Note: Descriptions are shown in the official language in which they were submitted.
~o75703
This invention relates to a process for preparing amidino-
sulphinic acid derivatives and to pharmaceutical compositions
containing these compounds.
Many physiologically active substances elicit their biological
actions by interaction with specific sites known as receptors.
Histamine is such a substance and it has a number of biological
actions. Those biological actions of histamine which are ~
inhibited by drugs commonly called "antihistamines" of which -
mepyramine, diphenyhydramine and chloropheniramine are examples,
are mediated through histamine Hl-receptors, and drugs with
this activity are hereinafter referred to as histamine
Hl-receptor antagonists. However, other of the biological
actions of histamine are not inhibited by histamine Hl-receptor --
antagonists and actions of this type which are inhibited by a
compound called burimamide are mediated through receptors which -
are defined as histamine H2-receptors. Thus histamine H2-receptors
are defined as those histamine receptors which are not blocked
by mepyramine but are blocked by burimamide. Compounds which --~
block histamine H2-receptors are referred to as histamine H2-
receptor antagonists.
. ~ ,
-;i Blockade of histamine H2-receptors is of utility in inhibiting
the biological actions of histamine which are not inhibited by
histamine Hl-receptor antagonists. Histamine H2-receptor
~ antagonists are therefore useful, for example, as inhibitors
,! of gastric acid secretion, as anti-inflammatory agents and as
~agents which act on the cardiovascular system, for e~ample as
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10757(~
inhibitors of the effects of histamine on blood pressure. In
the treatment of certain conditions, for example inflammation,
and in inhibiting the actions of histamine on blood pressure,
a combination of histamine Hl- and H2-receptor antagonists is
useful.
The compounds of this invention have histamine H2-receptor
antagonist activity and can be used in the treatment of
conditions wherein histamine H2-receptor antagonists are
useful.
The present invention provides a process for preparing
amidinosulphonic acid derivatives of the formula:
R CH2 S C~2 C~I2 N~ - C ~ 2
~ 3
.', . ' ' - ' .
where R is a lower alkyl group or hydrogen atom.
-
; Compounds of formula I are particularly useful as inhi~itors
of histamine stimulated gastric acid secretion.
Thr~ughout this specification by the term "lower alkyl" wemean an alkyl group containing from 1 to 4 carbon atoms.
.
The compounds of formula I can be re~resented by many
tautomeric structures, and can also be referred to as
t~iourea S,S-dioxides as sho~n by for~ulae II and TII.
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1075703
S102H l2
Z - .~'H - C = NR ~ - ~ Z - .~H - C - N~R
II III
Also certain of the heterocyclyl groups represented by Het
can exist in several tautomeric forms, and it will be understood
that all of the alternatiYe representations of these forms are
within the scope of the present invention. The compounds of
the invention can exist as acid addition salts but, for
convenience reference will be made throughout this specification
to the compounds as shown in formula I. Hydrates of compounds
of formula I and pharmaceutically acceptable hydrated salts of
compounds of formula I are also ~ithin the scope of this
invention. ~-
Compounds of formula 1 can be prepared by reacting a thiourea -
of the formula:
_ S
~ ~ CH2 S CH2 CH2 - N~ - C~
.,
i
-- ~where R ls as defined for formula I) with hydrogen peroxide.
Preferably this reaction is carried out under neutral conditions
~, at a temperature in the range -5C to +10C in a solvent such as
~3~ a lower alcohol.
~ Thioureas of formula IV are described and claimed inter alia
-- ~; in British Patent Specifications 1307539, 1338169, and 1395929
~ ~,
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iO~5703
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The compounds of formula I block histamine H2-receptors, that
is they inhibit biological actions of histamine which are not
inhibited by histamine Hl-receptor antagonists surh as mepyramine
but aTe inhibited by burimamide. For example, the compounds
produced in accordance with this invention have been found
to inhibit histamine-stimulated secretion of gastric acid from
the lumen-perfused stomachs or rats anaesthetised with urethane,
at doses of from 0.5 to 256 micromoles per kilograme intravenously.
The activity of these compounds as histamine H2-receptor
antagonists is also demonstrated by their ability to inhibit
other actions of histamine which are not mediated by histamine -
Hl-receptors. For example, they inhibit the àctions of histamine
on the isolated guinea pig atrium and isolated rat uterus.
Compounds produced in accordance with this invention have been
found to inhibit the basal secretion of gastric acid and also
that stimulated by pentagastrin or by food.
In addition, in a conventional test such as the measurement of
blood pressure in the anaesthetised cat, the actlon of the
compounds produced in accordance with this invention can inhibit
the vasodilator action of histamine when administered
intravenously at doses of from 0.5 to 256 micromoles per
Xilogram.
The level of activity of the compounds produced in accordance
wi-th this invention is illustrated by the effective dose
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producing 50~ inhibition of gastric acid secretion in the
anaesthetised rat and the dose producing 50~ inhibition of
histamine-induced tachycardia in the isolated guinea pig
atrium ~less than 10 4 Molar).
For therapeutic use, the pharmacologically active compounds
produced in accordance with this present invention will
normally be administered as a pharmaceutical composition
comprising as the or an essential active ingredient at least
one such compound in the neutral form or in the form of a
pharmaceutically acceptable addition salt with an acid and
in association with a pharmaceutical carrier therefore. Such
addition salts include those with hydrochloric, hydrobromic,
hydriodic, sulphuric and maleic acids and can conveniently
be formed from the corresponding compound of Formula I by
standard procedures, for example by treating the compound
with an acid in a lower alkanol or by use of ion exchange
resins to form the required salt either directly from the
neutral compound or from a different addition salt.
The invention also provides ph-armaceutical compositions
comprising a pharmaceutical carrier and a compound of formula
I or a pharmaceutically acceptable acid addition salt thereof.
The pharmaceutical carrier employed can be solid or liquid.
Examples of solid carriers are lactose, terra alba, sucrose,
i
-` talc, gelatin, agar, pectin, acacia, magnesium stearate,
' stearic acid and the like. Examples of liquid carriers are
. syrup, peanut oil, olive oil, water and the like.
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1075703
A wide variety of pharmaceutical forms can be employed. Thus,
if a solid carrier is used, the compositions can be tableted
in a hard gelatin capsule in powder or pellet form, or
in the form of a troche or lozenge. The amount of solid
carrier can be varied widely but preferably it is from
25 mg to 300 mg. If a liquid carrier is used, the preparation
can be in the form of a syrup, emulsion, in a soft gelatin
capsule, or as a sterile injectable liquid contained for
example in an ampoule, or as an aqueous or non-aqueous li~uid
suspension.
:
The pharmaceutical compositions can be prepared by conventional
techniques involving procedures such as mixing, granulating and
compressing or dissolving the ingredients as appropriate to the
desired preparation.
'
The active ingredient will be present in the compositions in an
~` effective amount to block histamine H2-receptors. The route of
administration can be oral or parenteral. - -
-'.'
- Preferably, each dosage unit will contain the active ingredient
in an amount of from about 50 mg to about 250 mg.
:~,
~-- The active ingredient will preferably be administered one to six
; , - . .
times per day. The daily dosage regimen will preferably be from
150 mg to l500 mg.
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Advantageously the composition will be made up in a dosa~c
form appropriate to the desired mode of administration for
example as a tablet, capsule injectable solution or as a
cream or ointment for topical application.
In our co-pending Canadian Patent application No.
Z73,246 we describe and claim processes for preparing
corresponding amidinoformic acid derivatives.
`:
This invention is illustrated by the following Examples
wherein all temperatures are in degrees Centigrade.
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EXAMPLE i
~' .
~ Z N-Methyl-N'[2-~5-methyl-4-imidazolylmethylthio)ethyl]-
.:
~ amidinosulphinic acid
s
N-Methyl-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]- -
thiourea ~2.93 g) was stirred in methanol (12 ml) with
cooling, in an ice bath. 30~ Hydrogen peroxide (2.72 g)
was added dropwise over 30 min. to give a clear solution
which was stored overnight at 0 to yield a white,
crystalline solid which was filtered off and dried to give
''~ the title product m.p. 120-121.
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1075703
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tFound: C 39.0; Il, 5.8; N, 20~0; S, 22.8; C~ 6N402S2
requires: C, 39.1; Il, 5.8; N, 20.3; S, 23.2~)
. . EXA~PLE 2
Substitution of the follo~ing thioureas
(a). N-Methyl-N'-[2-(5-ethyl-4-imidazolyl)methylthio)-
ethyl]thiourea
(b) N-Methyl-N'-[2-(S-bromo-4-imidazolyl)metllylthio)ethyl]-
thiourea
~c) N-Methyl-N'-C2-(5-trifluoromethyl-4-imidazolyl)methyl-
thio)ethyl]thiourea
(dj N-hlethyl-N'-[2-(5-hydroxymethyl-4-imidazolyl)methylthio)-
ethyl]thiourea
(e) N-Methyl-N'-[2-(2-pyridylmethylthio)ethyl]thiourea
(f) N-Methyl-N'-[2-(3-methyl-2-pyridylmethylthio)ethy-1] ~
thiourea - :
g).' N-Methyl-N'-E2-(3-hydroxy-2-pyridylmethylthio)ethyl]-
thiourea
(h) N-Methyl-N'-[2-(2-thiazolylmethylthio)ethyl]thiourea - :--
(i} N-Methyl-N'- [2-(3-isothiazolylmethylthio)ethyl]-
thiourea
(j) N-Methyl-N'- [2-(4-bromo-3-isothiazolylmethylthio)-
ethyl]thiourea
(k) N-Methyl-N'-[2-~3-isoxaazolylmethylthio)ethyl]thiourea
.
(1) N-Methyl-N'-[2-(5-amino-2-(1,3,4)thiadiazolylmethylthio)-
ethyl]thiourea
(m) N-Methyl-N'-[2-~2-imidazolyl)ethylthio)et}lyl]thiourea
(n) N-Methyl-N'[3-(2-imidazolylthio)propyl]thiourea
(o) N-Methyl-N'-a2-pyridylthio)propyl]thiourea
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~075703
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(p) N-Methyl-N'-~-(2-thiazolvlthio)propyl]thiourea
(q) N-Metllyl-N'-~3(2-oxazolylthio)pro~yl]thiourca
(r~ N-Methyl-N'-~3-(5-amino-2-(1,3,4)thiadiazolyltllio)-
. propyl]thiourea
(s) N-Methyl-N'-[2-(4-imidazolylmethyoxy)ethyl]thiourea
~t) N-Methyl-N'-[3-(4-imidazolylmethoxy)pro~yl]thiourea
for N-methyl-N'-[2-(5-methyl-4-imidazolylthio)ethyl]-
- thiourea in th2procedure of Example~leads to the production
of the corresponding amidinosulphinic acids. -
-
EXAMPLE 3
. Substitution of the following,thioureas:-
' . (a) . N-Methyl-N'-[4-(4-imidazolyl)butyl]thiourea
:,~ (bj N-Butyl-N'-~4-t4-imidazolyl)butyl]thiourea
. . (c) N-Methyl-N'-[4-(5-bromo-4-imidazolyl)butyl]thiourea
,, (d) N-Methyl-N'-[4-(5-methyl-4-imidazolyl)butyl]thiourea
(e) N-Methyl-N'-[5-(4-imidazolyl)pentyl]thiourea
tf) N-Methyl-N'-[4-~2-pyridyl)butyl]thiourea
- (g) N-Methyl-N'-~4-~2-thiazolyl)butyl]thiourea
(h) N-Methyl-N'-[4-(3-(1,2~4)triazolyl)butyl]thiourea
~, . .
for N-methyl-N'-[2-(5-methyl-4-imidazolylmethyltllio)ethvl]-
. thiourea in the procedure of Example 1 leads to the production
, of th: Forrespondin5 amidinosulphiAic acids
` 1
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` 1075703
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. EXAM~L~. 4
Substitution of the following thioureas:- -
(a) N-[2-t4-Imidazolylmethvlthio)ethyl]thiourea
(b) N-[2-(5-Methyl-4-imidazolylmethylthio)ethyl~thiourea
~c) N-[4-(4-Imidazolyl)butyl3thiourea
for N-methyl-N'-[2-(.5-methyl-4-imidazolylmethylthio)ethyl]-
thiourea ln the procedure of Example 1 leads to the production
of the corresponding amidinosulphinic acids.
- , :
. EXA~lPLE 5
Substituion of the following thioureas:-
(a) N,N'-bist2-(5-methyl-4-imidazolylmethylthio)ethyl]thiourea
(b) N-[2-(2-Pyridylmethylthio)ethyl]-N'-[2-~5-methyl-4-
imidazolylmethylthio)ethyl]thiourea
(c? N,N'-bis[4-(4-imidazolyl)butyl]thiourea . : -
~ '-
for N-methyl-N'-[2-(5-methyl-4-imidazolylmethylthio~ethy~ - ~
thiourea in the procedure of Example 1 leads to the production .-
of the corresponding amidinosulphinic acids.
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