DE2325159B2 - 1-METHYL-2- (PYRIDYLTHIOMETHYL) -5- NITRO-IMIDAZOLE AND 1-METHYL-2- (N-OXYPYRIDYLTHIOMETHYL) -5-NITROIMIDAZOLE - Google Patents
1-METHYL-2- (PYRIDYLTHIOMETHYL) -5- NITRO-IMIDAZOLE AND 1-METHYL-2- (N-OXYPYRIDYLTHIOMETHYL) -5-NITROIMIDAZOLEInfo
- Publication number
- DE2325159B2 DE2325159B2 DE19732325159 DE2325159A DE2325159B2 DE 2325159 B2 DE2325159 B2 DE 2325159B2 DE 19732325159 DE19732325159 DE 19732325159 DE 2325159 A DE2325159 A DE 2325159A DE 2325159 B2 DE2325159 B2 DE 2325159B2
- Authority
- DE
- Germany
- Prior art keywords
- methyl
- nitro
- imidazole
- pyridylthiomethyl
- infection
- 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
- IRVDBEMWNQAVEV-UHFFFAOYSA-N 2-[(1-methyl-5-nitroimidazol-2-yl)methylsulfanyl]pyridine Chemical compound C1=C([N+]([O-])=O)N(C)C(CSC=2N=CC=CC=2)=N1 IRVDBEMWNQAVEV-UHFFFAOYSA-N 0.000 title claims description 5
- NVKJOXRVEKMMHS-UHFFFAOYSA-N 5-nitro-1,2,4-triazol-3-one Chemical compound [O-][N+](=O)C1=NC(=O)N=N1 NVKJOXRVEKMMHS-UHFFFAOYSA-N 0.000 title description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 description 20
- 150000001875 compounds Chemical class 0.000 description 13
- 239000000126 substance Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- 244000052769 pathogen Species 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 7
- 229960000282 metronidazole Drugs 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000001717 pathogenic effect Effects 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 5
- 206010019692 hepatic necrosis Diseases 0.000 description 5
- 231100000149 liver necrosis Toxicity 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- -1 toluenesulphonic acid ester Chemical class 0.000 description 5
- 241000699800 Cricetinae Species 0.000 description 4
- 150000001204 N-oxides Chemical class 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 150000001340 alkali metals Chemical class 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 241000224432 Entamoeba histolytica Species 0.000 description 3
- 241000699673 Mesocricetus auratus Species 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 210000003754 fetus Anatomy 0.000 description 3
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- PDISGXFXQFGQFB-UHFFFAOYSA-N 2-(chloromethyl)-1-methyl-5-nitroimidazole Chemical compound CN1C(CCl)=NC=C1[N+]([O-])=O PDISGXFXQFGQFB-UHFFFAOYSA-N 0.000 description 2
- VYDWQPKRHOGLPA-UHFFFAOYSA-N 5-nitroimidazole Chemical compound [O-][N+](=O)C1=CN=CN1 VYDWQPKRHOGLPA-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000224421 Heterolobosea Species 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical class [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 241001502500 Trichomonadida Species 0.000 description 2
- 241000224526 Trichomonas Species 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 210000003001 amoeba Anatomy 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229940007078 entamoeba histolytica Drugs 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 210000000416 exudates and transudate Anatomy 0.000 description 2
- 150000005748 halopyridines Chemical class 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical class NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VRNQHXMQYBJYPJ-UHFFFAOYSA-N (1-methyl-5-nitroimidazol-2-yl)methanethiol Chemical class CN1C(CS)=NC=C1[N+]([O-])=O VRNQHXMQYBJYPJ-UHFFFAOYSA-N 0.000 description 1
- JSAQDPJIVQMBAY-UHFFFAOYSA-N (1-methyl-5-nitroimidazol-2-yl)methanol Chemical compound CN1C(CO)=NC=C1[N+]([O-])=O JSAQDPJIVQMBAY-UHFFFAOYSA-N 0.000 description 1
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- FHTDDANQIMVWKZ-UHFFFAOYSA-N 1h-pyridine-4-thione Chemical compound SC1=CC=NC=C1 FHTDDANQIMVWKZ-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- FTSJZRFRZMYOQU-UHFFFAOYSA-N 3-[(1-methyl-5-nitroimidazol-2-yl)methylsulfanyl]pyridine Chemical compound C1=C([N+]([O-])=O)N(C)C(CSC=2C=NC=CC=2)=N1 FTSJZRFRZMYOQU-UHFFFAOYSA-N 0.000 description 1
- RZFNCUVDFJOGFR-UHFFFAOYSA-N 4-[(1-methyl-5-nitroimidazol-2-yl)methylsulfanyl]pyridine Chemical compound C1=C([N+]([O-])=O)N(C)C(CSC=2C=CN=CC=2)=N1 RZFNCUVDFJOGFR-UHFFFAOYSA-N 0.000 description 1
- 208000004881 Amebiasis Diseases 0.000 description 1
- 206010001980 Amoebiasis Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- KRIOHRGAEHOREH-UHFFFAOYSA-N N1=C(C=CC=C1)SCC=1NC(=CN1)[N+](=O)[O-] Chemical compound N1=C(C=CC=C1)SCC=1NC(=CN1)[N+](=O)[O-] KRIOHRGAEHOREH-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- 208000005448 Trichomonas Infections Diseases 0.000 description 1
- 241000224527 Trichomonas vaginalis Species 0.000 description 1
- 206010044620 Trichomoniasis Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 150000004704 methoxides Chemical class 0.000 description 1
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/93—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by halogen atoms, attached to other ring members
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
worin η die Zahlen O oder 1 bedeutet, und der Pyridinriiig in 2-, 3- oder 4-Position an das Schwefelatom gebunden ist.where η denotes the numbers 0 or 1, and the pyridine ring is bonded to the sulfur atom in the 2-, 3- or 4-position.
2.1 -Methyl-2-(2-pyridylthiomethyl)-5-nitro-imidazol. 2.1 -Methyl-2- (2-pyridylthiomethyl) -5-nitro-imidazole.
3. Verfahren zur Herstellung der Verbindungen nach Anspruch 1, dadurch gekennzeichnet, daß man in an sich bekannter Weise entweder3. Process for the preparation of the compounds according to claim 1, characterized in that one in a manner known per se either
a) ein l-Methyl-2-substitmethyl-5-nitro-imidazol der allgemeinen Forme! Ha) a l-methyl-2-substitmethyl-5-nitro-imidazole of the general form! H
O2NO 2 N
2525th
CH5-XCH 5 -X
N
CH3 N
CH 3
in der X ein Halogenatom oder eine Arylsulfonsäureestergruppierung bedeutet, mit einem Mercaptopyridin bzw. dessen N-Oxid der allgemeinen Formel IIIin which X is a halogen atom or an arylsulfonic acid ester group means with a mercaptopyridine or its N-oxide the general formula III
3030th
YcYc
(HI)(HI)
4040
in der η die in Anspruch 1 genannte Bedeutung hat und Y ein Wasserstoffatom oder ein Alkalimetall- oder Ammonium bedeutet, umsetzt, oderin which η has the meaning given in claim 1 and Y is a hydrogen atom or an alkali metal or ammonium, or
ein 1 -Methyl^-mercaptomethyl-S-nitro-imidazol der allgemeinen Formel IVa 1-methyl ^ -mercaptomethyl-S-nitro-imidazole of the general formula IV
O2NO 2 N
(IV)(IV)
CH1 CH 1
5555
in der Y die bei der allgemeinen Formel III genannte Bedeutung besitzt, mit einem HaIogenpyridin bzw. dessen N-Oxid der allgemeinen Formel V noin which Y has the meaning given for general formula III, with a halopyridine or its N-oxide of the general formula V no
X'X '
(V)(V)
4. Arzneimittel, bestehend aus einer Verbindung nach den Ansprüchen 1 bis 2 in Mischung mit einem pharmazeutisch üblichen Trägerstoff.4. Medicament consisting of a compound according to claims 1 to 2 in admixture with one pharmaceutically usual carrier.
1 -(2'-Hydroxyäthyl)-2-methyl-5-nitroimidiu;ol (Metronidazol) wird zur Bekämpfung von Protozoenerkrankungen, wie Trichomoniasis und Amöbiasis angewen-1 - (2'-Hydroxyethyl) -2-methyl-5-nitroimidiu; ol (metronidazole) is used to combat protozoal diseases such as trichomoniasis and amebiasis
Gegenstand der Erfindung sind l-Methyl-2-(pyridylthiomethyl)-5-nitro-imidazole sowe 1-Methyl-2-(N-oxypyndylthiomethyl)-5-nitro-imidazole der allgemeinen Formel 1The invention relates to l-methyl-2- (pyridylthiomethyl) -5-nitro-imidazoles as well as 1-methyl-2- (N-oxypyndylthiomethyl) -5-nitro-imidazole of the general formula 1
0,N0, N
CH3 CH 3
CH,-SCH, -S
(O)n (O) n
worin η die Zahlen O oder 1 bedeutet und der Pyridinring in 2-, 3- oder 4-Position an das Schwefelatom gebunden istwhere η denotes the numbers O or 1 and the pyridine ring is bonded to the sulfur atom in the 2-, 3- or 4-position
Die erfindungsgemäßen Verbindungen zeigen eine ausgeprägte und dem erwähnten Metronidazol überlegene Wirkung gegen Trichomonaden und Amöben. Gegenstand der Erfindung ist weiterhin ein Verfahren zur Herstellung von l-Methyl-2-(pyridylthiomethyl)-5-nitro-imidazolen sowie 1-Methyl-2-(N-oxypyridylthiomethyl)-5-nitro-imidazolen der allgemeinen Formel I, das dadurch gekennzeichnet ist, daß man in an sich bekannter Weise entwederThe compounds according to the invention show a pronounced and superior to the mentioned metronidazole Effect against trichomonads and amoebas. The invention also relates to a method for the production of l-methyl-2- (pyridylthiomethyl) -5-nitro-imidazoles and 1-methyl-2- (N-oxypyridylthiomethyl) -5-nitro-imidazoles of the general formula I, which is characterized in that either in a known manner
a) ein l-Methy!-2-substit.methyi-5-nitro-imidazol der allgemeinen Formel Ila) a l-methy! -2-substit.methyi-5-nitro-imidazole der general formula II
O, NO, N
CH1-XCH 1 -X
N
CH3 N
CH 3
(II)(II)
in der X ein Halogenatom oder eine Arylsulfonsiiureestergruppierung bedeutet, mit einem Mercaptopyridin bzw. dessen N-Oxid der allgemeinen Formel IUin which X is a halogen atom or an arylsulfonic acid ester group means with a mercaptopyridine or its N-oxide of the general Formula IU
Y-SY-S
(IM)(IN THE)
(O)n (O) n
in der η die in Anspruch 1 genannte Bedeutung hat und Y ein Wasserstoffatom oder ein Alkalimetalloder Ammonium bedeutet, umsetzt, oderin which η has the meaning given in claim 1 and Y is a hydrogen atom or an alkali metal or ammonium, or
1 -Methyl^-mercaptomethyl-S-nitro-imidazol1 -Methyl ^ -mercaptomethyl-S-nitro-imidazole
eina
der allgemeinen Formel IVof the general formula IV
O, N-O, N-
-CH,- S—Y-CH, - S-Y
(IV)(IV)
CH3 CH 3
in der X' ein Halogenatom bedeutet, umsetzt.in which X 'denotes a halogen atom.
in der Y die bei der allgemeinen Formelin the Y that of the general formula
genannte Bedeutung besitzt, mit einem Haiogenpyridin bzw. dessen N-Oxid der allgemeinen Forme! Vhas mentioned meaning, with a halo pyridine or its N-oxide of the general form! V
(V)(V)
I
(O) I.
(O)
in der X' ein Halogenatom bedeutet, umsetztin which X 'denotes a halogen atom
Als Verbindungen der allgemeinen Formel H kommen beispielsweise in Frage l-Methyl-2-chlor-, -2-brom-, -2-jod-methyl-5-nitro-imidazole oder die entsprechenden Benzol-, bzw.Toluolsulfonsäureester.As compounds of the general formula H, for example, l-methyl-2-chloro, -2-bromo-, -2-iodo-methyl-5-nitro-imidazole or the corresponding benzene or toluenesulphonic acid ester.
Ah Verbindungen der allgemeinen Formel III kommen beispielsweise in Frage 2-, 3-, 4-Mercaptopyridin sowie 2-, 3-, 4-Mercapto-N-oxypyridin oder deren Alkalimetall- oder Ammoniumsalze.Ah compounds of the general formula III come, for example, 2-, 3-, 4-mercaptopyridine as well as 2-, 3-, 4-mercapto-N-oxypyridine or their alkali metal or ammonium salts.
Anstelle der Mercaptoverbindungen können auch Mercaptanbildner wie z. B. Isothiouroniumsalze verwendet werden.Instead of the mercapto compounds, mercaptan formers such as. B. Isothiouronium salts are used will.
Als Verbindungen der allgemeinen Formel IV kommen beispielsweise in Frage: l-Methyl-2-mercaptomethyl-5-nitro-imidazole oder deren Alkalimetall- oder Ammoniumsalze.Examples of possible compounds of the general formula IV are: 1-methyl-2-mercaptomethyl-5-nitro-imidazoles or their alkali metal or ammonium salts.
Anstelle der Mercaptoverbindungen können auch Mercaptanbildner wie z. EJ. Isothiouroniumsalze verwendet werden.Instead of the mercapto compounds, mercaptan formers such as. EJ. Isothiouronium salts used will.
Als Verbindungen der allgemeinen Formel V kommen beispielsweise in Frage: 2-, 3-, 4-Chlor-, -Brom-, -Jod-pyridin sowie 2-, 3-, 4-Chlor-, -Brom-, -Jod-N-oxy-pyridin.Examples of possible compounds of the general formula V are: 2-, 3-, 4-chloro-, -Bromo-, -iodopyridine as well as 2-, 3-, 4-chloro-, -Brom-, -Iodine-N-oxy-pyridine.
Die Umsetzungen erfolgen zweckmäßigerweise in äquimolaren Mengen. Sie werden vorteilhaft in e;nem Lösungs- oder Verteilungsmittel durchgeführt. Je nach Verfahrensweise arbeitet man in einem unpolaren oder in einem polaren aprotischen Lösungsmittel. Als unpolare Lösungsmittel kommen in Betracht: Benzol, Toluol, Xylol, Chlorbenzol. Als aprotische Lösungsmittel kommen in Betracht: Pyridin, Picolin, Chinolin, Dimethylformamid, Dimenhylacetamid, N-Methylpyrrolidon, Tetramethylharnstoff, Hexamethylphosphorsäuretriamid, Dimethylsulfoxid. Die Reaktionstemperaturen können je nach Verfahrensart zwischen O und 200° C betragen. In unpolaren Lösungsmitteln, zweckmäßigerweise bei 50—1500C, in aprotischen Lösungsmitteln 100—15O0C. Die Reaktionszeiten betragen je nach Verfahren wenige Minuten bis einige Stunden.The reactions are expediently carried out in equimolar amounts. They will be beneficial in e ; carried out nem solvent or distributing agent. Depending on the procedure, one works in a non-polar or in a polar aprotic solvent. Possible non-polar solvents are: benzene, toluene, xylene, chlorobenzene. The following aprotic solvents are suitable: pyridine, picoline, quinoline, dimethylformamide, dimenhylacetamide, N-methylpyrrolidone, tetramethylurea, hexamethylphosphoric acid triamide, dimethyl sulfoxide. The reaction temperatures can be between 0 and 200 ° C., depending on the type of process. In nonpolar solvents, conveniently at 50-150 0 C, in aprotic solvents 100-15O 0 C. The reaction times are, depending on the method a few minutes to several hours.
Bei Verwendung der freien Mercaptoverbindungen der allgemeinen Formeln MI und IV empfiehlt sich die Anwendung eines säurebindenden Mittels. Als säurebindende Mittel kommen Basen wie Triethylamin oder Pyridin sowie Alkali- und Erdalkalicarbonate und -bicarbonate, -hydroxyde und -alkoxyde, wie z. B. -methoxyde, -äthoxyde, -butoxyde in Frage. Die Isolierung der Verfahrenserzeugnisse erfolgt je nach Verfahrensweise nach üblichen Methoden durch Abdestillieren der verwendeten Lösungsmittel oder Verdünnen der Reaktionslösung mit Wasser. Gegebenenfalls kann eine Reinigung durch Umkristallisation aus einem geeigneten Lösungsmittel oder Lösungsmittelgemisch erfolgen.When using the free mercapto compounds of the general formulas MI and IV, the recommended Use of an acid-binding agent. Acid-binding agents are bases such as triethylamine or Pyridine and alkali and alkaline earth carbonates and bicarbonates, hydroxides and alkoxides, such as. B. methoxides, ethoxides, butoxides in question. The process products are isolated depending on Procedure according to customary methods by distilling off the solvents used or diluting the reaction solution with water. Optionally, a purification by recrystallization from a suitable solvent or solvent mixture take place.
Die erfindungsgemäßen l-Methyl-2-(pyridylthiomethyl)-5-nitro-imidazole sowie i-Methyl-2-(N-oxypyridvlthiomethvl)-5-nitro-imidazole eignen sich zur Bekämpfung von Protozeonerkrankungen bei Mensch und Tier, wie sie z. B. durch Infektionen mit T. vaginalis und E. histolytica hervorgerufen werden. Sie können oral oder lokal angewendet werden. Die orale Anwendung erfolgt üblicherweise in Form von Tabletten oder Kapseln, die pro Tagesdosis etwa 10 bis 750 mg des Wirkstoffs mit einem gebräuchlichen Zusatz von Verdünnungsmittel und/oder Streckmittel enthalten. Für die lokale Anwendung können Gelees, Cremes, ι ο Salben oder Suspensionen verwendet werden.The l-methyl-2- (pyridylthiomethyl) -5-nitro-imidazoles according to the invention as well as i-methyl-2- (N-oxypyridvlthiomethvl) -5-nitro-imidazoles are suitable for combating of protozoan diseases in humans and animals, such as. B. by infections with T. vaginalis and E. histolytica. You can take it orally or applied locally. Oral use is usually in the form of tablets or Capsules containing about 10 to 750 mg of the active ingredient per daily dose with a common addition of Contain diluents and / or extenders. Jellies, creams, ι ο ointments or suspensions are used.
Die erfindungsgemäßen Verbindungen zeichnen sich bei guter Verträglichkeit durch eine sichere, dem bekannten Vergleichspräparat Metronidazol deutlich überlegene Wirkung gegenüber Trichomonaden und Amöben in vivo aus, wie aus den folgenden Tabellen ersichtlich ist:The compounds according to the invention stand out with good tolerance by a safe, the known comparator preparation metronidazole clearly superior effect against trichomonads and amoebas in vivo, as shown in the following tables can be seen:
Die Prüfung gegen Trichomonas foetus erfolgt im allgemeinen an Albino-Mäusen (NMRI) beiderlei Geschlechte iius eigener Koloniezucht. Das Gewicht der Tiere beträgt zwischen 10 und 12 g.The test against Trichomonas fetus is generally carried out on albino mice (NMRI) of both types Sexes iius own colony breeding. The weight of the animals is between 10 and 12 g.
Die Applikation der Prüfsubstanz erfolgt oral mit Hilfe der Schlundsonde, entweder als wäßrige Lösung oder bei schwer wasserlöslichen Verbindungen als Carboxymethylcellulose-Suspension. Insgesamt werden zwei Einzeldosen appliziert, die erste zwei Stunden vor und die zweit.- zwei Stunden nach der Infektion. Pro Prüfsubstanz und Dosierung werden jeweils 4 Mäuse verwandt.The test substance is administered orally with the aid of the stomach tube, either as an aqueous solution or in the case of poorly water-soluble compounds as a carboxymethyl cellulose suspension. Total will be Two single doses are applied, the first two hours before and the second two hours after the infection. Per Test substance and dosage are used in each case 4 mice.
Die Infektion erfolgt intraperitoneal, 19 Mill. Erreger/ Tier, suspendiert in 0,5 ml Kulturmedium, Merck I. Der Standard Metronidazol wird wie die Prüfsubstanz dosiert und appliziert (vgl. Tabelle 1).The infection takes place intraperitoneally, 19 million pathogens / animal, suspended in 0.5 ml culture medium, Merck I. Der Standard metronidazole is dosed and applied like the test substance (see Table 1).
Als Infektionskontrollen werden im allgemeinen 10Infection controls are generally 10
Mäuse verwandt, die nach der Infektion keiner Behandlung mehr unterzogen werden. 5 weitere Mäuse dienen als O-Kontrolle (nicht behandelte, nicht infizierte Tiere).Related to mice that are no longer subjected to treatment after infection. 5 more mice serve as O control (untreated, uninfected Animals).
6 Tage nach der Infektion erfolgt die Tötung aller Versuchstiere und die Untersuchung des Peritonealexsudats auf T'iehomonaden. Die vorher gestorbenen Mäuse werden der gleichen Untersuchung unterzogen.6 days after infection, all test animals are sacrificed and the peritoneal exudate is examined on T'iehomonads. The mice that died previously are subjected to the same examination.
Anhand der E-regerdichte im Peritonealexsudat am ö.Tag p. i. v.iird die Beurteilung der Prüfsubstan/ vorgenommen. Dabei wird so vorgegangen, dab jeweils die festgestellte Erregerdichte des Prüfpräparates mit dem Standard und der Infektionskontrolle verglichen werden. Das Beurteilungsschema zur festgestellten Erregerdichte der Prüfsubstanz und des Standards ist wie folgt.Based on the E-excitation density in the peritoneal exudate on day p. i. v. the assessment of the test substance / performed. The procedure is so that the determined pathogen density of the test preparation is also included the standard and the infection control are compared. The assessment scheme for the established The excitation density of the test substance and the standard is as follows.
Unwirksam:Ineffective:
Erregerdichte gegenüber Infektionskontrolle nicht signifikant vermindert.
Bewertungsziffer: 3; 4.Pathogen density compared to infection control not significantly reduced.
Evaluation number: 3; 4th
Wirksam:Effective:
a) Angedeutet: Erregerdichte gegenüber Infektion;
kontrolle mäßig reduziert.
Bewertungsziffer: 2a) Indicated: pathogen density versus infection; control moderately reduced.
Evaluation number: 2
b) Unbefriedigend: Erregerdichte gegenüber Infekt onskontrolle deutlich reduziert.b) Unsatisfactory: pathogen density significantly reduced compared to infection control.
Bev ertungsziffer: IEvaluation number: I.
c) Keine Erreger nachweisbar.
Bewertungsziffer: 0.c) No pathogens detectable.
Evaluation number: 0.
PrürsubstanzTest substance
Dosis in mg/kg Maus per osDose in mg / kg mouse per os
Erregerdichte TrichüiTionas foetus an 4 MäusenPathogen-density TrichüiTionas fetus on 4 mice
I = Erfindungsgemäße Verbindung 1-Methyl-I = inventive compound 1-methyl-
2-(2-pyridylthiomethyl)-5-nitroimidazol Il = Vergleichsstoff Metronidazol2- (2-pyridylthiomethyl) -5-nitroimidazole II = comparison substance metronidazole
Weitere erfindungsgemäße Verbindungen:Further compounds according to the invention:
III = l-Methyl-2-(3-pyridylthiomethyl)-III = l-methyl-2- (3-pyridylthiomethyl) -
5-nitroimidazol5-nitroimidazole
IV = 1-Methyl-2-(4-pyridyithiomethyl)-IV = 1-methyl-2- (4-pyridyithiomethyl) -
5-nitro-imidazol V = l-Methyl-2-{N-oxy-2-pyridylthiomethyl)-5-nitro-imidazol 5-nitro-imidazole V = 1-methyl-2- (N-oxy-2-pyridylthiomethyl) -5-nitro-imidazole
VI = l-Methyl-2-(N-oxy-3-pyridylthiomethyl)-5-nitroimidazol. VI = 1-methyl-2- (N-oxy-3-pyridylthiomethyl) -5-nitroimidazole.
PrüfsubstanzTest substance
Dosis in mg/kg Maus, per osDose in mg / kg mouse, per os
Erregerdichte Trichomonas foetus in 4 Mäusen Die Prüfung gegen Entamoeba histolytica erfolgt im allgemeinen am Goldhamster beiderlei Geschlechts aus fremder Koloniezucht. Das Gewicht der Tiere beträgt im allgemeinen zwischen 50 und 60 g.Trichomonas fetus pathogen density in 4 mice. The test against Entamoeba histolytica is carried out in the general on golden hamsters of both sexes from foreign colony breeding. The weight of the animals is generally between 50 and 60 g.
Die Applikation der Prüfsubstanz erfolgt oral mit Hilfe der Schlundsonde, entweder als wäßrige Lösurg oder bei schwer wasserlöslichen Verbindungen als Carboxylmethylcellulose-Suspension. Insgesamt we-den vier Einzeldosen appliziert, derart, daß die ersie zwei Stunden vor, die zweite zwei Stunden, die dritte einen Tag und die vierte zwei Tage nach der Infektion gegeben werden. Pro Prüfsubstanz werden jeweils 4 Hamster verwandtThe test substance is administered orally with the aid of the stomach tube, either as an aqueous solution or in the case of poorly water-soluble compounds as a carboxylmethyl cellulose suspension. Overall we-den four single doses are applied in such a way that the first two hours before, the second two hours, the third one day and the fourth two days after infection. For each test substance, 4 Hamster related
Die Infektion erfolgt intrahepatical, 130 000 Erreger/ Tier, suspendiert in 0,1 ml/TTY-Medium (e.hist.-Crithidia Kultur). Der Standard Metronidazol wird wie die Prüfsubstanz dosiert und appliziert (vgl. Tabelle 1).The infection takes place intrahepatically, 130,000 pathogens / animal, suspended in 0.1 ml / TTY medium (e.hist.-Crithidia Culture). The standard metronidazole is dosed and applied like the test substance (see Table 1).
Als infektionskonirolien werden im allgemeinen !0 Hamster verwandt, die nach der Infektion keiner Behandlung mehr unterzogen werden. 5 weitere Hamster dienen als 0-Kontrolle (nicht behandelte, nicht infizierte Tiere).In general,! 0 Hamsters that are no longer treated after infection. 5 more Hamsters serve as a 0 control (untreated, not infected animals).
Frühestens 6. spätestens 8 Tage nach der Infektion erfolgt die Tötung aller Versuchstiere. Es schließt sich die Beurteilung der Leber nach dem Grad der sich ausgebildeten Lebernekrose an. Vorher gestorbene Hamster werden der gleichen Untersuchung unterzogen. All test animals are killed at the earliest 6th at the latest 8 days after the infection. It closes the assessment of the liver according to the degree of liver necrosis that has developed. Those who died before Hamsters are subjected to the same test.
Die ermittelten Leberbefunde des Prüfpräparates und des Standards werden mit denjenigen der Infekt ionskontrollen verglichen. Das Beurteilungsschema der Leberbefunde (Prüfpräparat und Standard) ist wie folgt:The liver findings of the test product and of the standard are compared with those of the infection controls. The assessment scheme of the Liver findings (test preparation and standard) are as follows:
Unwirksam:Ineffective:
Lebernekrosen zeigen gegenüber Infektionskontrollen keinen signifikanten Unterschied.
Mögliche Bewertungsziffer: 3; 4 (selten 2).Liver necrosis show no significant difference compared to infection controls.
Possible rating number: 3; 4 (rarely 2).
cn • 12.5
cn
ten 1)Possible rating number: heaped 2 (sel
ten 1)
22
2
• 12,5• 25
• 12.5
00
0
00
0
10
1
20
2
4 Goldhamsternper os (extraintestinal)
4 golden hamsters
4-25 0 0 0 0* -T_'U \ l \ f \ .i \ l
4-25 0 0 0 0
Erfindungsgemäße Verbindung 1-Methyl-2-(2-pyridyl-thio-methyl)-5-nitroimidazol. Vergleichspräparat Metronidazol.Compound according to the invention 1-methyl-2- (2-pyridyl-thio-methyl) -5-nitroimidazole. Comparative preparation metronidazole.
1-Methyl-2-(2-pyridylthiomethyl)-5-nitro-imidazol.1-methyl-2- (2-pyridylthiomethyl) -5-nitro-imidazole.
2,3 g (0,1 Mol) metallisches Natrium werden in kleinen Anteilen in 50 ml wasserfreiem Methanol gelöst. In diese Natriummethylat-Lösung werden 11,0g (0,1 Mol) 2-Mercaptopyridin gelöst in 70 ml wasserfreiem Methanol eingetragen und die Lösung im Vakuum restlos eingedampft. Dieser Rückstand wird mit einer Lösung von 17,55 g (0,1 Mol) 1-Methyl-2-chlormethyl-5-nitro-imidazol in 100 ml Dimethylacetamid versetzt und die Reaktionsmischung 1 Stunde lang auf 110°C erhitzt. Nach dem Abkühlen wird der Lösung Wasser bis zur beginnenden Kristallisation zugesetzt. Das2.3 g (0.1 mol) of metallic sodium are in small portions in 50 ml of anhydrous methanol solved. 11.0 g (0.1 mol) of 2-mercaptopyridine are dissolved in 70 ml of this sodium methylate solution entered anhydrous methanol and the solution was evaporated completely in vacuo. This The residue is treated with a solution of 17.55 g (0.1 mol) of 1-methyl-2-chloromethyl-5-nitro-imidazole in 100 ml of dimethylacetamide are added and the reaction mixture is heated to 110 ° C. for 1 hour. After cooling, water is added to the solution until crystallization begins. That
ISIS
thyl)-5-nitro-imidazol (entsprechend 80% derthyl) -5-nitro-imidazole (corresponding to 80% of the
Fp. 1470C.Mp. 147 0 C.
2. 1 -Methyl-2-(4-pyridylthiomethyl)-5-nitro-imidazol vom Fp. 143°C.2. 1 -Methyl-2- (4-pyridylthiomethyl) -5-nitro-imidazole, mp 143 ° C.
3. 1 -Methyl-2-(2-N-oxy-pyridylthiomethyl)-5-nitro-imidazol vom Fp. 257°C unter Zersetzung.3. 1 -Methyl-2- (2-N-oxy-pyridylthiomethyl) -5-nitro-imidazole, melting point 257 ° C. with decomposition.
4. 1 -Methyl-2-(4-N-oxy-pyridylthiomethyl)-5-nitro-imidazo! vom Fp. 2500C unter Zersetzung.4. 1 -Methyl-2- (4-N-oxy-pyridylthiomethyl) -5-nitro-imidazo! of melting point 250 ° C. with decomposition.
5. 1 -Methyl-2-{3-pyridylthiomethyl)-5-nitro-imidazolvom Fp. 127°C5. 1 -Methyl-2- {3-pyridylthiomethyl) -5-nitro-imidazole, mp 127 ° C
6. 1 -Methyl-2-(N-oxy-3-pyridy!thiomethyl)-5-nitro-imidazol vom Fp. 2310C unter Zersetzung.6. 1-methyl-2- (N-oxy-3-pyridy! Thiomethyl) -5-nitro-imidazole, mp. 231 0 C with decomposition.
Das als Ausgangsstoff verwendete l-Methyl-2-chlormethyl-5-nitro-imidazol wurde nach bekannten Methoden durch Umsetzung des literaturbekannten 1-Methyl-2-hydroxymethyl-5-nitro-imidazols mit Thionylchlorid dargestelltThe 1-methyl-2-chloromethyl-5-nitro-imidazole used as the starting material was prepared according to known methods by reacting 1-methyl-2-hydroxymethyl-5-nitro-imidazole with thionyl chloride, which is known from the literature shown
709526/521709526/521
Claims (1)
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19732325159 DE2325159C3 (en) | 1973-05-18 | l-methyl-2- (pyridylthiomethyl) -5nitro-imidazoles and l-methyl-2- (N-oxypyridylthiomethyl) -5-nitroimidazoles | |
| NL7406401A NL7406401A (en) | 1973-05-18 | 1974-05-13 | |
| AU69049/74A AU6904974A (en) | 1973-05-18 | 1974-05-16 | 1-alkyl-2-%pyridylthiomethyl<-5-nitro-imidazoles |
| FI1516/74A FI151674A7 (en) | 1973-05-18 | 1974-05-16 | |
| US470666A US3907816A (en) | 1973-05-18 | 1974-05-16 | 1-Alkyl-2-(pyridylthiomethyl)-5-nitro-imidazoles and derivatives thereof as well as process for their manufacture |
| ZA00743149A ZA743149B (en) | 1973-05-18 | 1974-05-17 | A-alkyl-2-(pyridylthiomathyl)-5-nitroimidazoles and derivatives thereof as well as process for their manufacture |
| HUHO1674A HU167769B (en) | 1973-05-18 | 1974-05-17 | |
| DK271374A DK134756C (en) | 1973-05-18 | 1974-05-17 | ANALOGICAL PROCEDURE FOR THE PREPARATION OF 1-ALKYL-2- (PYRIDYLTHIOMETHYL) -5-NITRO-IMIDAZOLES SAVEL AS 1-ALKYL-2- (N-OXYPYRIDYLTHIOMETHYL) -5-NITRO-IMIDA |
| GB2204074A GB1428628A (en) | 1973-05-18 | 1974-05-17 | 1,alkyl-2-pyridylthiomethyl-5-nitro-imidazoles and derivatives thereof as well as process for their manufacture |
| JP49055027A JPS5030879A (en) | 1973-05-18 | 1974-05-18 | |
| FR7417494A FR2229419B1 (en) | 1973-05-18 | 1974-05-20 | |
| BE144525A BE815279A (en) | 1973-05-18 | 1974-05-20 | 1-ALCOYL-2 (PYRIDYLTHIOMETHYL) -5-NITRO-IMIDAZOLES |
| US05/610,407 US3984560A (en) | 1973-05-18 | 1975-09-04 | Composition for and method of treating disease caused by protozon |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19732325159 DE2325159C3 (en) | 1973-05-18 | l-methyl-2- (pyridylthiomethyl) -5nitro-imidazoles and l-methyl-2- (N-oxypyridylthiomethyl) -5-nitroimidazoles |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE2325159A1 DE2325159A1 (en) | 1974-12-05 |
| DE2325159B2 true DE2325159B2 (en) | 1977-06-30 |
| DE2325159C3 DE2325159C3 (en) | 1978-02-09 |
Family
ID=
Also Published As
| Publication number | Publication date |
|---|---|
| HU167769B (en) | 1975-12-25 |
| ZA743149B (en) | 1975-05-28 |
| DE2325159A1 (en) | 1974-12-05 |
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