydridu sodného ve 200 ml vody obsahující 1,2 ml 20% roztoku hydroxidu sodného. Směs se vaří 1 h pod zpětným chladičem a ethanol se odpaří za sníženého tlaku. Zbytek se zředí vodou a extrahuje se benzenem. Extrakt se promyje 4% roztokem hydroxidu sodného a vodou, vysuší se uhličitanem draselným, odpaří se za sníženého tlaku a zbytek se krystaluje z ethanolu. Získá se 86,2 g (84%) 10,11-dihydrodibenzo (b,f) thiepin-10-karbonitrilu tajícího při 91,5 až 93 °C. Rekrystalisací z ethanolu še získá zcela čistá látka s t. t. 95 až 96 °C.To a stirred solution of 102 g of dibenzo (b, f) thiepine-10-carbonitrile in 2.8 L of ethanol was added dropwise a solution of 49.1 g of sodium borohydride in 200 ml of water containing 1.2 ml of 20% sodium hydroxide solution. The mixture was refluxed for 1 h and the ethanol was evaporated under reduced pressure. The residue was diluted with water and extracted with benzene. The extract was washed with 4% sodium hydroxide solution and water, dried over potassium carbonate, evaporated under reduced pressure and the residue crystallized from ethanol. 86.2 g (84%) of 10,11-dihydrodibenzo (b, f) thiepine-10-carbonitrile melting at 91.5 to 93 ° C is obtained. Recrystallization from ethanol gave the pure product, m.p. 95-96 ° C.
Příklad 2Example 2
2-Chlor-10,ll-dihydrodibenzo (b,f Jthiepin-10-karboxylová kyselina (I, R = Cl). Směs2-Chloro-10,11-dihydrodibenzo (b, f) thiepine-10-carboxylic acid (I, R = Cl).
4.3 g 2-chlor-10,ll-dihydrodibenzo-(b,fJthiepln-10-karbonitrilu (II, R = Cl], 30 ml vody a 20 ml kyseliny sírové se míchá a vaří 8 h pod zpětným chladičem v lázni o teplotě 150 °C. Po částečném ochlazení se zředí vodou, vyloučená pevná látka se přivede do roztoku přídavkem přebytečného teplého 5% roztoku hydroxidu sodného, nerozpuštěný podíl se odfiltruje (1,2 g příslušného amidu, který i v tomto případě vzniká jako vedlejší produkt), alkalický filtrát se okyselí kyselinou solnou a vyloučený žádaný produkt se isoluje filtrací, promyje se vodou, vysuší a krystaluje z benzenu. Získá se 2,8 g látky (61 %) tající při 181,5 až 183,5 °C.4.3 g of 2-chloro-10,11-dihydrodibenzo- (b, thiophene-10-carbonitrile (II, R = Cl), 30 ml of water and 20 ml of sulfuric acid are stirred and refluxed in a 150 ml bath for 8 hours. After partial cooling, it is diluted with water, the precipitated solid is brought into solution by the addition of excess warm 5% sodium hydroxide solution, the insoluble matter is filtered off (1.2 g of the corresponding amide, which in this case is also formed as a by-product), alkaline. the filtrate is acidified with hydrochloric acid and the desired product isolated by filtration, washed with water, dried and crystallized from benzene to give 2.8 g (61%) of melting point 181.5-183.5 ° C.
Použitý výchozí 2-chlor-10,ll-dihydrodlbenzo(b,f Jthiepin-10-karbonitril je látkou novou, kterou lze připravit ze známého 10-brom-2-chlordibenzo(b,f Jthiepinu (K. Šindelář a spol., Collect. Czech. Chem. Commuh. 42, 3605, 1977) tímto postupem:The starting 2-chloro-10,11-dihydrodibenzo [b, f] thiepine-10-carbonitrile used is a novel substance which can be prepared from the known 10-bromo-2-chlorodibenzo (b, f by Jthiepine (K. Sindelar et al., Collect.) Chem. Commuh., 42, 3605 (1977) by the following procedure:
Směs 22,3 g 10-brom-2-chlordibenzo(b,fJthiepinu, 12,5 g kyanidu měďného a 100 ml dimethylformamidu se vaří 4 h pod zpětným chladičem a po částečném ochlazení se vlije do 300 ml konc. vodného amoniaku. Produkt se extrahuje dichlormethanem, extrakt se promyje zředěnou kyselinou solnou a odpaří. Krystalisací zbytku z benzenu a zpracováním matečného louhu se získá 10,8 (58%) surového 2-chlordibenzo (b,f J thiepin-10-karbonitrilu tajícího při 156 až 166 °C, který je dostatečně čistý pro další zpracování. Zceja čistá látka se získá rekrystalisací vzorku z ethanolu, 1.1.161 až 168 °C.A mixture of 22.3 g of 10-bromo-2-chlorodibenzo [b] phthiepine, 12.5 g of copper (I) cyanide and 100 ml of dimethylformamide is refluxed for 4 hours and after partial cooling is poured into 300 ml of concentrated aqueous ammonia. Crystallization of the residue from benzene and treatment of the mother liquor gave 10.8 (58%) of crude 2-chlorodibenzo [b, f] thiepin-10-carbonitrile melting at 156-166 ° C. The pure substance is obtained by recrystallization of a sample from ethanol, m.p.
K roztoku 9,2 g předešlého nenasyceného nitrilu v 500 ml ethanolu se přidá roztokTo a solution of 9.2 g of the previous unsaturated nitrile in 500 ml of ethanol was added a solution
6.4 g borohydridii sodného, ve' 30 ml vody obsahující 3 kapky 20% roztoku hydroxidu sodného a směs se vaří 1 h pod zpětným chladičem. Ethanol se potom odpaří za sníženého tlaku, zbytek se zředí vodou a směs se extrahuje benzenem. Stáním se z benzenového extraktu vyloučí 0,7 g příslušného amidu tajícího při 222 až 223 σ0. Filtrát se odpaří a zbytek se krystaluje ze směsi benzenu a petroletheru. Vyloučí se 5,0 g (54 %) žádaného 2-chlor-10,ll-dihydrodibenzo(b,f )thiepin-10-karbonitrilu tajícího pří 113,5 až6.4 g of sodium borohydride in 30 ml of water containing 3 drops of a 20% sodium hydroxide solution and the mixture is refluxed for 1 h. Ethanol was then evaporated under reduced pressure, the residue was diluted with water and extracted with benzene. Upon standing, a benzene extract precipitated 0.7 g of the corresponding amide melting at 222-223 σ 0. The filtrate was evaporated and the residue crystallized from a mixture of benzene and petroleum ether. 5.0 g (54%) of the desired 2-chloro-10,11-dihydrodibenzo (b, f) thiepine-10-carbonitrile, m.p.
115,5 °C. Takto získaná látka je dostatečně čistá pro další zpracování. Vzorek zcela čisté substance se získá rekrystalisací z cyklohexanu, 1.1.114,5 až 116 °C.115.5 ° C. The material thus obtained is sufficiently pure for further processing. A sample of the pure substance is obtained by recrystallization from cyclohexane, m.p.
Claims (3)
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| Application Number | Priority Date | Filing Date | Title |
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| CS700982A CS225569B1 (en) | 1982-10-01 | 1982-10-01 | Preparation of 10,11-dihydrodibenzo/b,f/ thiepine-10-carboxylic acids |
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| Application Number | Priority Date | Filing Date | Title |
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| CS700982A CS225569B1 (en) | 1982-10-01 | 1982-10-01 | Preparation of 10,11-dihydrodibenzo/b,f/ thiepine-10-carboxylic acids |
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| CS225569B1 true CS225569B1 (en) | 1984-02-13 |
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