Note: Descriptions are shown in the official language in which they were submitted.
1068713
This invention relates to a process for preparing pharmacologically
active compounds which block histamine H2-receptors. The
compounds prepared by the invention can exist as acid addition
salts but, for convenience, reference will be made throughout
this specification to the free bases.
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 is a typical example, and diphenhydramine and
chlorpheniramine are other examples, are mediated through
histamine ~Il-receptors (Ash and Schild, Brit. .J. Pharmac.
Chemother, 27, 427, (1966). However, other biological actions
of histamine are not inhibited by "antihistamines" and actions
of this type which are inhibited by a compound described by
Black et al. (Nature, 236, 385 (1972)) and called burimamide
are mediated through receptors which are defined by Black et al.
as histamine H2-receptors. Thus histamine H~-receptors may
be defined as those histamillc receptors which are not blocked
by mepyramine but are blocked by burimamide. Compounds which
block histamine H2-receptors are referred to as histamine ll2-
antagonists.
Blockade of histamine H2-receptors is of utility in inhibiting
the biological actions of histamine which are not inhibited
by "antihistamines". Histamine H2-antagonists are therefore
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~0687~3
useful, for example, as inhibitors of gastric acid secretion,
as anti-inflammatory agents and as agents which act on the
cardiovascular system, for example as 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- antagonists is useful.
The compounds prepared by this invention are histamine H2-
antagonists. These compounds are represented by the following
formula:
~S
Rl - S - C~
NHR2
FORMULA 1
wherein Rl represents a grouping of the structure shown
in Formula 2:
llet - CH2S(CH2)2-
FORMULA 2
wherein ~let is imidazole optionally substituted by (Cl 4)
alkyl; and R2 is (Cl_4) alkyl. The (Cl_4) alkyl groups are
preferably methyl.
It will be understood that the structure illustrated in ~ormula
1 is only one of several possible representations and that
other tautomeric forms are also covered by the present invention.
-
~0687:13
Hydrates, pharmaceutically acceptable salts, and hydrated
pharmaceutically acceptable salts of compounds of Formula 1 are
also covered by the present invention.
Preferably Het is a 4-imidazolyl ring optionally substituted
by ~Cl 4) alkyl. Particularly preferably Het is a 5-methyl-4-
imidazolyl ring.
An example of a specific compound which can be prepared by
the present invention is 2-t5-methyl-a-imidazolylmethyl-
thio)ethyl N-methyldithiocarbamate.
Compounds of Formula 1 are prepared in accordance Wit]l the
invention by reacting a mercaptan of formula RlSH with an
isothiocyanate of formula R2NCS, Rl and R2 being as defined
for Formula 1. Preferably this reaction is carried out in a
solvent such as pyridine.
The mercaptans of formula RlSH can be prepared by reacting
ethanedithiol with a compound of formula Het C112 Y where
Het is as defined for formula I and Y is chlorine or bromine.
This reaction is preferably effected in a solvent in the
presence of a base, such as with sodium ethoxide in dry ethanol.
The compounds of Formula 1 block histamine H2-receptors, that
is they inhibit the biological actions of histamine which are
not inhibited by "antihistamines" such as mepyramine but are
inhibited by burimamide. For example, the compounds of this
invention have been found to inhibit histamine-stimulated secretion
~3687~3
of gastric acid from the lumen-perfused stomachs of rats
anaesthetized with urethane, at doses of from 0.5 to 256
micromoles per kiIogram intravenously. This procedure is
referred to in the above mentioned paper of Ash and Schild.
The activity o~ these compounds as histamine 112-antagonists
is also demonstrated by their ability to inhibit other actions
of histamine WiliCIl, according to the above mentioned paper of
Ash and Schilcl, are not mediated by histamine ~Il-receptors.
For example, they inhibit the actions of histamine on the
isolated guinea pig atrium and isolated rat uterus.
The compounds prepared by this invention inhibit the basal
secretion of gastric acid and also that stimulated by pentagastrin
or by food.
In addition, the compounds prepared by this invention show anti-
inflammatory activity in conventional tests such as the rat paw
oedema test, where the oedema is induced by an irritant, the
rat paw volume is reduced by subcutaneous injection of doses of
a compound of Formula 1. In a conventional test, such as the
measurement of blood pressure in the anaesthetised cat, the
action of the compounds prepared by this invention in inhibiting
the vasodilator action of histamine can also be demonstrated.
The level of activity of the compounds is illustrated by the
effective dose producing 50~ inhibition of gastric acid secretion
in the anaesthetized rat and the dose producing 50~ inhibition
of histamine-induced tachycardia in the isolated guinea pig atrium.
1~6B713
For therapeutic use, the pharmacologically active compounds
will normally be administered as a pharmaceutical composition
comprising as the or an essential active ingredient at least
one such compound in basic form or in the form of a pharmaceutically
acceptable acid addition salt and associated with a pharmaceutical
carrier therefor. Such addition salts include those with
hydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids
and they can conveniently be formed from the corresponding bases
of Formula 1 by standard procedures, for example by treating the
base with an acid in a lower alkanol or by the use of ion exchange
resins to form the required salt, either directly from the base or
from a different addition salt.
The pharmaceutical carrier employed can be solid or liquid.
Examples of solid carriers are lactose, terra alba, sucrose,
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.
A wide variety of pharmaceutical forms can be employed. Thus,
if a solid carrier is used, the compositions can be tableted,
placed in a hard gelatin capsule in powder or pellet form, or
in the form of a trochc or lozenge. The amount of solid carrier
can be varied widely but preferably will be from about 25 mg
to about 1 g. If a liquid carrier is used, the compositions
can be in the form of a syrup, emulsion, soft gelatin capsule,
sterile injectable liquid contained for example in an ampoule,
or an aqueous or non-aqueous liquid suspension.
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16~68'713
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 l~ill be present in the composition in an
effective amount to block histamine H2-receptors. The route of
administration can be oral or parenteral.
Advantageously the compositions will be made up in a dosage 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.
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 about 150 mg to about 1500 mg.
The invention is illustrated and in no way limited by the
following Example wherein all temperatures are given in
degrees Centigrade:
EXAMPLE
2-(5-Methy_ -imidazolylmet_lthio)ethyl N-methyl-dithiocarbamate_
hydrochloride.
1~368713
a) Sodium (5.2 g) was added, with stirring under nitrogen,
to dry ethanol (150 ml). After the sodium had dissolved
ethanedithiol (40 ml) was introduced and to this mixture
was added 4-methyl-5-chloromethylimidazole hydrochloride
(15 g), as a solid, over a period of 1.5 hours at room
temperature. The mixture was then stirred for a further
1 hour at room temperature. After this time a saturated
solution of hydrogen chloride in ethanol was added until
the mixture was acidic. The temperature was then raised
and the ethanol distilled off under nitrogen. The residue
was taken up in water and continuously extracted with ether
to remove the excess ethanedithiol. The a~ueous fraction
was then evaporated to dryness and the residue extracted with
hot isopropanol. Reducing the volume of the extract and
cooling afforded 2-~5-methyl-4-imidazolyl-methylthio)ethanethiol
hydrochloride as a white solid which was not purified further.
b) A solution of sodium carbonate was added to a solution
of 2-(5-methyl-4-imidazolylmethylthio) ethanethiol hydrochloride
(2.5 g) in water (50 ml) to pl-19 and the mixture extracted with
ethyl acetate. After drying (MgS04), the extract was evaporated
to dryness and the residue taken up in pyridine (25 ml). To
this solution was added methylisothiocyanate (1.1 g) and the
mixture stirred at room temperature for 1 hour. After this
time the mixture was evaporated to dryness, the residue taken
up in ethanol and a saturated solution of hydrogen chloride in
ethanol added until the mixture was acidic. Addition of ether
to this solution afforded a white solid which after repeated
1068713
recrystallisation :Erom ethanol/ether gave 2-(5-methyl-4-
imidazolylmethylthio)ethyl N-methyldithiocarbamate hydrochloride,
m.p. 171-172.
(Found: C, 36.5; H, 5.3; N, 14.1; S, 31.9; Cl, 12.2;
C9H,5N3S3.HCl requires: C, 36.3; H, 5.4; N, 14.1; S, 32.3;
Cl, 11.9~).
