Note: Descriptions are shown in the official language in which they were submitted.
: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~
- 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
- 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~
R1 CH2CC N
N NH CH2CH3
" . 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~
.
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/
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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)
-- 7 --
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
-- 8 --
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.
EXAMPLE 6
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
. , .
EXAMPLE 7
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.
EXAMPLE 9
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.
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