CA1036495A - Imidazole diagnostic agents - Google Patents
Imidazole diagnostic agentsInfo
- Publication number
- CA1036495A CA1036495A CA293,464A CA293464A CA1036495A CA 1036495 A CA1036495 A CA 1036495A CA 293464 A CA293464 A CA 293464A CA 1036495 A CA1036495 A CA 1036495A
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- Prior art keywords
- methyl
- ethyl
- imidazole
- formula
- hydrogen
- Prior art date
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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
:1~36495 This invention relates to diagnostic agents, In part~cular lt relates to agents which may be used to test the secretory action of the 6tomach. Diagnostic agents which are already available for the above purpose and which act by stimulating the secretlon of ga6tric acid are not particularly selective in this ackion and thus often give ri6e to distres~ing side-effects ~uch ae skin flu~hin~, nausea, abdominal cramps, headache, dizzineae and hypo-tension. It i~ an object of the present invention to provide a diagnostic agent which i8 more selective in ita actionO
.
The dia go6tic agent6 of the pre6ent irvention are the compounds of the following formula: ~ 2 HN ~ N 3 .
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 i6 methyl, R2 and R3 are not both hydrogen.
The compounds of the present invention wherein R1 is ~ethyl a~d R2 and R3 are not both ethyl may be formed from 4-methyl hi~tamine.
Treatment of this substance with formaldehyde and for~ic acid in the Clarke-E~chweiler reaction leada to the corresponding compound wherein R2 and R3 are both methyl. Treatment of 4-methyl hi6tamine with N,N'-carbonyl di-imidazole either alone or in a suitable sol~ent such as dimsthylformamide leads to the formation of a cyclic urea of Formula II, wherein R1 is methyl~
.
The dia go6tic agent6 of the pre6ent irvention are the compounds of the following formula: ~ 2 HN ~ N 3 .
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 i6 methyl, R2 and R3 are not both hydrogen.
The compounds of the present invention wherein R1 is ~ethyl a~d R2 and R3 are not both ethyl may be formed from 4-methyl hi~tamine.
Treatment of this substance with formaldehyde and for~ic acid in the Clarke-E~chweiler reaction leada to the corresponding compound wherein R2 and R3 are both methyl. Treatment of 4-methyl hi6tamine with N,N'-carbonyl di-imidazole either alone or in a suitable sol~ent such as dimsthylformamide leads to the formation of a cyclic urea of Formula II, wherein R1 is methyl~
- 2 -1~36~95 R~
N N NH
O
FORMULA II
Reaction of thi6 cyclic urea with lithium aluminium hydride yield~
the compound of Formula I wherein R1 and R2 are ~ethyl and R3 i~
hydrogen. Treatment of the cyclic urea of Formula II with a base such as sodium hydride and then with an ethyl ha1lde yields the compound of Formula III wherein R1 i8 methyl r~ N-CH2CH3 FORMULA III
which may be hydrolysed, for example with hot aqueous aIkali, to give the compound of Formula I wherein R1 is methyl~ R2 i8 ethyl and R3 ifi hydrogen. The compound of Formula III may alternatively 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 i6 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 Example 5 below. The compounds wherein R1 i8 ethyl and R2 and R3 are not both ethyl are produced from this compou~d according to the methods as described above, Rl ~n the intermediAtes of formulae II and III being in this oase ethylO
N N NH
O
FORMULA II
Reaction of thi6 cyclic urea with lithium aluminium hydride yield~
the compound of Formula I wherein R1 and R2 are ~ethyl and R3 i~
hydrogen. Treatment of the cyclic urea of Formula II with a base such as sodium hydride and then with an ethyl ha1lde yields the compound of Formula III wherein R1 i8 methyl r~ N-CH2CH3 FORMULA III
which may be hydrolysed, for example with hot aqueous aIkali, to give the compound of Formula I wherein R1 is methyl~ R2 i8 ethyl and R3 ifi hydrogen. The compound of Formula III may alternatively 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 i6 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 Example 5 below. The compounds wherein R1 i8 ethyl and R2 and R3 are not both ethyl are produced from this compou~d according to the methods as described above, Rl ~n the intermediAtes of formulae II and III being in this oase ethylO
- 3 ~
~)36~95 The synthesis of the compounds of Formula I wherein R2 and R3 are both ethyl may commence from a compound of Formul~ IV wherein R1 is methyl or ethyl.
R1 ~ CH2CN
N N~
FORMULA IV
Acid or basic hydrolysis of this cyanomethylimidazole yield6 the correspondlng carboxylic acid and reaction of the acid chloride1 derived therefrom by standard methods, with diethylamine glves the compound of Formula V wherein Rl is methyl or ethyl.
CH2CH~
" . W
FORMULA V
The compound of Formula V when treated with lithium aluminium hydride yields the required compounds of Formula I wherein R1 is methyl or ethyl and R2 and R3 are both ethyl.
As stated above, the compounds of the present invention are useful diagnostic agents in that they selectively stimulate the secretio~
of gastric acid. This action is due to the fact that the compounds of the present invention are H-2 receptor agonists,the characterisation o~
which i~ explained in detail by Black et al (Nature 1972, 2~6, 385).
At the same time because of their selectivity the compou~ds pos6e6s very little H-l r~c~ptor agonist activity, the ratio o~ H-2 to H-l agonist activity relative to histamine being at lea~t 50 to 1~
.
;`
/
`
1~36495 Compounds of Formula I wherein either R2 or ~ is not hydrogen pos6ess a further advantage in that they are particularly metabolically stable in vivo.
The activity of the compounds of Formula I may be demonetrated by their stimulation of the secretion o~ ga~trie aeid from the perfused stomachs of rats anaestheti~ed with urethane. The~e compounds ~re given intravenously and show aetivity within the dose range of from 1 to 256 mieromoles per kilogram.
' According to the prefient invention we also provide pharmaeeutieal compositions which comprise a compound of Formula I together with a pharmaceutically acceptable diluent or carrier.9inc~ administratio~
o~ the eompounds ls preferably by in~ection which may be intravenous, subcutaneous or intramuscular, the pharmaceutical carrier employed is preferably a liquid. Exemplary of l~quid carriers are distilled water and physiological sal;ne. The preparation in the form of a sterile injectable liquid may suitably be contained in an ampoule.
The pharmaceutical compositions are prepared by conventional technique involving procedures sueh as mixing or dis~ ing the ingredients a~
appropria~ to the de6ired preparation.
Preferably, each dosage unit will conta~n the active lngredient in an amount of from about 25 mg to about 250 mg most preferably from about 25 mg to about lQ0 mg.
The compounds of the present invention may be administered 1~ ba~ie form or in the form of an addition salt with a pharmaceutically acceptablo acid and in association with a pharmaceutical carrier therefor. Such addition salt6 include those with hydrochlorie, hydrobromie, hydriodie~
sulphuric, phosphoric and maleic acid~.
The invention is illu6trated but in no way limited by the following examples:
~ 5 --EXA~iP~,~369r9s
~)36~95 The synthesis of the compounds of Formula I wherein R2 and R3 are both ethyl may commence from a compound of Formul~ IV wherein R1 is methyl or ethyl.
R1 ~ CH2CN
N N~
FORMULA IV
Acid or basic hydrolysis of this cyanomethylimidazole yield6 the correspondlng carboxylic acid and reaction of the acid chloride1 derived therefrom by standard methods, with diethylamine glves the compound of Formula V wherein Rl is methyl or ethyl.
CH2CH~
" . W
FORMULA V
The compound of Formula V when treated with lithium aluminium hydride yields the required compounds of Formula I wherein R1 is methyl or ethyl and R2 and R3 are both ethyl.
As stated above, the compounds of the present invention are useful diagnostic agents in that they selectively stimulate the secretio~
of gastric acid. This action is due to the fact that the compounds of the present invention are H-2 receptor agonists,the characterisation o~
which i~ explained in detail by Black et al (Nature 1972, 2~6, 385).
At the same time because of their selectivity the compou~ds pos6e6s very little H-l r~c~ptor agonist activity, the ratio o~ H-2 to H-l agonist activity relative to histamine being at lea~t 50 to 1~
.
;`
/
`
1~36495 Compounds of Formula I wherein either R2 or ~ is not hydrogen pos6ess a further advantage in that they are particularly metabolically stable in vivo.
The activity of the compounds of Formula I may be demonetrated by their stimulation of the secretion o~ ga~trie aeid from the perfused stomachs of rats anaestheti~ed with urethane. The~e compounds ~re given intravenously and show aetivity within the dose range of from 1 to 256 mieromoles per kilogram.
' According to the prefient invention we also provide pharmaeeutieal compositions which comprise a compound of Formula I together with a pharmaceutically acceptable diluent or carrier.9inc~ administratio~
o~ the eompounds ls preferably by in~ection which may be intravenous, subcutaneous or intramuscular, the pharmaceutical carrier employed is preferably a liquid. Exemplary of l~quid carriers are distilled water and physiological sal;ne. The preparation in the form of a sterile injectable liquid may suitably be contained in an ampoule.
The pharmaceutical compositions are prepared by conventional technique involving procedures sueh as mixing or dis~ ing the ingredients a~
appropria~ to the de6ired preparation.
Preferably, each dosage unit will conta~n the active lngredient in an amount of from about 25 mg to about 250 mg most preferably from about 25 mg to about lQ0 mg.
The compounds of the present invention may be administered 1~ ba~ie form or in the form of an addition salt with a pharmaceutically acceptablo acid and in association with a pharmaceutical carrier therefor. Such addition salt6 include those with hydrochlorie, hydrobromie, hydriodie~
sulphuric, phosphoric and maleic acid~.
The invention is illu6trated but in no way limited by the following examples:
~ 5 --EXA~iP~,~369r9s
4-Methyl-5(2-dimethylaminoeth~yl)imidazole dihydrochloride A 601ution 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 ~olutlon was filtered and evaporated to dryness under reduced pressure. Formaldehydo ~1.7 ml.
4G%) and then formic acld (2.3 g. 98%) were each added to the re6idue and the resulting solution heated under reflux for 24 hour~.
Evaporation of the reaction mixture furnished a residual oil wh~ch gave a crude picrate (5.77 g.) m.p. 225-229 on addition of a solution of p~cric acid in ethanol. This picrate was recrystalli6ed tw~ from ethanol~dimeth~lformamide to give 4-methyl-5-(2-dimethyl-aminoethyl)imidazole dipicrate m.p. 237-240. An analytical sample (ex dimethylformamide) had m.p. 241-242.
Thi~ dipicrate was converted to a hygro6copic dihydrochloride, m.p.
193-196, (ex ethanol~ether), by addition Or concentrated hydrochloric acid, extraction with toluene, and eYaporat~on to dryne~s.
EXAMPLE 2.
ti) A stirred mixture of 4-methyl-5-(2-aminoethyl)imidazole (8 g.) and N,N'-carbonyl di-imidazole (13 g.) was heated in a dry atmosphere to 100 for 1 hour and then at 110-130~ for a further 30 ¢inute~. After cooling, the solid cake was ground to a fine powder under ethanol and left to ~tand. Filtration and washing with ethanol9 ga~e 3-methyl-5-oxo-5,6,7,8-tetrahydroimldazo (1,5-c) pyr~midine (406 ~ m-p 232-4.
(ii) A solution of l-methyl-5-oxo-5,6,7,o-t0trahydroimidazo (1,5-c) lU3f~9~
pyrimidine (2.1 e~) in tetrahydroruran was added ~ropwise to ~ stirred suspension of lithium aluminium hydride (2 g,) in tetrahydrofuran and the solution heated under reflux for 2 hour~, After cooling, water wa~ added carefully, the mixture was ~iltered and the residue wa~ washed with tetrahydrofuran and ethanol. The filtrate was evaporated to d~yness, to give the crude basa which was acidi~ied with éthanolic hydrogen chloride to give 4-methyl-5-(2-methylaminoethyl)imidazole dihydrochloride (2.4 g.~,m.p. 275-277C (dec.).
4-Meth~1-5-(2-eth~laminoethyl)imidazole dihydrochloride (i) A solutiln of 1-methyl-5-oxo-5,6~7~8 tetrahydroimidazo (1~5-c) pyrimidine in dimethylformamide was added to a stirred 6u~pension Or sodium hydride in dimethylformamide. A~ter stirring under nitro~en at room temperature ~or 45 minutes, a eolution of ethyl bromide in dimethylformamide was then added rapidly and the mixture was 6tirred for a further 24 hours, filtered and evaporated to dryness. The residue wa6 extracted with chloro~orm, the chloroform remo~ed and the residual base was acidified with i~opropanolic hydrogen chloride to gi~e l-methyl-6-ethyl-5-oxo-5,6,7,8-tetrahydroimidazo (115-c) pyri~idine hydrochloride.
(ii) A solution o~ the above hydrochloride in aqueous 5N potass1um hydroxide was heated under reflux overnight. The reaction mixture was acidified with concentrated hydrochloric acid, ~iltered and the filtr~te was evaporated to drynes3. The residue was extracted with ethanol, tho extracts evaporated to dryness and the crude product recry~tallised to give the required dihydrochloride~
EXAMPLE 4.
4-Meth~1-5-(2-methylethylaminoethyl)imidazole Treatment of 3-methyl-6-ethyl-5-oxo-5,6,7,8-tetrahydroimidazo (1,5-c) pyrimidine derived from the ~d~ro3c~ e Or ~xarnple 3(i~ with lithium aluminium hydride by the method of Examplfl 2(ii) result~d in the production of 4-methyl-5-(2-methylethylaminoethyl)imidazole~
E~AMPLE ~
4-Eth~1-5-(2-aminoethyl)i~idazole dihydrochloride.
Hex-3-yn-1-ol (49 g.) was added 510wly to a stirred slurry o~ toluene-p-sulphonyl chloride (108 g.) in pyridine (50 ml.) at room t~mper~ture and after stirring for a further 2 hours, the mixture Was poured on to ice~ extracted with ether, dried and evapor~ted to giYe h~x-3-ynyl-toluene-p-s~lphonate (123 g.) as a crude oil~ which was u~ed without further purification.
A stirred mixture of hex-3-ynyl toluene-p-sulphona~e (63 g.) and potassium phthalimide (47 e~) was heated on a 6team bath for two hours, concentrated under reduced pressure and poured into water. The precipitated crude product was dissolved in a minimum of hot benzene and, after cooling the solution was filtered to remove unreacted phthalimide. The filtrate was eYaporated to dryness and the residue recrystallised from aqueous ethanol to give l-phthalimidohex-3-yne (33 g.) m.p. 81-83.
An analytical sample had m.p. 84-85.
A solution of hydrated magnesium sulphate (48 e. ) in water was added to a solutlon of l-phthalimidohex-3-yne (17.2 g.) in acetone. To this stirred, cooled mixture was added rapidly a sclution of potassium permanganate (21.5 g.) in water. After stirring for 6 hour6 at a temperature below 25C the solution was filtered and evaporated to give l-phthalimido-3~4-hexanedione (14.1 g.) m.p. 87-89. An analytical sample ( ex ethanol~water) had m.p. 89-91.
, Paraformaldehyde (3.7g~) was added to a ~olution of 1-phthalimido-3, 4-hexanedione ~10.2 g,) and ammoniu~ acetate (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 r~
~LWf~;4~1S
extract6 were eYaporated to drynes~ and the residue dissolved in ethanolic hydrogen chloride. Addition of ethyl acetate ~ave 4-ethyl-
and water (2 ml.) After coolin~, the ~olutlon was filtered and evaporated to dryness under reduced pressure. Formaldehydo ~1.7 ml.
4G%) and then formic acld (2.3 g. 98%) were each added to the re6idue and the resulting solution heated under reflux for 24 hour~.
Evaporation of the reaction mixture furnished a residual oil wh~ch gave a crude picrate (5.77 g.) m.p. 225-229 on addition of a solution of p~cric acid in ethanol. This picrate was recrystalli6ed tw~ from ethanol~dimeth~lformamide to give 4-methyl-5-(2-dimethyl-aminoethyl)imidazole dipicrate m.p. 237-240. An analytical sample (ex dimethylformamide) had m.p. 241-242.
Thi~ dipicrate was converted to a hygro6copic dihydrochloride, m.p.
193-196, (ex ethanol~ether), by addition Or concentrated hydrochloric acid, extraction with toluene, and eYaporat~on to dryne~s.
EXAMPLE 2.
ti) A stirred mixture of 4-methyl-5-(2-aminoethyl)imidazole (8 g.) and N,N'-carbonyl di-imidazole (13 g.) was heated in a dry atmosphere to 100 for 1 hour and then at 110-130~ for a further 30 ¢inute~. After cooling, the solid cake was ground to a fine powder under ethanol and left to ~tand. Filtration and washing with ethanol9 ga~e 3-methyl-5-oxo-5,6,7,8-tetrahydroimldazo (1,5-c) pyr~midine (406 ~ m-p 232-4.
(ii) A solution of l-methyl-5-oxo-5,6,7,o-t0trahydroimidazo (1,5-c) lU3f~9~
pyrimidine (2.1 e~) in tetrahydroruran was added ~ropwise to ~ stirred suspension of lithium aluminium hydride (2 g,) in tetrahydrofuran and the solution heated under reflux for 2 hour~, After cooling, water wa~ added carefully, the mixture was ~iltered and the residue wa~ washed with tetrahydrofuran and ethanol. The filtrate was evaporated to d~yness, to give the crude basa which was acidi~ied with éthanolic hydrogen chloride to give 4-methyl-5-(2-methylaminoethyl)imidazole dihydrochloride (2.4 g.~,m.p. 275-277C (dec.).
4-Meth~1-5-(2-eth~laminoethyl)imidazole dihydrochloride (i) A solutiln of 1-methyl-5-oxo-5,6~7~8 tetrahydroimidazo (1~5-c) pyrimidine in dimethylformamide was added to a stirred 6u~pension Or sodium hydride in dimethylformamide. A~ter stirring under nitro~en at room temperature ~or 45 minutes, a eolution of ethyl bromide in dimethylformamide was then added rapidly and the mixture was 6tirred for a further 24 hours, filtered and evaporated to dryness. The residue wa6 extracted with chloro~orm, the chloroform remo~ed and the residual base was acidified with i~opropanolic hydrogen chloride to gi~e l-methyl-6-ethyl-5-oxo-5,6,7,8-tetrahydroimidazo (115-c) pyri~idine hydrochloride.
(ii) A solution o~ the above hydrochloride in aqueous 5N potass1um hydroxide was heated under reflux overnight. The reaction mixture was acidified with concentrated hydrochloric acid, ~iltered and the filtr~te was evaporated to drynes3. The residue was extracted with ethanol, tho extracts evaporated to dryness and the crude product recry~tallised to give the required dihydrochloride~
EXAMPLE 4.
4-Meth~1-5-(2-methylethylaminoethyl)imidazole Treatment of 3-methyl-6-ethyl-5-oxo-5,6,7,8-tetrahydroimidazo (1,5-c) pyrimidine derived from the ~d~ro3c~ e Or ~xarnple 3(i~ with lithium aluminium hydride by the method of Examplfl 2(ii) result~d in the production of 4-methyl-5-(2-methylethylaminoethyl)imidazole~
E~AMPLE ~
4-Eth~1-5-(2-aminoethyl)i~idazole dihydrochloride.
Hex-3-yn-1-ol (49 g.) was added 510wly to a stirred slurry o~ toluene-p-sulphonyl chloride (108 g.) in pyridine (50 ml.) at room t~mper~ture and after stirring for a further 2 hours, the mixture Was poured on to ice~ extracted with ether, dried and evapor~ted to giYe h~x-3-ynyl-toluene-p-s~lphonate (123 g.) as a crude oil~ which was u~ed without further purification.
A stirred mixture of hex-3-ynyl toluene-p-sulphona~e (63 g.) and potassium phthalimide (47 e~) was heated on a 6team bath for two hours, concentrated under reduced pressure and poured into water. The precipitated crude product was dissolved in a minimum of hot benzene and, after cooling the solution was filtered to remove unreacted phthalimide. The filtrate was eYaporated to dryness and the residue recrystallised from aqueous ethanol to give l-phthalimidohex-3-yne (33 g.) m.p. 81-83.
An analytical sample had m.p. 84-85.
A solution of hydrated magnesium sulphate (48 e. ) in water was added to a solutlon of l-phthalimidohex-3-yne (17.2 g.) in acetone. To this stirred, cooled mixture was added rapidly a sclution of potassium permanganate (21.5 g.) in water. After stirring for 6 hour6 at a temperature below 25C the solution was filtered and evaporated to give l-phthalimido-3~4-hexanedione (14.1 g.) m.p. 87-89. An analytical sample ( ex ethanol~water) had m.p. 89-91.
, Paraformaldehyde (3.7g~) was added to a ~olution of 1-phthalimido-3, 4-hexanedione ~10.2 g,) and ammoniu~ acetate (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 r~
~LWf~;4~1S
extract6 were eYaporated to drynes~ and the residue dissolved in ethanolic hydrogen chloride. Addition of ethyl acetate ~ave 4-ethyl-
5-(2-phthalimidoethyl)imidazole hydrochloride m.p. 246-248 ~dec.) Hydroly6is of 4-ethyl-5-~2-phthalimidoekhyl)lmidAzole hydro¢hloride (1.23 g.) with ~ hydrochloric acid gave 4-ethyl-5-(2-aminoethyl) imidazole dihydrochloride (0.73 g.) m.p. 1~8.5-170.5. An analytical sample, recrystallised from ethanol /ether had m.p. 170L171.
By submitting 4-ethyl-5-(2-aminoethyl)imidazole to the reaction~
described in Example 1 to 4~ the following compound~ were produced:
4-ethyl-5-(2-dimethylaminoethyl)imidazole 4-ethyl-5-(2-aethylaminoethyl)imidazole 4-ethyl-5-(2-ethylaminoethyl)imidazole 4-ethyl-5-(2-methylethylaminoethyl)imidazole . , .
4-Methyl-5-(2-dieth~laminoethyl)imidazole dihydrochloride 4-methyl-5-cyanomethylimidazole hydrochloride was heated un~er reflux overnight with concentrated hydrochloric acid and the resultant (4-methylimidazol-5-yl) acetic acid was i~olated and treated with an exce6s of boiling thionyl chlori~e for 1.5 hours. The excess Or thionyl chloride was removed by distillation ~nd to the residusl acid chloride was carefully added, with cooling and shaXing, fre6hly distilled diethylamine. The resulting product wa6 dis601ved in aqueous ethanol9 treated with decolourising charcoal, and the produot cry6tallised. This N,N-diethyl(4-methylimidazole-5-yl)acetamide was dissolved in dry tetrahydrofuran and reduced with lithiu~ alu~inium hydride under condit$0n6 si~ r to those described in Example 2(ii) _ 9 _ 1~3~ 5 to giYe the required4-methyl-5-(2-d~ethylaminoethyl)imidazol0 dihydr~chloride.
EXA~PLE 8 ~y subjecting 4-ethyl-5-cyanomethylimidazole to the reaction~
de6cribed in Example 7~ 4-ethyl-5-(2-diethylaminoethyl)imidazole may ~, be ohtained.
By dissolving 100 m~. of 4-methyl-5-(2-methylaminoethyl)imidazole dihydrochloride in 2 ml. of sterile water or normal saline solution a pharmaceutical composition suitable for parenteral administration i8 produced.
In the same way solutions o~ the compound~ produced according to ~ny e of Exa~pl-~ 1 a~d ~ to ô m~y be prod~oed.
.; ' , ~'
By submitting 4-ethyl-5-(2-aminoethyl)imidazole to the reaction~
described in Example 1 to 4~ the following compound~ were produced:
4-ethyl-5-(2-dimethylaminoethyl)imidazole 4-ethyl-5-(2-aethylaminoethyl)imidazole 4-ethyl-5-(2-ethylaminoethyl)imidazole 4-ethyl-5-(2-methylethylaminoethyl)imidazole . , .
4-Methyl-5-(2-dieth~laminoethyl)imidazole dihydrochloride 4-methyl-5-cyanomethylimidazole hydrochloride was heated un~er reflux overnight with concentrated hydrochloric acid and the resultant (4-methylimidazol-5-yl) acetic acid was i~olated and treated with an exce6s of boiling thionyl chlori~e for 1.5 hours. The excess Or thionyl chloride was removed by distillation ~nd to the residusl acid chloride was carefully added, with cooling and shaXing, fre6hly distilled diethylamine. The resulting product wa6 dis601ved in aqueous ethanol9 treated with decolourising charcoal, and the produot cry6tallised. This N,N-diethyl(4-methylimidazole-5-yl)acetamide was dissolved in dry tetrahydrofuran and reduced with lithiu~ alu~inium hydride under condit$0n6 si~ r to those described in Example 2(ii) _ 9 _ 1~3~ 5 to giYe the required4-methyl-5-(2-d~ethylaminoethyl)imidazol0 dihydr~chloride.
EXA~PLE 8 ~y subjecting 4-ethyl-5-cyanomethylimidazole to the reaction~
de6cribed in Example 7~ 4-ethyl-5-(2-diethylaminoethyl)imidazole may ~, be ohtained.
By dissolving 100 m~. of 4-methyl-5-(2-methylaminoethyl)imidazole dihydrochloride in 2 ml. of sterile water or normal saline solution a pharmaceutical composition suitable for parenteral administration i8 produced.
In the same way solutions o~ the compound~ produced according to ~ny e of Exa~pl-~ 1 a~d ~ to ô m~y be prod~oed.
.; ' , ~'
Claims
1. A pharmaceutical composition comprising from about 25 mg to about 250 mg of 4-methyl-5-(2-methyl-aminoethyl)imidazole or a pharmaceutically acceptable acid addition salt thereof and a non-toxic diluent or carrier.
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 |
|---|---|
| CA1036495A true CA1036495A (en) | 1978-08-15 |
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 Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA185,153A Expired CA1038873A (en) | 1973-11-06 | 1973-11-06 | 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 |
|---|---|
| CA1038873A (en) | 1978-09-19 |
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