Note: Descriptions are shown in the official language in which they were submitted.
107570Z
1 This invention relates to pharmacologically active
compounds, to methods for preparing these compounds, to
pharmaceutical compositions containing these compounds
and to methods of blocking histamine H2-receptors by
administering these compounds. The compounds of the
invention can exist as acid addition salts but, for
convenience, reference will be made throughout this
specification to the parent compounds.
Many physiologically active substances elicit ~heir
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 is
a typical e~ample, and diphenhydramine and chlorpheniramine
are other examples, are mediated through histamine Hl-
; i receptors (Ash and Schild, Brit. J. Pharmac. Chemother,
¦ 27, 427, (1966). However, other of the biological actions
20 1 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
~i are defined ~y Black et al, as histamine H2-receptors.
:- 25 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.
Elockade of histamine H2-receptors is of utility in
- inhibiting the biological actions of histamine which are
not inhibited by "antihistamines". Histamine H2-antagonists
- are t~erefore~useful, for example, as inhibitors of gastric
acid secretion, as anti-inflammatory agents and as agents
~hich act on the cardiovascular system, for example as
inhibitors of the effects of histamine on blood pressure.
,~, .
-~ - -2- - -
. ~. - - . ' " .
~r
' :.' ' . ' ' ' ' '. ': ' ' ' . , '' :. ~ - ', .
1075702
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 of this invention are histamine H2- antagonists. These
s compounds are represented by the following formula:
HOCH2 ~ CH2Z (CH2) nNH-c\
- ~ NHY
FO~MULA I
wherein n is 2 or 3; Z is sulphur or methyiene; X is sulphur
CHNO2 or N.CN; Y is hydrogen, lower alkyl or HetCH22'(CH2)n,;
Z' is sulphur or methylene; n' is 2 or 3; and Het is 5-hydroxy- -
methyl-4-imidazolyl, an imidazole ring optionally substituted
by methyl or bromo, a pyridine ring optionally substituted by
hydroxy, methoxy, chloro or bromo, a thiazole ring or an
isothiazole ring.
. .
Thus, in accordance with the prese~t pro~ess, a process i5
provided for the produc~ion of a compound of the formula:
HOCH2 ~ CH2-s-cH2-cH2-NH-c-NHy
H-N ~ N N-CN
~'
wherein Y is a lower alkyl group; or a pharmaceutically acceptable
acid addition salt thereof, which process comprises reacting an
-~ amine of the formula:
'~'''~ ' ' .
. ~ .
~ -3-
: ':
i~
.. ~ . ...... . .- .. . ~ - . . . .
. -.- :: ' . - , .
, - . - :
:. . - ,. ' .. ' ' .
.
` 107570Z
HOCH2~e~ CH2-s-cH2-cH2 NH2
H-N ~ N
with a di lower alkyl dithioiminocarbonate of the formula
QS\
C--N-CH
QS
. 10
where Q is a lower alkyl group to produce a compound of the
formula:
NCN
HOCH2 ~ C~I2SCH2CH2NH-C
H N
and the compound of formula IV produced is reacted with an
amine of formula YNH2 wherein Y is as hereinbefore defined.
, .
~-` Throughout the present specification, by the term "lower Alkyln
we mean an alkyl group containing from 1 to 4 carbon atoms.
.' . .
A useful group of compounds according to our invention are those
wherein Y is lower alkyl, e.g., methyl. Another useful group is -
that wherein Z is sulphur, and n is 2.
Z,~ i8 preferably sulphur, n' is preferably 2 and Het is preferably
5-methyl-4-imidazolyl, 5-bromo-4-imidazolyl, 3-hydroxy-2-pyridyl,
--~ 3-methoxy-2-pyridyl, 3-chloro-2-pyridyl, 3-bromo-2-pyridyl, 2-
thiazolyl or 3-isothiazolyl. Specific compounds within the scope
of the present invention incl~de:
N-methyl-N'- 2-(5-hydroxymethyl-4-imidazolyl)-
methylthio)ethyl thiourea and
~ 35
...
. '~ .
-
~;
~-~ -3a-
.'~ ~j - .
., ~ ..
- . , . , . . . ~ . . . . .. .
,'. . . - , -' . ' : :
',~. . , ', - ,: . '
~ .. . . . .
1075702
1 N-methyl-N'-cyano-N"-[2-((5-hydroxymethyl-4-
imidazolyl)methylthio)ethyl]guanidine
The compounds o~ the present invention~y.be produced
~r.om the amine of Formula II: .
HOCR2 _C~2Z (CH2)nNE~2
. HN~6~N .
.: ` 10
FOR~ULA_II -
.- ~herein n and Z have the above significance by-reactions
. such as those disclosed in our British specification
: 15 Nos. 1338169, 1397436, 1421792 and 1431589 the particular
~ reaction used depending of course on the nature of X and
-~. Y in Formula I. For example, the compounds wherein X is
-~ I sulphur and Y is lower alkyl may be produced by- reaction
I of the amine of Formula II with a lower alkyl isothiocyanate
~0 o~ Formula III:
. I - - .
.~ ~ Y'-N-C~S
~ : -. . -
. FOR~ULA III
wherein Y' is lower alkyl. A similar reaction using
benzoyl;isothiocyanate yields an N-benzoyl thiourea which,
on acid hydralysis to remove the benzoyl group yields the
. compounds of For.mula I wherein X is sulphur and Y is
hydrogen. The compounds wherein X is sulphur and Y is
~ Het ~ Z':( ~ )n,~may be prepared by first reacting the
:. ~ amine of Formula II with carbon disulphide to give a
dlthlocarbàmic.acid of ~ormu}a I~: S
~ 35 ~ ~ SR
1::
FORMULA IV
4--
.. . . . .
..... . . . ... . ~ : .. . .
~075'70Z
1 wherein Z and n have the above signlficance and R i9
hydrogen, ~hich compound is then reacted with methyl
halide to give the corresponding methyl ester (Formula
IV, R-methyl), and finally reacting this ester with an
amine of formula HetCH2Z'(C~ )n,NH2 to yield the required
compound.
The compounds wherein X is CEN02 or N.CN may be produced
by reaction of the amine of Formula II with a di(lower
alkyl) dithioimino carbonate o~ formula Va: .
,
QS
~ C ~ X'
, QS ~
FOR~ ~ A Va
wherein Q is lower alkyl and X' is CHN02 or N.CN or, when
X' is CEN02, the co,rresponding monosulphoxide compound of
', 20 ~3rmu:La Vb:
QSO
: ~ - C ~ X'
. QS
, . , FORMULA Vb
.:- X'
to give a compound Vl: ~ - -
- HOCH2 ~ .cH25tc~ )nNH SQ
HN~6~N
.-, . - '.
~ FORMULA VI
.,~
- ., ;, ~ ,
. i'ollowed by reaction o~ this latter compound with an amine
oS formula. r ~ to'give the required compound,of Formula I.
~ ~ - - . ' , . . ' .
5_
- .
~. ~
107570Z
1 Ihe amine o~ Formula II wherein Z is ~ulphur 18
conveniently prepared by reduction o~ the corresponding
carbo~yl~c acid o~ Formula VII:
S HO-CO C~2S(CH2)nNH2
~ ' '
FORM~LA VII
This reductio~ is conveniently c~rried ,out by electrolytic -
mean~ or, alternatively by chemical reduction o~ the ' -
corresponding ester ~ith lithium aluminium hydride.
.
The synthesis of the compound o~ Formula VII may suitably -.
commence irom ethyl ethoxyacetcacetate which is ~irst
converted with nitrous acid to the known compound o~
iormula VIII: -
C2H50CH2CO~ C2H5
¦ ' OH
.. FOR~nLA VIII ,
.
Reduction of this compound with stannous chloride gives
the corresponding amine which, without isolation, is reacted
, ~ith ammonium thiocyanate to give,the.imidazo~e-2-thione of
'. Formula IX: . ~
. _:
',~ . C2~50CO ~ OC2~5
:, ~ ' ' - S
' 35 - FORYDIA I~
.
~: ~ -6-
` ~ ' ' - . '
' . . . ' .
. ~
': - .
~. . -,, ~ ~ ' , '.. ' -' '
- - . , .
1075702
1 Desulphurisation oi this compound gives the imidazole
derivative o~ Formula X:
C2H50Co~_C~I20C2H5
~H
FORMULA X
.
~hen this compound is sub~ected to a series o~ reactions
which can be effected without isolation of any intermediate
and which comprise (a) hydrolysis of the ethyl ester to
~he acia (b) cleavage o-f th~e ethyl ether to the hydroxy
compound and (c) reaction o~ the resultant, 4-hydro~ymethyl-
5-carboxy compound with an aminothiol o~ the formula
HS(CH2)nNH2, the required compound of Formula VII is
produced.
Preparation of the amine o~ Formula II wherein Z is
methylene may commence from a compound of Formula XI: -
.E~N(CH2)n+
, .
FORMULA XI
~herein n has the same significance as in Formula I and
E ~ N is a suitably protected amine group e.g., phthalimido.
Reaction of the compound of Formula XI with acetylene-~n a
~ - suitable solvent and in the presence of a Le~is acid e.g.,
-~ AlC13 gives the c--ompound of Formula ~II:
- E~N(C~2)n~2c~C~-cH
. - .
FORMULA XII
.
:
which, on treatment with triphenyl phosphine gives the
compound o~ Formula XIII:
-7-
.. . .
~ .
. ~ .
, . ~-_.
, .
:''- . .
`` ` ~ i07570Z
E8N(CH2)n+2COCH'CHpph3 Cl
FORMULA XIII
When this com~ound is reacted with S-methylisothiourea
the product is the imidazole derivative of Formula XIV:
(CH2)n+2 ~ CH2PPh3 Cl-
HN yN
,', .
FOR~DLA ~IV
-
. and when this is treated with sodium methoxide (cf. the
process described in German OL5 2,649,~591,. - -
t~e.p~oduct
is the compound of Formula XV~
A` E-N(CH2)n+2 CH20CH3
~ ' ' '
~ .
25 - SC~3
.~ FORMULA XV
Desulphurisation of the compound of Formula XV with Raney
nickel to remove the 2-methylthio group and treatment with
, ~ concentrated hydrochloric acid to convert the methoxymethyl
.~ : to a hydroxymethyl group and to remove the amine protestin~g
group yields the amine of Formula Il wherein Z is methylene.
The c~mpounds of Formula I block histamine H2-reccptors, that
.
--8--
.~
.~
-' :'. " ~ ~ '
1075702
.
1 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 o~ from 0.5 to
256 micromoles per kilogram intravenously. This
- procedure is referred to in the above mentioned paper
- 10 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 of this invention inhibit the basal
secretion of gastric acid and also that stimulated by
pentagastrln or by food.
In addition, the compounds of this invention show anti-
inflammatory activity in conventional tests such as the
rat paw oedema test, wh-ere the oedema is induced by an
irritant; the rat paw volume is reduced by subcutaneous
injection of doses of a compound of Formula I. In a
conventional test, such as the measurement of ~blood
pressure in the anaesthetised cat, the action of the compounds
o~ this invention-in inhibiting the vasodilator action of
histamine can also be demonstrated. The level of activity
of the- compounds of this invention 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 àtrium.
.
- -
- _9_
.
...
107570Z
1 For therapeutic use, the pharmacologically active compounds
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 pharmaceutically
acceptable acid and in association with a pharmaceutical
csrrier therefor. Such addition salts include those with
hydrochloric, hydrobromic) hydri~dic, sulphuric and maleic
acids and may conveniently be formed from the corresponding
bases of Formula I by standard procedures, for example, by
treating the base ~ith an acid in a lower alkanol oi by the
use of ion exchange resins to form the required salt either
directly from the base or from a different;addition salt.
Pharmaceutical compositions comprising a pharmaceutical carrier
and a compound of Formula I or a pharmaceutically acceptable
acid addition salt thereof and methods of blocking histamine
H2-receptors which comprise administering a compound of
Formula I or a pharmaceutically acceptable acid addition
salt thereof are also objects of this invention. The
pharmaceutical carrier employed may be, for example, either
a solid or liquid. Exemplary of solid carriers are lactose,
terra al-ba, sucrQse, talc, g~latin, agar, pectin, acacia,
magnesium stearate, stearic acid and the like. E~emplary
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 preparation can be
tableted, placed in a hard gelatin capsule in powder or
pellet form, or in the form of a troche or loze~ge The
amount of solid carrier will ~ary widely but preferably
will be from about 25 mg to about 1 g. If a liquid
carrier is used, the preparation may be in the ~orm of a
syrup, emulsion, soft gelatin capsule, sterile injectable
liquid contained for example in an ampoule, or an aqueous
or nonaqueous liquid suspension.
--10--
:
.
107570Z
1 The pharmaceutical compositions are prepared by con-
ventional techniques involving procedures such as mixing,
granulating and compressing or dissolving the ingredient~
as appropriate to the desired preparation.
The active ingredient will be present in the composition
- 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 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 -
preferably be from about 150 mg to about lS00 mg.
.
-~ j Advantageously the composition will be made up in a dosage
I form appropriate to the desired mode of administration, for
201 example as a ~et, capsule, injectable solution or as a
I cream or ointment for topic?l application.
The invention is illustrated but in no way limited by the
following Examples in which all temperatures are in degrees
Centigrade:
EXAMPLE l
N-Methrl~ 2-((5-hydroxymethyl-4-imidazolyl)methylthio)-
- ethyl]thiourea.
,, .
- (i) Ethyl a-oximino-~-oxo-y-ethoxybutyrate (24.8 g) was
added slowly in 30 minutes to cooled (15), well stirred
~olution/suspension of stannous chloride dihydrate (58.5g)
in concentrated hydrochloric acid (97 ml) and then powdered
tin (1.2 g) was added. After 2 hours the mixture was diluted
with wa~er (300 ml), cooled to 0C and hydrogen sulphide
.. , - ~ .
-11-
... .
. ~
._
.` ~'
-: .
.
- ": ' '
107570Z
passed into the solution which waq then filtered. The
pH of the solution was adjusted to about 1.0 with sodium
hydro~ide and an aqueous solution of ammonium thiocyanate
(10.3 g) added together with further sodium hydroxide to
adjust the pH to about 2Ø AIter warming with stirring
to 95 for lS minutes the reaction mixture was cooled to
0 and, on standing, a sandy coloured precipitate was
obtained which oll recrystallisation Irom water yielded
4-ethoxycarbonyl-5-ethoxymethyl-2-mercaptoimidazole, (11.9 g),
m.p. 162.5 - 163.
(Found: C, 47.14; H, 6.04; N, 11.97; S, 13.6870 CgH14N203S
requires: C, 46.94; H, 6.13; N, 12.17; S, 13.9270).
(ii) To a stirred solution at 40 of 4-ethoxycarbonyl-5-
ethoxymethyl-2-mercaptoimidazole (11.9 g) in ethanol (700
ml) was added Raney nickel tS5 g) and the mixture heated
under reflux for 2.5 hours. After cooling, filtration and -
evaporation of the filtrate the residue was recrystallised
from water to give 4-ethoxycarbonyl-5-eth~xymethylimidazole
t6.1 g) m.p. 143-144.
tFound: C, 54.71; H, 7.05; N, 14.00% CgH14N203
requires: C, 54.53; H, 7.12; N, 14.13O
(iii) 4-Ethoxycarbonyl-5-ethoxymethylimidazole (6.0 g)
was dissolved in 48~o aqueous-hydrobromic acid t650 ml) and
refluxed together with cysteamine hydrochloride t3.4 g) for
- 17 hours. Evaporation of the reaction mixture to dryness
and recrystallisation from butano}/ether tl5:85) gave 4-
carboxy-5-~2-aminoethylthio~methylimidazole dihydrobromide
(10.9 g), m.p. 219-220.
(Found: C, 23.11: ~I, 3.64; ~, 11.58; Br, 44.417c C7~ 30;,S;~IBr
requires: C, 23.16; H, 3.61; N, 11.57; Br, 44.02aO.
- (iv) A solution o~ 4-carboxy-5-~2-aminoethylthio~methyl- -
imidazole dihydrobromide (1.0 g) inlOaO by volume sulphuric
acid t2~ ml) was electrolysed for 3 hours at constant curre~t
(1.0 amp) a~d 8-10 volts over a stirred mercury cathode
and plat~num anode separated by a porous disc.
--12--
-- , ~
.
:' ' ~ "''
~075702
Adjustment OI the pH to 9-10 with potassium carbonate
(8.3 g) and evaporation to dryness yielded a residue
which was extracted with hot isopropanol and this extract
evaporated to give 5-hydroxymethyl-4-[2-aminoethylthio~-
methylimidazole (0.4 g).
(v) An aqueous ethanolic (1:5, 6 ml) solution of the 5-
hydroxymethyl-4-[2-aminoethylthio~methylimidazole (0.4 g)
was refluxed with methyl isothiocyanate (0.2 g) for 0.5
hours. After cooling a precipitate separated on standing
and the supernatant liquid evaporated to yield an oil which
was recrystallised from acetonitrile to give, as a white
solid, N-methyl-N'-[2-((5-hydroxymethyl-4-imidazolyl)-
methylthio)ethyl]thiourea (0.1 g), m.p. 138.5 - 139.5.
(Found: C, 41.59; H, 6.37; N, 21.38% CgH16N40S2
requires: C, 41.51; H, 6.19; N, 21.52%
: . ' . ~.
Ea~AlQPLE 2
.
N-Methyl-N'-cyano-N"-[2-((5-hydroxymethyl-4-imidazolyl)-
methylthio)ethyl]guanidine.
.
To a solution of 5-hydroxymethyl-4_(2-aminoethylthio)-
methylimidazole (0.4 g) in ethanol (3 ml) was added an
ethanolic solution of dimethyl cyanodithioimidocarbonate
(0.3g) and stirred at 15 for 2 hours. Evaporation of
- the solvent yielded, as an oil, S-methyl-N-cyano-N'-~2-((5-hydroxymethyl-4-imidazolylmethylthio?ethyl]isothiourea
- to which was added excess of an ethanolic solution of
methylamine (7 g). ;~fter stirring for 70 hours, the reaction
` 30 mixture was purified by preparative thin layer chromato-
graphy to yield the title product, as an oil (0.1 g). The
structure of the product was confirmed ~y the n.m.r.
spectrum in D20 which showed the following resoIlances: -
imidazole-2-H ; Singlet at~; 8.69 integral 0.7 protons
calculated 1.0 protons
' .'. - - `
--13--
.
. . .
~07570Z
.
1 imidazole-CH2-0 ; singlet at ~4.72 integral obscured by
HDO .
imidazole-CH2-S ; singlet at ~ 3.92 integral 1.9 proton~
calculated 2.0 protons
-CH2-N ; triplet at ~ 3.34 integral 1.9 protons
calculated 2.0 protons
CH3-ND ; singlet at ~ 2.78~ integral 5.0 protons
S- ~ CH2 ; triplet at 62.71~ calculated 5.0 protons
- EXAMPLE 3
When 5-hydroxymethyl-4-(2-aminoeth~lthio)methyl imidazole
is reacted ~ith l-nitro-2,2-bis-methylthioethylene the
''- 15 product is 1-nitro-2-methylthio-2-[2-((5-hydroxymethyl-4- -'
imidazolyl)methylthio)ethylamino]ethylene.
EXA~PLE 4
.~ j' ', . . .
' ' ~hen, S-methyl-N-cyano-N'-[2-((5-hydroxymethyl-4-imi-dazolyl)-
- '¦ methylthio)ethyl]isothiourea is re~luxed in pyridine for
! 7 hours with'the following compounds:
. :
.' 5-hydroxymethyl-4-(~-aminoethylthio)methylimidazole,
'~ 25 ~.j 5-~ethylJ4-(2-aminoethyLthio)methylimidazole,
'5-brbmo-4-(2-am'inoethylthio)methylimidazole,
~- 3-hydroxy-2-(2-aminoetkylthio)methylpyridine, -
`~ ~ ' 3-methoxy-2-(2-aminoethylthio)methylpyridine,
3-chloro-2-(2-aminoethylthio)methyl~pyridine,
3-bromo-2-(2-aminoethyithio)methylpyridine, --~
-'~` - - 2-(2-aminoethylthio)methylthiazole,
.
3-(2-aminoethylthio)methylisothiazole and'
4-(4-aminobutyl)imidazole ~ '
the products are, respectively:
:
~- 35
H:~ . N-cyano-N,N'-bis-12-((~-hydroxymethyl-4-imidazolyl)- . ~:
methylthio)ethyl]guanidine,
- -14- - _
, _
. ~ '
: .
-~, - .
- - - . . . -
1~7570Z
1 N-cyano-N'-~2-((5-hydroxymethyl-4-imidazolyl)methyl-
thio)ethyl]-N"-[2-((5-methyl-4-imidazolyl)methylthio)-
ethyl]guanidine,
N-cyano-N'-[2-((5-hydroxymethyl-4-imidazolyl)methyl-
S thio)ethyl]-N"-[2-((5-bromo-4-imidazolyl)methylthio)-
ethyl~guanidine,
N-cyano-N'-[2-((5-hydroxymethyl-4-imidazolyl)methyl-
thio)ethyl]-N"-[2-((3-hydroxy-2-pyridyl)methylthio)-
ethyl]guanidine,
N-cyano-N'-~2-((5-hydroxymethyl-4-imidazolyl)methyl-
thio)ethyl]-N"-[2-((3-methoxy-2-pyridyl)methylthio)-
ethyl~guanidine,
.N-cyano-N'-~2-((S-hydroxymethyl-4-imidazolyl)methyl- . .
thio)ethyl]-N"-[2-((3-chloro-2-pyridyl)methylthio)-
ethyl~guanidine,
N-cyano-N'-[2-((5-hydroxymethyl-4-imidazolyl)methyl-
thio)ethyl]-N"-[2-((3-bromo-2-pyridyl)methylthio?ethyl]-
guanidine,
: . N-cyano-N'-[2-((5-hydroxymethyl-4-imidazolyl)methyl-
`~ 20 thio)ethyl]-N"-[2-(2-thi-azolylmethylthio)ethyl~guanidine,
N-cyano-N'-[2-((5-hydroxymethyl-4-imidazolyl)methyl-
thio)ethyl]-N"-[2-(3-isothiazolylmethylthio)ethyl]- :-
guanidine and
N-eyano-N'-[2-((5-hydroxymethyl-4-imidazolyl)methyl-
thio)ethyl]-N"-~4-(4-imidazolylbutyl)~guanidine.
EXAMPLE 5
~' .
Reaction of 5-hydroxymethyl-4-.[2-aminoethylthio)methyl-
.,
imidazole with benzoylisothiocyanate and acid hydrolysis
of the product to remove the N-benzoyl group yields N-
[2-((5-hydroxymethyl-4-imidazolyl)methylthio)ethyl]thiourea.
. EXAMPLE 6
~hen in the process of Example 1, 3-mercaptopropylamine
hydrochloride is used in place of cysteamine hydrochloride
. , - -
-15-
.~ . ' .
r_ .~
-
~`
.
1075702
1 (see Ex. 1 tiii)), the resultant product is N-methyl-
N'-[3-((5-hydroxymethyl-4-imidazolyl)methylthio)propyl]-
thiourea.
. -EXA~PLE 7
i
Reaction of 5- hydroxymethyl-4-(4-aminobutyl)imidazole
with dimethyl cyanodithioimidocarbonate and subsequently
with methyliamine according to the process of Example 2
IO yields`N-methyl-N'-cyano-N"-[4-(5-hydroxymethyl-4-imidazolyl)-
butyl]guanidine.
,
., ~ .
.
~ 2J
.
.
-
~ 25
.'
j ~ .
. ~ .
`
, , ~ . .
-~- 30 -
.
, ~, .
.
~ -}6-
,. . ..................................................................... .
. .
.' ~' ' .
~ : . . . ~ . . , :
i ~ , . .
' ~
.. . .
