CA1161847A - Imidazole derivatives - Google Patents
Imidazole derivativesInfo
- Publication number
- CA1161847A CA1161847A CA000377230A CA377230A CA1161847A CA 1161847 A CA1161847 A CA 1161847A CA 000377230 A CA000377230 A CA 000377230A CA 377230 A CA377230 A CA 377230A CA 1161847 A CA1161847 A CA 1161847A
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- CA
- Canada
- Prior art keywords
- formula
- hydrogen
- methyl
- group
- alkyl
- 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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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
- C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
ABSTRACT
There are provided novel imidazole derivatives of the formula I
wherein X is hydrogen or C1-4-n-alkyl and Y is thienyl, optionally substituted by methyl or fluorine, or a group of the formula Y1 wherein R1, R2 and R3 are hydrogen, methyl, fluorine, hydroxy, methoxy or two of R1, R2 and R3 on adjacent carbon atoms are together methylenedioxy or ethylenedioxy or one of R1, R2 and R3 is mono- or di-(C1-4-n-alkyl)--amino and the other two are hydrogen, and physiologically compatible acid addition salts thereof.
These compounds inhibit the aggregation of the blood platelets.
There are provided novel imidazole derivatives of the formula I
wherein X is hydrogen or C1-4-n-alkyl and Y is thienyl, optionally substituted by methyl or fluorine, or a group of the formula Y1 wherein R1, R2 and R3 are hydrogen, methyl, fluorine, hydroxy, methoxy or two of R1, R2 and R3 on adjacent carbon atoms are together methylenedioxy or ethylenedioxy or one of R1, R2 and R3 is mono- or di-(C1-4-n-alkyl)--amino and the other two are hydrogen, and physiologically compatible acid addition salts thereof.
These compounds inhibit the aggregation of the blood platelets.
Description
~AN 4044/55 The present invention is concerned with novel imida201e derivatives of the formula ~ N\
~ / ~ Y
~ N
wherein X is hydrogen or Cl_4-n-alkyl and Y i5 thienyl, optionally substituted by methyl or fluorine, or a group oi the formula yl ~RR3 yl wherein Rl, R2 and R3 are hydrogen, methyl, fluorine, hydroxy, methoxy or two of Rl, R2 and R3 on adjacent carbon atoms are together methylenedioxy Mé/3.4.1981 or ethylenedioxy or one of R , R2 and R is mono- or di-(Cl_4-n-alkyl)--amino and the other two are hydrogen, and physiologically compatible acid addition salts thereof.
The expression Cl 4-n-alkyl used herein relates to the straight-chain alkyl groups methyl, ethyl~propyl and butyl.
Among the compounds of formula I there are preferred those in which X is hydrogen and those in which Y is a 10 group of ~ormula yl~ especially p-fluorophenyl.
4,5-Di-t-butyl-2-(4-fluorophenyl)-imida~ole is especially pxeferred.
The inv~ntion is also concerned with a process for the manufacture of the aforementioned compounds as well as pharma-ceutical preparations based on the aforementioned compounds.
Examples o~ physiologically compatible acid addition sal~s are mineral acid salts such as hydrochlorides, hyc'ro-bromides, sulphates and phosphates~ salts of organic sulphonic acids such as alkylsulphona~es or arylsulphonates and carboxylic acid salts such as succinates or citrates.
The aforementioned compounds and sal~s can be manufactured in accordanca with ~he invention by treating a thiepinoimidazole of the formula ~ N ~ II
wherein X and Y have the above significance, or an acid addition salt thereof with a desulphurising catalyst and, if desired, converting a compound of formula I
into an acid addition salt.
Examples of desulphurising catalysts are metal catalysts such as nickel catalysts or palladium catalysts, preferably nickel catalysts, especially Raney-nic~el. ~he desulphurisation is conveniently carried out in a solvent, preferably a polar solvent such as dioxan or tetrahydro~
: 15 uran at a temperature up to the reflux temperature.
The compounds of formula II in which X is hydrogen can be prepared by reacting 3,3,6,6-tetramethyl-4,5--thiepanedione with an aldehyde Y-CH=O in the presence o~
ammonium ions, preferably in the presence of an ammonium salt such as ammonium acetate in a polar solvent such as dimethyl sulphoxide or dimethylformamide at a temperature up to the reflux temperature. The compounds of formula II
S obtained can be N-alkylated by reaction with an alkali metal hydride such as sodium hydride in a solvent such as dimethyl-formamide and reaction of the resulting compound with an alkyl halide such as methyl iodide.
The compounds of formula I and the physiologically compatible salts thereof can be used as medicaments. They inhibit the aggregation of the blood platelets and can therefore be used for the prevention of thromboses.
The compounds of formula I can be used as medicaments;
for example in the form of pharmaceutical preparations which contain them or their salts in admixture with an organic or inorganic inert carrier material which is suitable for enteral or parenteraL administration such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols or Vaseline. The pharmaceutical preparations can be made up in solid form (e.g. as tablets, drayees, suppositories or capsules) or in liquid form (e.g. as solutions, suspensions or emulsions). The pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preserving, IL8 ~7 stabilising, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They can also contain still other therepeutically valuable substances. The oral administration of the compounds in accordance with the invention is preferred. For adults there come into consideration an oral daily dosage of 0.5 to 30 mg/kg and a parenteral daily dosage of 0~05 to 10 mg/kg.
The aggregation-inhibiting activity was demonstrated according to the aggregometer method of BORN [Nature 194, 927 (1962)] and MICHAL and BORN [Nature 231, 220 (1971)].
The maximum aggregation velocity was taken as the test parameter and the effective concentration (EC50) was ascertained from dosage-activity curves.
Human platelet-rich plasma was obtained by centri~ugation from citrated venous blood. The experiments were carried out with suspensions of the test substances in 0.9% sodium chloride. 0.~8 ml of citrate plasma was treated with a 10 ~1 suspension of the test compound and incubated at 37C for 10 minutes, whereupon the aggregation was initiated by adlding 10 ~1 of a suspension of collagen fibrils.
- 6 - ~6~7 The results are reproduced in the following Table.
Table Collagen-induced blood plateLet ag~re~ation Compound 50 (~M) . .
4,5 Di-t-butyl-2-phenylimidazole 0.6 4/5-Di-t-butyl-2-(.4-fluorophenyl)--imidazole 0.5 4,5-Di-t-butyl-2-(3,4-methylene-dioxyphenyl)-imidazole 0.55 4,5-Di-t-butyl-2-(5-methoxy-3,4--methylenedioxyphenyl)-imidazo:Le 14.4 .
4,5-Di-t-butyl-2-(3,4,5-tximethoxy-phenyl)-imidazole 0.72 . . . . . . . . .
_ 7 - ~6~ ~7 The following Examples illustrate the present invention:
Example l 5 g of 2-phenyl-4,5,7,8-tetrahydro-4,4,8,8-tetra-S methyl-l-H-thiepino[4,5-a]imidazole and 200 ml of dioxan are heated at reflux temperature for 20 hours while stirring in the presence of a nickel catalyst (obtained by dehydrating 85 g of moist nic~el catalyst with 300 ml of dioxan, whirling followed by sedimentation of the catalyst and suc~ing-off the solvent~.
The catalyst is then left t:o sediment in the reaction solution. The solution is suction filtered. The catalyst is treated witll 200 ml of dioxan and heated to boiling while stirring. After the catalyst has settled, the solution is again suction filtered. This procedure is carried out once more.
The combined extracts are iltered and concentrat~d.
After recrystallisation from n-heptane, there are obtainlsd 1.2 g of 4,5-di-t-butyl-2-phenylimidazole, m.p. 156-158C.
In order to prepare the hydrochloride, 604 mg of the base are dissolved in ether and the solution ls neutralised by the dropwise addition o~ ethereal hydrochloric acid. The - 8 - ~ 7 precipitate is filtered off and washed with ether and ethanol.
There are obtained 680 mg of the hydrochloride, m.p. 250--255C (decomposition).
The thiepinoimidazole used as the starting material can be prepared as follows:
16 g of 3,3,6,6-tetramethyl-4,5-thiepanedione and 8 g of ~enzaldehyde are dissolved in 200 ml of dimethyl suLphoxide, 60 g of anhydrous ammonium acetate are added thereto whi:Le stirring and the mixture is heated at 90C.
After cooling, the reaction mixture is poured into ic~-water while stirring, the solution is made alkaline with concentrated sodium hydroxide and extracted wi1:h ether. The organic phase is washed with ice-water and concentxated to dryness.
The residue is covered with petro:Leum ether and rubbed with lS a glass rod. The filtered-off precipitate is recrystallised from toluene. There is o~tained 2-phenyl-4,5,7,8-tetrahydro--4,4,8,8-tetramethyl-l-H-thiepino[4,5-d]imidazole, m.p. 225--227C.
Example 2 In a manner analogous to Example l there are obtained 4,5-Dl-t~butyl-2-(4-fluorophenyl)-imida~ole, m.p.
185C; m.p. of the hydrochloride 240C (decomposition), . .
~6~
g 4.5-di-t-butyl-2-(4-methoxyphenyl)-imidazole, m.p.
145-147C; m.p. of the hydrochloride 250C (decomposition), 4,5-di-t-butyl-2-(5-methoxy-3,4-methylenedioxyphenyl)-~imidazole, m.p. 110-113C; m.p. of the hydrochloride 210C
5 (decomposition), 4,5-di-t-butyl-2-(3,4,5-trimethoxyphenyl)-imidazole, m.p. 140-142C, m.p. of the hydrochloride 230C (decomposition), 4,5-di-t-butyl-2-phenyl-N-methylimidazole, m.p~ 115--117C; m.p. of the hydrochloride 205C (decomposition).
The thiepinoimidazole starting material used for the manufacture of the last-named N-methylimidazole can be prepared as follows:
A suspension of 0.44 g of sodium hydride (55~ in paraffin) in 10 ml of dimethyl~ormamide is cooled to 0C under 15 nitrogen or argon. Thereupon, there is added dropwise a solution of 2.~6 g of 2-phenyl-4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-l-H-thiepino[4,5-d~imidazole dissolved in 10 ml of dimethylformamide. The mixture is th~n left to react-out at room temperature for 20 minutes. Then, 2.1 g of methyl 20 iodide in 10 ml of dimethylformamide are added dropwise.
The mixture is left to react-out at room temperature for a further 30 minutes. The reaction mixture is poured into ice--water while stirring, the precipitate is filtered off and washed in water. The filter residue is dissolved in ether 25 and the solution is dried and concentrated. The suspension is treated with petroleum e-ther. After crystallisation, the mixture is filtered and the product is recxystallised from n-heptane. The 2-phenyl-4,5,7,8-tetrahydro-1,4,4,8,8--pentamethyl-l-H-thiepino[4,5-d]imidazole melts at 158-160C.
M.p. of the hydrochloride: 240C (decomposition~.
S Example 3 5.8 g of 2-(3,4-methylenedioxyphenyl)~4,5,7,8--tetrahydro-4,4,8,8-tetramethyl-l-H-thiepino[4,5-d]imidazole, 200 ml of tetrahydrofuran and a nickel catalyst (obtained by dehydrating 85 g of moist nickel catalyst with 300 ml of tetrahydrofuran, whirling followecl by sedimentation of the catalyst and suc~ing-off of the solvent) are heated at reflux temperature for 24 hours. The reaction solution is treated as described in Example l, but usi.ng tetrahydrofuran in place of dioxan. After recrystall.isation from n-hexane, there are obtained 3.5 g of 4,5-di-t-but:yl-2-(3,4-methylenedioxy-phenyl)-imida~ole, m.p. 175-178C.
In a manner analogous to Example l, from 3.2 g of base there are obtained 3.5 g of hydrochloride, m.p. 200~'C
tdecomposition).
Example 4 Tablets of the following composition are produced in the usual manner:
4,5-Di-t-butyl-2-(4-~luorophenyl)--imidazole hydrochloride 185.0 mg Lactose 15.0 mg Maize starch 37.9 mg Water-soluble polyvinylpyrrolidone10.0 mg Magnesium stearate 2.5 mg Total weight per tablet 250.0 mg Example c~
Interlocking gelatin capsules of the followlng composition are produced in the usual manner: -4,5-Di-t-butyl-2-(4-fluorophenyl)--imidazole hydrochloride 200.0 mg Water-soluble poly~inylpyrrolidone 2.Q mg Maize starch 43.0 mg Talc 4.5 mg Magnesium stearate O.S mg Total weight per capsule 250.Q mg An injection solution of the following composition is produced in the usual manner:
4,5-Di-t-butyl-2-(4-fluorophenyl)--im1dazole hydrochloride 115.0 mg Glycerinformal 2.4 ml Water 4.0 ml
~ / ~ Y
~ N
wherein X is hydrogen or Cl_4-n-alkyl and Y i5 thienyl, optionally substituted by methyl or fluorine, or a group oi the formula yl ~RR3 yl wherein Rl, R2 and R3 are hydrogen, methyl, fluorine, hydroxy, methoxy or two of Rl, R2 and R3 on adjacent carbon atoms are together methylenedioxy Mé/3.4.1981 or ethylenedioxy or one of R , R2 and R is mono- or di-(Cl_4-n-alkyl)--amino and the other two are hydrogen, and physiologically compatible acid addition salts thereof.
The expression Cl 4-n-alkyl used herein relates to the straight-chain alkyl groups methyl, ethyl~propyl and butyl.
Among the compounds of formula I there are preferred those in which X is hydrogen and those in which Y is a 10 group of ~ormula yl~ especially p-fluorophenyl.
4,5-Di-t-butyl-2-(4-fluorophenyl)-imida~ole is especially pxeferred.
The inv~ntion is also concerned with a process for the manufacture of the aforementioned compounds as well as pharma-ceutical preparations based on the aforementioned compounds.
Examples o~ physiologically compatible acid addition sal~s are mineral acid salts such as hydrochlorides, hyc'ro-bromides, sulphates and phosphates~ salts of organic sulphonic acids such as alkylsulphona~es or arylsulphonates and carboxylic acid salts such as succinates or citrates.
The aforementioned compounds and sal~s can be manufactured in accordanca with ~he invention by treating a thiepinoimidazole of the formula ~ N ~ II
wherein X and Y have the above significance, or an acid addition salt thereof with a desulphurising catalyst and, if desired, converting a compound of formula I
into an acid addition salt.
Examples of desulphurising catalysts are metal catalysts such as nickel catalysts or palladium catalysts, preferably nickel catalysts, especially Raney-nic~el. ~he desulphurisation is conveniently carried out in a solvent, preferably a polar solvent such as dioxan or tetrahydro~
: 15 uran at a temperature up to the reflux temperature.
The compounds of formula II in which X is hydrogen can be prepared by reacting 3,3,6,6-tetramethyl-4,5--thiepanedione with an aldehyde Y-CH=O in the presence o~
ammonium ions, preferably in the presence of an ammonium salt such as ammonium acetate in a polar solvent such as dimethyl sulphoxide or dimethylformamide at a temperature up to the reflux temperature. The compounds of formula II
S obtained can be N-alkylated by reaction with an alkali metal hydride such as sodium hydride in a solvent such as dimethyl-formamide and reaction of the resulting compound with an alkyl halide such as methyl iodide.
The compounds of formula I and the physiologically compatible salts thereof can be used as medicaments. They inhibit the aggregation of the blood platelets and can therefore be used for the prevention of thromboses.
The compounds of formula I can be used as medicaments;
for example in the form of pharmaceutical preparations which contain them or their salts in admixture with an organic or inorganic inert carrier material which is suitable for enteral or parenteraL administration such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols or Vaseline. The pharmaceutical preparations can be made up in solid form (e.g. as tablets, drayees, suppositories or capsules) or in liquid form (e.g. as solutions, suspensions or emulsions). The pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preserving, IL8 ~7 stabilising, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They can also contain still other therepeutically valuable substances. The oral administration of the compounds in accordance with the invention is preferred. For adults there come into consideration an oral daily dosage of 0.5 to 30 mg/kg and a parenteral daily dosage of 0~05 to 10 mg/kg.
The aggregation-inhibiting activity was demonstrated according to the aggregometer method of BORN [Nature 194, 927 (1962)] and MICHAL and BORN [Nature 231, 220 (1971)].
The maximum aggregation velocity was taken as the test parameter and the effective concentration (EC50) was ascertained from dosage-activity curves.
Human platelet-rich plasma was obtained by centri~ugation from citrated venous blood. The experiments were carried out with suspensions of the test substances in 0.9% sodium chloride. 0.~8 ml of citrate plasma was treated with a 10 ~1 suspension of the test compound and incubated at 37C for 10 minutes, whereupon the aggregation was initiated by adlding 10 ~1 of a suspension of collagen fibrils.
- 6 - ~6~7 The results are reproduced in the following Table.
Table Collagen-induced blood plateLet ag~re~ation Compound 50 (~M) . .
4,5 Di-t-butyl-2-phenylimidazole 0.6 4/5-Di-t-butyl-2-(.4-fluorophenyl)--imidazole 0.5 4,5-Di-t-butyl-2-(3,4-methylene-dioxyphenyl)-imidazole 0.55 4,5-Di-t-butyl-2-(5-methoxy-3,4--methylenedioxyphenyl)-imidazo:Le 14.4 .
4,5-Di-t-butyl-2-(3,4,5-tximethoxy-phenyl)-imidazole 0.72 . . . . . . . . .
_ 7 - ~6~ ~7 The following Examples illustrate the present invention:
Example l 5 g of 2-phenyl-4,5,7,8-tetrahydro-4,4,8,8-tetra-S methyl-l-H-thiepino[4,5-a]imidazole and 200 ml of dioxan are heated at reflux temperature for 20 hours while stirring in the presence of a nickel catalyst (obtained by dehydrating 85 g of moist nic~el catalyst with 300 ml of dioxan, whirling followed by sedimentation of the catalyst and suc~ing-off the solvent~.
The catalyst is then left t:o sediment in the reaction solution. The solution is suction filtered. The catalyst is treated witll 200 ml of dioxan and heated to boiling while stirring. After the catalyst has settled, the solution is again suction filtered. This procedure is carried out once more.
The combined extracts are iltered and concentrat~d.
After recrystallisation from n-heptane, there are obtainlsd 1.2 g of 4,5-di-t-butyl-2-phenylimidazole, m.p. 156-158C.
In order to prepare the hydrochloride, 604 mg of the base are dissolved in ether and the solution ls neutralised by the dropwise addition o~ ethereal hydrochloric acid. The - 8 - ~ 7 precipitate is filtered off and washed with ether and ethanol.
There are obtained 680 mg of the hydrochloride, m.p. 250--255C (decomposition).
The thiepinoimidazole used as the starting material can be prepared as follows:
16 g of 3,3,6,6-tetramethyl-4,5-thiepanedione and 8 g of ~enzaldehyde are dissolved in 200 ml of dimethyl suLphoxide, 60 g of anhydrous ammonium acetate are added thereto whi:Le stirring and the mixture is heated at 90C.
After cooling, the reaction mixture is poured into ic~-water while stirring, the solution is made alkaline with concentrated sodium hydroxide and extracted wi1:h ether. The organic phase is washed with ice-water and concentxated to dryness.
The residue is covered with petro:Leum ether and rubbed with lS a glass rod. The filtered-off precipitate is recrystallised from toluene. There is o~tained 2-phenyl-4,5,7,8-tetrahydro--4,4,8,8-tetramethyl-l-H-thiepino[4,5-d]imidazole, m.p. 225--227C.
Example 2 In a manner analogous to Example l there are obtained 4,5-Dl-t~butyl-2-(4-fluorophenyl)-imida~ole, m.p.
185C; m.p. of the hydrochloride 240C (decomposition), . .
~6~
g 4.5-di-t-butyl-2-(4-methoxyphenyl)-imidazole, m.p.
145-147C; m.p. of the hydrochloride 250C (decomposition), 4,5-di-t-butyl-2-(5-methoxy-3,4-methylenedioxyphenyl)-~imidazole, m.p. 110-113C; m.p. of the hydrochloride 210C
5 (decomposition), 4,5-di-t-butyl-2-(3,4,5-trimethoxyphenyl)-imidazole, m.p. 140-142C, m.p. of the hydrochloride 230C (decomposition), 4,5-di-t-butyl-2-phenyl-N-methylimidazole, m.p~ 115--117C; m.p. of the hydrochloride 205C (decomposition).
The thiepinoimidazole starting material used for the manufacture of the last-named N-methylimidazole can be prepared as follows:
A suspension of 0.44 g of sodium hydride (55~ in paraffin) in 10 ml of dimethyl~ormamide is cooled to 0C under 15 nitrogen or argon. Thereupon, there is added dropwise a solution of 2.~6 g of 2-phenyl-4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-l-H-thiepino[4,5-d~imidazole dissolved in 10 ml of dimethylformamide. The mixture is th~n left to react-out at room temperature for 20 minutes. Then, 2.1 g of methyl 20 iodide in 10 ml of dimethylformamide are added dropwise.
The mixture is left to react-out at room temperature for a further 30 minutes. The reaction mixture is poured into ice--water while stirring, the precipitate is filtered off and washed in water. The filter residue is dissolved in ether 25 and the solution is dried and concentrated. The suspension is treated with petroleum e-ther. After crystallisation, the mixture is filtered and the product is recxystallised from n-heptane. The 2-phenyl-4,5,7,8-tetrahydro-1,4,4,8,8--pentamethyl-l-H-thiepino[4,5-d]imidazole melts at 158-160C.
M.p. of the hydrochloride: 240C (decomposition~.
S Example 3 5.8 g of 2-(3,4-methylenedioxyphenyl)~4,5,7,8--tetrahydro-4,4,8,8-tetramethyl-l-H-thiepino[4,5-d]imidazole, 200 ml of tetrahydrofuran and a nickel catalyst (obtained by dehydrating 85 g of moist nickel catalyst with 300 ml of tetrahydrofuran, whirling followecl by sedimentation of the catalyst and suc~ing-off of the solvent) are heated at reflux temperature for 24 hours. The reaction solution is treated as described in Example l, but usi.ng tetrahydrofuran in place of dioxan. After recrystall.isation from n-hexane, there are obtained 3.5 g of 4,5-di-t-but:yl-2-(3,4-methylenedioxy-phenyl)-imida~ole, m.p. 175-178C.
In a manner analogous to Example l, from 3.2 g of base there are obtained 3.5 g of hydrochloride, m.p. 200~'C
tdecomposition).
Example 4 Tablets of the following composition are produced in the usual manner:
4,5-Di-t-butyl-2-(4-~luorophenyl)--imidazole hydrochloride 185.0 mg Lactose 15.0 mg Maize starch 37.9 mg Water-soluble polyvinylpyrrolidone10.0 mg Magnesium stearate 2.5 mg Total weight per tablet 250.0 mg Example c~
Interlocking gelatin capsules of the followlng composition are produced in the usual manner: -4,5-Di-t-butyl-2-(4-fluorophenyl)--imidazole hydrochloride 200.0 mg Water-soluble poly~inylpyrrolidone 2.Q mg Maize starch 43.0 mg Talc 4.5 mg Magnesium stearate O.S mg Total weight per capsule 250.Q mg An injection solution of the following composition is produced in the usual manner:
4,5-Di-t-butyl-2-(4-fluorophenyl)--im1dazole hydrochloride 115.0 mg Glycerinformal 2.4 ml Water 4.0 ml
Claims (10)
1. Process for the preparation of imidazole derivatives of the formula I
wherein X is hydrogen or C1-4-n-alkyl and Y is thienyl, optionally substituted by methyl or fluorine, or a group of the formula Y1 Y1 wherein R1, R2 and R3 are hydrogen, methyl, fluorine, hydroxy, methoxy or two of R1, R2 and R3 on adjacent carbon atoms are together methylenedioxy or ethylenedioxy or one of R1, R2 and R3 is mono- or di-(C1-4-n-alkyl)-amino and the other two are hydrogen, and physiologically compatible acid addition salts thereof, which comprises treating a thiepinoimidazole of the formula II
wherein X and Y have the above significance, or an acid addition salt thereof with a desulphurising Ni or Pd catalyst and, if desired, converting a compound of formula I into an acid addition salt.
wherein X is hydrogen or C1-4-n-alkyl and Y is thienyl, optionally substituted by methyl or fluorine, or a group of the formula Y1 Y1 wherein R1, R2 and R3 are hydrogen, methyl, fluorine, hydroxy, methoxy or two of R1, R2 and R3 on adjacent carbon atoms are together methylenedioxy or ethylenedioxy or one of R1, R2 and R3 is mono- or di-(C1-4-n-alkyl)-amino and the other two are hydrogen, and physiologically compatible acid addition salts thereof, which comprises treating a thiepinoimidazole of the formula II
wherein X and Y have the above significance, or an acid addition salt thereof with a desulphurising Ni or Pd catalyst and, if desired, converting a compound of formula I into an acid addition salt.
2. A process as in claim 1 wherein in the compounds of formula II, X is hydrogen.
3. A process as in claim 1 wherein in the compounds of formula II, Y is a group of formula Y1.
4. A process as in claim 2 wherein in the compounds of Formula II, Y is a group of formula Y1.
5. A process as in claim 2 wherein in the compound of formula II, Y is p-fluorophenyl.
6. Imidazole derivatives of the formula I
wherein X is hydrogen or C1-4-n-alkyl and Y is thienyl, optionally substituted by methyl or fluorine, or a group of the formula y1 y1 wherein R1, R2 and R3 are hydrogen, methyl, fluorine, hydroxy, methoxy or two of R1, R2 and R3 on adjacent carbon atoms are together methylenedioxy or ethylenedioxy or one of R1, R2 and R3 is mono- or di-(C1-4-n-alkyl)-amino and the other two are hydrogen, and physiologically compatible acid addition salts thereof, whenever prepared according to the process of claim 1 or by an obvious chemical equivalent thereof.
wherein X is hydrogen or C1-4-n-alkyl and Y is thienyl, optionally substituted by methyl or fluorine, or a group of the formula y1 y1 wherein R1, R2 and R3 are hydrogen, methyl, fluorine, hydroxy, methoxy or two of R1, R2 and R3 on adjacent carbon atoms are together methylenedioxy or ethylenedioxy or one of R1, R2 and R3 is mono- or di-(C1-4-n-alkyl)-amino and the other two are hydrogen, and physiologically compatible acid addition salts thereof, whenever prepared according to the process of claim 1 or by an obvious chemical equivalent thereof.
7. Compounds according to claim 6, wherein X is hydrogen, whenever prepared according to the process of claim 2 or by an obvious chemical equivalent thereof.
8. Compounds according to claim 6, wherein Y is a group of formula y1, whenever prepared according to the process of claim 3 or by an obvious chemical equivalent thereof.
9. Compounds according to claim 6, wherein X is hydrogen and Y is a group of formula y1, whenever prepared according to the process of claim 4 or by an obvious chemical equivalent thereof.
10. 4,5-Di-t-butyl-2-(4-fluorophenyl)-imidazole, whenever prepared according to the process of claim 5 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH4347/80 | 1980-06-05 | ||
| CH434780 | 1980-06-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1161847A true CA1161847A (en) | 1984-02-07 |
Family
ID=4274400
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000377230A Expired CA1161847A (en) | 1980-06-05 | 1981-05-08 | Imidazole derivatives |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US4582844A (en) |
| EP (1) | EP0041652B1 (en) |
| JP (1) | JPS5731667A (en) |
| KR (1) | KR850000126B1 (en) |
| AT (1) | ATE6369T1 (en) |
| AU (1) | AU7111581A (en) |
| BR (1) | BR8103553A (en) |
| CA (1) | CA1161847A (en) |
| CS (1) | CS220340B2 (en) |
| DE (1) | DE3162356D1 (en) |
| DK (1) | DK193181A (en) |
| ES (1) | ES502777A0 (en) |
| FI (1) | FI811527L (en) |
| GR (1) | GR77076B (en) |
| IL (1) | IL63009A0 (en) |
| MC (1) | MC1394A1 (en) |
| NO (1) | NO811908L (en) |
| NZ (1) | NZ197248A (en) |
| PH (1) | PH15876A (en) |
| PT (1) | PT73143B (en) |
| ZA (1) | ZA813644B (en) |
| ZW (1) | ZW10781A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4501892A (en) * | 1982-07-28 | 1985-02-26 | The Upjohn Company | Pyridyl benzenediols |
| IT1193608B (en) * | 1983-01-21 | 1988-07-21 | Pierrel Spa | ARYOXYPROPANOLAMINE DERIVATIVES, PROCEDURE FOR THEIR PREPARATION PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR THERAPEUTIC USE |
| US4790775A (en) * | 1988-02-09 | 1988-12-13 | E. I. Du Pont De Nemours And Company | Transition connector |
| US8182528B2 (en) | 2003-12-23 | 2012-05-22 | Sadra Medical, Inc. | Locking heart valve anchor |
| JP6064653B2 (en) * | 2013-02-15 | 2017-01-25 | 東洋インキＳｃホールディングス株式会社 | Fluorescent material, fluorescent resin composition and compound |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE585555A (en) * | 1960-03-31 | |||
| US3473901A (en) * | 1963-02-08 | 1969-10-21 | Rohm & Haas | Fuel compositions |
| CH496710A (en) * | 1967-12-16 | 1970-09-30 | Basf Ag | Process for the preparation of substituted imidazoles |
| DD99787A1 (en) * | 1969-06-23 | 1973-08-20 | ||
| US3707475A (en) * | 1970-11-16 | 1972-12-26 | Pfizer | Antiinflammatory imidazoles |
| DE2701372A1 (en) * | 1977-01-14 | 1978-07-20 | Veba Chemie Ag | Prepn. of cyclic amidine cpd. used as pharmaceutical intermediate - from carboxylate ester cpd. and di:amine cpd. without using catalyst |
| DE2733466A1 (en) * | 1977-07-25 | 1979-02-22 | Basf Ag | Imidazole derivs. prodn. - by reacting 1,2-di:amine with carboxylic acid or dehydrogenating imidazoline in presence of zinc oxide |
-
1981
- 1981-04-30 DK DK193181A patent/DK193181A/en not_active Application Discontinuation
- 1981-05-07 ZW ZW107/81A patent/ZW10781A1/en unknown
- 1981-05-08 CA CA000377230A patent/CA1161847A/en not_active Expired
- 1981-05-14 CS CS813581A patent/CS220340B2/en unknown
- 1981-05-18 FI FI811527A patent/FI811527L/en not_active Application Discontinuation
- 1981-05-27 DE DE8181104077T patent/DE3162356D1/en not_active Expired
- 1981-05-27 EP EP81104077A patent/EP0041652B1/en not_active Expired
- 1981-05-27 AT AT81104077T patent/ATE6369T1/en not_active IP Right Cessation
- 1981-05-28 AU AU71115/81A patent/AU7111581A/en not_active Abandoned
- 1981-05-29 ZA ZA00813644A patent/ZA813644B/en unknown
- 1981-05-29 NZ NZ197248A patent/NZ197248A/en unknown
- 1981-06-01 IL IL63009A patent/IL63009A0/en unknown
- 1981-06-02 JP JP8392681A patent/JPS5731667A/en active Pending
- 1981-06-03 MC MC811517A patent/MC1394A1/en unknown
- 1981-06-03 GR GR65141A patent/GR77076B/el unknown
- 1981-06-04 KR KR1019810002007A patent/KR850000126B1/en active
- 1981-06-04 PT PT73143A patent/PT73143B/en unknown
- 1981-06-04 BR BR8103553A patent/BR8103553A/en unknown
- 1981-06-04 NO NO811908A patent/NO811908L/en unknown
- 1981-06-04 ES ES502777A patent/ES502777A0/en active Granted
- 1981-06-04 PH PH25717A patent/PH15876A/en unknown
-
1985
- 1985-09-10 US US06/774,393 patent/US4582844A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| DK193181A (en) | 1981-12-06 |
| FI811527L (en) | 1981-12-06 |
| NO811908L (en) | 1981-12-07 |
| ES8300755A1 (en) | 1982-11-16 |
| ZW10781A1 (en) | 1981-12-30 |
| ATE6369T1 (en) | 1984-03-15 |
| KR830006229A (en) | 1983-09-20 |
| ES502777A0 (en) | 1982-11-16 |
| MC1394A1 (en) | 1982-04-27 |
| PT73143A (en) | 1981-07-01 |
| CS220340B2 (en) | 1983-03-25 |
| PH15876A (en) | 1983-04-13 |
| DE3162356D1 (en) | 1984-03-29 |
| US4582844A (en) | 1986-04-15 |
| GR77076B (en) | 1984-09-06 |
| BR8103553A (en) | 1982-03-02 |
| NZ197248A (en) | 1984-07-31 |
| PT73143B (en) | 1983-05-11 |
| AU7111581A (en) | 1981-12-10 |
| KR850000126B1 (en) | 1985-02-27 |
| EP0041652A1 (en) | 1981-12-16 |
| EP0041652B1 (en) | 1984-02-22 |
| JPS5731667A (en) | 1982-02-20 |
| IL63009A0 (en) | 1981-09-13 |
| ZA813644B (en) | 1982-06-30 |
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| MKEX | Expiry |