CA1038873A - Imidazole diagnostic agents - Google Patents
Imidazole diagnostic agentsInfo
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- CA1038873A CA1038873A CA185,153A CA185153A CA1038873A CA 1038873 A CA1038873 A CA 1038873A CA 185153 A CA185153 A CA 185153A CA 1038873 A CA1038873 A CA 1038873A
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- ethyl
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Abstract
ABSTRACT OF THE DISCLOSURE
A pharmaceutical compound and preparation thereof for use as a diagnostic agent to test the secretory action of the stomach is disclosed, which comprises a compound of the following formula wherein R1 is methyl or ethyl; R2 is hydrogen, methyl or ethyl;
and R3 is hydrogen, methyl or ethyl, provided that, when R1 is methyl, R2 and R3 are not both hydrogen or its pharmaceutically acceptable acid addition salts and a non-toxic diluent or carrier.
A pharmaceutical compound and preparation thereof for use as a diagnostic agent to test the secretory action of the stomach is disclosed, which comprises a compound of the following formula wherein R1 is methyl or ethyl; R2 is hydrogen, methyl or ethyl;
and R3 is hydrogen, methyl or ethyl, provided that, when R1 is methyl, R2 and R3 are not both hydrogen or its pharmaceutically acceptable acid addition salts and a non-toxic diluent or carrier.
Description
1~)3~3~73 This invention relates to diagnostic agents, In parti~ular it relates to agents which may be used to test the secretory action of the stomach. Diagnostic agents which are already available for the above purpose and which act by stimulating the secretion of gastric acid are not particularly selective in this action and thus often give rise to distressing side-effects such as skin flushing, nausea, abdominal cramps, headache, dizziness and hypo-tension. It i8 an object of the present invention to provide a diagnostic agent which i8 more selective in its action.
The diagnostic agent6 of the present invention are the compo~d6 of the following formula: ~ R2 R1 ~ CH2CH2 N
HN ~ N
FORMULA I
wherein R1 may be methyl or ethyl; R2 may be hydrogen, methyl or ethyl; and R3 may be hydrogen, methyl or ethyl, provided that when R1 is methyl, R2 and R3 are not both hydrogen.
The compound~ of the present invention wherein R1 i~ methyl a~d R2 and R3 are not both ethyl may be formed from 4-methyl histAmin~.
Treqtment of this substance with formaldehyde and formic acid in the Clarke-Eschweiler reaction lead~ to the corresponding compound wherein R2 and R3 are both methyl. Treatment of 4-methyl histamine with N,N'-carbonyl di-imidazole either alone or in a ~uitable solvent such as dimsthylformamide leads to the formation of a cyclio urea of Formula II, wherein R1 is methyl.
`:
~1~;)38'B73 R1~
I
N N NH
O
FORXUIA II
Reaction of this cyclic urea with lithlum aluminium hydride yields the compound of Formula I wherein Rl and R2 are ~ethyl and R3 is hydrogen. Treatment of the cyclic urea of Formula II with a base such as sodium hYdride and then with an ethyl hallde yields the compound of Formula III wherein R1 is methyl N ~ ~ N-CH2CH3 O
FORMULA III
which may be hydrolysed, for example with hot aqùeous aIkali, to give thé compound of Formula I wherein R1 i6 methyl, R2 is ethyl and R3 iB hydrogen. The compound of Formula III may alternati~ely be reduced with lithium aluminium hydride in which case the product is the compound of Formula I wherein R1 and R2 are methyl ~d R3 ie ethyl.
The substance wherein R1 is ethyl and R2 and R3 are both hydrogen may be formed by a series of reactions commencing with hex-3-yn-1-ol as described in Bxample 5 below. The compounds wherein R1 is ethyl and R2 and R3 are~not both ethyl are produced ~rom this compound according to the methods as described above, R1 in the intermediates of formulae II and III being in this case ethyl.
~381~73 The synthesis of the compounds of Formula I wherein R2 and R3 are both ethyl may commence from a compound of Formula IV wherein Rl is methyl or ethyl.
Rl ~ ~ CH2CN ' N NH
~/
~O~MULA IV
Acid or basic hydrolysis of this cyanomethylimidazole yields the corresponding carbo~ylic acid and reaction of the acid chloride, derived therefrom by standard methods, with diethylamine gives the compound of Formula V wherein Rl is methyJ. or ethyl.
Ri. CH2CON
The diagnostic agent6 of the present invention are the compo~d6 of the following formula: ~ R2 R1 ~ CH2CH2 N
HN ~ N
FORMULA I
wherein R1 may be methyl or ethyl; R2 may be hydrogen, methyl or ethyl; and R3 may be hydrogen, methyl or ethyl, provided that when R1 is methyl, R2 and R3 are not both hydrogen.
The compound~ of the present invention wherein R1 i~ methyl a~d R2 and R3 are not both ethyl may be formed from 4-methyl histAmin~.
Treqtment of this substance with formaldehyde and formic acid in the Clarke-Eschweiler reaction lead~ to the corresponding compound wherein R2 and R3 are both methyl. Treatment of 4-methyl histamine with N,N'-carbonyl di-imidazole either alone or in a ~uitable solvent such as dimsthylformamide leads to the formation of a cyclio urea of Formula II, wherein R1 is methyl.
`:
~1~;)38'B73 R1~
I
N N NH
O
FORXUIA II
Reaction of this cyclic urea with lithlum aluminium hydride yields the compound of Formula I wherein Rl and R2 are ~ethyl and R3 is hydrogen. Treatment of the cyclic urea of Formula II with a base such as sodium hYdride and then with an ethyl hallde yields the compound of Formula III wherein R1 is methyl N ~ ~ N-CH2CH3 O
FORMULA III
which may be hydrolysed, for example with hot aqùeous aIkali, to give thé compound of Formula I wherein R1 i6 methyl, R2 is ethyl and R3 iB hydrogen. The compound of Formula III may alternati~ely be reduced with lithium aluminium hydride in which case the product is the compound of Formula I wherein R1 and R2 are methyl ~d R3 ie ethyl.
The substance wherein R1 is ethyl and R2 and R3 are both hydrogen may be formed by a series of reactions commencing with hex-3-yn-1-ol as described in Bxample 5 below. The compounds wherein R1 is ethyl and R2 and R3 are~not both ethyl are produced ~rom this compound according to the methods as described above, R1 in the intermediates of formulae II and III being in this case ethyl.
~381~73 The synthesis of the compounds of Formula I wherein R2 and R3 are both ethyl may commence from a compound of Formula IV wherein Rl is methyl or ethyl.
Rl ~ ~ CH2CN ' N NH
~/
~O~MULA IV
Acid or basic hydrolysis of this cyanomethylimidazole yields the corresponding carbo~ylic acid and reaction of the acid chloride, derived therefrom by standard methods, with diethylamine gives the compound of Formula V wherein Rl is methyJ. or ethyl.
Ri. CH2CON
2 3 N ~ ~
FO~MDL~ V
The compound of Formula V when treated with lithium aluminium hydrld~yields the required compounds of Eormula I where-in Rl is methyl or ethyl and R2 and R3 are both ethyl.
~ s stated above, the compounds of the present inventionare useful diagnostic agents in that they selectively stimulate the secretion of gastric acidO This action is due to the fact that the compounds of the present invention are H~2 recleptor agonists, the characterisatiQn of which is e~plained in detail by Black et al (Nature 1972, 236, 385). At the same time because of their selectivity the compounds possess.very little H-l receptor agonist activity, the ratio of H~2 to H~l agonist activity relative to histamine being at least 50 to 1, ~L~3~3873 Compounds of Formula I wherein either R2 or R3 is not hydrogen possess a further advantage in that they are particularly metabolically stable in ~ivo.
The activity of the compounds of Formula I may be demonstrated by their stimulation of the secretion of gastric acid from the perfused stomachs of rats anaesthetised with urethane. These compounds are given intravenously and show activity w~thin the dose range of from 1 to 256 micromoles per ki~ogram.
According to the present invention we also provide pharmaceutical compositions which comprise a compound o~ Formula I together with a pharmaceutically acceptahle diluent or carrier.
Since administration of the compounds is preferably by injection which may be intravenous, subcutaneous or intramuscular, the pharmaceutical carrier employed is preferably a liquid,- Exem-plary of liquid carriers are distilled water and physiological saline. The preparation in the form of a sterile injectable liquid may suitably be contained in an ampoule.
The pharmaceutical compositions are prepared by conventional techniques involving procedures such as mixing or dissolving khe ingredients as appropriate to the desired prepar-ation.
Preferably, each dosage unit will contain the active ingredient in an amount of from about 25 mg to about 25~ mg most prefera~ly from about 25 mg to about 100 mg.
The compounds of the present invention may be admin-istered in basic form or in the form of an addition salt with a pharma~eutically acceptable acid and in association with a pharmaceutical carrier therefor. Such addition salts include those with hydrochloric, hydrobromic hydriodic, sulphuric, phosphoric and maleic acids.
The invention is illustrated but in no way l:imited by the following examples:
EXA~ 1 ~38873 ~ de A solution of sodium ethoxide (prepared from o.46 g. of sodium) in ethanol (100 ml,) was added to a hot solution of 4-methyl-5-(2 aminoethyl)imidazole dihydrochloride (1~98 g.) in ethanol (50 ml.) and water (2 ml~) After coolin~, the solution Wa6 filtered and evaporated to dryness under reduced pressure. ~ormaldehyde (1.7 ml.
40%) and then formic acid (2.3 g. 98%) were each added to the residue and the resulting solution heated u~der reflux for 24 hours.
Evapor~tion of the reaotion mixture furnished a residual oil which gave a crude picrate (5,77 g.) m.p. 225-229 on additlon of a solutlon of picric acid in ethanol. Thls picrate wa~ r~crystallised tw~e from ethanol/dimethylformamide to give 4-methyl-5-(2-dimethyl-amlnoethyl)imidazole dipi¢rata m.p. 237-240. An analytical sample (ex dimethylformamide) had m.p. 241-242.
This dipicrate was converted to a hygroscopic dihydrochloride, m.p.
193-196, (ex ethanol~ether), by addition o~ concentrated hydrochloric acid, extraction with toluene, and evaporatlon to dryne6s.
EXAMPLE 2, 4-Methyl-5-(2-methylaminoethyl)imidazole dihydrochlorido (i) A ~tirred mixture of 4-methyl-5-(2-aminoethyl)imidazole (8 g.) and N,N'-carbonyl di-imidazole (13 g.) WaB heated in a dry atmosphere to 100 for 1 hour and then at 110-130 for a further 30 minutes/ After cooling, the ~olid cake was ground to a fina powder under ethanol and left to stand. Filtration and washing with ethanol, gave 3-methyl-5-oxo-5,6,7,8 tetrahydroimidazo (1,5-c) pyrimidine (406 g.~, m.p. 232-4.
(ii) A solution of l-methyl-5-oxo-5,6,798-tetrahydroimidAzo (1,5-c) ~ .
38~73 pyrimidine (2,1 g.) in tetrahydrofuran was added dropwise to a stirred suspen~ion of lithium aluminium hydride (2 g.) in tetrahydro~uran and the solution heated under reflux for 2 hour~. After cooling1 water was added carefully, the mixture wa6 filtered and the residue w 8 washed with tetrahydrofuran and ethanol. The filtrate was evaporated to d~yness, to give the crude base which was acidified with ethanolic hydrogen chloride to give 4-methyl-5-(2-methylaminoethyl)imidazole c~hydrochloride (2.4 g.~,m.p. 275-277C (dec.).
EXA~LE 3 (i) A solutiln Or l-methyl-5-oxo-5,6~7~8-tetrahydro~miclazo ~1~5-c) pyrimidine in dimethylformamide was added to a stirred ~u~pension o~
sodium hydride in dimethyl~ormamide. After 6tirrin~ under nitro~en at room temperature for 45 mlnutes, a solution of ethyl bromide in dimethylformamide was then added rapidly and the mixture wa6 stirred for a further 24 hours, filtered and e~aporated to dryness. The residue was extracted with chloroform, the chloroform removed and the residual base W~R acidified with isopropanolic hydrog0n chloride to give l-methyl-6-ethyl-5-oxo-5,6,7,8-tetrahydroimidazo (1,5-c) pyri~idine hydrochloride.
(ii) A solution of the above hydrochloride ln aqueous 5N potass1um hydroxide was heated under reflux overnight, The reaction mixture was acidified with concentrated hydrochloric acid, filtered and the filtrate was eraporated to dryneRs. The residue wa6 extracted with ethanol, the extracts evaporated to dryness and the crude product reorystallised to gire the required dihydrochloride.
EXAMPL3 4.
4-Methyl-5-(2-methylethylaminoethyl)imidazole Treatment of 3-methyl-6-ethyl-5-oxo-5,6,7,8-tetrahyc~oimiclazo (1,5-c) - r~
~L~3~873 pyrimidine derived from the hydrochloride of Example 3(i) with lithium aluminium hydride by the method of Example 2(ii~resulted in the production of 4-methyl-5-(2-methylethylaminoethyl)imid-azole.
4-Ethyl-5-(2-aminoe*hyl)imidazole dihydrochloride.
Hex-3-yn-1-ol (49 g.) was added slowly to a stirred slurry of toluene-p-sulphonyl chloride (108 g.) in pyridine (50 ml.) at room temperature and after stirring for a further 2 hours, the mixture was poured on to ice, extracted with ether, dried and evaporated to give hex~3-ynyl-toluene~p-sulphonate (123 g.) as a crude oil, which was us2d without further purifi-cation.
A stirred mixture of hex-3-ynyl toluene-p-sulphonate (63 g.) and potassium phthalimide (47 g.) was heated on a steam bath for two hours, concentrated under reduced pressure and poured into water. ~he precipitated crude prod~ct was dissolved in a minimum of hot benzene and, after cooling the solution was filtered to remove unreacted phthalimide. The filtrate was evaporated to dryness and the residue recrystallised from aqueous ethanol to give l-phthalimidohex~3-yne (33 g.) m.p.
81-83. An an~lytical sample had m.p. 84-85.
A solution of hydrated magnesium sulphate (48 g.) in water ~as added to a solution of l-phthalimidohex-3-yne (17.2 g. ?
in acetone. To this stirred, cooled mixture was added rapidly a solution of potassium permanganate (21.5 g.) in water. After stirring for 6 hours at a temperature belo~ 25C the solution was filtered and evaporated to give l-phthalimi~o-3,4-hexanedione (14.1 gO) m.p. 87-89. An analytical sample teX ethanol/water) had m.p. 89-91.
Paraformaldehyde ~3.7 g.~ was added to a solution of l-phthalimido-3,4-hexanedione (10~2 g.) and ammonium acetate ~ -8-~)3~873 (2.5 g.) in acetic acid at 50C and kept at this temperature with stirring for 3 hours. After cooling and dilution with water, the solution was neutralised with potassium carbonate and extracted with chloroform. The combined ,.~
-8a-
FO~MDL~ V
The compound of Formula V when treated with lithium aluminium hydrld~yields the required compounds of Eormula I where-in Rl is methyl or ethyl and R2 and R3 are both ethyl.
~ s stated above, the compounds of the present inventionare useful diagnostic agents in that they selectively stimulate the secretion of gastric acidO This action is due to the fact that the compounds of the present invention are H~2 recleptor agonists, the characterisatiQn of which is e~plained in detail by Black et al (Nature 1972, 236, 385). At the same time because of their selectivity the compounds possess.very little H-l receptor agonist activity, the ratio of H~2 to H~l agonist activity relative to histamine being at least 50 to 1, ~L~3~3873 Compounds of Formula I wherein either R2 or R3 is not hydrogen possess a further advantage in that they are particularly metabolically stable in ~ivo.
The activity of the compounds of Formula I may be demonstrated by their stimulation of the secretion of gastric acid from the perfused stomachs of rats anaesthetised with urethane. These compounds are given intravenously and show activity w~thin the dose range of from 1 to 256 micromoles per ki~ogram.
According to the present invention we also provide pharmaceutical compositions which comprise a compound o~ Formula I together with a pharmaceutically acceptahle diluent or carrier.
Since administration of the compounds is preferably by injection which may be intravenous, subcutaneous or intramuscular, the pharmaceutical carrier employed is preferably a liquid,- Exem-plary of liquid carriers are distilled water and physiological saline. The preparation in the form of a sterile injectable liquid may suitably be contained in an ampoule.
The pharmaceutical compositions are prepared by conventional techniques involving procedures such as mixing or dissolving khe ingredients as appropriate to the desired prepar-ation.
Preferably, each dosage unit will contain the active ingredient in an amount of from about 25 mg to about 25~ mg most prefera~ly from about 25 mg to about 100 mg.
The compounds of the present invention may be admin-istered in basic form or in the form of an addition salt with a pharma~eutically acceptable acid and in association with a pharmaceutical carrier therefor. Such addition salts include those with hydrochloric, hydrobromic hydriodic, sulphuric, phosphoric and maleic acids.
The invention is illustrated but in no way l:imited by the following examples:
EXA~ 1 ~38873 ~ de A solution of sodium ethoxide (prepared from o.46 g. of sodium) in ethanol (100 ml,) was added to a hot solution of 4-methyl-5-(2 aminoethyl)imidazole dihydrochloride (1~98 g.) in ethanol (50 ml.) and water (2 ml~) After coolin~, the solution Wa6 filtered and evaporated to dryness under reduced pressure. ~ormaldehyde (1.7 ml.
40%) and then formic acid (2.3 g. 98%) were each added to the residue and the resulting solution heated u~der reflux for 24 hours.
Evapor~tion of the reaotion mixture furnished a residual oil which gave a crude picrate (5,77 g.) m.p. 225-229 on additlon of a solutlon of picric acid in ethanol. Thls picrate wa~ r~crystallised tw~e from ethanol/dimethylformamide to give 4-methyl-5-(2-dimethyl-amlnoethyl)imidazole dipi¢rata m.p. 237-240. An analytical sample (ex dimethylformamide) had m.p. 241-242.
This dipicrate was converted to a hygroscopic dihydrochloride, m.p.
193-196, (ex ethanol~ether), by addition o~ concentrated hydrochloric acid, extraction with toluene, and evaporatlon to dryne6s.
EXAMPLE 2, 4-Methyl-5-(2-methylaminoethyl)imidazole dihydrochlorido (i) A ~tirred mixture of 4-methyl-5-(2-aminoethyl)imidazole (8 g.) and N,N'-carbonyl di-imidazole (13 g.) WaB heated in a dry atmosphere to 100 for 1 hour and then at 110-130 for a further 30 minutes/ After cooling, the ~olid cake was ground to a fina powder under ethanol and left to stand. Filtration and washing with ethanol, gave 3-methyl-5-oxo-5,6,7,8 tetrahydroimidazo (1,5-c) pyrimidine (406 g.~, m.p. 232-4.
(ii) A solution of l-methyl-5-oxo-5,6,798-tetrahydroimidAzo (1,5-c) ~ .
38~73 pyrimidine (2,1 g.) in tetrahydrofuran was added dropwise to a stirred suspen~ion of lithium aluminium hydride (2 g.) in tetrahydro~uran and the solution heated under reflux for 2 hour~. After cooling1 water was added carefully, the mixture wa6 filtered and the residue w 8 washed with tetrahydrofuran and ethanol. The filtrate was evaporated to d~yness, to give the crude base which was acidified with ethanolic hydrogen chloride to give 4-methyl-5-(2-methylaminoethyl)imidazole c~hydrochloride (2.4 g.~,m.p. 275-277C (dec.).
EXA~LE 3 (i) A solutiln Or l-methyl-5-oxo-5,6~7~8-tetrahydro~miclazo ~1~5-c) pyrimidine in dimethylformamide was added to a stirred ~u~pension o~
sodium hydride in dimethyl~ormamide. After 6tirrin~ under nitro~en at room temperature for 45 mlnutes, a solution of ethyl bromide in dimethylformamide was then added rapidly and the mixture wa6 stirred for a further 24 hours, filtered and e~aporated to dryness. The residue was extracted with chloroform, the chloroform removed and the residual base W~R acidified with isopropanolic hydrog0n chloride to give l-methyl-6-ethyl-5-oxo-5,6,7,8-tetrahydroimidazo (1,5-c) pyri~idine hydrochloride.
(ii) A solution of the above hydrochloride ln aqueous 5N potass1um hydroxide was heated under reflux overnight, The reaction mixture was acidified with concentrated hydrochloric acid, filtered and the filtrate was eraporated to dryneRs. The residue wa6 extracted with ethanol, the extracts evaporated to dryness and the crude product reorystallised to gire the required dihydrochloride.
EXAMPL3 4.
4-Methyl-5-(2-methylethylaminoethyl)imidazole Treatment of 3-methyl-6-ethyl-5-oxo-5,6,7,8-tetrahyc~oimiclazo (1,5-c) - r~
~L~3~873 pyrimidine derived from the hydrochloride of Example 3(i) with lithium aluminium hydride by the method of Example 2(ii~resulted in the production of 4-methyl-5-(2-methylethylaminoethyl)imid-azole.
4-Ethyl-5-(2-aminoe*hyl)imidazole dihydrochloride.
Hex-3-yn-1-ol (49 g.) was added slowly to a stirred slurry of toluene-p-sulphonyl chloride (108 g.) in pyridine (50 ml.) at room temperature and after stirring for a further 2 hours, the mixture was poured on to ice, extracted with ether, dried and evaporated to give hex~3-ynyl-toluene~p-sulphonate (123 g.) as a crude oil, which was us2d without further purifi-cation.
A stirred mixture of hex-3-ynyl toluene-p-sulphonate (63 g.) and potassium phthalimide (47 g.) was heated on a steam bath for two hours, concentrated under reduced pressure and poured into water. ~he precipitated crude prod~ct was dissolved in a minimum of hot benzene and, after cooling the solution was filtered to remove unreacted phthalimide. The filtrate was evaporated to dryness and the residue recrystallised from aqueous ethanol to give l-phthalimidohex~3-yne (33 g.) m.p.
81-83. An an~lytical sample had m.p. 84-85.
A solution of hydrated magnesium sulphate (48 g.) in water ~as added to a solution of l-phthalimidohex-3-yne (17.2 g. ?
in acetone. To this stirred, cooled mixture was added rapidly a solution of potassium permanganate (21.5 g.) in water. After stirring for 6 hours at a temperature belo~ 25C the solution was filtered and evaporated to give l-phthalimi~o-3,4-hexanedione (14.1 gO) m.p. 87-89. An analytical sample teX ethanol/water) had m.p. 89-91.
Paraformaldehyde ~3.7 g.~ was added to a solution of l-phthalimido-3,4-hexanedione (10~2 g.) and ammonium acetate ~ -8-~)3~873 (2.5 g.) in acetic acid at 50C and kept at this temperature with stirring for 3 hours. After cooling and dilution with water, the solution was neutralised with potassium carbonate and extracted with chloroform. The combined ,.~
-8a-
3~3~73 extract~ were e~aporated to dryne6s and the residue dissolved in ethanolic hydro~en chloride. Addition of ethyl acetate ~ave 4-ethyl-5-(2-phthalimidoethyl)imidazole hydrochloricle m.p. 246-248 (dec.) ~ydrolysi~ of 4-ethyl-5-(2-phth~limidoethyl)imidazole hydrochloride (1.23 g.) with 5N hydrochloric acid ga~e 4 ethyl-5-(2-aminoethyl) imidazole dihydrochloride (0.73 g.) m.pD 168.5-170.5. An analytical sample, recryRtallised from ethanol /ether had m.p. 170L171.
' By submitting 4-ethyi-5-(Z-aminoethyl)imidazole to the reactions described in Example 1 to 4, the following compound~ were produced:
' By submitting 4-ethyi-5-(Z-aminoethyl)imidazole to the reactions described in Example 1 to 4, the following compound~ were produced:
4-ethyl-5-~2-dimethylaminoethyl)imldazol~
4-ethyl-5-t2-methylaminoethyl)imidazole 4-ethyl-5-(2-ethylaminoethyl)imidazole 4-ethyl-5-(2-methylethylaminoethyl)imidazole EXAMPIE ?
4-Meth~1-5-(2 diethylaminoethyl)imidazole dihydrochloride 4-methyl-5-cyanomethylimidazole hydrochloride was heated undar reflux overnight with concentrated hydrochloric acid and the re6ultant (4-methylimidazol-5-yl) acetic aoid was isolated and treated with an exce66 of boiling thionyl chloride for 1~5 hours. The exce6~ of thionyl chlorlde wa3 removed by distillation and to the re6idua1 acid chloride was carefully added, with cooling and shaking, fre~hly dis~illed diethylamine. The resulting product wa~ dissolvea in aqueous ethanol, treated with decolouri6ing charcoal, and the product CryBtalli6ed- Thi6 N,N-diethyl(4-methylimidazole-5-yl)acetamide was di6solved in dry tetrahydrof~ran and reduced with lithium aluminium hydride under conditions similar to those described in Example 2(ii) .
~ `~
~38873 to give the required~-methyl-5-(2-diethylaminoethyl)imidazole dlhydrQchloride.
~; EXAMPLE 8 _ By subjecting 4-ethyl-5-cyanomethylimidazole to the reactions described in Example 7, 4-ethyl-5-(2-diethylaminoethyl)imidQzole may be ohtained, ~.
By dissolving 100 m~. of 4-methyl-5-(2 methylaminoethyl)lmidazole dihydrochloride in 2 ml. of sterile wAter or normal saline solution a pharmaceutical composition suitable for parenteral ad~lnistration i8 pioducQd.
In the 6ame way 601ution6 of the compounds produced accordin~ to _y Qne of E~nmples 1 and 3 to 8 may be produced.
.
-- 10 _
4-ethyl-5-t2-methylaminoethyl)imidazole 4-ethyl-5-(2-ethylaminoethyl)imidazole 4-ethyl-5-(2-methylethylaminoethyl)imidazole EXAMPIE ?
4-Meth~1-5-(2 diethylaminoethyl)imidazole dihydrochloride 4-methyl-5-cyanomethylimidazole hydrochloride was heated undar reflux overnight with concentrated hydrochloric acid and the re6ultant (4-methylimidazol-5-yl) acetic aoid was isolated and treated with an exce66 of boiling thionyl chloride for 1~5 hours. The exce6~ of thionyl chlorlde wa3 removed by distillation and to the re6idua1 acid chloride was carefully added, with cooling and shaking, fre~hly dis~illed diethylamine. The resulting product wa~ dissolvea in aqueous ethanol, treated with decolouri6ing charcoal, and the product CryBtalli6ed- Thi6 N,N-diethyl(4-methylimidazole-5-yl)acetamide was di6solved in dry tetrahydrof~ran and reduced with lithium aluminium hydride under conditions similar to those described in Example 2(ii) .
~ `~
~38873 to give the required~-methyl-5-(2-diethylaminoethyl)imidazole dlhydrQchloride.
~; EXAMPLE 8 _ By subjecting 4-ethyl-5-cyanomethylimidazole to the reactions described in Example 7, 4-ethyl-5-(2-diethylaminoethyl)imidQzole may be ohtained, ~.
By dissolving 100 m~. of 4-methyl-5-(2 methylaminoethyl)lmidazole dihydrochloride in 2 ml. of sterile wAter or normal saline solution a pharmaceutical composition suitable for parenteral ad~lnistration i8 pioducQd.
In the 6ame way 601ution6 of the compounds produced accordin~ to _y Qne of E~nmples 1 and 3 to 8 may be produced.
.
-- 10 _
Claims (6)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of an imidazole deriva-tive of the formula wherein R1 is methyl or ethyl; R2 is hydrogen, methyl or ethyl and R3 is hydrogen, methyl or ethyl, provided that, when R1 is methyl, R2 and R3 are not both hydrogen, which comprises:
(a) treating 4-methylhistamine or 4-ethylhistamine with formaldehyde and formic acid to give compounds wherein R2 and R3 are methyl, or (b) hydrolysis of a compound of formula wherein R1 is methyl or ethyl, to give compounds wherein R2 is ethyl and R3 is hydrogen, or (c) reduction of a compound of formula wherein R1 is methyl or ethyl to give compounds wherein R2 is methyl and R3 is ethyl, or (d) treatment of 1-phthalimido-3,4-hexanedione with ammonium acetate and formaldehyde, and subsequent removal of the phthalimido protecting group to give the compound wherein R1 is ethyl and both R2 and R3 are hydrogen, or (e) reduction of a compound of formula wherein R1 is methyl or ethyl, to give compounds wherein R2 and R3 are both ethyl.
(a) treating 4-methylhistamine or 4-ethylhistamine with formaldehyde and formic acid to give compounds wherein R2 and R3 are methyl, or (b) hydrolysis of a compound of formula wherein R1 is methyl or ethyl, to give compounds wherein R2 is ethyl and R3 is hydrogen, or (c) reduction of a compound of formula wherein R1 is methyl or ethyl to give compounds wherein R2 is methyl and R3 is ethyl, or (d) treatment of 1-phthalimido-3,4-hexanedione with ammonium acetate and formaldehyde, and subsequent removal of the phthalimido protecting group to give the compound wherein R1 is ethyl and both R2 and R3 are hydrogen, or (e) reduction of a compound of formula wherein R1 is methyl or ethyl, to give compounds wherein R2 and R3 are both ethyl.
2. The process of Claim 1(a) for preparing 4-methyl-5-(2-dimethylaminoethyl)-imidazole which comprises treating 4-methylhistamine with formaldehyde and formic acid.
3, The process of Claim 1(d) for preparing 4-ethyl-5-(2-aminoethyl)-imidazole which comprises treating 1-phthalimido-
3, The process of Claim 1(d) for preparing 4-ethyl-5-(2-aminoethyl)-imidazole which comprises treating 1-phthalimido-
3,4-hexanedione with ammonium acetate and formaldehyde and removing the phthalimido protecting group.
4. A compound of the following general formula:
wherein R1 is methyl or ethyl; R2 is hydxogen, methyl or ethyl and R3 is hydrogen, methyl or ethyl, provided that, when R1 is methyl, R2 and R3 are not both hydrogen or a pharmaceutically acceptable acid addition salt thereof whenever prepared or produced by the process as claimed in Claim 1 or an obvious chemical equivalent thereof.
wherein R1 is methyl or ethyl; R2 is hydxogen, methyl or ethyl and R3 is hydrogen, methyl or ethyl, provided that, when R1 is methyl, R2 and R3 are not both hydrogen or a pharmaceutically acceptable acid addition salt thereof whenever prepared or produced by the process as claimed in Claim 1 or an obvious chemical equivalent thereof.
5. 4-Methyl-5-(2-dimethylaminoethyl)-imidazole or a pharmaceutically acceptable acid addition salt thereof whenever prepared or produced by the process as claimed in claim 2 or an obvious chemical equivalent thereof.
6. 4-Ethyl-5-(2-aminoethyl)imidazole or a pharmaceutically acceptable acid addition salt thereof whenever prepared or produced by the process as claimed in Claim 3 or an obvious chemical equivalent thereof.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA185,153A CA1038873A (en) | 1973-11-06 | 1973-11-06 | Imidazole diagnostic agents |
| CA293,464A CA1036495A (en) | 1973-11-06 | 1977-12-20 | Imidazole diagnostic agents |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA185,153A CA1038873A (en) | 1973-11-06 | 1973-11-06 | Imidazole diagnostic agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1038873A true CA1038873A (en) | 1978-09-19 |
Family
ID=4098320
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA185,153A Expired CA1038873A (en) | 1973-11-06 | 1973-11-06 | Imidazole diagnostic agents |
| CA293,464A Expired CA1036495A (en) | 1973-11-06 | 1977-12-20 | Imidazole diagnostic agents |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA293,464A Expired CA1036495A (en) | 1973-11-06 | 1977-12-20 | Imidazole diagnostic agents |
Country Status (1)
| Country | Link |
|---|---|
| CA (2) | CA1038873A (en) |
-
1973
- 1973-11-06 CA CA185,153A patent/CA1038873A/en not_active Expired
-
1977
- 1977-12-20 CA CA293,464A patent/CA1036495A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CA1036495A (en) | 1978-08-15 |
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