PROCESS FOR THE PREPARATION OF BIS(HETEROARYLMETHYLTHIOETHYLGUANIDINO) ALKANES AND THE BIS(HETEROARYLMETHYLTHIOETHYLGUANIDINO) ALKANES SO FORMED

PROCEDE POUR LA PREPARATION DE BIS (HETEROARYLMETHYLTHIOETHYLGUANIDINO) ALCANES ET PRODUITS OBTENUS

English Abstract

ABSTRACT OF THE DISCLOSURE
A compound of the formula
<IMG>
wherein X3 and X4, which may be the same or different, are NY wherein Y is
hydrogen, lower alkyl, or cyano; R3 and R4 which may be the same or different,
each represent a grouping of the structure
Het-(CH2)mZ(CH2)n-
where Het is 4-imidazolyl, or a 4-imidazolyl ring substituted by lower alkyl,
or is 2-thiaszolyl; Z is sulphur; m is 1 and n is 2; W is NH, and when X3 and
X4 are both NH, W may also be sulphur; and p is an integer from 9 to 12; or
a pharmaceutically acceptable acid addition salt thereof is provided herein
by means of an addition reaction and optionally a further hydrolysis reaction.
These compounds are useful as histamine H2-antagonist, which are useful as
inhibitors of gastric acid secretion, as antiinflammatory agents, and as
agents, and as agents which act on the cardiovascular system.

Claims

The embodiments of the invention in which an exclusive prop-
erty or privilege is claimed are defined as follows:
1. A process for the production of a compound of the Formula 1
<IMG>
Formula 1
wherein X3 and X4 which may be the same or different, are NY wherein Y
is hydrogen, lower alkyl or cyano; R3 and R4, which may be the same or
different, each represents a grouping of the structure:
Het-(CH2)mZ(CH2)n-
wherein Het is 4-imidazolyl, or a 4-imidazolyl ring substituted by lower
alkyl, or is 2-thiazolyl; Z is sulphur; m is 1 and n is 2; and W is
NH, and when X3 and X4 are both NH, W may also be sulphur and p is an
integer from 9 to 12 or a pharmaceutically acceptable acid addition salt
thereof, which comprises the step of:
(a) treating a compound of the formula R3NHE, where E is hydro-
gen or <IMG> , (where A is lower alkyl, X5 is X3 or -NY' where Y' is a
guanidine protecting group selected from benzoyl, benzyloxycarbonyl and
ethoxycarbonyl) with a compound of the formula GNHR4, where G is
<IMG> when E is hydrogen, and G is <IMG> when E
is <IMG>, (where A and X5 are as defined above and X6 is X4 or NY'
where Y' is as defined above) to eliminate a mercaptan of formula ASH,
and when X5 or X6 is NY', removing the guanidine protecting group to give
the compounds where X3 or X4 is NH;
and where at least one of X3 and X4 is NCN, subjecting the com-
pound so formed to acid hydrolysis, thereby to provide a compound in which
at least one of X3 and X4 is NH.
2. A process according to claim 1 wherein a compound of Formula
24

1, wherein X3 is NH, is prepared by the acid hydrolysis of a compound of
Formula 1 wherein X3 is NCN.
3. A process according to claim 1 wherein a compound of For-
mula 1 wherein X4 is NH is prepared by the acid hydrolysis of a compound
of Formula 1 wherein X4 is NCN.
4. A process according to claim 1 wherein W is sulphur and X3
and X4 are both NH, which comprises treating a compound of the formula
Hal-(CH2)p-Hal, where Hal is chlorine, bromine or iodine, with a thio-
urea of formula R3NHCSNH2 or, when R3 is not the same as R4, successively
treating with thioureas of formulas R3NHCSNH2 and R4NHCSNH2.
5. A process according to claim 1 wherein W is NH and X3 and X4
are both =NH (where Y is hydroxy or lower alkyl), which comprises treat-
ing an isothiourea of formula
SA SA
R3NH-C=N(CH2)pN=C-NHR4
(where A is lower alkyl) with a compound of formula YNH2 where Y is
hydroxy or lower alkyl.
6. A process of claim 1 wherein R3 and R4 are the same.
7. A process according to claim 1 wherein R3 is Het-Ch2S(CH2)2-.
8. A process according to claim 1 wherein Het is a 4-imidozolyl
ring substituted by methyl.
9. A process according to claim 1 wherein X3 or X4 is NH.
10. A process according to claim 1 wherein X3 and X4 are both NH.
11. A process according to claim 1 wherein p is 9 or 10.
12. A process according to calim 1 which comprises treating
1,9-nonane with 5-methyl-N-[2-(5-methyl-4-imidazolylmethylthio)-ethyl]-
isothiouronium iodide, thereby to form 1,9-bis-[N'(]-(5-methyl-4-imidaz-
olylmethylthio)ethyl)guanidino]nonane.
13. A process according to claim 1 which comprises treating
1,10-diaminodecane with S-methyl-N-[2-(5-methyl-4-imidozolylmethylthio)-
ethyl]isothiouronium iodide, thereby to form 1,10-bis-[N'-)])5-methyl-4-
- 25 -

imidazolylmethylthio)ethyl)guanidino decane.
14. A process according to claim 1 which comprises treating
1,12-diaminododecane with S-methyl-N-[2-(5-methyl-4-imidazolylmethyl-
thio)ethyl]isothiouronium iodide, thereby to form 1,12-bis-[N'-(2(5-
methyl-4-imidazolylmethylthio)ethyl)guanidino]dodecane.
15. A process according to claim 1 which comprises treating
1,10-diaminodecane with S-methyl-N-cyano-N'-(2-thiazolylmethylthio)-
ethyl-isothiourea and refluxing the so-formed product with hydrochloric
acid, thereby to form 1,10-bis-[N'-(2-(2-thiazolymethylthio)ethyl)-
guanidino]decane.
16. A compound of the formula
<IMG>
wherein X3 and X4, which may be the same or different, are NY wherein Y
is hydrogen, lower alkyl or cyano; R3 and R4, which may be the same or
different, each represents a grouping of the structure
Het-(CH2)mZ(CH2)n-
wherein Het is 4-imidazolyl, or a 4-imidazolyl ring substituted by lower
alkyl or is 2-thiazolyl; Z is sulphur; m is 1 and n is 2; W is NH, and
when X3 and X4 are both NH, W may also be sulphur; and p is an integer
from 9 to 12; or a pharmaceutically acceptable acid addition salt thereof,
whenever prepared by the process of claim 1 or by its obvious chemical
equivalent.
17. A compound of claim 16 wherein X3 is NH,whenever prepared by
the process of claim 2 or by its obvious chemical equivalent.
18. A compound of claim 16 wherein X4 is NH, whenever prepared
by the process of claim 3 or by its obvious chemical equivalent.
19. A compound of claim 16 wherein W is sulphur and X3 and X4
are both NH, whenever prepared by the process of claim 4 or by its obvious
chemical equivalent.
- 26 -

20. A compound of claim 16 wherein W is NH and X3 and X4 are
both =NY (where Y is hydroxy or lower alkyl), whenever prepared by the
process of claim 5 or by its obvious chemical equivalent.
21. A compound of claim 16 wherein R3 and R4 are the same,
whenever prepared by the process of claim 6 or by its obvious chemical
equivalent.
22. A compound according to claim 16 wherein R3 is
Het-CH2S(CH2)2-, whenever prepared by the process of claim 7 or by its
obvious chemical equivalent.
23. A compound according to claim 16 wherein Het is a
4-imidazolyl ring substituted by methyl, whenever prepared by the pro-
cess of claim 8 or by its obvious chemical equivalent.
24. A compound according to claim 16 wherein X3 or X4 is NH,
whenever prepared by the process of claim 9 or by its obvious chemical
equivalent.
25. A compound according to claim 16 wherein X3 and X4 are
both NH, whenever prepared by the process of claim 10 or by its obvious
chemical equivalent.
26. A compound according to claim 16 wherein p is 9 or 10, when-
ever prepared by the process of claim 11 or by its obvious chemical
equivalent.
27. A compound of claim 16, 1,9-bis-[N'(2-(5-methyl-4-
imidazolylmethylthio)ethyl)guanidino]nonane, whenever prepared by the
process of claim 12 or by its obvious chemical equivalent.
28. A compound of claim 16, 1,10-bis-[N'-(2-(5-methyl-4-
imidazolylmethylthio)ethyl)guanidino]decane, whenever prepared by the
process of claim 13 or by its obvious chemical equivalent.
29. A compound of claim 16, 1,12-bis-[N'-2-(5-methyl-4-
imidazolylmethylthio)ethyl)guanidino]dodecane, whenever prepared by the
process of claim 14 or by its obvious chemical equivalent.
- 27 -

30. A compound of claim 16, 1,10-bis-[N'-(2-(2-thiazolylmethyl-
thio)ethyl-guanidino]decane, whenever prepared by the process of claim
15 or by its obvious chemical equivalent.
28

Description

~07(~3~5
This invention relates to pharmacologically active compounds, and to
processes for preparing these compounds. The compounds of aspects
of the invention can exist as acid addition salts, but, for convenience,
reference will be made throughout this specification to the present
compounds.
Many physiologically active substances elicit their
biological actions by interaction with specific sites
known as receptors. Histamine is such a substance and
has a number of biological actions. Those biological
actions of histamine which are inhibited by drugs
commonly called "antihistamines", of which mepyramine,
diphenhydramine and chlorpheniramine are typical
examples, are mediated throu~gh histamine Hl-receptors
(Ash and Schild, Brit. J. Pharmac. Chemother, _ , 427J
(1966)). However, other of the 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 H2-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 cardiovascular system,
-- 2 --

~070315
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.
In German Offenlegungschrift 2504794 is described and claimed
inter alia histamine H2-antagonists of Formula 1:
xl X2
R ~ -C-W-(CH2) -W-l-NHR
Formula 1
wherein Xl and x2 are sulphur, CHN02 or NY wherein Y is hydrogen,
hydroxy, lower alkyl, cyano or CONH2; W is NH or, when Xl and x2 are
both NH, sulphur; Rl and R2 are heterocyclicalkyl or heterocyclicalkyl-
thioalkyl groups and q:is an integer from 2 to 8.
Surprisingly, it has been found that certain related compounds
wherein q is greater than 8 are also useful as histamlne H2-antagonists,
and it is to these compounds that the present application relates in one
of its broad aspects.
Accordingly, by one aspect of this invention, compounds of
Formula 2 are provided which are histamine H2-antagonists:
X3- X4
R NH-C-W-(CH2) W-~-NHR
Formula 2
wherein X3 and X4, which may be the same or different, are NY wherein Y
is hydrogen, lower alkyl, or cyano; R3 and R4, which may be the same or
tifferent, each represents a grouping of the structure shown in Formula 3:
( 2)m (CH2)n
Formula 3
wherein Het is 4-imidazolyl, or a 4-imidazolyl substituted by lower alkyl
(preferably methyl), or is 2-thiazolyl; Z is sulphur; m is 1 and n is 2;
W is NH and when X3 and X4 are both NH, W may also be sulphur; p i5 an

1~7031S
integer fr~m 9 to 12; or pharmaceutically acceptable acid addition salts
thereof.
It will be understood that the structure illustrated in Formula
2 is only one of several representations and that other taut~meric forms
are also covered by other aspects of the present invention. It will also
be understood that because of the symmetry of the molecular structure,
the meanings of R3 and R4 and X3 and X4 may be interchanged~ Hydrates,
pharmaceutically acceptable salts, and hydrated pharmaceutically accep-
table salts of compounds of Formula 2 are also covered by other aspects
of the present invention.
Throughout the present specification and claims the term "lower
alkyl~ is intended to mean an alkyl group containing from 1 to 4 carbon
atoms and the term "lower alkoxy" is intended to mean an al~oxy group
containing from 1 to 4 carbon atoms.
In a preferred group of compounds R3 and R are the same. R3
and/or R are preferably Het-CH2S(CH2)2- and it is particularly prefer-
ably that Het is 4-imidazolyl, or is a 4-imidazolyl ring substituted by
methyl~ or is 2-thiazolyl.
Preferably X3 or X4 is NH, and most preferably X3 and X4 are
both NH. Preferably p is 9 or 10. Examples of specific compounds falling
within the scope of aspects o the present invention are:
1~9-bis-[N~-(2-(5-methyl-4-imidazolylmethylthio)ethyl-
guanidlno~nonane;
1,lO~bis-lN~-(2-(5-methyl-4-imidazolylmethylthio)ethyl-
guanidino]decane;
1,12-bis-~N~-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-
guanidino~dodecane; and
1,10-bis-~N'-(2-(2-thiazolylmethylthio)ethyl)guanidinoJ-
decane.
By another aspect of this invention, a process is provided for

- 10~70315
the production of a compound of Formula 1
X3 X4
R NH-C-W(CH2)pW-C-NHR
Formula 1
wherein X3 and X4 which may be the same or different, are NY wherein Y
is hydrogen, lower alkyl or cyano; R3 and R4, which may be the same or
different, each represents a grouping of the structure:
( 2)m ( 2)n
wherein Het is 4-imidazolyl, or a 4-imidazolyl ring substituted by lower
alkyl or is 2-thiazolyl; Z is sulphur; m is 1 and n is 2; W is NH, and
when X3 and X4 are both NH, W may also be sulphur and p is an integer
from 9 to 12 or a pharmaceutically acceptable acid addition salt thereof,
which comprises the step of: treating a compound of the formula R3NHE
where E is hydrogeD or ~ , (where A is lower alkyl, X5 is X3 or -NY'
where Y' is a guanidine protecting group, e.g. benzoyl, benzyloxycarbonyl
or ethoxycarbonyl) with a compound of the formula GNHR4j where G is
X5 X16
AS-CNH(CH2)pNHC- l~6
when E is hydrogen, and G is NH2(CH2) NHC-
X
when E is -NHlSA , ~where A and X5 are as defined above and x6 is X4 or
NY' where Y' is as defined above) to eliminate a mercaptan of formula ASH
and when X5 or x6 is NY', removing the guanidine protecting group to give
the compounds where X3 or X4 is NH; and where X3 and/or X4 are NCN, sub-
~ecting the compound to acid hydrolysis to give compounds where X3 and/or
X is NH.
By a variant thereof, the compound where X is NH is prepared by
the acid hydrolysis of a compound of Formula 1 wherein X3 is NCN.
By another variant, the compound where X4 is NH is prepared by
the acid hydrolysis of a compound of Formula wherein X4 is NCN.
b
_ 5 _

~070315
` By still another variant, the compound where W i8 sulphur and
--~ X3 and X4 are both NH, is prepared by treating a compounf of the for~ula
Hal-(CH2) -Hal, where Hal is chlorine, bromine or iodine, with a thio-
urea of formula R3NHCSNH2 or, when R3 is not the same as R4, successively
treaeing with thioureas of formulas R3NHCSNH2 and R4NHCSNH2.
By a further variant, the compound where W is NH and X3 and X4
are both =NY (where Y is hydroxy or lower alkyl) is prepared by treating
an isothiourea of formula
SA SA
3 li 11 4
R NH-C=N(CH2) N=C-NHR
(where A is lower alkyl) with a compound of formula YNH2, where Y is
hydroxy or lower alkyl.
Compounds of Formula 2 wherein W is NH, and X3 and X4 are NH,
or N (lower alkyl), may be prepared by a process outlined above.
. .
- 5a -
... . .

~7~)31S
lS:
X =
Z
V
_, .
f~ I N
= V N X
$ 1:~ ~
r_ ~
~; ~\ Gq
'~1 ' \
/ \
X=C~ / \
N Z /
~/ '
/ ¢
~ I
X--~
Z;
r-l / N ~ :
N ~ --I
~3 ~ ~ O
~ ~C ~ = O
X u~
CQX--c~ O
~l ~ .
C
C~ $z
~ ~ ~ a~
5~ U~
~ ~ ¢
V ~ X =C)
X u~
N ~1
X
C) ~
O
X= C~ Z
X ~ C ~
O V~
~ ¢
¢
~ -- 6 --
-

107~)315
1 In Scheme 1, A is lo~er a:Lkyl, ~3 a~d R4, which may be
the same or different, are as defined in Formula 2, and
X~ and X6, which may be the same or different are sulphur,
CHN02, NH, N-(lower alkyl), NCN or NY' where Y' is a
guanidine protecting group e.g. benzoyl, benzyloxy-
carbonyl or ethoxycarbonyl. In Scheme
1 preferably X5 is not NH or N-(lower alkyl) unless R
is the same as R4. Compounds of ~ormula 2 wherein X3 and
X4 are both NH and R3 is not the same as R4 may be
prepared by the acid hydrolysis of compounds of Formula 6
wherein X5 and x6 are NCN or N-benzoyl. Compounds of
Formula 2 wherein X3 and/or X4 are CONH2 may be prepared
by the hydrolysis under mild acid conditions of the
corresponding cyanoguanidine of Formula 6 wherein X and/or
x6 is NCN.
Step 1 of Route A may be carried out in the presence of,
or in the absence of, a solvent. Preferably this reaction
is carried out using an excess of the amine NH2(CH2)pNH2
as solvent. Preferably Step 2 of Route A is carried out
in the absence of a solvent or in the presence of a polar
solvent e.g. a lower alcohol or pyridine. Preferably
this reaction is carried out at an elevated temperature,
e.g. 100C. When R3 and R4 are the same and X5 and x6
are the same Step 1 and Step 2 of Route A may be carried
out simultaneously, without isolating the intermediate of
Formula 5.
Preferably both steps of Route B are carried out in a
polar solvent, e.g. a lower alcohol or pyridine, and
at an elevated temperature, e.g. 100C. When R3 is not
the same as R4 preferably one equivalent of the amine
R NH2 is used in the first step of Route B and an excess
of the amine R ~H2 is used in the second step.
Compounds of formula R NH2 may be prepared by processes
3_ described in British Patent specifications Nos. 1305547,
1338169 and 1421999 and German Offenlegungschrift 2634433.
-- 7 --
-

1~'7~31S
1` Compounds of Formula 4 wherein X5 is sulphur may be
prepared from an amine of folmula R NH2 by successive
reaction thereof with carbon disulphide and an alkylating
agent, e.g. methyl iodide.
Compounds of Formula 4 wherein X5 is CHN02, N~benzoyl or
NCN may be prepared by treating a compound of Formula 9
(AS)2C=X5
FORMULA 9
wherein X is CHN02, N-benzoyl or NCN, and A is alkyl,
with an equivalent amount of an amine of Formula R NH2.
This reaction is conveniently carried out in a solvent
e.g. ethanol. The compounds of Formula 4 wherein X
is CHN02 may alternatively be prepared by treating
l-methylsulphinyl-l-methylthio-2-nitroethylene (described
in German Offenlegungschrift 2634430) with an equivalent
amount of an amine of Formula R NH2.
The compounds of ~ormula 4 wherein X5 is NH are conveniently
prepared by alkylating a thiourea of formula R NHCSNH2.
These thioureas may be prepared by treating an amine of
formula R NH2 with benzoyl isothiocyanate, and hydrolysing
the product under alkaline conditions.
The compounds of Formula 7 may be prepared by pr~cesses analogous
to those described for the preparation of compounds of Formula 4.
The compounds of Formula 2 wherein X3 and/or X are NY and
Y is hydroxy or lower alkyl may be prepared from the
corresponding thioureas of Formula 2 wherein X3, and/or X4
are sulphur, and neither X3 nor X4 are NH by alkylating the
thiourea, e.g., by treatment with hydrogen chloride in
methanol or with methyl iodide, and then treating the
resulting isothiourea with hydroxylamine or a lower
alkylamine, respectively.
The compounds of Formula 2 wherein X3 and/or X4 are NCN may

` ` lC~70315
alternatively be prepared from the corresponding thioureas
of Formula 2 wherein X and/or X4 are sulphur, and neither
X3 nor X4 are NH, by alkylation and treatment of the product
with cyanamide and a strong base e-g- potassium t-butoxide.
The compounds of Formula 2 wherein X3 or X4 are NCN may also
be prepared from the corresponding compounds of ~ormula 2
wherein X3 or X4 are sulphur by reaction of the latter with
a heavy metal salt of cya~amide e.gO lead, mercury or
cadmium cyanamide in a solvent e.g. acetonitrile and/or
dimethylformamide.
The compounds of ~ormula 2 whereir~ W is sulphur and X3`and
X4 are both NH may be prepared by alkylating a thiourea of
formula R3NHCSNH2 wherein ~3 is as defined in Formula 2
with a dihaloalkane of formula Hal-(CH2)p-Hal, wherein Hal
represents chlorine, bromine~ or iodine. Preferably the
reaction is carried out on an acid addition salt of the
thiourea. Preferably Hal is bromine and the reaction is
carried out in a solvent e.g. ethanol. When R3 is not
the same as R4 this reaction will be carried out in two
s',ages. Preferably there will be an excess of the compound
of formula Hal-(CH2)p-Hal in the first stage of the reactlon.
The compounds of aspects of this invention of Formula 2 block histamine H2-receptors,
that is they inhibit the biological actions of histamine
which are not inhibited by "antihistamines" e.g.
mepyramine but are inhibited by burimamide. For example,
the compounds of aspects 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 kilo~ram intra-
venously. 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
, . :: ., . , -, .," ., , - -,
. : . . :: .: - . :-: . :- . -: . .

1.070315
Schild, are not mediated by histamine Hl-receptors. For
example, they inhibit the actions of histamine on the
isolated gu nea pig atrium and isolated rat uterus.
The compounds of aspects of this invention inhibit the basal secretion
of gastric acid and also that stimulated by pentagastrin
or by food.
In addition, in a conventional test, e.g. the measure-
ment of blood pressure in the anaesthetized rat, the action
of the compounds of aspects o~ this invention in inhibiting the vaso-
dilator action of histamine can~also be demonstrated. The
level of activity of the compounds of aspects of this invention is
illustrated by the effective dose producing 50% inhibition
of gastric acid secretion in the ana-esthetized rat and the
dose producing 50% inhibition of histamine-induced tachy-
cardia in the isolated guine~a pig atrium.
For therapeutic use, the pharmacologically active compounds
of aspects of the 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 basic
form or in the form of an addition salt with a pharmaceuti-
cally acceptable acid and in association with a pharmaceutical
carrier therefor. Such addition salts include those with
hydrochloric, hydrobromic, hydriodic, sulphuric and maleic
acids and may conveniently be formed from the corresponding
bases of Formula 2 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.
Pharmaceu~ical compositions comprising a pharmaceutical
carrier and a compound of Formula 2 or a pharmaceutically
acceptable acid addition salt thereof and methods of
blocking histamine H2-receptors which comprise administering
-- 10 --

~ ()315
l to an animal ~ compound of Formula 2 or a pharmaceutically
acceptable acid addition salt thereof are also provided by the
present teaching9. The pharmaceu'lcal carrier employed may
be, for example, either a solid or li~uid. Exemplary of
solid carriers are lactose, maize or potato or modified
starches, dicalcium phosphate, terra alba, sucrose,
celluloses, talc, gelatin, microfine silica, agar, pectin,
acacia, magnesium stearate, stearic acid and the like.
Exemplary of liquid carriers are syrup, peanut oil, olive
oil, alcohol, propylene glycol, polyethylene glycols, water
and the like.
A wide variety of pharmaceutical forms can be employed.
Thus, if a solid carrier is used, the preparation 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 will~ vary widely but preferably
will be from 25 mg to 1 g. If a liquid carrier
is used, the preparation may be in the form of a syrup,
emulsion, soft gelatin capsule, sterile injectable liquid
or an aqueous or nonaqueous liquid suspension. Other
additives e.g. preservatives e.g. antioxidants or
antibacterials and/or flavourilng or colouring agents may
also be included. The liquidiforms may also be prepared in
soft gelatin capsules or micracapsules. The sterile solution
may be prepared in ampoules, multidose vials or unit dose
disposable syringes. The preparation may also be in a semi-
solid form e.g. a cream, p~ste, ointment or gel or a
liquid or aerosol form for topical administration.
The pharmaceutical compositions are prepared by conventional
techniques involving proce~ures e.g. mixing, granulating
and compressing or dissolving the ingredients as appropriate
to the desired preparation.
-
3~ The active ingredient will be present in the compositions

10~0315
_ in an effective amount to block histamine H2-receptors.
The route of administration may be oral or parenteral.
Preferably, each dosage unit will contain the active
ingredient in an amount of from 50 mg to 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 1500 mg.
Advantageously the composition 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 applicatibn.
This invention in its various aspects is illustrated but in no way limited by
the following examples, wherein all temperatures are in
degrees Centigrade:-
EXAMPLE 1
1,10-bis-~N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl)-
guanidino~decane
(a) A solution of N-L2-(5-methyl-4-imidazolylmethylthio)-
ethyl~thiourea (2.29 g) and methyl iodide (1.56 g) in
methanol (5 ml) was kept at room temperature for 18
hours affording S-methyl-N- ~2-(5-methyl-4-imidazolyl-
methylthio)ethyl~ isothiouronium iodide (2.3 g) m.p.
128-131.
(b) l,10-Diaminodecane (1.72 g) was added to a solution
of S-methyl-~-[2-(5-methyl-4-imidazolylmethylthio)-
ethyl]isothiouronium iodide (7.44 g) in water (25 ml)
and the mixture was heated under reflux for 2 hours.
Following concentration the residue was converted into
the dipicrate with an aqueous solution of sodium
picrate. Recrystallisation from ethanol afforded the
title compound as the dipicrate (4.79 g) m.p. 104-105.
- 12 -
: :; , .
. , , . , ~ . . . . .. . .

170315
1 (Found: C, 43.65; H, 5.4; N~ 21.1~ S~ 6.0;
C26H48NloS2(C6H3N307)2.H20
requires: C, 43.8; H, ~.4; N, 21.5; S, 6. 2~o)
The dipicrate was dissolved in aqueous methanol and treated
with ion-exchange resin IRA 400 (Cl ) to afford the
dihydrochloride of the title compound.
EXA~IPLE 2
1,12-bis-~N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl)-
guanidinoldodecane
Substitution of 1,12-diaminododecane for l,10-diaminodecane
in the procedure of Example 1 (b) resulted in the preparation
of the dipicrate of the title compound m.p. 68-70.
(Found: C, 45.75; H, 5.6; N, 20.i5; S, 6.0
C28H52HloS2 (C6H3N307)2
requires: C, 45.7; H, 5.6, N, 21.3; S, 6.1%)
The dipicrate was dissolved in aqueous methanol and treated
with ion-exchange resin IRA 400 (Cl ) to afford the
dihydrochloride of the title compound.
EXAMPLE 3
l,9-bis-rN' - (2-(5-Methyl-4-imidazolylmethylthio)ethyl)-
guanidinol nonane
Substitution of 1,9-nonane for l,10-diaminodecane in the
procedure of Example l(b) resulted in the preparation of
the dipicrate of the title compound m.p. 90-93.
This dipicrate was dissolved in aqueous methanol and
treated with ion-exchange resin IRA 400 (Cl ) to afford
the dihydrochloride of the title compound.
- 13 -
~ . , :. ... .

1~70315
EXAMPLE 4
1,10-bis-~N'-(2-(2-thiazolylmethylthio)ethyl)-guanidino]-
decane
_ a) A mixture of S-methyl-N-cyano-N'-(2-(2-thiazolyl-
methylthio)ethyl)-isothiourea (2.72 g), l,10-diamino-
decane (0.9 g) and ethanol (5 ml) was heated on a
steam-bath for 20 hours and the mixture was chroma-
tographed on silica gel, eluting with ethyl acetate/
isopropanol (5:1). The crude product was re-
crystallised from aqueous ethanol to give l,10-bis-
N'-cyano-N"-(2-(2-thiazolylmethylthio)ethyl)-
guanidino~-decane (0.49 g) m.p. 74-75 .
Found: C, 50.15; H, 6.6; N, 22.7; S, 20.7;
C26H40N10S4
requires: C, 50.3; H, 6.5; N, 22.6; S, 20.7%
b) l,10-bis ~N'-Cyano-N"-(2-(2-thiazolylmethylthio)ethyl)-
guanidino3decane (2.0 g) was refluxed with concentrated
hydrochloric acid (25 ml) for 24 hours and the mixture
was evaporated to dryness. The residue was triturated
with ice-cold ethanol, ammonium chloride was filtered
off and the filtrate was evaporated to give the title
compound, which was converted into the dipicrate by
treatment with an excess of sodium picrate solution.
The dip-crate was recrystallised from nitromethane
and had m.p. 155-157.
Found: C, 41.55; H, 4.8; N, 19.1; S, 11.8;
C24H42N8S4- (C6H3N307)2
requires: C, 42.0; H, 4.7; N, 19.1; S, 12.5%
Thedipicrate was converted into the tetrahydrochloride
of the title compound by treatment with IRA 400 (Cl )
and acidification to pH 2 with concentrated hydro-
chloric acid.
3~
- 14 -
- . . ..

1070315
. - .
i EXAMPLE 5
1,9-bis-rN-(2-(5-Methyl-~-imidazolylmethylthio)ethyl)-
thioureido~nonane
A mixture of S-methyl-N-[2-(5-methyl-4-imidazolylmethyl-
thio)ethyl~dithiocarbamate, l,9-diaminononane and iso-
propanol is boi;ed under reflux for 24 hours and the
mixture is evaporated to dryness and the residue purified
by chromatography on silica gel to give the title product.
EXAMPLE 6
l,9-bis- ~-~2-((5-Methyl-4-imidazolyl)methylthio)ethylamino~-
2-nitrovinyl-1-amino~nonane
A solution of l-nitro-2-methylthio-2-l2-('5-methyl-4-
imidazolyl)methylthio)ethylamino~ethylene (1.15 g) and
l,9-diaminononane (0.31 ~3 in ethanol (15 ml) is heated
under reflux for 2 hours. The product is purified on an
ion-exchange resin (CG 50(H+)) and then on silica gel to
yield the title compound.
EXA~PLE 7
a) l,9-Diaminononane is treated with two moles of
dimethyl N-cyanodithiocarbamate in ,ethanol at room
temperature to give l,9-bis(N'-cyano-S-methyl-
thioureido)nonane.
b) l,9-bis-(N'-Cyano-S-methylthioureido)nonane is
treated with one equivalent of 2-(5-methyl-4-imidazolyl-
methylthio)ethylamine and the mixture is refluxed in
pyridine for 12 hours. The pyridine is removed by
evaporation and the residue is purified by chroma-
tography on silica gel to give l-(N'-cyano-S-methyl-
thioureido)-9{N'-cyano-N"-(2-(5-methyl-4-imidazolyl-
methylthio)ethyl)guanidino]nonane.
- 15 -
..

1~70315
,1 ,~
_ c) l-(N'-Cyano-S-methylthioureido)-9-[N!cyano-N"-(2-
(5-methyl-4-imidazolylmethylthio)ethyl)guanidino~-
nonane is treated with two mcles of 2-(2-thiazolyl-
methylthio)ethylamine and the mixture is refluxed in
pyridine for 12 hours. The pyridine is removed by
evaporation and the residue is purified by chroma-
tography on silica gel to give l-[N'-cyano-N"-(2-
(2-thiazolylmethylthio)ethyl)guanidino~-9-~N'-cyano-
, N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidin~ -
1~ nonane,
This guanidine is refluxed with concentrated hydro-
chloric acid for 24 hours to give 1-[N'-(2-(2-
- thiazolylmethylthio)ethyl~guanidino~ -9-[N'-(2-(5-
methyl-4-imidazolylmethylthio)ethyl)guanidin~ nonane
tetrahydrochloride.
d) Substitution o~ (a) 2-(2-imidazolylmethylthio)ethylamine
(b) 2-(4-imidazolylmethylthio)ethylamine
(c) 2-(5-bromo-4-imidazolylmethylthio)-
ethylamine
(d) 2-(5-trifluoromethyl-4-imidazolylmethyl-
thio)ethylamine
(e) 2-(5-hydroxymethyl-4-imidazolylmethyl-
thio)ethylamine
(f) 2-(2-pyridylmethylthio)ethylamine
(g) 2-(3-methyl-2-pyridylmethylthio)ethylamine
(h) 2-(3-methoxy-2-pyridylmethyIthio)ethylamine
(i) 2-(3-chloro-2-pyridylmethylthio)ethylamine
(j) 2-(3~amino-2-pyridylmethylthio)ethylamine
(k) 2-(3-hydroxy-2-pyridylmethylthio)ethylamine
(1) 2-(3-isothiazolylmethylthio)ethylamine
(m) 2-(4-bromo-3-isothiazolylmethylthio)-
ethylamine
(n) 2-(3-(1,2,5)-thiadiazolylmethylthio)-
ethylamine
- 16 -
,, . . , , ~ .

3L07~)315
(o) 2- (4-chloro-3- (1, 2, 5) -thiadiazolylmethyl-
thio)ethylamine
(p) 2-(5-amino-2-(1,3,4)-thiadiazolylmethyl-
thio)ethylamine
for 2-(2-thiazolylmethylthio)ethylamine in procedure (c)
above gives:-
(a) l-[N'-cyano-N"- ~2-(2-imidazolylmethylthio)ethyl)guanidino~-
9-[N' -cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-
guanidino~ nonane
(b) 1- lN'-cyano-N"- (2-- (4-imidazolylmethylthio)ethyl)-
guanidinoJ ~9~ LN ' -cyano-N" - (2- (5-methyl-4-imidazolylmethyl-
. thio)ethyl)guanidino~nonane
(c) l~CN'-cyano-N''- (2--(5-bromo-4-imidazolylmethylthio)ethyl)-
guanidin~9-~N ' -cyano-N" - (2- (5-methyl-4-imidazolylmethyl-
thio)ethyl)guanidino~nonane
(d) l-¦N'-cyano-N"-(2 (5-triIluoromethyl-4-imidazolyl-
methylthio)ethyl)guanidino~ -9-LN' -cyano-N"-(2-(5-methyl-
4-imidazolylmethylthio)ethyl)guanidin~ nonane
(e) l-LN'-cyano-N"-(2 ---- (5-hydroxymethyl-4-imidazolylmethyl-
thio)ethyl)guanidino~¦-9-LN'-cyano-N"-(2-(5-methyl-4-
imidazolylmethylthio)ethyl)guanidinolnonane
(f ) I- ~N' -cyano-N"- ~2--(2-pyridylmethylthio)ethyl)guanidin~
9-LN' -cyano-N"`-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-
guanidino~ nonane
(g) l-~N' -cyano-N"- (2--(3-methyl-2-pyridylmethylthio)ethyl)-
guanidino~-9-~N' -cyano-N"-(2-(5-methyl-4-imidazolylmethyl-
thio)ethyl)guanidino.~ nonane
(h) 1- LN' -cyano-N"- ~2 (3-methoxy-2-pyridylmethylthio~ethyl-
guanidino~ -9-L~' -cyano-N"-(2-(5-methyl-4-imidazolylmethyl-
3 thio)ethyl)guanidino~nonane
(i) 1- ~N' -cyano-N"- l2 (3-~ ro-2-pyridylmethylthio)ethyl)-
guanidino~l -9- ~' -cyano-N"~-(2-(5-methyl-4-imidazolylmethyl-
thio)ethyl)guanidino~ nonane
(j ) l-l;N' -cyano-N"-(2 (3-amino-2- pyridylmethylthio)ethyl)-
guanidino~-9- rN' -cyano-N"-(2-(5-methyl-4-imidazolylmethyl-
thio)ethyl)guanidino~nonane
-- 17 --
:.

107031S
i (k) l-LN'-cyano-N"-(2 (3-hydroxy-2-pyridylmethylthio)ethyl)-
guanidino~-9- LN'-cyano-N"-(2-(5-methyl-4-imidazolylmethyl-
thio)ethyl)guanidino~nonane
(1) 1-~N'-cyano-N"-(2 (3-isothiazolylmethylthio)ethyl)-
guanidino~-9-~N'-cyano-N"-(2-(5-methyl-4-imidazolylmethyl-
thio)ethyl)guanidino~nonane
(m) 1- ~N'-cyano-N"-~2 - (4-bromo-3-isothiazolylmethylthio)-
ethyl)guanidino~-9-~N'-cyano-N"-(2-(5-methyl-4-imidazolyl-
methylthio)ethyl)guanidinoJnonane
(n) 1-~N'-cyano-N"-(2 - (3-(1,2,5)-thiadiazolylmethylthio)-
ethyl)guanidino]-9- ~'-cyano-N"-(2-(5-methyl-4-imidazolyl-
methylthio)ethyl)guanidino~nonane
(o) l-~N'-cyano-N"-(2 (4-chloro-3-(1,2,5)-thiadiazolyl-
methylthio)ethyl)guanidino]-9-LN'-cyano-N"-(2-(5-methyl-
4-imidazolylmethylthio)ethyl)guanidino~nonane
(p) l-~N'-cyano-N"-~2 (5-amino-2-(1,3,4)-thiadiazolyl-
methylthio)ethyl)guanidino~-9-G~'-cyano-N"-(2-(5-methyl-
4-imidazolylmethylthio)ethyl)guanidino~nonane
and acid hydrolysis gives the corresponding N,N'-substituted
guanidine derivatives~
Treatment of the above amines with benzoyl isothiocyanate
and hydrolysis of the products gives the corresponding
thioureas, which, when substituted for N-~2-(5-methyl-4-
imidazolylmethylthio)ethy~ thiourea in the procedure of
Example 1, can be converted into bis-guanidinodecanes.
EXAMPLE 8
(i) Reaction of 2-chloro-3-nitropyridine with 2-(2~
cyanoethyl)malonic acid diethyl ester and sodium
hydride in tetrahydrofuran gives l-(3-nitro-2-
pyridyl)-l,l-bis-(carbethoxy)butyronitrile, m.p.
93 5-94.5, which after alkaline hydrolysis and
acidificatiQn gives 2-(3-cyanopropyl)-3-nltropyridine
hydrochloride 142-145.5. Reduction with hydrogen
- 18 -
.
,
.:, . .: .
: .. : : - -, ; .
.. , . . ~ . " .

1(~703~S
_ and palladium on charcoal gives 3-amino-2-(3-
cyanopropyl)pyridine, and treatment of this with
sodium nitrite and sulphuric acid and subsequent
warming gives 2-(3-cyanopropyl)-3-hydroxypyridine.
Methylation with methyl iodide and sodium ethoxide
in dimethylsulphoxide and subsequent reduction
with lithium aluminium hydride gives 4-(3-methoxy-
2-pyridyl)butylamine! Reduction o~ 3-amino-2-
(3-cyanopropyl)-3-hydroxypyridine with lithium
aluminium hydride gives 4-(3-amino-2-pyridyl~-
butylamine. Diazotisation of 4-(3-amino-2-pyridyl)
butylamine at pH 1 and treatment with cuprous
chloride or cuprous bromide gives 4-(3-chloro-2-
pyridyl)butylamine and 4-(3-bromo-2-pyridyl)-
butylamine, respectively.
(ii) Substitution of (a) 4-~4-imidazolyl)butylamine
(b) 4-(3-methoxy-2-pyridyl)-
butylamine
(c) 4-(3-chloro-2-pyridyl)-
2~ bu,tylamine
(d) 4-(3-bromo-2-pyridyl)butylamine
(e) 4-(3-amino-2-pyridyl)butylamine
for 2-(2-thiazolylmethylthio)ethylamine in the procedure
of Example 7 (c) gives:-
(a) 1-¦N'-cyano-N"-(4-(4-imidazolyl)butyl)guanidino~-
9-LN'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)-
ethyl)guanidino~nonane.
(b) 1- CN -cyano-N~-(4-(3-methoxy-2-pyridyl)bUtY1)-
guanidino~-9-¦N'-cyano-N"-(2-(5-methyl-4-imidazolyl-
methylthio)ethyl)gu~nidino~nonane,
-
(c) l-~N'-cy~no-N"-(4-(3-chloro-2-pyridyl)butyl)-
guanidino~-9-~N'-cyano-N"-(2-(5-methyl-4-imidazolyl-
methylthio)ethyl)guanidino~nonane.
(d) 1- ~N' -cyano-N"-(4-(3-bromo-2-pyridyl)butyl)-
guanidino~-9-LN'-cyano-N"-(2-(5-methyl-4-imidazolyl-
-- 19 --

107031S
methylthio)ethyl)guanidinolnonane.
(d) l-LN'-cyano-N"-(4-(3-amino-2-pyridyl)butyl)-
guanidino]-9-~N'-cyano-N"-(2-C5-methyl-4-
imidazolylmethylthio)ethyl)guanidino~nonane.
and acid hydrolysis gives the corresponding N,N'- .*
substituted guanidine derivatives.
Treatment of the above amines with benzoyl iso-
thiocyanate and hydrolysis of the products gives
the corresponding thioureas, which, when substituted
~or N-~2-(5-methyl-4 imidazolylmethylthio)ethyll-
thiourea in the procedure of Example 1, can be
converted into bis-guanldinodecanes.
EXAMPLE15
Substitution of (a) 2-(2-(4-imidazolyl)ethylthio)-
ethylamine
(b) 3-(4-imidazolylmethylthio)-
propylamine
(c) 3-(2-thiazolyl)propylamine
~or 2-(2-thiazolylmethylthio)ethylamine in the procedure
o~ Example 7(c) gives:-
(a) l-LN'-cyano-N"-(2-(2-(4-imidazolyl)ethylthio)ethyl)-
guanidino~-9-tN'-cyano-N"-(2-(5-methy1-4-imidazolyl-
methylthio)ethyl)guanidino3nonane
(b) 1-[N'-cyano-N"-(3-(4-imidazolylmethylthio)propyl)-
guanidino~ -9-[N'-cyano-N"-(2-(5-methyl-4-imidazolyl-
methylthio)ethyl)guanidino~nonane.
(c) l-[N'-cyano-N"-(3-(2-thiazolyl)propyl)guanidino~- 9
N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)-
ethyl)guanidin~ nonane
and acid hydrolysis o~ the ~ormer two Products gives
the corresponding N,N'-substituted guanidine derivatives.
- 20 -

- 10703~5
1 EXAMPLE 10
N-L2-(5-Methyl-4-imidazolylmethylthio)ethyl~thiourea
hydrobromide is refluxed with l,9-dibromononane in
ethanol to give l,9-bis-C~(N-(2-(5-methyl-4-
imidazolylmethylthio)ethyl))isothioureido] nonane
tetrahydrobromide.
EXA~PLE 11
Treatment of l,9-bis LN -cyano-N"-(2-(5-methyl-4-
imidazolylmethylthio)ethyl)guanidino~nonane with
dilute hydrochloric acid at 40 gives l,9-bis-
~N'-carbamPyl-N"-(2-(5-methyl-4-imidazolylmethylthio)-
ethyl)guanidino~nonane.
1S EXAMPLE 12
1-) Dry hydrogen chlorid~e is bubbled through a solu~i on
of l,9-bis-LN'-(2-(5-methyl-4-imidazolylmethylthio)-
ethyl)thioureido~nonane in methanol at 80 for 12
hours and the solvent is removed to gi~e l,9-bis Ls-
methyl-N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)- .
isothioureido]nonane tetrahydrochloride.
2) This product is treated with (a) hydroxylamine hydro-
chloride and potassium bicar~onate in dry dimethyl-
formamide or (b) methylamine in ethanol, to give
(a)-l,9-bis-~N'-hydroxy-N"-(2-(5-methyl-4-imidazolyl-
methylthio)ethyl)guanidinolnonane, or
(b) 1,9-bis[N'-methyl-N"-(2-(5-methyl-4-imidazolyl-
methylthio)ethyl)guanidino~nonane
EXAMPLE 13
N-Cyano-N'-L2-((5-methyl-4-imidazolylmethylthio)ethyl~-
S-methylisothiourea is added to an excess of l,9-diamino-
nonane, and the mixture was stirred at room te~erature
for 15 hours, and extracted with ether. The residue is
purified by chromatOgraphy on silica gel, eluting with
3~
. - 21 -

.- lC~7~315
1 isopropanol to glve N-cyano-N'-(9-amlnononyl)-N"-
~2-(5-methyl-4-lmldazolylmethylthio)ethyl~guanidine.
This aminoncnyl guanidine is re~luxed in isopropanol
with
(a) S-methyl-N'-~2-(5-methyl-4-lmldazolylmethylthlo)-
ethyl~-thiourea hydroiodide .`
(b) S-methyl-N'- ~2-(2-thiazolylmethylthio)ethyll- :
thiourea hydroiodide
(c) l-nitro-2-methylthio-2-L2-((5~methyl-4~imidazolyl)-
methylthio)ethylamino~ethylene
0 (d) S-methyl-N-L2-((5-methyl-4-imidazolyl)methylthio)-
ethyl~dithiocarbamate
to give
(a) l-~N'-cyano-N"-(2-(5-methyl-4-imidazolylmethyl-
thio)ethyl)guanidino~-9-LN'-~2-(5-methyl-4-
imidazolylmethylthio)ethyl~-guanidino~nonane.
(b) l-~N'-cyano-N"-(2-~5-methyl-4-imidazolylmethyl-
thio)ethyl)guanidino~- 9-LN'-~2-(2-thiazolyl-
methylthio)ethy~ guanidinolnonane
(c) l-¦N'-cyano-N"-L2-(5-methyl-4-imidazolylmethylthio)-
ethyl3guanidino]-9-~1-(2-(5-methyl-4-imidazolyl-
methylthio)ethylamino.)-2-nitrovinyl-1-amino~nonane
(d) l-~N'-cyano-N"-[2-(5-methyl-4-imidazolylmethylthio)-
ethyl~ guanidinol-9-LN'-(2-(.5-methyl-4-imidazolyl-
methylthio)ethyl)thioureido~nonane
and hydrolysis of these products gives
(a) 1,9-bis- LN (2-(5-methyl-4-imidazolylmethylthio)-
ethyl)guanidino~nonane
(b) l-~N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-
guanidino~-9-[N'-(2-(2-thiazolylmethylthio)ethyl)-
guanidino~nonane
(c) 1-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-
guanidino~-9-~1-(2-(5-methyl-4-imidazolylmethylthio)-
. ethylamino)-2-nitrovinyl-1-amino]nonane
(d) 1- LN -(2-(5-methyl-4-imidazolylmethylthio)ethyl)-
guanidino~-9-~N'-(2-(5-methyl-4-imidazolylmethylthio)-
3S ethyl)thioureidolnonane
- 22 -
;,, " ,,,. ~.,. , " " ",, . "... .. ................. ....... . . ..... ...

' 107~3~5
. - EXAMPLE 14
Ingredients Amounts
l"9-bis- CN (2-(5-methY1-4-imidaZO1Y1
methylthio)ethyl)guanidino~nonane
dihydrochloride 150 mg
Sucrose 75 mg
Starch 25 mg
Talc 5 mg
Stearic Acid 2 mg
The ingredients are screened, mixed and filled into
a hard gelatin capsule.
EXA~PLE 15
By dissolving 50 mg of l,9-bis- LN ( 2-(5-methyl-4-
imidazolylmethylthio)ethyl)guanidino~ nonane di-
hydrochloride in 2 ml Qf sterile water, normal saline
or buffered saline, a pharmaceutical composition
suitable for parenteral administration is prepared.
Similarly, the other compounds of Formula 1 may be
formulated into pharmace.utical compositions by the
procedures of Examples 14 and 15. These pharmaceutical
compositions are administered to a subject within the
dose ranges given hereabove to block histamine H2-
receptors.
- 23 -
-
.