Note: Descriptions are shown in the official language in which they were submitted.
` 10687:15
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 througllout this specification to the free bases.
Many physiologically active substances elicit their biological
actions by interaction with specific sites known as receptors.
Histamine is SUC]I 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 Hl-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 H2-receptors may be
defined as those histamine receptors which are not blocked by
mepyramine but are blocked by burimamide. Compounds which block
histamine ll2-receptors are referred to as histamine H2-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 useful,
for example, as inhibitors of gastric acid secretion, as anti-
inflammatory agents and as agents which act on the cardio-
vascular system, for example as inhibitors of the effects of
--2--
106871S
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 1~ and H2-antagonists is useful.
The compounds prepared by this invention are histamine H2-
antagonists. These compounds are represented by the following
formula:
N~l
Rl - S - C~
NHR2
FORMULA 1
wherein Rl represents a grouping of the structure shown in
Formula 2:
}let - CH2S(C~12)2
FORMULA 2
wherein Het is imidazole optionally substituted by (Cl 4)
alkyl, preferably methyl and R2 is hydrogen, (Cl 4) alkyl,
preferably methyl.
1~ 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. Ilydrates, pharmaceutically acceptable salts, and
hydrated pharmaceutically acceptable salts of compounds of
Formula 1 are also covered by the present invention.
687ll5
Preferably }-let 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 S-[2-(S-methyl-4-imidazolyl-
methylthio)ethyl]isothiourea.
Compounds of Formula 1 are prepared in accordance with the
invention by reacting a compound of Formula 3:
/ N~2
S = C
\ NHR2
FORMULA 3
wherein R2 is as defined for Formula 1, with a compound of
formula RlY where Rl is as defined for Formula 1 and Y is
chlorine or bromine. The compounds of formula RlY can be
prepared from the corresponding alcohols of formula R10H
by standard techniques, e.g., the chlorides can be prepared
from the corresponding alcohols by reaction with thionyl
chloride.
The alcohols of formula R101-1 can be prepared by the reaction
of mercaptoethanol with a compound of formula HetCH2Y, in
which Het has the same significance as in Formula 2 and Y
represents chlorine or bromine. Preferably this reaction is
carried out in a solvent in the presence of a base, such as
with sodium ethoxide in dry ethanol.
1~:)68715
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 of gastric acid from the
lumen-perfused stomachs of rats anaesthetized with urethane,
at doses of from 0.5 to 256 micromoles per kilogram
intravenously. This procedure is referred to in the above
mentioned paper of Ash and Schild. The activity of these
compounds as histamine H2-antagonists is also demonstrated
by their ability to inhibit other actions of histamine which,
according to the above mentioned paper of Ash and Schild,
are not mediated by histamine Hl-receptors. For example,
they inhibit the actions of histamine on the isolated guinea
pig atrium and isolated rat uterus.
The compounds prepared by the process of this invention inllibit
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 of this invention
in inhibiting the vasodilator action of histamine can also be
demonstrated. The level of activity of the compounds is
1068'7~5
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.
For therapeutic use, the pharmacologically active compounds
will normally be administered as a pharmaceutical composltion
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 thc 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 troche or lozenge. The amount of solid
carrier can be varied widely but preferably will be from about
1~:)68715
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.
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 composition in an
effective amount to block histamine ll2-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 about
150 mg to about 1500 mg. 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.
The invention is illustrated and in no way limited by the
follawing Example wllerein all temperatures are given in degrees
Centigrade:
1~68715
LXAMI'LE
S-[2-(5-Methyl-4-imidazolylmethylthio)ethyl~isothiouronium
sulphate.
a) Sodium (3.0 g) was added, with stirring under nitrogen,
to dry ethanol (75 ml). After the sodium had dissolved
mercaptoethanol (9.0 ml) was introduced and to this mixture
was added 4-methyl-5-chloromethylimidazole hydrochloride (10 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 the reaction was warmed and the
ethanol distilled off at reduced pressure. The residue was
taken up in water, acidified with concentrated hydrochloric
acid, and continuously extracted with ether to remove the
excess mercaptoethanol. The aqueous fraction was then basified
using solid sodium carbonate and continuously extracted with
ethyl acetate. To the extract was added a further volume of
ethyl acetate and the whole warmed to re-dissolve the crude
product which had deposited. After drying (MgS04) and reducing
the volume, crystallisation from this solution below 40 and
cooling to -15 afforded 2-(5-methyl-4-imidazolylmethylthio)
ethanol, m.p. 7 4- 7 6 .
(Found: C, 49.1; H~ 6.8; N, 16.2; C7H12N20 S
requires: C, 48.8; H, 7.0; N, 16.3~o).
b) 2-(5-Methyl-4-imidazolylmethylthio)ethanol (O. 34 g,
2 mmol) and thionyl chloride (0.238 g, 2 mmol) were heated
together, with stirring, at reflux temperature in chloro-
form (10 ml) for one hour, giving a grey solution and a green
oil. A second equivalent of thionyl chloride (0.238 g) was
1068715
added at reflux temperature and immediately the oil went into
solution and a solid started to crystallise. After a further
15 minutes at reflux temperature the mixture was cooled and
the solid collected (0.395 g). Recrystallisation from
acetonitrile gave l-chloro-Z-(5-methyl-4-imidazolyl-methylthio)
ethane hydrochloride, m.p. 163-165, (0.29 g).
(Pound: C, 37.1; Il, 5.2; N, 12.6; S, 14.1; Cl, 31.2;
C7HllCl N2S requires: C, 37.0; H, 5.3; N, 12.3; S, 14.1;
Cl, 31. 2%) .
c) l-Chloro-2-(5-methyl-4-imidazolylmethylthio)ethane
hydrochloride (3.9 g, 17 mmol) and thiourea (1.30 g, 17 mmol)
were heated together at reflux temperature for 48 hours in
ethanol (50 ml). After cooling the ethanol was evaporated
and the residual oil converted to the sulphate salt by
dissolution in water (220 ml) and passage down an ion-exchange
column. The water was evaporated and the residual oil
triturated with boiling methanol to give a white solid (4~33 g).
Crystallisation of this solid from aqueous methanol gave
S~ [ 2- ( 5-methyl ~4 -imidazolylmethylthio)-ethyl]isothiouronium
sulphate, ( 3~70 g) ~ m.p. 217~220.
~ound: C, 29.4; H, 5.1; N, 17.1; S~ 29.0; C8H14N4S2.H2S04
requires: C, 29.3; Il~ 4.9; N, 17.1; S~ 29.3~o).
