Note: Descriptions are shown in the official language in which they were submitted.
107V316
1 This invention relates to pharmacologically active
compounds, to methods for preparing these compounds, to ~
pharmaceutical compositions containing these compounds
and to methods ol' blocking histamine ~2-receptors by
admini terlng these co~pounds. The compounds oi' the
S invention can exist a~ acid addition salts and/or hydrates
but, l'or convenience, re~erence will be made throughout
this speci~ication to the parent compound-~.
~any phrslologically active substances elicit their
biological actions by interaction with speci~ic qites
known as receptors. Histamine is such a substance and
has a number o~ biological actions. Those biological
action~ oi' histamine which are inhibited by drugs commonly
called "antihistamines" oi which mepyramine is a typical
e~ample, and diphenhydramine and chlorpheniramine are
other examples are mediated through histamine Hl-receptors
(AF,h and Schild, Brit. J. Pharmac. Chemother, 27, 427,
(1966)). ~owever, other oi' the biologlcal actions oi
hi~tamlne are not inhibited by "antihistæmines" and actions
oi' thi~ type which are inhibited by a compound described
by Black et. al (Nature, 236, 385 (1972)) and called
burimamid~ are medlated through receptors ~hich are dei'ined
C ~ by Black et al. as histamine ~2-receptors. Thu-~ histamine
~2-receptors may be de~ined as those histamine receptors
~hich are not blocked by mepyramine but are blocked by
burimamide. Compounds ~hich block hlstamine H2-receptors
are re~erred to as histamine H2-antagonists.
Blockade ol' histamine ~2-receptors is oi' utility in inhibitlng
the biological actions oi histamine which are not inhibited
by "antihistaminea". Histami~e ~2-antagonists are thereiore
useiul i'or example, as inhibitors of gastric acid secretion,
as anti-ini'lam~atory agents and as agents which act on the
cardiovascular system, l'or example as inhibitors o~ the
el'l'ects oi' histamine on blood pressure. In the treatment
oi' certain conditions, l'or example inl'lammation and in
` -2- ~
. ., . . .. . . . . - .
- : :- , , -
107()316
1 inhibiting the actions o~ histamine on blood pressure,
a combination o~ histamine H1- and H2-antagonists is
useful.
The compounds of this invention are histamine H2-antagonists.
These compounds are represented by the i'ollowing Formula 1:
11
Hetl-CH2 S Bl-NH C NH-B2S CH2-Het2
FO~MULA 1
.
wherein Hetl and Het2 may each be imidazole optionally
substituted by methyl or bromo, pyridine optionally
substituted by hydroxyl, methoxy, chloro or bromo, thiazole
or isothiazole: X is sulphur, NH, NOH, NCN, or CHN02: and
Bl and B2 are lower alkylene~groups such that either Bl is
- (CH2)2 or (CH2)3 and
B2 i9 -CH2CHR-, -CHR~H2-- -1CHCH2CH2-~ or -CH2CH2¦H-
ao CH3 CH3
R is ~ethy} or ethy or ~ r~ both_se~ec~2~ ~rom
-CHaCH- and CHCH2-
CH~ CH3
It wlll be understood that the structure illustrated in Formula
1 is only one o~ several possible representations and that
other tautomeric i'orms are also covered by the present invention.
Throughout the present speci~ication by the term "lower alkyl",
we mean an alkyl group containing from 1 to 4 carbon atoms.
In one pre~erred group o~ compounds Bl is (CH2)i2 and B2 is
-CH21CH-. It is also pre~erred that Hetl and Het2 are
CH3
selected ~rom 4-imidazolyl optionally substituted by 5imethyl
or 5-bromo; 2-pyridyl optionally substituted by 3-hydroxyl,3-methoxy
...-
'
-- 1070316 - ~
1 3-bromo or 3-chloro; 2-thiazolyl and 3-isothiazolyl.
X is preferably NH, N.CN, sulphur or CHN02.
Specific compounds falling within the scope of the present
invention include:
. N-~2-((4-methyl-5-imidazolyl)methylthio)propyl]-N'-~2-((4-
methyl-5-imidazolyl-)methylthio)ethyl]guanidine a~d
N,N'-bis-[2-((4-methyl-5-imidazolyl)methylthio)prQpyl]guanidine.
The compounds of Formula 1 may be prepared ~rom the
correspond1n3 a~ines o~ Formulae IIa and IIb.
~Ietl-CH2S~Bl N~2 Het2-CH25~B2-NH2
FORMULA IIa - FOR~ULA IIb
'~
wherein Het1, Het2, Bl and B2 have the same significance
as in Formula I.
Production of the compound of Formula I wherein X is NH
results ~rom the reaction of the amine of Formula IIa or
IIb with the lsothiourea of Formula IIIb or IIIa:
2 2 B2 Nll C
_RM~LA IIIb
~ SA
Hetl-C~2S-Bl_NH_C
FORMULA IIIa
,~ .
... .. .
1070316
1 wberein Hetl, Het2, Bl and B2 have the above significance and A is lower alkyl, The is~thiourea of Formula IIIa is
formed from the corresponding amine of Formula IIa by
reaction of the latter with benzoylisothiocyanate to give
the compound of Formula IV:
S
Hetl - CH2S - Bl - NH - C
NHQ
FORMULA IV
wherein Hetl and Bl have the above significance and Q is
( benzoyl; hydrolysis of this compound to yield the
corresponding thiourea wherein Q is hydrogen; and reaction
of the latter with a lower alkyl halide such as lower alkyl
iodide. Similarly the isothiourea of Formula IIIb may be
prepared from th~ amine of Formula IIb.
Alternatively the compounds of ~ormula I wherein X is NH
may be produced by reaction of a compound o~ Formula V:
(AS)2C = X
~ FORMULA V
( 25 wherein A i~ lower alkyl and Xl is NQ, Q being benzoyl,
~irst ~ith an equimolar amount o~ one of the amines of
Formula IIa or Formula IIb and then reacting the re~ultant
product with the other amine of Formula IIb or IIa. Finally
the benzoyl group is removed by hydrolysis. In this case,
where it i8 desired to produce the compound oi' Formula I
wherein each Hetl and Bl is identical to the corresponding
Het2 and B2, the compound of-Formula V may be reacted in a
single stage reaction with two or more equivalents of the ---r
amine of Formula IIa. In a variation of this method, the
compound of Formula V may be replaced by a compound of the
i'ormula C12C~Xl wherein Xl has the above signi~icance.
- -- - ,
.-. ~- - ,., .. ~ .; .
~071 )3~6
1 The reactions described in the preceding paragraph may
also be used for the production of compounds o~ Formula
I wherein X is N.CN or CHN02. In this case Xl in Formula
V is N.CN or CHN02 and the final hydrolysis step is not of
course necessary.
The compounds o~ Formula I wherein X is sulphur are
produced by reacting the amine of Formula IIa or IIb
with a dithiocarbamic ester o~ Formula VIb or VIa.
~ SA ~ SA
Het2-l~H2s-B2-NH-c ~etl-cH2s-Bl-NH-c
S ' S
FORMULA VIb FORM~LA VIa
wherein Hetl, Het2, ~ and B2 have the above significance
and A is lower alkyl. The dithiocarbamic esters of
Formula VIa and VIb are ~ormed from the corresponding amines
of Formula IIa and IIb by reaction o~ the latter with carbon
. 20 di~ulphide and a lower alkyl halide or sulphate. When HetlB
is identical to Het2B2 the required compounds of Formula I
wherein X is sulphur can be produced directly by the reaction
of carbon disulphide with two equivalents o~ the amine of
Formula II.
The compound~ o~.Formula I wherein X is N.OH may be ~ormed
~om those wherein X is sulphur by reaçting the latter with
a lower alkyl halide to yield the corresponding isothiourea
and then reacting this isothiourea with hydroxylamine.
The amines o~ Formula II may be produced by the reaction of
a compound o~ FormulaVII.
H~t - CH2L
FORMULAVII
1070316
1 wherein Het has the same signiflcance as ~etl and Het2 in
Formula I and L is hydroxyl, halogen or methoxy, with an
aminethiol of Formula VIII.
HS-B -NH2
FORMULA VIII
wherein Bl has the same significance as Bl and B2 in
Formula I. The aminethiols of Formula XI are known
compounds.
The compounds o~ Formula I block histamine H2-receptors
that is they inhibit the biological actions o~ histamine
whieh are not inhibited by "antihistamines" such as
mepyramine but are inhibited by burimamide. For example,
the eompounds o~ this invention have been iound to
inhibit histamine-stimulated secretion o~ gastrlc acid
~r~m the lumen-per$used stomachs o~ rats anaesthetised
2 with ur~thane, at doses oi ~rom 0.5 to 256 micromoles
per kilogram intravenously. This procedure is referred
to in the above mentioned paper oi' Ash and Schild. The
activlty oi these eompounds a histamine H2-antagonists
is also demonstrated by their ability to inhibit other
aetions o~ histamlne whieh, aeeording to the above-mentioned
paper o~ Ash and Sehild, are not mediated by histamine Hl-
reeeptors. For example, they inhibit the actions o~ hi~tamine
on the isolated guinea pig atrium and isolated rat uterus.
The eompounds o~ this invention inhibit the basal seeretion
o~ gastrie aeld and also that stimulated by pentagastrin or
by iood.
In addition, the eompounds oi' this invention show anti-
in~lammatory activity in conventional tests such as the
rat paw oedema test, where the oedema is induced by an
irritant, the rat paw volume is redueed by subcutaneous
injeetion of doses o~ a eompound o~ Formula I. In a
- ; , :. , ~. .
10~70316
conventional test, such as the measurement o~ blood pressure
~ in the anaesthetised rat, the action o~ thé compounds o~ this
invention in inhibiting the vasodilator action oi' histamine
can also be demonstrated. The level oi' activity of the
compounds of this ~nvention is illustrated by the effective
dose producing ~0% 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.
For therapeutic use, the pharmacologically active compounds
, .... .. ..... . . ........ . . . .. . . . . . .
o~ the present invention will normally be administered
as a pharmaceutical compositiQn comprising as the or an
essential active ingredient at lea.st one such compound
in the basic ~orm or in the ~orm o~ an addition salt with
a pharmaceutically acceptable acid and in associated with
a pharmaceutical carrier there~or. Such addition salts
include those with hydrochloric, hydrobromic, hydriodic,
sulphuric and maleic acids and may conveniently be ~ormed
~rom the corresponding bases of Formula I by standard
procedures, ~or example by treating the base with an acid
in a lower alkanol or by the use o~ ion exchange resins to
iorm the required salt either directly i'rom the base or
~rom a dii'~erent addition salt.
Pharmaceutical compositions comprising a pharmaceutie21-
carrier and a compound o~ Formula I or a pharmaceutically
acceptable acid addition salt thereo~ and methods o~
blocking histamine H2-receptors which comprise administering
3 a compound o~ Formula I or a pharmaceutically acceptable
acid addition salt thereoi are also objects o~ this invention.
The pharmaceutical carrier employed may be, ~or example,
either a solid or liquid. Exemplary of solid carriers are
lactose, terra alba, sucrose, talc, gelatin, agar, pectin,
acacia, magnesium stearate, stearic acid and the like.
Exemplary o~ liquid carriers are syrup, peanut oil, olive
oil, water and the l~ke.
.
- 10703~6
1 A wide variety of pharmaceutical forms can be employed. Thus
i~ a solid carrier ~ 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 pre~erably will be ~rom about
25 mg to about 1 g. I~ a liquid carrier is used, the
preparation may be in-the form o~ a syrup, emulsion, soft
gelatin capsule, sterile in~ectable liquid contained i'or
~ example in an ampoule, or an aqueous or nonaqueous liquid
suspension.
The pharmaceutical compositions are 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 e~fective amount to block h~stamine H2-receptors.
The route of administration may be oral or parenteral.
Preierably, each dosage unit will contain the active *
ingredient in an amount o~ ~rom about 50 mg to about 250 mg.
The active ingredient will pre~erably be administered one
to six times per day. The daily dosage regimen will
pre~erably be i'rom about 150 mg to about 1500 mg.
Advantageously the composition will be made up in a dosage
i'orm appropriate to the desired mode oi' administration, ~or
example as a tablet, capsule, inJectable solution or as a
cream or ointment ~or topical application.
,
The invention is illustrated but in no Wdy limited by the
~ollowing examples:
: . ,... . ~ . . . .. :
`. 1070316 `
1 EgAMPLE 1
N-~2-(4-Methyl-5-imidazolylmethylthio)ethyl]-N'-~2-(4-
methyl 5-imidazolylmethylthio)propyl~guanidine trihydrochloride.
-
(i) A solution of 4-hydroxymethyl-5-methylimidazole
hydrochloride (14.8 g) and 2-mercaptopropylamine hydrochloride
(12.8 g) in aqueous hydrobromic acid (48~o~ 100 ml) was heated
under reflux for 6 hours, concentrated and recrystallised
from ethanol-ether to give 2-[4-methyl-5-imidazolylmethylthio]-
propylamine dihydrobromide (30.0 g), m.p. 177-178.
(ii) A solution of N-[2-((5-methyl-4-imidazolyl)methylthio)-
ethyl]thiourea (2.29 g) and methyl iodide (1.56 g) in methanol
(5 ml) was kept at room temperature Por 18 hours affording
S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-
thiouronium iodide (2.3 g), m.p. 128-i31. The iodide was.
converted into the corresponding sulphate by ion-exchange
' on an ion-exchange resin (IRA 401) in the sulphate ~orm.
(iii) A solution of 2-[4-methyl- ~imidazolylméthylthio]-
propylamine (4.0 g., from the dihydrobromide) and S-methyl-
N-~2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiouronium
sulphate (3.35 g) in water (25 ml) was heated under reflux
for 4 hours. Concentration, followed by purification on
ion-exchange resin C.G.50(~+), with-elution by 0.02N
hydrochloric acid, treatment with sodium hydroxide and
picrolonic acid a~forded N-~2-(4-methyl-5-imidazolylmethylthio)-
propyl]guanidine tripi$rolonate (1.75 g, m.p. 173-175, from ~;
aqueous dimethylformamide).
tFound: C, 46.9; H, 4.5; N, 21.9; S, 5.1% C16H27N7S2
3 CloH8N405 requires: C, 47.1; H, 4.4; N, 22.7; S, 5.5%).
The tripicrolonate was suspended in aqueous ethanol and
treated with io~-exchange resin IRA 400 (Cl ) and acidified
with the hydrochloric acid to form the corresponding
trihydrochloride salt.
(Found: Cl, 22.1%. Cl ~27N7S2. 3HCl requires: Cl, 21.7%)
-10-
L~
., ., ~. -
10703~6
1 EXAMPLE 2
N,N'-bis-[2-(4-Methyl-5-imidazolylmethylthio)propyl]guanidine.
trihydrochloride
(i) A solution o~ 2-[4-methyl-5-imidazolylmethylthio]-
propylamine (from the dihydrobromide, 13.0 g) in ethanol
(50 ml) was cooled to 0 and stirred during the gradual
addition of benzoylimino dichloromethane (3.78 g). A~ter
addition the reaction mixture was set aside at r~om
temperature for 2 hours and heat~d on the steam bath for
- 0.5 hours. Following addition to water and removal of
insoluble material by filtration, the filtrate was adjusted
to pH 9. The crude product obtained was purified by
chromatog aphy on a column of alumina ~ollowed by chromatographic
puriiication on a column o~ -~ilica gel (chloroform-methanol)
to give N-benzoyl-N',-N"-bis-~2-(4-methyl-5-imidazolylmethylthio)-
propyl]guanidine.
. . . ~
(ii) The benzoyl compound (3.2 g) was hydrolysed in
concentrated hydrochloric acid (40 ml) at steam bath
- temperature ior S hours. Following cooling, dilution
~ith water and extraction with ether to remove benzoic
acid, the product was puri~ied as in Example 1 and
cQ~centrated to the picrolonate (1.35 g), m.p. 230(decomp).
The picrolonate was disQolved in aqueous methanol and treated
with ion~exchange resin IRA 401 (Cl ) and acidiiied with
hydrochloric acid to give N,N'-bis-[2-(4-methyl-5-imidazolyl-
methylthio)propyl]guanidine trihydrochloride.
The NMR spectrum o~ a solution in D20 recorded at 100
mHz sho~ed the iollowing resonances:
imidazole-2H : singlet ~8.60 integral 2.0 protons
calculated 2.0 protons
imidazole-CH2- : singlet ~3.94 integral 4.4 protons
calculated 4.0 protons
--11--
., - ,-~ :. ,
.. .. . . , . ; , . -.............. . .
- , . .
- . . . . , , -
- ..
,
107V316
NH - CH2 - : doublet ~3.39 ~ integral 6.6 protons
CH2-CH-S : multiplet ~3.04 calculated 6.0 protons
imidazole-CH3: singlet ~2.37 integral 6.0 protons
(internal standard)
-CH- : doublet ~1.34
CH3
EXAMPLE 3
N-11-((4-Methyl-5-imidazolyl)methylthio)but-2-yl]-N'-
[2-((4-meth~yl-5-i~idazolyl)methylthio)ethyl]guanidine
trihydrochloride
Reaction of 4-hydroxymethyl-5-methylimidazole and l-mercapto-
2-aminobutane in the procedure o~ Example l(i) Yields 4-methyl-
5-[(2-aminobutyl)thiomethyl]imidazolyl and, when ~his is r~acted
with S-methyl-N-[2-((4-methyl-5-imidazolyl)'methylthio)ethyl]-
thiouronium ~ulphate in ~he procedure of Example l(iii), the
title compound is produced.
EXA~PLE 4
' W~n~-hydroxyme~hyl-5-methylimidazole is reacted in the
procedure oi Example 1 with the ~ollowing aminethiols:
2-mercaptobutylamine,
l-mercapto-2-aminopropane,
3-mercaptobutylamine and
l-mercapto-3-aminobutane
; 30
the ~ollowing amines are produced respectively:
2-[(4-methyl-5-imidazolyl)methylthio]butylamine,
4-methyl-5-'[(2-aminopropyl)thiomethyl]imidazole,
3-[(4-methyl-5-imidazolyl~ethylthio]butylamine and
4-methyl-5-[(3-aminobutyl)thiomethyl]imidazole,
which, on reaction with S-methyl-N-[2-((4-methyl-5-imidazolyl)-
methylthio)ethyl]thiouronium sulphate according to the
:, . - ....... . .,: . .. - ;;
:. : :; . . - - .. - - .. - . . ;. : .:.... -, . . . .
. 1070316
1 procedure of Example l(iii), yield the following compounds
respectively:
N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-[2-((4-
, methyl-5-imidazolyl)methylthio)butyl]guanidine trihydrochloride,
N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-[1-((4-
methyl-5-imidazol`yl)methylthio)prop-2-yl]guanidine trihydrochlorid~
~-[2-((4-methyl-5-imidazolyl)methylthio3ethyl]-N~-[3-((4-
methyl-5-imidazolyl)methylthio)butyl]guanidine trihydrochloride
and
N-[2-((4-methyl-5-imidazolyl)methiylthio)ethyl~NL;1-((4- , ,
methyl-5-imidazolyl)methylthio)but-S-yl]guanidine trihydrocyloride.
EXAMPLE 5
N-Cyano-N'-[2-(4-methyl-5-imidazolylmethylthio)ethyl]-N"-[2-
(4-methyl-5-imidazolylm,ethylthio)propyl~guanidine
A mixture of 2-(4-methyl-5-imidazolylmethylthio)propylamine
(3.7 g. 0.2 mole) and N-cyano-N'-[2-((4-methyl-5-imidazolyl)-
methylthio)ethyl]-S-methylisothiourea (2.69 g. 0.1 mole) was
heated at 130-140 i'or 6 hours. The coo~ed mixtura was
treated with picroliDic acid in ethanol, and the resulting
2S solid was recrystal]ised i'rom dimethylformamide/ethanol to
give the picrolonate salt oi' the titls compou~,d (3.5 g) m.p.
217-219.
The picrolonate salt was suspended in a~ueous methanol and
stirred with ion-exchange resin IRA 401 (Cl ) until the yellow
colour disappeared. The mixture wai $iltered and the filtrate
was evaporated to give the dihydrochloride of the title
compound.
-13-
. -
,,: ~ , , - , , . -
, . ~ - . . . ..
,. . ~. - , , : , . .
`` 11D70316
1 60 mHz n.m.r. in D20:-
integral
~ multiplicity assignment observed calculated
1.35 d CH3 partially ob~cured
-S-~H-CH2-
2.33 s CH3 imidazole 6.0 ref 6
2.5 - 3.75 m -SCH2C~2
m ~NC-2
m CH2SCH
3.90 s (b~ imidazole 4.18 4
CH2S
8.40 ~ (b) N~rO N 1.58
The dihydrochloride was dissolved in iscpropanol and was treated
with one equivalent oi sodium ethoxide in ethanol. The mixture was
~-20- evap~rated-t~-dryne~s-and~he-s~lid--reæidue extracted with iso-
propanol. The lsopropanol extract was evaporated to dryness to glve
, the title compound as a ~oam.
.. . . _............................. .
EXA~PLE_6
l-Nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-
~2-((4-methyl-5-imidazolyl)methylthio)propylamino]ethylene
A mixture o~ 2-1(4-methyl-5-imidazolyl)methylthio]propylamine
(0;46 g) and 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)-
methylthio)ethylamino]ethylene (0.72 g) is heated on a steam
bath ~or two hours and the cooled melt recrystallised to give
the title product.
EXAMPLE 7
3S N-~2-((4-Methyl-5-imidazolyl)methylthio)ethyll-N'-L2-((4-methyl-
5-imidazolyl)methylthio)propyl]thiourea dihydrochloride
A solution prepared ~rom S-methyl-N-[2-((4-methyl-5-imidazolyl)-
methylthio)ethyl]dithiocarbamate hydrochloride (0.69 g) and
-14-
- .. - . ... ` . . .- . - . . , - . .
' ' 1071V316
1 2-~(4-methyl-5-imidazolyl)methylthio]propylamine (0.37 g)
in ethanol containing sodium (0.05 g) was heated under
reflux for 20 hours. Concentration followed by chromatographic
purification of the product on a column of silica gel gave
the title compound.
EXAMP,LE 8
N-Hydroxy-N'-~2-~(4-methyl-5-imidazolyl)methylthio)ethyl~-
N'-[2-((4-methyl-5-inlidazolyl)methylthio)propyl]guanidine
dihydrochloride
- ~
Dry hydrogen chloride was passed into a solution o~ N-[2-
((4-methyl-5-lmidazolyl)methylthio)ethyl]-N'-[2-(t4-methyl-
5-imidazolyl)~ethylthio)propyl]thiourea (0.23 g) in methanol
(10 ml) and the mixture was refluxed for 5 hours. Concentration
yielded S-methyl-N-[2-((4-mèthyl-5-imidazolyl)methylthio)ethyl]-
N'-[2-((4-methyl-5-imidazolyl)methylthio)propyl]isothiourea
dihydrochloride. A mixtur~ o~ the isothiourea dihydrochloride,
h ydroxylamine hydrochloride, potassium hydrogen carbonate and
anhydrous dimethyl formamide was ~tirred vigorously for 4
hours at 85C, Cooling and concentration o~ the product
yielded the title compound.
EXA~PLE 9
2S
When the procedure o~ Example 1 is carried out,using in
place oi 4-hydroxymethyl 5-~ethylimidazole hydrochloride,
the hydrochlorides o~ the ~ollowing compounds:
4-hydroxymethyl-5-bromoimidazole,
4-hydroxymethylimidazole,
2-hydroxymethylpyridine,
3-hydroxy-2-hydroxymethylpyridine,
3-methoxy-2-hydroxymethylpyridine,
3-chloro-2-hydroxymethylpyridine,
3-bromo-2-hydroxymethylpyridine,
-15-
, .: , .
.,: - - , -
~, . , ~ , . - .
, . .. .. . ~ . -
`` 107V316
1 2-hydroxymethylthiazole and
3-hydroxymethylisothiazole
the trihydrochlorides of the ~ollowing products are
5 respectively produced:
N-[2-((4-bromo-5-imidazolyl)methylthio)propyl]-N'-[2-((4-
methyl-5-imidazolyl)methylthio)ethyl]guanidine,
N [2-(4-imidazolylmethylthio)propyl]-N'-[2-((4-methyl-5-
imidazolyl)methylthio)ethyl]~uanidine, .. -
N-[2-(2-pyridylmethylthio)propyl]-N'-[2-((4-methyl-5-
imidazolyl)methylthio)ethyl]guanidine,
---N-[2-((3-hydroxy-2-pyridyl)methylthio3propy.1]-N'-~2-((4-
methyl-5-imidazolyl)methylthio)ethyl]guanidine,
N-[2-((3-methoxy-2-pyridyl)methylthio)propyl]-N'-~2-((4-
methyl-5-imidazolyl)methylthio)ethyl]~uanidine,
N-[2-((3-chloro-2-pyridyl~methylthio)propyl]-N'-[2-((4-
methyl-5-imidazolyl)methylthio)ethyl]guanidine,
N-[2-((3-bromo-2-pyridyl)methyithio)propyl]-N'-[2-((4-
. 20 methyl-5-imidazolyl)methylthio)ethyl]guanidine,
N-[2-(2-thiazolylmethylthio)propy}]-N'-[2-((4-methyl-5-
lmidazolyl)methylthio)ethyl]guanidine and
N-[2-(3-isothiazolyl)methylthio)propyl]-N'-[2-((4-methyl-5-
imidazoly-l)me~hylthio~ethyl]guanlidine.
-16-
