CS235177B1 - J-carboxyalkylamino-1,3-dimethyl-1h-pyrazolo-(3,4-b)quinolines and method of their preparation - Google Patents
J-carboxyalkylamino-1,3-dimethyl-1h-pyrazolo-(3,4-b)quinolines and method of their preparation Download PDFInfo
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- CS235177B1 CS235177B1 CS787183A CS787183A CS235177B1 CS 235177 B1 CS235177 B1 CS 235177B1 CS 787183 A CS787183 A CS 787183A CS 787183 A CS787183 A CS 787183A CS 235177 B1 CS235177 B1 CS 235177B1
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- pyrazolo
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- 238000000034 method Methods 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims description 4
- -1 methoxy, ethoxy Chemical group 0.000 claims description 4
- CLRNUDVGJVDYTG-UHFFFAOYSA-N 4-chloro-1,3-dimethylpyrazolo[3,4-b]quinoline Chemical compound C1=CC=C2C(Cl)=C3C(C)=NN(C)C3=NC2=C1 CLRNUDVGJVDYTG-UHFFFAOYSA-N 0.000 claims description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 241000700605 Viruses Species 0.000 abstract description 17
- 241000699670 Mus sp. Species 0.000 abstract description 12
- 241000710188 Encephalomyocarditis virus Species 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 4
- 230000000840 anti-viral effect Effects 0.000 abstract description 3
- 229940111121 antirheumatic drug quinolines Drugs 0.000 abstract description 3
- 150000003248 quinolines Chemical class 0.000 abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 241000712461 unidentified influenza virus Species 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 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 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000011421 subcutaneous treatment Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Vynález se týká 4-karboxylalkylamino-l,3- -dimethyl-lH-pyrazolo( 3,4-b jchinolinů obecného vzorce I kde n je 1 nebo 2 a způsobu jejich přípravy. Tyto nové, dosud nepopsané látky vykazují protivirovou aktivitu proti viru A2-Honkong a proti viru encefalomyokarditldy u myší.The invention relates to 4-carboxylalkylamino-1,3- -dimethyl-1H-pyrazolo (3,4-b quinolines) of Formula I where n is 1 or 2 and the process for their preparation. These new, not yet described substances show antiviral activity against A2-Honkong virus and against encephalomyocarditis virus mice.
Description
Vynález se týká 4-karboxylalkylamino-l,3-dimethyl-lH-pyrazolO' (3,4-b) chinolinů obecného vzorce IThe invention relates to 4-carboxylalkylamino-1,3-dimethyl-1H-pyrazolo [3,4-b] quinolines of the general formula I
kde n je 1 nebo 2. Vynález se týká rovněž způsobu přípravy látek obecného vzorce I.wherein n is 1 or 2. The invention also relates to a process for the preparation of compounds of formula I.
Tyto nové, dosud nepopsané látky, vykazují protivirovou aktivitu proti viru A2-Honkong a proti viru encefalomyokarditidy (EMC) u myší.These novel substances, which have not been described yet, show antiviral activity against A2-Honkong virus and against encephalomyocarditis virus (EMC) in mice.
Sloučeniny obecného vzorce I lze podle vynálezu připravit reakcí o sobě známého 4-chlor-l,3-dimethyl-lH-pyrazolo (3,4-b Jchinolinu [Stein R. G., Biel J. H.: J. Med. Chem. 13, 153 (1973)] s příslušnou aminokyselinou, výhodně s přebytkem 0,1 molárním, ve fenolu při teplotě 80 °C až 120 °C, výhodně při teplotě 100 °C.The compounds of the formula I according to the invention can be prepared by the reaction of the known 4-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] quinoline [Stein RG, Biel JH: J. Med. Chem. 13, 153 (1973)]. with a corresponding amino acid, preferably with an excess of 0.1 molar, in phenol at a temperature of 80 ° C to 120 ° C, preferably at 100 ° C.
Sloučeniny obecného vzorce I lze také připravit zmýdelněním 4-alkoxykarbonylalkylamino-l,3-dimethyl-lH-pyrazolo (3,4-b) chinolinů, kde alkoxy je methoxy, ethoxy nebo propoxy a alkyl je methyl nebo ethyl, vodné methanolickým roztokem hydroxidu sodného při teplotě 0 až 30 °C.Compounds of formula I may also be prepared by saponification of 4-alkoxycarbonylalkylamino-1,3-dimethyl-1H-pyrazolo (3,4-b) quinolines wherein the alkoxy is methoxy, ethoxy or propoxy and the alkyl is methyl or ethyl with aqueous methanolic sodium hydroxide solution at 0 to 30 ° C.
Uvedené sloučeniny obecného vzorce I podle vynálezu, patří do skupiny látek s protivirovým účinkem. Uvedené sloučeniny byly hodnoceny ve formě hydrochloridů proti viru A2-Honkong a proti viru encefalomyokarditidy (EMC) u myší.The compounds of the formula I according to the invention belong to the group of substances having antiviral activity. The compounds were evaluated in the form of hydrochlorides against A2-Honkong virus and against encephalomyocarditis virus (EMC) in mice.
Hodnocení účinnosti proti viru chřipky A2-Honkong u myší:Evaluation of efficacy against A2-Honkong influenza virus in mice:
Byly užity samice bílých myší SPF (Velaz) o hmotnosti 10 až 11 g. Virus byl aplikován myším v lehké etherové narkose intranasálně. Množství LDso viru bylo stanoveno v samostatném pokuse a bylo vypočítáno podle REEDA a MUENCHA (Reed L. J., Muench H.: Amer. J. Hyg. 27, 493 (1938)]. Pro každou koncentraci viru bylo užito 7 myší. Neléčené myši hynuly na pneumonii podle použité koncentrace viru 3 až 10 dní po infekci. Zkoušené látky byly suspendovány pomocí monoesteru kyseliny olejové s tripolyethylenglykolanhydrosorbitetherem (Tween 80).Female white SPF mice (Velaz) weighing 10 to 11 g were used. The virus was administered intranasally to mice under light ether anesthesia. The amount of LD 50 of the virus was determined in a separate experiment and was calculated according to REED and MUENCH (Reed LJ, Muench H .: Amer. J. Hyg. 27, 493 (1938)) .7 mice were used for each virus concentration. pneumonia, depending on the virus concentration used, 3 to 10 days after infection The test substances were suspended with monoester of oleic acid with tripolyethylene glycol anhydride sorbitol (Tween 80).
Zvířatům byly látky aplikovány per os sondou, nebo byly podávány subktutánně do řasy kůže na hřbetu vždy v objemu 0,2 mililitrů. Myši byly léčeny perorálně nebo subkutánně 2 X denně po dobu 5 dní (1 den před a 4 dny po infekci). Denní dávka byla 2 X 150 mg/kg. Účinnost byla posuzována podle prodloužení průměrné doby přežití v porovnání s neléčenou kontrolou.Animals were administered per os by gavage or administered subcutaneously into the back of the skin at 0.2 milliliters. Mice were treated orally or subcutaneously 2 times daily for 5 days (1 day before and 4 days after infection). The daily dose was 2 X 150 mg / kg. Efficacy was assessed by increasing the average survival time compared to the untreated control.
Po subkutánním podání byla účinná sloučenina obecného vzorce I, kde n je 1 (prodlužuje dobu přežití proti 5 LDso viru o 23 % a proti 50 LDso viru o 74 %). Po perorálním podání je účinná sloučenina obecného vzorce I, kde n je 2 (prodlužuje dobu přežití proti 50 LDso viru o 23,5 %).Following subcutaneous administration, the compound of formula I was active, wherein n is 1 (extending survival time against 5 LD 50 virus by 23% and against 50 LD 50 virus by 74%). After oral administration, the active compound of formula I is active, wherein n is 2 (extends the survival time against 50 LD 50 of the virus by 23.5%).
Hodnocení proti viru EMC u myší:Evaluation against EMC in mice:
Byly užity samice bílých myší SPF (Velaz) o hmotnosti 10 až 11 g. Virus byl myším aplikován subkutánně v objemu 0,2 ml do záhybu kůže zad. Neléčené myši hynuly v závislosti na koncentraci viru 3 až 7 dní po infekci. Množství viru bylo stanoveno způsobem uvedeným u hodnocení účinnosti proti viru chřipky. Subkutánní léčba byla prováděna čtyřmi dávkami po 100 mg/kg vždy 28, 22, 2 hodiny před a 2 hodiny po infekci. Perorální léčba byla provedena 24 hodin před Infekcí jenorázovou dávkou 400 mg/kg. Vyhodnocení účinnosti bylo prováděno stejně jako při hodnocení účinnosti látek proti viru chřipky.Female white SPF mice (Velaz) weighing 10-11 g were used. The virus was injected subcutaneously in a volume of 0.2 ml into the fold of the back skin. Untreated mice died depending on the virus concentration 3 to 7 days after infection. The amount of virus was determined as described for efficacy against influenza virus. Subcutaneous treatment was performed with four doses of 100 mg / kg each 28, 22, 2 hours before and 2 hours after infection. Oral treatment was performed 24 hours prior to infection with a single dose of 400 mg / kg. The efficacy evaluation was performed in the same way as the efficacy evaluation of the anti-influenza agents.
Po subkutánním podání byla účinná sloučenina obecného vzorce I, kde n je 2 (prodlužuje dobu přežití proti 50 LDso viru o 80%). Po perorálním podání sloučenina obecného vzorce I, kde n je 1, prodlužuje dobu přežití proti 50 LDso viru o 15 %, sloučenina obecného vzorce I, kde n je 2, prodlužuje dobu přežití proti 50 LDso viru o 16 %.Following subcutaneous administration, the active compound of formula I was the active compound wherein n is 2 (extending the survival time against 50 LD 50 of the virus by 80%). Following oral administration, a compound of formula I wherein n is 1 increases the survival time against 50 LD 50 of the virus by 15%, a compound of formula I wherein n is 2 increases the survival time against 50 LD 50 of the virus by 16%.
Jak plyne z uvedených údajů, jsou sloučeniny obecného vzorce I, kde n je 1 nebo 2, účinné proti viru A2-Honkong a proti viru EMC u myší. Způsob přípravy je jednoduchý a poskytuje žádané produkty v uspokojivých výtěžcích. Bližší podrobnosti vyplývají z následujích příkladů provedení. Uvedené příklady vynález pouze ilustrují, nikoliv omezujíAs can be seen from the above data, compounds of formula I wherein n is 1 or 2 are active against A2-Honkong virus and against EMC virus in mice. The method of preparation is simple and provides the desired products in satisfactory yields. Further details are given in the following examples. The examples given are merely illustrative and not limiting
Příklad 1Example 1
Hydrochlorid 4- (2-karboxyethylamino) -1,3-dimethyl-lH-pyrazolo (3,4-b J chinolinů4- (2-Carboxyethylamino) -1,3-dimethyl-1H-pyrazolo (3,4-b) quinolines hydrochloride
Směs 2,32 g 4-chlor-l,3-dimethyl-lH-pyrazolo(3,4-b)chinolinů (10 mmolj, 1,09 g 3-aminopropionové kyseliny (12 mmol) a 10 gramů fenolu byla míchána 6 hodin při teplotě 100 °C. Reakční směs byla zředěna 25 mililitry ethanolu a po ochlazení byl roztok srážen etherem. Nerozpustný podíl byl odsát, promyt etherem a překrystalován z ethanolu. Bylo získáno 2,28 g látky (71,7 %) o t. t. 297,2 až 300,0 °C.A mixture of 2.32 g of 4-chloro-1,3-dimethyl-1H-pyrazolo (3,4-b) quinolines (10 mmol), 1.09 g of 3-aminopropionic acid (12 mmol) and 10 g of phenol was stirred for 6 hours at 100 DEG C. The reaction mixture was diluted with 25 ml of ethanol and, after cooling, the solution was precipitated with ether and the insoluble material was filtered off with suction, washed with ether and recrystallized from ethanol to give 2.28 g (71.7%). 2 to 300.0 ° C.
Příklad 2Example 2
Hydrochlorid 4-karboxymethylamino-l,3-dimethyl-lH-pyrazolo (3,4-b) chinolinů4-Carboxymethylamino-1,3-dimethyl-1H-pyrazolo (3,4-b) quinoline hydrochloride
Směs 1,67 g hydrochloridu 4-ethoxykarbonylmethylamino-l,3-dimethyl-lH-pyrazolo235177 (3,4-bjchinolinu (5 mmol), 30 ml 1,5 M roztoku hydroxidu sodného a 30 ml methanolu byla míchána 5 hodin při teplotě 20 °C. Vzniklý roztok byl okyselen kyselinou octovou, vyloučená látka byla odsáta a promyta vodou. Surová látka byla za horka rozpuštěna v 90% vodném ethanolu a roztok byl okyselen kyselinou chlorovodíkovou. Krystaly vyloučené po ochlazení byly promyty malým množstvím ethanolu. Překrystalováním z 90 procentního vodného ethanolu bylo získáno 1,1 g látky (71,7%j o t. t. 298 až 304 °C.A mixture of 1.67 g of 4-ethoxycarbonylmethylamino-1,3-dimethyl-1H-pyrazolo [2,3-b] quinoline (5 mmol), 30 ml of 1.5 M sodium hydroxide solution and 30 ml of methanol was stirred at 20 DEG C. for 5 hours. The resulting solution was acidified with acetic acid, the precipitate was filtered off with suction and washed with water, the crude material was dissolved hot in 90% aqueous ethanol, and the solution was acidified with hydrochloric acid. aqueous ethanol gave 1.1 g (71.7% at 298-304 ° C).
Claims (3)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS787183A CS235177B1 (en) | 1983-10-26 | 1983-10-26 | J-carboxyalkylamino-1,3-dimethyl-1h-pyrazolo-(3,4-b)quinolines and method of their preparation |
| CS839744A CS235189B1 (en) | 1983-10-26 | 1983-12-21 | 4-alcoxycarbonylmethylamino-1,3-dimethyl-1h-pyrazolo-(3,4-b) quinolines and method of their preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS787183A CS235177B1 (en) | 1983-10-26 | 1983-10-26 | J-carboxyalkylamino-1,3-dimethyl-1h-pyrazolo-(3,4-b)quinolines and method of their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS235177B1 true CS235177B1 (en) | 1985-05-15 |
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ID=5428601
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS787183A CS235177B1 (en) | 1983-10-26 | 1983-10-26 | J-carboxyalkylamino-1,3-dimethyl-1h-pyrazolo-(3,4-b)quinolines and method of their preparation |
| CS839744A CS235189B1 (en) | 1983-10-26 | 1983-12-21 | 4-alcoxycarbonylmethylamino-1,3-dimethyl-1h-pyrazolo-(3,4-b) quinolines and method of their preparation |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS839744A CS235189B1 (en) | 1983-10-26 | 1983-12-21 | 4-alcoxycarbonylmethylamino-1,3-dimethyl-1h-pyrazolo-(3,4-b) quinolines and method of their preparation |
Country Status (1)
| Country | Link |
|---|---|
| CS (2) | CS235177B1 (en) |
-
1983
- 1983-10-26 CS CS787183A patent/CS235177B1/en unknown
- 1983-12-21 CS CS839744A patent/CS235189B1/en unknown
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| Publication number | Publication date |
|---|---|
| CS235189B1 (en) | 1985-05-15 |
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