CA1078390A - Nitroimidazoles - Google Patents
NitroimidazolesInfo
- Publication number
- CA1078390A CA1078390A CA262,606A CA262606A CA1078390A CA 1078390 A CA1078390 A CA 1078390A CA 262606 A CA262606 A CA 262606A CA 1078390 A CA1078390 A CA 1078390A
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- Canada
- Prior art keywords
- methyl
- thiadiazole
- nitroimidazol
- ethyl
- hydrogen
- 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.)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Tropical Medicine & Parasitology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE:
The invention is concerned with novel nitroimidazolyl-vinylthiadiazoles having the general formula:
The invention is concerned with novel nitroimidazolyl-vinylthiadiazoles having the general formula:
Description
1~78390 O~Z 31,601~32,183 NEW NITROIMIDAZOLES
This invention relates to nitroimidazolylvinylthiadiazoles, their production, and formulations containing same for use as chemotherapeutics in the treatment of microbial infections in humans and animalsO .
It is known that nitroheterocycles such as nitrofurans, nitrothiazoles and nitroimidazoles are effective as agents for treating baoteria, fungi and Proto~oa. The minimum inhibition concentrations of prior art preparations, for example metroni-dazol or tinidazol, are of the order of between Ool and 2 /ug/mlO .
However, their action and tolerance levels are not always satis-factory. There is therefore a need to synthesize new compounds with increased effectivenessO
We have now found that compounds of formula I
02N~ -CH = C~,~ -113 where R1 i8 alkyl of 1 to 4 carbon atoms which may be substi-tuted by hydroxy or alkoxy of 1 to 4 carbon atoms in the alkyl, R2 is hydrogen or methyl, and R3 is hydrogen, alkyl of 1 to 24 carbon atoms, unsubstituted or substituted phenyl, or hetro-aryl have valuable pharmacological propertiesO
, , , . . ; j~. .,... ~
O.Z. 31,601/32,183 Examples of R are methyl, ethyl, isopropyl, n~t~, ~-hydroxyethyl, ~-methoxyethyl or ~-ethoxyethylO
Examples of suitable alkyl radicals of 1 to 24 carbon ^
atoms for R3 are methyl, ethyl, n-propyl, i-propyl, n-butyl, sec. butyl, isobutyl, amyl, n-hexyl, n-heptyl, n-octyl, 2-ethyl-hexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl, octadecyl, cosyl, docosyl and tetradocosylO -When R~ is phenyl, the latter may be substituted once or several times, preferably once or twice, by radicals inert under the conditions of preparationO Special mention should be made of the ~ollowing as inert substit~lents D halogen, such as fluoro, chloro, bromo, iodo, nitro and alkyl of 1 to 4 carbon atoms which in their turn may be substituted by one or more halogen atoms, such as trifluoromethyl, alkoxy of 1 to 4 carbon atoms, acylated and dialkylated amino groups each w;th 1 to 4 carbon atoms in the alkyl or acylO Examples of substituted phenyl are 2-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl,
This invention relates to nitroimidazolylvinylthiadiazoles, their production, and formulations containing same for use as chemotherapeutics in the treatment of microbial infections in humans and animalsO .
It is known that nitroheterocycles such as nitrofurans, nitrothiazoles and nitroimidazoles are effective as agents for treating baoteria, fungi and Proto~oa. The minimum inhibition concentrations of prior art preparations, for example metroni-dazol or tinidazol, are of the order of between Ool and 2 /ug/mlO .
However, their action and tolerance levels are not always satis-factory. There is therefore a need to synthesize new compounds with increased effectivenessO
We have now found that compounds of formula I
02N~ -CH = C~,~ -113 where R1 i8 alkyl of 1 to 4 carbon atoms which may be substi-tuted by hydroxy or alkoxy of 1 to 4 carbon atoms in the alkyl, R2 is hydrogen or methyl, and R3 is hydrogen, alkyl of 1 to 24 carbon atoms, unsubstituted or substituted phenyl, or hetro-aryl have valuable pharmacological propertiesO
, , , . . ; j~. .,... ~
O.Z. 31,601/32,183 Examples of R are methyl, ethyl, isopropyl, n~t~, ~-hydroxyethyl, ~-methoxyethyl or ~-ethoxyethylO
Examples of suitable alkyl radicals of 1 to 24 carbon ^
atoms for R3 are methyl, ethyl, n-propyl, i-propyl, n-butyl, sec. butyl, isobutyl, amyl, n-hexyl, n-heptyl, n-octyl, 2-ethyl-hexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl, octadecyl, cosyl, docosyl and tetradocosylO -When R~ is phenyl, the latter may be substituted once or several times, preferably once or twice, by radicals inert under the conditions of preparationO Special mention should be made of the ~ollowing as inert substit~lents D halogen, such as fluoro, chloro, bromo, iodo, nitro and alkyl of 1 to 4 carbon atoms which in their turn may be substituted by one or more halogen atoms, such as trifluoromethyl, alkoxy of 1 to 4 carbon atoms, acylated and dialkylated amino groups each w;th 1 to 4 carbon atoms in the alkyl or acylO Examples of substituted phenyl are 2-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl,
2-bromophenyl, 3-bromophenyl, 4-iodophenyl, 2,4-dichlorophenyl,
3,5-dichlorophenyl, 2-methylphenyl, 3-ethylphenyl, 4-i-propyl-phenyl, 2,4-dimethylphenyl, 3,5-dimethylphenyl, 4-nitrophenyl, 3,5-dimethoxyphenyl, 4-dimethylaminophenyl, 4-trifluoromethyl-phenyl and 4-acetylaminophenyl.
Examples of suitable heteroaryl radicals for R3 are pyridyl, furyl, thienyl, oxadiazolyl and thiadiazolylO
Of the radicals mentioned above the following are pre-ferred: for R methyl, ethyl, R hydroxyethyl, ~-methoxyethyl and ~-ethoxymethyl, for R2 hydrogen and methyl, and for R3 alkyl of 1 to 13 carbon atoms, of which alkyl of 1 to 6 carbon ~0783go Or Z~ 31,601/32,183 atoms and phenyl are particularly preferred; of the heteroaro-matic radicals pyridine, which may be attached in the 2-, 3- or
Examples of suitable heteroaryl radicals for R3 are pyridyl, furyl, thienyl, oxadiazolyl and thiadiazolylO
Of the radicals mentioned above the following are pre-ferred: for R methyl, ethyl, R hydroxyethyl, ~-methoxyethyl and ~-ethoxymethyl, for R2 hydrogen and methyl, and for R3 alkyl of 1 to 13 carbon atoms, of which alkyl of 1 to 6 carbon ~0783go Or Z~ 31,601/32,183 atoms and phenyl are particularly preferred; of the heteroaro-matic radicals pyridine, which may be attached in the 2-, 3- or
4-position, is particularly preferredO Preferred substituted phenyl radicals are 2-chlorophenyl, 3-chlorophenyl, 4-chloro-phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-di-methylaminophenyl and 4-nitrophenyl.
Of these compounds those in which R1 is methyl, R2 is hydrogen or methyl and R3 is hydrogen, methyl, ethyl, phenyl or pyridyl are particularly preferred~
The compounds of the ;nvention may be prepared by reacting in known manner 2-substituted 1,3,4-thiadiazoles of the general formula II
3 ~ ~ R,2 II
where R2 and R3 have the above meanings with a 5-nitroimidazole-2-carboxaldehyde of the general formula III
N
..
where R1 has the above meanings at elevated temperatures and in the presence or absence of an acid condensation catalyst and in the presence or absence of a solvent. The aldehydes of formula III may also be used as acetals or acy~a~ls; special mention should be made here of acetals obtained from reactions with methanol and ethanol and the acylal obtained from reaction with acetic acid.
~078390 OOZ~ 31,601/32,183 The reaction can be represented by the following equation N - N ~ N- N
2 ,~ CH0 R ~ 02N ~ -CH=CH ~S~ -R3 Some of the 1,3,4-thiadiazoles of formula II used as starting materials are known compounds or can be easily obtained for example by the process described by Ro Stollé, BerO dtschr chemr Ges. 32~ 797 (1899)3 in which N,N'-diacylhydrazines are reacted at elevated temperature with P2S5 in an aromatic hydro-carbon, eOgO, xyleneO
The compounds of the invent;on may be advantageously pre-pared by reacting a compound of formula II with a compound of formula III or its acetal or acylal at temperatures of between 50 and 220C preferably in the presence of an acid condensation catalyst, e.gO a Lewis acid, a mineral acid or an acid ion exchanger, and, if desired, in the presence of a solvent~
When a solvent is used the preferred temperature range is between 90 and 150C, and when no solvent is used the preferred range is between 150 and 200Co Suitable catalysts are the acid condensation catalysts con-ventionally used in aldehyde condensation which are employed in amounts of 00005 to 1 mole, preferably 0O05 to 002 mole, of catalyst per mole of starting material IIo Examples of acid con-densation catalysts are polyphosphoric acid, borofluoride and zinc chlorideO The preferred catalyst ;s zinc chloride.
The starting materials are generally used in a stoichio-metric ratio, although one of the compounds may be used in an excessO The reaction is generally carried out at atmospheric ,. .
1(~78390 O.Z. 31,601/32,183 pressure; superatmospheric or subatmospheric pressure may how-ever be an advantage in specific cases. The reaction may be ef~ected in the presence or absence of a solventO Solvents that have proved particularly suitable are lower carboxylic acids such as acetic acid and propionic acid, their anhydrides and mixtures of a lower carboxylic acid and the particular anhydrideO
In the mixtures of carboxylic acid and carboxylic anhydride the ratio is advantageously between 9:1 and 1~9~
Generally the reaction is over within a few hours. Working up presents no problems; it can be effected for example by the :
addition of a precipitating agent, especially water or acetone, to the reaction mixture, precipitation o~ the reaction product, suction ~iltration, washing with water and alcohol, and recry-stallization ~rom a suitable solvent~
The ~ollowing compounds are specified in addition to those described in the Examples:
2-thienyl-5- C~ methyl-5-nitroimidazol-2-yl~-vinyl]-1,3,4-thiadiazole 2-n-propyl-5- C-ethyl-2-(l-methyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-thiadiazole 2-ethyl~5-~1-methyl-2-(1-ethyl-5-nitroimidazol-2-~ lny~ -1,3,4-thiadiazole 2-methyl-5-~2-(1-ethyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole 2-thienyl-5- ~-methyl-2-(1-methyl-5-nitroimidazol-2-yl)-vinyl~-1,3,4-thiadiazole 2-furyl-5- L2-(1-methyl-5-nitroimidazol-2-yl)-~11,3,4-thiadia-zole ,. . .: . . : ::~: . :: ,.
~078390 OOZo 31,601/32,183 2-methyl-5-L2-~1-hydroxyethyl-5-nitroimidazol-2-yl)-viny ~-1,3,4-thiadiazole 2-ethyl-5-~1-methyl-2-(1-hydroxyethyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-thiadiazole.
The compounds of the invention exhibit a good action on microorganisms. They are outstandingly ef~ective for the treat-ment o~ infections by Flagellata, especially Trichomonas and Trypanosoma, and by Entamoaba histolytica in humans and animalsO
They may also have a very good bacterial action in thresh-1~ hold concentrations of ~10 5, for example the compounds of Working Examples 6 and 70 Table 1 Minimum inhibition concentrations (MIC) on Trichomonas ~aginalis Compound MICRelat;ve effectiveness ~ug/ml~Metronidazol = loO
Example 1 0.02 500 Example 2 0.01 10.0 Example 5 0~01 10.0 Example 10 ~ Or Ol~ 10 o O
Example 6 ~ 0.01 >lOoO
Example 7 ~ 0.01> lOo O
Metronidazol 0.1 loO
Trinidazol Ool 100 The tests were carried out in vitro using the quantitative tube-dilution test described by P0 Klein, Bakteriologische Grundlagen der chemotherapeutischen Laboratoriumspraxis, Springer-Verlag Berlin-Goettingen-Heidelberg, 1957.
.......
:1078390 O~Z~ 31,601/32,183 It is surprising that with the introduction of a thiadia-zole radical attached via an ethylene bridge it has been possible to exceed the e~fectiveness of prior art commercial products, e.gO, metronidazol and tinidazol, against Trichomonada infec-tion~ up to more than ten times~
Special mention is made of the compounds of Examples 1,5, 7 and 10 for their action on Trichomonada7 The action against infections caused by Trypanosomas and `
Entamoeba histolytica can be illustrated on the mouse (NMRI
strains) using methods described in Handbuch ~r experimentelle Pharmakologie, Erganzungswerk 16, Erzeugung von Krankheitszu-~tanden durch das Experiment, Part 9, pages 150 to 292, Springer-Verlag, Berlin-Goettingen-Heidelberg, 1964~
1. Trypanosoma brucei - ;nfections o~ the mouse Various dosages were ;nvestigatedO The curing o~ the in-fection was determined microscopically and in a culture~ There was also po~t-observation for 25 days after treatment was dis-continued in order to establi~h whether there was any recidivation.
Example 1 lx50 mg/kg perorally, acute 100% action, 70%
recidivation Example 2 llx50 mg/kg perorally, no action Example 5 llx50 mg/kg perorally~ no action Example 10 llx50 mg/kg perorally, acute 100% action, no recidivation Example 6 llx50 mg/kg perorally, no action Example 7 llx50 mg/kg, acute 100% action, 30~ recidivation Suramin, 7x50 mg/kg intraperitoneally, acute 80% action, no recidivation -- 7 ~
O~ZO 31,601/32,813 Metronidazol llx50 mg/kg perorally, no action Tinidazol 22x50 mg/kg perorally, no action 20 Trypanosoma gambiense - infection of mouse Same method as in the case of Trypanosoma brucei Example 1 llx50 mg/kg perorally, acute 100% action, 80%
recidivation Example 2 llx50 mg/kg perorally, no action Example 5 llx50 mg/kg perorally, no action Example 10 llx50 mg/kg perorally9 acute 100% action, 60%
recidivation Example 6 llx50 mg/kg perorally, no action Example 7 llx50 mg/kg perorally, no action Suramin 7x50 kg/kg intraperitoneally, acute 50% action, no recidivation 3. Trypanosoma congolense - infection of mouse Same method as in the case of ~rypanosoma brucei Example 1 llx50 mg/kg perorally9 acute 100% action, 20% no recidivation Example 2 llx50 mg/kg perorally, no action Example 5 llx50 mg/kg perorally, no action Example 10 llx50 mg/kg perorally, acute 100% action, no recidication Example 6 llx50 mg/kg perorally, no action Example 7 llx50 mg/kg perorally, no action Suramin 7x50 mg/kg intraperitoneally, acute 70% action.
no recidivation ". ~: , ~078390 OOZ. 31,601/32,183 4. Entamoeba histolytica (tube-dilution test) The PN and Q strains were tested.
The minimum inhibition concentrations were as follows:
Example 1 ~ 0.01 /ug/ml Example 2 0.1 "
Example 5 ~ 0.01 "
Example 10 < 0.01 "
Example 6 ~ 0.01 "
Example 7 ~ OoOl tt Mentronidazol 0.1 "
The experiments were carried out in vitro using the quantitative tube-dilution test described by PO Klein, Bakteriologische Grundlagen der chemotherapeutischen Laboratoriums-praxis, Springer-Verlag, Berlin-Goettingen-Heidelberg, 19570 The results show that special mention should be made of the compounds of Examples 1 and 10 by virtue of their action and in comparison with Suramin,which is the constituent of the prior art preparations Germanin and Naganol. The action on Entamoeba histolytica in vitro can also be described as very good to good. As can be seen from the Table the action of metronidazol is surpassed more than 10 times~
Of these compounds those in which R1 is methyl, R2 is hydrogen or methyl and R3 is hydrogen, methyl, ethyl, phenyl or pyridyl are particularly preferred~
The compounds of the ;nvention may be prepared by reacting in known manner 2-substituted 1,3,4-thiadiazoles of the general formula II
3 ~ ~ R,2 II
where R2 and R3 have the above meanings with a 5-nitroimidazole-2-carboxaldehyde of the general formula III
N
..
where R1 has the above meanings at elevated temperatures and in the presence or absence of an acid condensation catalyst and in the presence or absence of a solvent. The aldehydes of formula III may also be used as acetals or acy~a~ls; special mention should be made here of acetals obtained from reactions with methanol and ethanol and the acylal obtained from reaction with acetic acid.
~078390 OOZ~ 31,601/32,183 The reaction can be represented by the following equation N - N ~ N- N
2 ,~ CH0 R ~ 02N ~ -CH=CH ~S~ -R3 Some of the 1,3,4-thiadiazoles of formula II used as starting materials are known compounds or can be easily obtained for example by the process described by Ro Stollé, BerO dtschr chemr Ges. 32~ 797 (1899)3 in which N,N'-diacylhydrazines are reacted at elevated temperature with P2S5 in an aromatic hydro-carbon, eOgO, xyleneO
The compounds of the invent;on may be advantageously pre-pared by reacting a compound of formula II with a compound of formula III or its acetal or acylal at temperatures of between 50 and 220C preferably in the presence of an acid condensation catalyst, e.gO a Lewis acid, a mineral acid or an acid ion exchanger, and, if desired, in the presence of a solvent~
When a solvent is used the preferred temperature range is between 90 and 150C, and when no solvent is used the preferred range is between 150 and 200Co Suitable catalysts are the acid condensation catalysts con-ventionally used in aldehyde condensation which are employed in amounts of 00005 to 1 mole, preferably 0O05 to 002 mole, of catalyst per mole of starting material IIo Examples of acid con-densation catalysts are polyphosphoric acid, borofluoride and zinc chlorideO The preferred catalyst ;s zinc chloride.
The starting materials are generally used in a stoichio-metric ratio, although one of the compounds may be used in an excessO The reaction is generally carried out at atmospheric ,. .
1(~78390 O.Z. 31,601/32,183 pressure; superatmospheric or subatmospheric pressure may how-ever be an advantage in specific cases. The reaction may be ef~ected in the presence or absence of a solventO Solvents that have proved particularly suitable are lower carboxylic acids such as acetic acid and propionic acid, their anhydrides and mixtures of a lower carboxylic acid and the particular anhydrideO
In the mixtures of carboxylic acid and carboxylic anhydride the ratio is advantageously between 9:1 and 1~9~
Generally the reaction is over within a few hours. Working up presents no problems; it can be effected for example by the :
addition of a precipitating agent, especially water or acetone, to the reaction mixture, precipitation o~ the reaction product, suction ~iltration, washing with water and alcohol, and recry-stallization ~rom a suitable solvent~
The ~ollowing compounds are specified in addition to those described in the Examples:
2-thienyl-5- C~ methyl-5-nitroimidazol-2-yl~-vinyl]-1,3,4-thiadiazole 2-n-propyl-5- C-ethyl-2-(l-methyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-thiadiazole 2-ethyl~5-~1-methyl-2-(1-ethyl-5-nitroimidazol-2-~ lny~ -1,3,4-thiadiazole 2-methyl-5-~2-(1-ethyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole 2-thienyl-5- ~-methyl-2-(1-methyl-5-nitroimidazol-2-yl)-vinyl~-1,3,4-thiadiazole 2-furyl-5- L2-(1-methyl-5-nitroimidazol-2-yl)-~11,3,4-thiadia-zole ,. . .: . . : ::~: . :: ,.
~078390 OOZo 31,601/32,183 2-methyl-5-L2-~1-hydroxyethyl-5-nitroimidazol-2-yl)-viny ~-1,3,4-thiadiazole 2-ethyl-5-~1-methyl-2-(1-hydroxyethyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-thiadiazole.
The compounds of the invention exhibit a good action on microorganisms. They are outstandingly ef~ective for the treat-ment o~ infections by Flagellata, especially Trichomonas and Trypanosoma, and by Entamoaba histolytica in humans and animalsO
They may also have a very good bacterial action in thresh-1~ hold concentrations of ~10 5, for example the compounds of Working Examples 6 and 70 Table 1 Minimum inhibition concentrations (MIC) on Trichomonas ~aginalis Compound MICRelat;ve effectiveness ~ug/ml~Metronidazol = loO
Example 1 0.02 500 Example 2 0.01 10.0 Example 5 0~01 10.0 Example 10 ~ Or Ol~ 10 o O
Example 6 ~ 0.01 >lOoO
Example 7 ~ 0.01> lOo O
Metronidazol 0.1 loO
Trinidazol Ool 100 The tests were carried out in vitro using the quantitative tube-dilution test described by P0 Klein, Bakteriologische Grundlagen der chemotherapeutischen Laboratoriumspraxis, Springer-Verlag Berlin-Goettingen-Heidelberg, 1957.
.......
:1078390 O~Z~ 31,601/32,183 It is surprising that with the introduction of a thiadia-zole radical attached via an ethylene bridge it has been possible to exceed the e~fectiveness of prior art commercial products, e.gO, metronidazol and tinidazol, against Trichomonada infec-tion~ up to more than ten times~
Special mention is made of the compounds of Examples 1,5, 7 and 10 for their action on Trichomonada7 The action against infections caused by Trypanosomas and `
Entamoeba histolytica can be illustrated on the mouse (NMRI
strains) using methods described in Handbuch ~r experimentelle Pharmakologie, Erganzungswerk 16, Erzeugung von Krankheitszu-~tanden durch das Experiment, Part 9, pages 150 to 292, Springer-Verlag, Berlin-Goettingen-Heidelberg, 1964~
1. Trypanosoma brucei - ;nfections o~ the mouse Various dosages were ;nvestigatedO The curing o~ the in-fection was determined microscopically and in a culture~ There was also po~t-observation for 25 days after treatment was dis-continued in order to establi~h whether there was any recidivation.
Example 1 lx50 mg/kg perorally, acute 100% action, 70%
recidivation Example 2 llx50 mg/kg perorally, no action Example 5 llx50 mg/kg perorally~ no action Example 10 llx50 mg/kg perorally, acute 100% action, no recidivation Example 6 llx50 mg/kg perorally, no action Example 7 llx50 mg/kg, acute 100% action, 30~ recidivation Suramin, 7x50 mg/kg intraperitoneally, acute 80% action, no recidivation -- 7 ~
O~ZO 31,601/32,813 Metronidazol llx50 mg/kg perorally, no action Tinidazol 22x50 mg/kg perorally, no action 20 Trypanosoma gambiense - infection of mouse Same method as in the case of Trypanosoma brucei Example 1 llx50 mg/kg perorally, acute 100% action, 80%
recidivation Example 2 llx50 mg/kg perorally, no action Example 5 llx50 mg/kg perorally, no action Example 10 llx50 mg/kg perorally9 acute 100% action, 60%
recidivation Example 6 llx50 mg/kg perorally, no action Example 7 llx50 mg/kg perorally, no action Suramin 7x50 kg/kg intraperitoneally, acute 50% action, no recidivation 3. Trypanosoma congolense - infection of mouse Same method as in the case of ~rypanosoma brucei Example 1 llx50 mg/kg perorally9 acute 100% action, 20% no recidivation Example 2 llx50 mg/kg perorally, no action Example 5 llx50 mg/kg perorally, no action Example 10 llx50 mg/kg perorally, acute 100% action, no recidication Example 6 llx50 mg/kg perorally, no action Example 7 llx50 mg/kg perorally, no action Suramin 7x50 mg/kg intraperitoneally, acute 70% action.
no recidivation ". ~: , ~078390 OOZ. 31,601/32,183 4. Entamoeba histolytica (tube-dilution test) The PN and Q strains were tested.
The minimum inhibition concentrations were as follows:
Example 1 ~ 0.01 /ug/ml Example 2 0.1 "
Example 5 ~ 0.01 "
Example 10 < 0.01 "
Example 6 ~ 0.01 "
Example 7 ~ OoOl tt Mentronidazol 0.1 "
The experiments were carried out in vitro using the quantitative tube-dilution test described by PO Klein, Bakteriologische Grundlagen der chemotherapeutischen Laboratoriums-praxis, Springer-Verlag, Berlin-Goettingen-Heidelberg, 19570 The results show that special mention should be made of the compounds of Examples 1 and 10 by virtue of their action and in comparison with Suramin,which is the constituent of the prior art preparations Germanin and Naganol. The action on Entamoeba histolytica in vitro can also be described as very good to good. As can be seen from the Table the action of metronidazol is surpassed more than 10 times~
5~ Trichomonas vaginal - infection of mice ~arious dosages were investigatedO The curing of the in-fection was determined microscopically and in a culture.
Example 1 100% cure with 5x25 mg/kg perorally Example 2 10% cure with 5x50 mg/kg perorally Example 5 100% cure with 5x25 mg/kg perorally ~783gO
O.Z. 31,601/32,183 Example 10 100% cure with 5x25 mg/kg perorally Example 6 50% cure with 5x50 mg/k~ perorally Example 7 100% cure with 5x50 mg/kg perorally Metronidazol 100% cure with 5x25 mg/kg perorally Tinidazol 100% cure with 5x25 mg/kg perorally The LD 50 toxicity figures for the compounds of Examples 1, 7 and 10 on mice, NMRI strain, administered orally and with a week's observation period are over 1500 mg/kg~
The compounds of the invention can therefore be administered to humans and animals for therapeutic purposes ~or the treat-ment of trichomoniasis, trypanosomiasis and amoebic dysentery.
They are also suitable for treating leishmaniasis~
~ention should be made of the following preferred active compounds:
2-phenyl-5- C2-(l-methyl-5-nitroimidazol-2-yl)-vinyl~-1,3,4-thiadiazole 2-(4-pyridyl)-5- C2~ methyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole 2-~2-(1-methyl-5-nitroimidazol-2-yl)-viny ~ -1,3,4-thiadiazole 2-ethyl-5- ~ -(1-methyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-thia-diazole.
Particularly preferred compounds are:
2-methyl-5-~2-(1 methyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-thiadiazole and 2-ethyl-5- C-methyl-2-(l-methyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-thiadiazole.
The present invention accordingly also relates to chemo-therapeutic agents or formulations for treating microbial in-10783~0 .
OOZo 31,601/32,183 fections in humans and animals which contain a compound of for-mula I as active ingredient in addition to the conventional carriers and diluents, and also to the use of the new compounds for therapeutic purposes.
The chemotherapeutic agents or formulations are manufactured in a conventional manner using conventional carriers or diluents -~and the conventionally used pharmaceutical auxiliaries in accordance with the desired mode of administration in a suit-able dosage unitO
The preferred formulations are suitable for oral admini-strationO They may be in the form for example of tablets, coated tablets, dragées, capsules, pills, powders or suspensionsO
On account of the relatively sparing solubility of the compounds of the invention oral administration is preferredO
Naturally parenteral formulations, such as injection solutions, are also suitable~ Suppositories are a further example of formulations that can be used. For the treatment of trichomoniasis pharmaceutical formulations for the vagina, such as vaginal tablets, globuli and powders, are also suitable.
The dose to be administered depends on the nature and the severity of the disorderO Amounts of up to 5 g per day may be administered Single doses to be administered several times a day if desired are advantageously 50 to 1000 mg per doseO In the case of Trypanosoma infections the single doses are advantageously between 500 and 1000 mg, in the case of Entamoeba infections between 100 and 500 mg, and in the case of Trichomonada infec-tions between 100 and 300 mg.
O.Z. 31,601/32,183 As a rule the single doses are administered from two to five daily and generally treatment of Trypanosoma infections lasts from 14 to 20 days, that of Entamoeba infections from 5 to 8 days, and that of Trichomonada infections al50 from 5 to 8 days.
For use in practise the compounds according to the invention can be processed with the carriers conventionally used in galenical pharmacy D
Tablets can be made for example by mix;ng the active ingre-dient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitolg PVP, calcium carbonate, calcium phosphate and lactose, disintegrants such as lndian corn, starchor alginic acid, binders such as starch or gelatines, lubricants such as magnesium stearate or talcg and/or agents for achieving a depot effect, such as carboxy~polymethylene, carboxymethylcellulose, cellulose acetate phthalate or poly-vinyl acetate. The tablets may also consist of a plurality of coatings.
Accordingly~ dragees may be prepared by coating cores made in the same way as the tablets with agents conventionally used in dragee coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The shell of the dragée may also consist of a plurality of coatings, and the auxiliaries mentioned above in connection with the tablets may be usedO
Suspensions of the active ingredients according to the invention may also conta;n flavoring agents such as saccharine, cyclamate and sugar, and for example aromatics such as vanillin -`` 1078390 OOZo 31,601/32,183 or orange extractO They may also contain auxiliaries that pro-mote suspension such as sodium carboxymethylcellulose, and pro-tective colloids such as p-hydroxybenzoatesO Capsules containing active ingredients may be manufactured for example by mixing the active ingredient with an inert carrier such as lactose or sorbi-tol and encapsulating the mixture in gelatine capsulesO Suitable suppositories may be manufactured for example by mixing the active ingredient with the appropriate carriers such as neutral fats or polyethylene ~slycol or derivatives thereofO
Preparation of 2-methyl-5- [-(1-methyl-5-nitroimidazol-2-yl)-vinyl~ -1,3,4-thiadiazole 11.4 g of 2,5-dimethyl-1,3,4-thiadiazole, 1505 g of 1-methyl-5-nitroimidazole-2-carboxyaldehyde with 002 g of zinc chloride are heated in a stirred apparatus for 10 hou~s at reflux tempera-ture in a mixture of 50 ml of glacial acetic acid and 20 ml of acetic anhydrideO After cooling, the precipitated solid is washed with glacial acetic acid and recrystallized from dimethyl-formamideO 1506 g of colored crystals, ~p = 248C, is obtained, corresponding to 62% of the theoryO
2-phenyl-5-~-(1-methyl-5-nitroimidazol-2-yl)-vinyl~l-1,3,4-thiadiazole 1706 g of 2-methyl-5-phenyl-1,3,ll-thiadiazole, 1505 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde and 005 g of ZnC12 are heated in 100 ml of acetic acid and 50 ml of acetic anhydride for 7 hours at reflux temperatureO After water has been added to the reaction mixture, the precipitated solid is recrystallized ` :1078390 OOZo 31,~01/32,183 from glacial acetic acidO 1705 g of a product melting at 257C
is obtained, corresponding to 56% of the theory.
2-(2-chlorophenyl)-5- ~-(1-methyl-5-nitroimidazol-2-yl)-viny ~ -1,3,4-thiadiazole 21 g of 2-methyl-5-(2-chlorophenyl)-1,3,4-thiadiazole and 15.5 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde are heated with 005 g of ZnCl2 in a mixture of 100 ml of acetic acid and 50 ml of acetic anhydride for 6 hours at reflux temperatureO
After cooling, ether is added to the reaction mixture, and the precipitated solid is washed with water and recrystallized from dimethylformamideO 1805 g of product is obtained, corresponding to 53% of the theoryO The compound melts at 239Co 2-~4-chlorophenyl)-5- ~-(1-methyl-5-nitroimidazol-2-yl)-vinyl~-1,3,4-thiadiazole 21 g of 2-methyl-5-(4-chlorophenyl)-1,3,4-thiadiazole and 2208 g of 1-methyl-5-nitroimidazol-2-carboxaldehyde are heated with 0~5 g of ZnC12 in a mixture of 100 ml of acetic acid and 50 ml acetic anhydride for 5 hours at reflux temperatureO After cooling, ether is added to the reaction mixture, and the pre-cipitated solid is washed with water and recrystallized from dimethylformamideO 2705 g of product of obtained, corresponding to 77% of the theoryO The compound melts at 268Co 2-(4-pyridyl)-5- ~2-(1-methyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-thiadiazole 808 g of 2-methyl-5-(4-pyridyl)-1,3,4-thiadiazole and 7.7 g `" 1078390 OOZo 31,601/32,183 of 1-methyl-5-nitroimidazole-2-carboxaldehyde are heated with 0.2 g of ZnC12 in a mixture of 50 ml of glacial acetic acid and 25 ml of acetic anhydride for 6 hours at reflux temperature.
After cooling, the precipitated solid is suction filtered, washed with concentrated ammonia and recrystallized from dimethyl-formamide. The melting point of the product obtained is 240 -_ 2- 2-(1-methyl-5-nitroimidazol-2-yl)-viny ~ -1,3,4-thiadiazole 0.3 g of zinc chloride is added to 15.5 g of 1-methyl-5-nitroimidazol-2-carboxaldehyde which has been dissolved in 100 ml of acetic acid and 50 ml of acetic anhydride and the whole is dripped into 10 g of 2-methyl-1,3,4-thiadiazole, which has been dissolved in a mixture of 100 ml of acetic acid and 50 ml of acetic anhydride, over a period of 5 hours at reflux tempera-tureO After 24 hours the reaction mixture is freed of the solvent by evaporation and ether is addedO After the reaction product has been washed with water it is recrystallized from xylene.
9.3 g of product, corresponding to 39% of the theory, is ob-tained. The compound melts at 214C.
2-ethyl-5- C2~ methyl-5-nitroimidazol-2-yl)-vinyl} 1,3,4-thiadiazole A solution of 15O5 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde in 50 ml of acetic acid and 25 ml of acetic an-hydride is added at reflux temperature over a period of 10 hours to 12.8 g of 5-ethyl-2-methyl-1,3,4-thiadiazole and 0.5 g of ZnCl2 which have been dissolved in 100 ml of acetic acid and . . . ;: .
` 1~78350 OOZo 31,601/32,183 50 ml of acetic anhydrideO The mixture is kept at reflux tem-perature for a further 20 hours and the solvent is then eva-poratedO The residue is washed with acetone and passed through a ready-to-use silica gel column (Type A of MessrsO ~lerck) and eluted with C~Cl3/CH30H = 98 : 2~ 5.6 g of the abovementioned reaction product with a melting point of 165C is obtained; this corresponds to 21% of the theory 2-methyl-5- C-methyl-2-(1-methyl-5-nitroimidazol-2-yl)-vinyl~-1,3,4-thiadiazole The acetone solution from Example 7 is concentrated, the residue passed through a ready-to-use silica gel column (Type A
of Messrs Merck) and eluted with CHCl3/CH30H = 98 ~ 20 Yield 5.4 g, melting point 249Co There is also obtained 304 g of the stereoisomeric compound with a melting point of 155Co The total yield from Examples 7 and 8 is 54% of the theoryO
2-n-tridecyl-5-~2-(1-methyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-thiadiazole 8045 g of 2-tridecyl-5-methyl-1,3,4-thiadiazole, 4,65 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde and 005 g of zinc chloride are heated in 40 ml of acetic acid and 15 ml of acetic anhydride for 24 hours at reflux temperatureO After the solvent has been removed, the residue is recrystallized from alcoholO
701 g of product is obtained, corresponding to 61% of the theory.
The melting point is 91C.
2-ethyl-5~ methyl-2-(1-methyl-5-nitroimidazol-2-yl)-vinyl~-1,3,4-thiadiazole ` 1(~783~0 O~ZO 31,601/32,183 4.65 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde, which has been dissolved in 80 ml of acetic acid and 35 ml of acetic anhydride, is dripped into 1701 g of 2,5-diethyl-1,3,4-thiadiazole, which has been dissolved in a mixture of 60 ml of acetic acid, 25 ml of acetic anhydride and 0~5 g of zinc chloride, over a period of 5 hours at reflux temperature. After being heated for a further 24 hours at reflux temperature the reaction mixture is concentrated by removing the solvent and water is added. The precipitated reaction product is then sub-jected to sublimation and recrystallized from propanolO 2 9 g of product, corresponding to 35% of the theory, is obtainedO
The compound melts at 125Co Examples of formulations prepared in conventional manner 1. Tablet lo An active ingredient of formula I 120 mg Lactose 200 mg Methylcellulose 15 mg Cornstarch 50 mg Talc 11 mg Magnesium stearate 4 mg 400 mg 20 An active ingredient of formula I 120 mg Lactose 178 mg Avicel 80 mg Polywachs 6000 20 mg Magnesium stearate 2 mg 400 mg . ~ ~
` ` ~ 10783~0 O~Z~ 31~601/32~183 2. Vaginal tablet 1. An active ingredient of formula I 80 mg Lactic acid 30 mg Glucose 670 mg Lactose 200 mg Hydroxypropylmethylcellulose20 mg 1 g 2. An active ingredient of formula I 80 mg Boric acid 30 mg Lactose 890 m~
1 g 30 Example of a tablet 1. Compound of Example 1 or Example 10 as active ingredient 200 mg 2~ Polyvinylpyrrolidone (mean MoWo 25~000) 20 mg 3. Polyethylene glycol tmean M~Wo 4~000) 14 mg 4~ Hydroxypropylmethyl cellulose40 mg 5~ Talc 4 mg 60 Magnesium stearate 2 mg 2 80 mg The active ingredient is moistened with polyvinylpyrrolidone in a 10% aqueous solution, passed through a sieve with 1.0 mm apertures and dried at 50Co This granulated material is mixed with polyethylene glycol (mean M.W. 4,000) hydroxypropylmethyl-cellulose, talc and magnesium stearate and pressed into tablets à 280 mg.
4. Example of a dragée `- 1078390 OOZo 31,601/32,183 1. Compound o~ Example 1 or Example 10 as active in~redient 150 mg 2. Lactose 60 mg 3. Cornstarch 30 mg 4. Polyvinylpyrrolidone 4 mg 50 Magnesium stearate 1 mg 245 mg The mixture of active ingredient with lactose and corn-starch is granulated through a 1. 5 mm sieve dried at 50C and then passed through a lo 0 mm sieveO The granulated material thus obtained is mixed with magnesium stearate and pressed into dragée cores. The latter are then covered in conventional manner with a coating consisting essentially of sugar and talcO
5. Example of a suppository 1 suppository contains Active ingredient 250 mg Suppository composition (eOg., Witepsol H 19) 1500 mg 1750 mg The suppository composition is melted. At 38C the finely pulverized ingredient is dispersed homogeneously in the melt. It is then poured into precooled suppository molds at 35co . . -
Example 1 100% cure with 5x25 mg/kg perorally Example 2 10% cure with 5x50 mg/kg perorally Example 5 100% cure with 5x25 mg/kg perorally ~783gO
O.Z. 31,601/32,183 Example 10 100% cure with 5x25 mg/kg perorally Example 6 50% cure with 5x50 mg/k~ perorally Example 7 100% cure with 5x50 mg/kg perorally Metronidazol 100% cure with 5x25 mg/kg perorally Tinidazol 100% cure with 5x25 mg/kg perorally The LD 50 toxicity figures for the compounds of Examples 1, 7 and 10 on mice, NMRI strain, administered orally and with a week's observation period are over 1500 mg/kg~
The compounds of the invention can therefore be administered to humans and animals for therapeutic purposes ~or the treat-ment of trichomoniasis, trypanosomiasis and amoebic dysentery.
They are also suitable for treating leishmaniasis~
~ention should be made of the following preferred active compounds:
2-phenyl-5- C2-(l-methyl-5-nitroimidazol-2-yl)-vinyl~-1,3,4-thiadiazole 2-(4-pyridyl)-5- C2~ methyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole 2-~2-(1-methyl-5-nitroimidazol-2-yl)-viny ~ -1,3,4-thiadiazole 2-ethyl-5- ~ -(1-methyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-thia-diazole.
Particularly preferred compounds are:
2-methyl-5-~2-(1 methyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-thiadiazole and 2-ethyl-5- C-methyl-2-(l-methyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-thiadiazole.
The present invention accordingly also relates to chemo-therapeutic agents or formulations for treating microbial in-10783~0 .
OOZo 31,601/32,183 fections in humans and animals which contain a compound of for-mula I as active ingredient in addition to the conventional carriers and diluents, and also to the use of the new compounds for therapeutic purposes.
The chemotherapeutic agents or formulations are manufactured in a conventional manner using conventional carriers or diluents -~and the conventionally used pharmaceutical auxiliaries in accordance with the desired mode of administration in a suit-able dosage unitO
The preferred formulations are suitable for oral admini-strationO They may be in the form for example of tablets, coated tablets, dragées, capsules, pills, powders or suspensionsO
On account of the relatively sparing solubility of the compounds of the invention oral administration is preferredO
Naturally parenteral formulations, such as injection solutions, are also suitable~ Suppositories are a further example of formulations that can be used. For the treatment of trichomoniasis pharmaceutical formulations for the vagina, such as vaginal tablets, globuli and powders, are also suitable.
The dose to be administered depends on the nature and the severity of the disorderO Amounts of up to 5 g per day may be administered Single doses to be administered several times a day if desired are advantageously 50 to 1000 mg per doseO In the case of Trypanosoma infections the single doses are advantageously between 500 and 1000 mg, in the case of Entamoeba infections between 100 and 500 mg, and in the case of Trichomonada infec-tions between 100 and 300 mg.
O.Z. 31,601/32,183 As a rule the single doses are administered from two to five daily and generally treatment of Trypanosoma infections lasts from 14 to 20 days, that of Entamoeba infections from 5 to 8 days, and that of Trichomonada infections al50 from 5 to 8 days.
For use in practise the compounds according to the invention can be processed with the carriers conventionally used in galenical pharmacy D
Tablets can be made for example by mix;ng the active ingre-dient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitolg PVP, calcium carbonate, calcium phosphate and lactose, disintegrants such as lndian corn, starchor alginic acid, binders such as starch or gelatines, lubricants such as magnesium stearate or talcg and/or agents for achieving a depot effect, such as carboxy~polymethylene, carboxymethylcellulose, cellulose acetate phthalate or poly-vinyl acetate. The tablets may also consist of a plurality of coatings.
Accordingly~ dragees may be prepared by coating cores made in the same way as the tablets with agents conventionally used in dragee coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The shell of the dragée may also consist of a plurality of coatings, and the auxiliaries mentioned above in connection with the tablets may be usedO
Suspensions of the active ingredients according to the invention may also conta;n flavoring agents such as saccharine, cyclamate and sugar, and for example aromatics such as vanillin -`` 1078390 OOZo 31,601/32,183 or orange extractO They may also contain auxiliaries that pro-mote suspension such as sodium carboxymethylcellulose, and pro-tective colloids such as p-hydroxybenzoatesO Capsules containing active ingredients may be manufactured for example by mixing the active ingredient with an inert carrier such as lactose or sorbi-tol and encapsulating the mixture in gelatine capsulesO Suitable suppositories may be manufactured for example by mixing the active ingredient with the appropriate carriers such as neutral fats or polyethylene ~slycol or derivatives thereofO
Preparation of 2-methyl-5- [-(1-methyl-5-nitroimidazol-2-yl)-vinyl~ -1,3,4-thiadiazole 11.4 g of 2,5-dimethyl-1,3,4-thiadiazole, 1505 g of 1-methyl-5-nitroimidazole-2-carboxyaldehyde with 002 g of zinc chloride are heated in a stirred apparatus for 10 hou~s at reflux tempera-ture in a mixture of 50 ml of glacial acetic acid and 20 ml of acetic anhydrideO After cooling, the precipitated solid is washed with glacial acetic acid and recrystallized from dimethyl-formamideO 1506 g of colored crystals, ~p = 248C, is obtained, corresponding to 62% of the theoryO
2-phenyl-5-~-(1-methyl-5-nitroimidazol-2-yl)-vinyl~l-1,3,4-thiadiazole 1706 g of 2-methyl-5-phenyl-1,3,ll-thiadiazole, 1505 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde and 005 g of ZnC12 are heated in 100 ml of acetic acid and 50 ml of acetic anhydride for 7 hours at reflux temperatureO After water has been added to the reaction mixture, the precipitated solid is recrystallized ` :1078390 OOZo 31,~01/32,183 from glacial acetic acidO 1705 g of a product melting at 257C
is obtained, corresponding to 56% of the theory.
2-(2-chlorophenyl)-5- ~-(1-methyl-5-nitroimidazol-2-yl)-viny ~ -1,3,4-thiadiazole 21 g of 2-methyl-5-(2-chlorophenyl)-1,3,4-thiadiazole and 15.5 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde are heated with 005 g of ZnCl2 in a mixture of 100 ml of acetic acid and 50 ml of acetic anhydride for 6 hours at reflux temperatureO
After cooling, ether is added to the reaction mixture, and the precipitated solid is washed with water and recrystallized from dimethylformamideO 1805 g of product is obtained, corresponding to 53% of the theoryO The compound melts at 239Co 2-~4-chlorophenyl)-5- ~-(1-methyl-5-nitroimidazol-2-yl)-vinyl~-1,3,4-thiadiazole 21 g of 2-methyl-5-(4-chlorophenyl)-1,3,4-thiadiazole and 2208 g of 1-methyl-5-nitroimidazol-2-carboxaldehyde are heated with 0~5 g of ZnC12 in a mixture of 100 ml of acetic acid and 50 ml acetic anhydride for 5 hours at reflux temperatureO After cooling, ether is added to the reaction mixture, and the pre-cipitated solid is washed with water and recrystallized from dimethylformamideO 2705 g of product of obtained, corresponding to 77% of the theoryO The compound melts at 268Co 2-(4-pyridyl)-5- ~2-(1-methyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-thiadiazole 808 g of 2-methyl-5-(4-pyridyl)-1,3,4-thiadiazole and 7.7 g `" 1078390 OOZo 31,601/32,183 of 1-methyl-5-nitroimidazole-2-carboxaldehyde are heated with 0.2 g of ZnC12 in a mixture of 50 ml of glacial acetic acid and 25 ml of acetic anhydride for 6 hours at reflux temperature.
After cooling, the precipitated solid is suction filtered, washed with concentrated ammonia and recrystallized from dimethyl-formamide. The melting point of the product obtained is 240 -_ 2- 2-(1-methyl-5-nitroimidazol-2-yl)-viny ~ -1,3,4-thiadiazole 0.3 g of zinc chloride is added to 15.5 g of 1-methyl-5-nitroimidazol-2-carboxaldehyde which has been dissolved in 100 ml of acetic acid and 50 ml of acetic anhydride and the whole is dripped into 10 g of 2-methyl-1,3,4-thiadiazole, which has been dissolved in a mixture of 100 ml of acetic acid and 50 ml of acetic anhydride, over a period of 5 hours at reflux tempera-tureO After 24 hours the reaction mixture is freed of the solvent by evaporation and ether is addedO After the reaction product has been washed with water it is recrystallized from xylene.
9.3 g of product, corresponding to 39% of the theory, is ob-tained. The compound melts at 214C.
2-ethyl-5- C2~ methyl-5-nitroimidazol-2-yl)-vinyl} 1,3,4-thiadiazole A solution of 15O5 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde in 50 ml of acetic acid and 25 ml of acetic an-hydride is added at reflux temperature over a period of 10 hours to 12.8 g of 5-ethyl-2-methyl-1,3,4-thiadiazole and 0.5 g of ZnCl2 which have been dissolved in 100 ml of acetic acid and . . . ;: .
` 1~78350 OOZo 31,601/32,183 50 ml of acetic anhydrideO The mixture is kept at reflux tem-perature for a further 20 hours and the solvent is then eva-poratedO The residue is washed with acetone and passed through a ready-to-use silica gel column (Type A of MessrsO ~lerck) and eluted with C~Cl3/CH30H = 98 : 2~ 5.6 g of the abovementioned reaction product with a melting point of 165C is obtained; this corresponds to 21% of the theory 2-methyl-5- C-methyl-2-(1-methyl-5-nitroimidazol-2-yl)-vinyl~-1,3,4-thiadiazole The acetone solution from Example 7 is concentrated, the residue passed through a ready-to-use silica gel column (Type A
of Messrs Merck) and eluted with CHCl3/CH30H = 98 ~ 20 Yield 5.4 g, melting point 249Co There is also obtained 304 g of the stereoisomeric compound with a melting point of 155Co The total yield from Examples 7 and 8 is 54% of the theoryO
2-n-tridecyl-5-~2-(1-methyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-thiadiazole 8045 g of 2-tridecyl-5-methyl-1,3,4-thiadiazole, 4,65 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde and 005 g of zinc chloride are heated in 40 ml of acetic acid and 15 ml of acetic anhydride for 24 hours at reflux temperatureO After the solvent has been removed, the residue is recrystallized from alcoholO
701 g of product is obtained, corresponding to 61% of the theory.
The melting point is 91C.
2-ethyl-5~ methyl-2-(1-methyl-5-nitroimidazol-2-yl)-vinyl~-1,3,4-thiadiazole ` 1(~783~0 O~ZO 31,601/32,183 4.65 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde, which has been dissolved in 80 ml of acetic acid and 35 ml of acetic anhydride, is dripped into 1701 g of 2,5-diethyl-1,3,4-thiadiazole, which has been dissolved in a mixture of 60 ml of acetic acid, 25 ml of acetic anhydride and 0~5 g of zinc chloride, over a period of 5 hours at reflux temperature. After being heated for a further 24 hours at reflux temperature the reaction mixture is concentrated by removing the solvent and water is added. The precipitated reaction product is then sub-jected to sublimation and recrystallized from propanolO 2 9 g of product, corresponding to 35% of the theory, is obtainedO
The compound melts at 125Co Examples of formulations prepared in conventional manner 1. Tablet lo An active ingredient of formula I 120 mg Lactose 200 mg Methylcellulose 15 mg Cornstarch 50 mg Talc 11 mg Magnesium stearate 4 mg 400 mg 20 An active ingredient of formula I 120 mg Lactose 178 mg Avicel 80 mg Polywachs 6000 20 mg Magnesium stearate 2 mg 400 mg . ~ ~
` ` ~ 10783~0 O~Z~ 31~601/32~183 2. Vaginal tablet 1. An active ingredient of formula I 80 mg Lactic acid 30 mg Glucose 670 mg Lactose 200 mg Hydroxypropylmethylcellulose20 mg 1 g 2. An active ingredient of formula I 80 mg Boric acid 30 mg Lactose 890 m~
1 g 30 Example of a tablet 1. Compound of Example 1 or Example 10 as active ingredient 200 mg 2~ Polyvinylpyrrolidone (mean MoWo 25~000) 20 mg 3. Polyethylene glycol tmean M~Wo 4~000) 14 mg 4~ Hydroxypropylmethyl cellulose40 mg 5~ Talc 4 mg 60 Magnesium stearate 2 mg 2 80 mg The active ingredient is moistened with polyvinylpyrrolidone in a 10% aqueous solution, passed through a sieve with 1.0 mm apertures and dried at 50Co This granulated material is mixed with polyethylene glycol (mean M.W. 4,000) hydroxypropylmethyl-cellulose, talc and magnesium stearate and pressed into tablets à 280 mg.
4. Example of a dragée `- 1078390 OOZo 31,601/32,183 1. Compound o~ Example 1 or Example 10 as active in~redient 150 mg 2. Lactose 60 mg 3. Cornstarch 30 mg 4. Polyvinylpyrrolidone 4 mg 50 Magnesium stearate 1 mg 245 mg The mixture of active ingredient with lactose and corn-starch is granulated through a 1. 5 mm sieve dried at 50C and then passed through a lo 0 mm sieveO The granulated material thus obtained is mixed with magnesium stearate and pressed into dragée cores. The latter are then covered in conventional manner with a coating consisting essentially of sugar and talcO
5. Example of a suppository 1 suppository contains Active ingredient 250 mg Suppository composition (eOg., Witepsol H 19) 1500 mg 1750 mg The suppository composition is melted. At 38C the finely pulverized ingredient is dispersed homogeneously in the melt. It is then poured into precooled suppository molds at 35co . . -
Claims (10)
1. A process for the production of nitroimidazolyl-vinylthiadiazoles having the general formula:
(I) wherein R1 is alkyl of 1 to 4 carbon atoms, R2 is hydrogen or methyl, and R3 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or pyridyl, which comprises reacting a 2-substituted 1,3,4-thiadiazole of the general formula:
(II) wherein R2 and R3 have the aforesaid meanings, with a 5-nitroimidazole-2-carboxaldehyde of the general formula:
(III) or the acetal or acylal thereof, wherein R1 has the aforesaid meanings, at elevated temperatures in the presence or absence of an acid condensation catalyst and in the presence or absence of a solvent.
(I) wherein R1 is alkyl of 1 to 4 carbon atoms, R2 is hydrogen or methyl, and R3 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or pyridyl, which comprises reacting a 2-substituted 1,3,4-thiadiazole of the general formula:
(II) wherein R2 and R3 have the aforesaid meanings, with a 5-nitroimidazole-2-carboxaldehyde of the general formula:
(III) or the acetal or acylal thereof, wherein R1 has the aforesaid meanings, at elevated temperatures in the presence or absence of an acid condensation catalyst and in the presence or absence of a solvent.
2. A process according to claim 1, wherein R1 is methyl, R2 is hydrogen or methyl, and R3 is hydrogen, methyl, ethyl, phenyl or pyridyl.
3. A process according to claim 1, for the production of 2-methyl-5-[2-(1-methyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole, wherein 2,5-dimethyl-1,3,4-thiadiazole is reacted with 1-methyl-5-nitroimidazole-2-carboxaldehyde.
4. A process according to claim 1, for the production of 2-ethyl-5-[2-(1-methyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole, wherein 5-ethyl-2-methyl-1,3,4-thiadiazole is reacted with 1-methyl-5-nitroimidazole-2-carboxaldehyde.
5. A process according to claim 1, for the production of 2-ethyl-5-[1-methyl-2-(1-methyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole, wherein 2,5-diethyl-1,3,4-thiadiazole is reacted with 1-methyl-5-nitroimidazole-2-carboxaldehyde.
6. Nitroimidazolylvinylthiadiazoles having the general formula:
(I) where R1 is alkyl of 1 to 4 carbon atoms, R2 is hydrogen or methyl, and R3 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or pyridyl, whenever obtained by a process according to claim 1 or its obvious chemical equivalents.
(I) where R1 is alkyl of 1 to 4 carbon atoms, R2 is hydrogen or methyl, and R3 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or pyridyl, whenever obtained by a process according to claim 1 or its obvious chemical equivalents.
7. Compounds according to claim 6, wherein R1 is methyl, R2 is hydrogen or methyl and R3 is hydrogen, methyl, ethyl, phenyl or pyridyl, whenever obtained by a process according to claim 2 or its obvious chemical equivalents.
8. 2-Methyl-5-[2-(1-methyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole, whenever obtained by a process according to claim 3 or its obvious chemical equivalents.
9. 2-Ethyl-5-[2-(1-methyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole, whenever obtained by a process according to claim 4 or its obvious chemical equivalents.
10. 2-Ethyl-5-[1-methyl-2-(1-methyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole, whenever obtained by a process according to claim 5 or its obvious chemical equivalents.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2544702A DE2544702C3 (en) | 1975-10-07 | 1975-10-07 | Nitroimidazolyl vinyl thiadiazoles |
| DE19762640504 DE2640504A1 (en) | 1976-09-09 | 1976-09-09 | Antimicrobial (5)-nitro-imidazolyl vinyl derivs. of thiadiazole - esp. effective against amobae, trichomonads and trypanosomes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1078390A true CA1078390A (en) | 1980-05-27 |
Family
ID=25769484
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA262,606A Expired CA1078390A (en) | 1975-10-07 | 1976-10-04 | Nitroimidazoles |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS5248667A (en) |
| AR (1) | AR210289A1 (en) |
| AT (1) | AT352714B (en) |
| AU (1) | AU505058B2 (en) |
| CA (1) | CA1078390A (en) |
| CH (1) | CH624953A5 (en) |
| DK (1) | DK142850C (en) |
| ES (1) | ES452151A1 (en) |
| FI (1) | FI61488C (en) |
| FR (1) | FR2326921A1 (en) |
| GB (1) | GB1561529A (en) |
| HU (1) | HU172614B (en) |
| IL (1) | IL50563A (en) |
| LU (1) | LU75937A1 (en) |
| NL (1) | NL176780C (en) |
| NO (1) | NO146397C (en) |
| YU (1) | YU240376A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4664707A (en) * | 1985-04-09 | 1987-05-12 | Georgia-Pacific Corporation | Fire resistant gypsum composition |
| JPH06313620A (en) * | 1994-02-25 | 1994-11-08 | Takara Standard Co Ltd | Hot water feeder |
-
1976
- 1976-09-28 FI FI762765A patent/FI61488C/en not_active IP Right Cessation
- 1976-09-28 IL IL50563A patent/IL50563A/en unknown
- 1976-09-29 AU AU18204/76A patent/AU505058B2/en not_active Expired
- 1976-09-30 YU YU02403/76A patent/YU240376A/en unknown
- 1976-10-04 CA CA262,606A patent/CA1078390A/en not_active Expired
- 1976-10-05 NO NO763400A patent/NO146397C/en unknown
- 1976-10-05 CH CH1258976A patent/CH624953A5/en not_active IP Right Cessation
- 1976-10-05 LU LU75937A patent/LU75937A1/xx unknown
- 1976-10-06 GB GB41425/76A patent/GB1561529A/en not_active Expired
- 1976-10-06 FR FR7630047A patent/FR2326921A1/en active Granted
- 1976-10-06 HU HU76BA00003458A patent/HU172614B/en not_active IP Right Cessation
- 1976-10-06 DK DK449876A patent/DK142850C/en not_active IP Right Cessation
- 1976-10-06 ES ES452151A patent/ES452151A1/en not_active Expired
- 1976-10-06 AT AT741676A patent/AT352714B/en not_active IP Right Cessation
- 1976-10-07 NL NLAANVRAGE7611119,A patent/NL176780C/en not_active IP Right Cessation
- 1976-10-07 JP JP51119929A patent/JPS5248667A/en active Granted
- 1976-10-07 AR AR265023A patent/AR210289A1/en active
Also Published As
| Publication number | Publication date |
|---|---|
| FI762765A (en) | 1977-04-08 |
| FI61488B (en) | 1982-04-30 |
| NO146397C (en) | 1982-09-22 |
| FR2326921A1 (en) | 1977-05-06 |
| AT352714B (en) | 1979-10-10 |
| JPS6152154B2 (en) | 1986-11-12 |
| CH624953A5 (en) | 1981-08-31 |
| ATA741676A (en) | 1979-03-15 |
| NO763400L (en) | 1977-04-13 |
| LU75937A1 (en) | 1977-05-06 |
| AU1820476A (en) | 1978-04-06 |
| NL176780B (en) | 1985-01-02 |
| FR2326921B1 (en) | 1978-11-17 |
| DK142850C (en) | 1981-10-12 |
| GB1561529A (en) | 1980-02-20 |
| ES452151A1 (en) | 1977-11-16 |
| NO146397B (en) | 1982-06-14 |
| YU240376A (en) | 1982-10-31 |
| IL50563A (en) | 1979-10-31 |
| HU172614B (en) | 1978-11-28 |
| DK449876A (en) | 1977-04-08 |
| DK142850B (en) | 1981-02-09 |
| JPS5248667A (en) | 1977-04-18 |
| NL7611119A (en) | 1977-04-13 |
| FI61488C (en) | 1982-08-10 |
| AR210289A1 (en) | 1977-07-15 |
| AU505058B2 (en) | 1979-11-08 |
| NL176780C (en) | 1985-06-03 |
| IL50563A0 (en) | 1976-11-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |