Note: Descriptions are shown in the official language in which they were submitted.
; ~ ~
This application relates to certain N-cyano-
; N'-~2-[(4-methyl-5-imidazolyl)methylthio]ethyl~ -
; N"-alkynylguanidines which axe H2 receptor blocking
agents, which inhibit gastric acid secretion and which
` ~ are useful in the treatment of ulcers.
, :
' ~ The clinical objective in treatment of peptic
ulcer disease is to decrease gastric acid secretion,
based on the principle "no acid, no ulcer." Traditional
peptic ulcer disease therapy involves control of diet
and the use of antacids and anticholinergics.
There is evidence indicating that histamine may be
the final common pathway for stimulation of gastric
secretion. This effect of histamine is mediated via H2
receptors and is not inhibited by the classical antihist-
amines, which are Hl receptor blockers. A number of
~pecific H2 receptor blocking agents (H2 receptor anta-
gonists~ are now known. These compounds inhibit basal
acid secretion, as well as secretion by other known gastric
acid stimulants, and are useful in the treatment of peptic
ulcer~.
'
~3~306
Th2~ ~nyent~on relates to hista~ine H2 receptcr
antagon~sts ~h~ch ~re ef~ecti~e inhlbitors of ~astric
secretion in ani~als, including man, which are useful
in the treatment of peptic ulcer disease, and which
have the ~ormula
CH3
~CN
H CH2scH2cH2NHcNH-R
wherein Rl is a straight or branched chain alkynyl group
containing from 3 to 9 carbon atoms, inclusive, and non-
toxic pharmaceutically acceptable acid addition salts
thereof.
A preferred embodiment of the invention is a compound
o~ the formula
CH3
N /
N ~ IlCN
H CH2SCH2CH2NHCNH-~HC--CR
H3
wherein R4 is hydrogen or methyl, or a nontoxic pharmaceut-
ically acceptable acid addition salt thereof.
Another preferred em~odiment of the invention is a
compound of the formula
~L~ 3~)306
CH3
~ CH2SCH2CH2NHCNH - (CH2)nC9 CR
wherein R4 is hydrogen or methyl and n is an integer
of from 1 to 6, inclusive, or a nontoxic pharmaceutically
acceptable acid addition salt thereof.
Another preferred embodiment of the invention is a
compound of the formula
N ~CH3
N ~ ~CN f 3
H CH2SCH2CH2NH NH - f-C -CR
CH3
.
wherein ~4 is hydrogen or methyl, or a nontoxic pharmaceut-
ically acceptable acid addition salt thereof.
A more preferred embodiment of the invention is N-
~; 20 cyano~ {2- r(4-methyl-5-imidazolyl)methylthio] ethyl} -
N"-(2-butyn-1-yl)guanidine or a nontoxic pharmaceutically
acceptable acid addition salt thereof.
Another more preferred embodiment of the invention is
N-Cyano-N'-{2-~(4-methyl-5-imidazolyl~methylthio]ethyl}-
; N"-t3-butyn-1-yl~guanidine or a nontoxic pharmaceutically
acceptable ~alt thereof.
~ 4 -
~13(~306
~nother more p~e~erxed e,mbodiment o~ the invention
is N~c~ano~N~-12-[(4~methy1~5~i~idazol~1),methylthio]-
ethyl}-N"-(4-pentyn-1-yl)guanidine or a nontoxic pharm-
aceutically acceptable acid addition salt thereof.
Another more preferred embodiment of the invention
is N-cyano-N'-~2- [(4-methyl-5-imidazolyl)methylthio]- -
ethyl}-N"-(2-methyl-3-butyn-2-yl)guanidine or a nontoxic
pharmaceutically acceptable acid addition salt thereof.
~10 Another more preferred embodiment of the invention
is N-cyano-N'-{2- [t4-methyl-5-imidazolyl)methylthio]ethyl}-
N"-(3-butyn-2-yl)guanidine or a nontoxic pharmaceutically
acceptable acid addition salt thereof.
The most preferred embodiment of the invention is N-
cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-
N"-propargyl guanidine or a nontoxic phaxmaceutically
acceptable acid addition salt thereof.
The present invention also provides for the prepara-
tion of a compound of the formula
CH3
N ~ ~
N / ~ ~CN
H CH2SCH2CH2
wherein Rl is a straight or branched chain alkynyl group
containing from 3 to 9 caxbon atoms, inclusive, or a non-
toxic pharmaceutically acceptable acid addition salt thereof
characterized by reacting a compound of the formula
~3030~
CH3
N , ~
~1 1 II
- N ~ \
H 2 2 2 5
or an acid addition salt thereof with a compound of the
formula
R6NHRl III
wherein R is as defined above and R5 and R6 are non-identical
and are either H or the group
NCN
-C-SR
where R is any substituent such that -SR is a ~uitable leaving
group, and, if desired, converting the resulting compound of
formula I in basic form or an acid addition salt thereof to the
corresponding non-toxic pharmaceutically acceptable acid
addition salt or free base form.
The reaction is conducted in a non-reactive solvent at
a temperature above room temperature. In a preferred embodi-
ment equimolar quantities of the compounds of formulae II and
III are used.
These processes are illustrated by the reaction schemes
I and II below for a preferred compound of the invention.
Scheme I
~H3
N
N ~I\ CH25CH2CH2NNC-SR + H2NCH2C= CH
1:1303~G
~H3
N ~
[l ~,
N ~CN
H CH2scH2cH2NHcNHcH2c = CH
The reaction is conducted in a non-reactive solvent
at a temperature above room temperature. As will be
appreciated by those skilled in the art, R may be any
substituent such that -SR will be a suitable leaving
group. Thus, R may be (lower) alkyl, aryl, substituted
aryl (e.g. p-nitrophenyl), aralkyl, -CH2CN, -CH2COOH,
-CH2COORI, or the like. The N-cyano-N~ [(4-methyl-
5-imidazoly)methylthio~ethyl~-S-R isothiourea starting
materials may be prepared by the procedures described in
Belgian Patent 804,144. The alkynylamine starting
materials are either commercially available or may be
prepared by methods described in Bull. Soc. Chim. Fr.,
490 (195B), Bull.Soc. Chim. Fr., 592 (1967) and Annales
de Chimie (Paris), 3~ 656 (1958).
: ~
113~1306
Scheme II
CH3
N ~ ~CN
H CH2scH2cH2NH2 + S N 2
N ~
N \ ~CN
CH2NHcNHCH2c Z CH
The reaction is conducted in a non-reactive solvent
at a temperature above room temperature. The substituent
R may be as indicated in Scheme I, aboYe. The 2- r(4-
methyl-5-imidazolyl)methylthio]ethylamine starting material
may be prepared as described in U. S. Patent 3,950,353. The
disubstituted cyanodithioiminocarbonate which is used as a
starting material for thP preparation of the N-cyano-N'-
propargyl-SR isothiourea (see step b of Example 2) may itself
be prepared by procedures described in J. Org. Chem., 32,
1566 (1967)
~.
~13~306
.
It has additionally been di~covered that in the prep-
aratlon o~ N~cyano-N~-{2- [(4-methyl~5-imidozolyl)methylthio]
ethyl`}-N"-propargylguanidine via Reaction Scheme I, selected
reaction conditions in the last step thereof give greatly
impro~ed yields of product as well as a product containing
less impurities. The latter condition has the added advantage
of permitting the initial ("crude") product to be isolated as
a crystalline solid which may be more highly purified by simple
recrystallization, and avoids the chromatographic purifica-
tion of the initial crude product which we previously
considered desirable when using other reaction conditions.
The selected reaction conditions referred to above
consist of using methanol as solvent, utilizing a more
concentrated solution in the reaction (approximately 1 gram
of the substituted isothiourea per 5 ml of methanol), the
use of a nitrogen sweep of the reaction apparatus during
the reaction, and the utilization of freshly distilled
propargylamine in the reaction.
Experiments have shown that the use of a nitrogen
sweep during the reaction avoids the formation of small
amounts of two as yet unidentified by-products which are
formed in the absence of a nitrogen sweep. These by-products,
when present, resisted removal by column chromatography and
recrystallization. It is believed that the nitrogen sweep
prevents the formation of these by-products by removing the
methyl mercaptan gas as quickly as it is formed.
: ~
3L~L3V3~6
The pre~ent inventlon also pxovides the process for
the production of a compound having the structure
N 3
~CN
H CH2scH2cE~2NH NH_R
; wherein Rl is a straight or branched chain alkynyl group
containing from 3 to 9 carbon atoms, inclusive, or a non-
toxic pharmaceutically acceptable acid addition salt thereof
which comprises reacting a compound of the formula
CH3
N
N
H CH2SCH2C~2NH2 V
with a compound of the formula
S= C _NR
wherein Rl is as defined above, to produce the compound
CH3
N /
N CH25CH2CH2NHCNHH
which is then reacted with methyliodide and cynamide to pro-
duce compound I in basic form and, if desired, converting the
product by procPsses known ~ se to the corresponding non-
toxic pharmaceutically acceptable acid addition salt.
This process is illustrated by the following reaction
scheme III for a preferred compound of the invention.
--10--
`, ~ '!,
~3~3~Z6
Scheme III
CE~3
H CH2SCH2CH~NH2 ~ S=C=NCH2C--CH
C~3 \ /
N I 1/
N / ~ 11
H CH2SCH2CH2NH NHCH2C--CH
) H /CH 3 I
2 ) H 2NCN
N
3CN
H CH 2SCH 2CH 2NH NHCH 2C ~ CH
~3~)3~36
The ~nyentian of ~his ~pplication further provides a
process for t~e prepa~tion ~f a compound o~ the formula
Nl ~ CH3
N CH2SCH2CH2NH~NH-Rl
wherein Rl is a straight or branched chain alkynyl group con-
taining from 3 to 9 carbon atoms, inclusive, or a non-toxic
pharmaceutically acceptable acid addition salt thereof
characterized by reacting a compound of the formula
CH3
VII
H CH2X
or an acid addition salt thereof in which X is hydroxy or a
conventional leaving group with a compound of the formula
~CN
HSCH2CH2NH~NH R VIII
wherein R is as described above and, if desired, converting
the resulting compound of formula I in basic form or an acid
addition salt thereof to the corresponding non-toxic pharmaceu-
tically acceptable acid addition salt or free base form.
The reaction is conducted in an inert organic solvent.
In a preferred em~odiment eguimolar quantities of the
compounds of formulae VII and VIII are used and the reaction is
carried out in the presence of a base.
Suitable leaving groups "X" for use in this reaction
are well-known to those skilled in the art. They include, for
example, fluoro, chloro, bromo, iodo, -O3SR2 wherein R2 is
(lower)alkyl [e.g. methanesulfonate], -o3SR3 wherein R3 is aryl
or substituted aryl [e.g. benzenesulfonate, p-bromobenæenesul-
-12
~1~3(~306
fonate or p~toluenesulfonate], -O3S~, acetoxy and 2,4-dinitro-
phenoxy~. For convenience and econom~ we normally prefer to
utilize compound I~ in which X is chloro.
In the process of this invention, the compound of Form-
ula ~II preferably is utilized in the form of an acid addition
salt. Compound VII is relatively unstable in its free base
~orm and therefore is preferably prepared and stored as an acid
addition salt. Although the free base of the compound of
~ormula II may be re-gener~ted prior to the reaction, no
advantage is obtained by so doing. It will be appreciated by
those skilled in the art that any inorganic acid or organic acid
may be utilized to form the acid addition salt of compound VII,
e.g. hydrochloric, sulfamic, sulfuric, oxalic, benzoic,
succinic, acetic, nitric, citric or the like. For convenience
and economy we normally prefer to utilize compound II in the
form of its hydrochloride.
The reaction of compounds VII and UIII to produce
compound I may be conducted in any inert organic solvent such
as an alkanol, acetonitrile, dimethylformamide, dimethylsulfox-
ide, acetone, or the like. We prefer to conduct the reaction
in an alkanol such as ethanol or 2-propanol.
The reaction temperature is not critical; the reaction
may be conducted at temperatures of from about to about
200. At low temperatures the reaction is slow, while high
temperatures normally lead to less pure products due to de-
composition and the formation of side-products. We normally
prefer to conduct the reaction at room temperature.
The reaction of compounds VII and VIII to produce
compound I is preferably conducted in the presence of a base,
which facilitates the reaction by acting as an acid acceptor.
Suitable baais for use in this reaction include both inorganic
and organic basis such as NaOH, KOH, LioH, triethylamine,
-13-
~13~306
.,
di~eth~lan~line~ sodiu~ ethoxide and the like.
Th~s p~ocess is illustrated by the reaction scheme IV
illustrated below for a preferred compound of the invention.
Scheme IV
CH
~CN
HSCH2CH2NHCNHCH2C - CH
N \ +
1: CH20EI/~: 1
N CH3
\ N ~ ~CN
H CH2SCH2CH2NHCNHCH2C~ CH
- 14 -
1~3~30~;
Th~s inYent~on ~urther xel~tes to no~el intermediates
of the fo~ula ~CN
HSCH2CH2NHCNH-Rl VIII
wherein R1 is a straight or branched chain alkynyl group
containing from 3 to 9 carbon atoms, inclusive, and acid
addition salts thereof, which are useful in the preparation
of histamine H2 receptor antagonists of Formula I.
In a pre~erred embodiment, Rl of the compound of Form-
ula VIII is -CHC_ CR4 in which R4 is hydrogen or methyl: in
another preferred embodiment Rl is -(CH2)nC-- CR4 in which n
is an integer of from 1 to 6 and R4 is hydrogen or methyl; in
~H3
another preferred embodiment Rl is -f-C - CR4 in which R is
C~I3
hydrogen or methyl.
In a more preferred embodiment, ~1 of the compound of
Formula VIII is the 2 butyn-1-yl group; in another more
preferred embodiment Rl i8 the 3 butyn-1-yl group; in another
more pref~rred embodiment Rl is the 4-pentyn-1-yl group; in
another more preferred embodLment Rl is the 2-methyl-3-butyn-
2-yl group; in another more preferred embodiment Rl is the
3-butyn-2-yl group. In the most preferred embodiment, Rl of
the compound of Formula VIII is the propargyl group.
-15-
,. ~ ....
~3~3()6
This invention further relates to a process for
preparing the novel intermediate compounds of the formula
NCN
2CH2NHCNH-~ VIII
wherein R1 is a strai.ght or branched chain alkynyl group
containing from 3 to 9 carbon atoms, characterized by
reacting a compound of the formula
P SCH2CH2N 2 IX
wherein P is any of the group of suitable sulfhydryl
protecting groups with a compound of the formula
NICN
RSCNHR X
where R is any substituent such that -SR is a suitable
leaving group, and thereafter removing the sulfhydryl
; protecting group of the resulting compound to produce
the intermediate VIII.
This process is illustrated by the scheme V below.
Scheme V
INCN
SC 2 2 2 RSCNHCH2-CH
1) heat
2) deblock
HscH2cH2NHcNHcx2c=cH
NCN
;I When reacting cysteamine compound with. an N-cyano-
N'-alkynyl-S-methylisothiourea to produce an N-cyano-N'-
alkynyl-N"-(2-mercaptoethyllguanidine of Formula VIII, it
~as found desirable to conduct the reaction in the presence
of a small amount of hydroqui.none and to bubble nitrogen
~L3~J13(~6
through the reaction mixture ~see, for example, step B of
Example 14~. These reaction conditions were found to produce
compounds of Formula VIII in higher yield and of higher
purity. The nitrogen sweep is believed to remove the methyl
mercaptan produced in the reaction and thereby avoid second-
ary reactions arising from the addition of methyl mercaptan
to the carbon-carbon triple bond. It is believed that the
hydroquinone prevents the formation of free radicals and
secondary reactions arising from their presence.
In another aspect, this invention relates to
intermediates of the formula
NCN
RS~CNH-R IV
wherein Rl is an alkynyl group containing from 3 to 9
carbon atoms, and R is Clower)-aIkYl, and acid addition
salts thereof.
A preferred intermediate is a compound of the formula
NCN
Rs-cNH-ccH2)nc 5CR IVa
wherein R is as described above, R4 is hydrogen or methyl
and n is an integer of from 1 to 6, inclusive, or an acid
addition salt thereof.
A more preferred intermediate is a compound of
Formula IVa in which R is methyl, or an acid addition
salt thereof.
The most preferred intermediate is N-cyano-N'-(2-
propyn-l-yl)-S-methyl lsothiourea or an acid addition salt
thereof.
The invention further relates to a process for the
preparation of a compound of the formula
~13~30~;
NCN
~ RS-CNH-R IV
¦ wherein Rl is an alkynyl group containing from 3 to 9
carbon atoms, inclusive, and R ls (lower~alkyl or an acid
addition salt thereof,
characterized by reacting a compound of the formula
~RS)2 C = NCN
- wherein R is as described above with a compound of the
formula
X2N - R
i wherein Rl is as described above, and, if desired, converting
the product to the corresponding acid addition salt.
I The most preferred compound N cyano-N'-(2-propyn-
! l-yl~-S-methyl isothiourea is prepared by reacting
~¦ dimethyl cyanodithio imLnocarbonate with propargylamine.
¦ The dimethyl cyanodithioiminocarbonate may itself
be prepared by procedures described in J. Org. Chem., 32,
1566 (1967). The alkynylamine starting-materials are either
commercially available or may be prepared by methods described
in Bull. Soc. Chim. Fr., 490 (1958); Bull Soc. Chim. Fr.,
592 (1967) and Annales de Chimie (Paris), 3, 656 (1958).
As used herein, the term nontoxic pharmaceutically
acceptable acid addition salt means the mono- or di-salt
of a compound of this invention with a nontoxic pharm-
aceutically acceptable organic or inorganic acid. Such
acids are ~ell known and include hydrochloric, hydrobromic,
sulfuric, sulfamic, phosphoric, nitric, maleic, fumaric
succinic, oxalic, benzoic, methanesulfonic, ethanedisulfonic,
benzenesulfonic, acetic, propionic, tartaric, citric,
-17a-
~1303~6
ca~phQ~sul~on~c~ and the l~ke~ The ~alts are ~ade by
~ethDds kno~n ~n the art.
As used herein the term tlower~alkyl is intended to
mean straight or branched alkyl groups containing from l to
6 carbon atoms.
Fbr therapeutic use, the pharmacologically active
compounds of this 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 a nontoxic pharmaceutically
acceptable acid addition salt, in association with a pharma-
ceutically acceptable carrier.
The pharmaceutical compositions may be administered
orally, parenterally or by rectal suppository. A wide
variety of pharmaceutical forms may be employed. Thus,
if a solid carrier is used, the preparation may be tableted,
placed in a hard gelatin capsule in powder or pellet form,
or in the form of a troche or lozenge. If a liquid carrier
is employed, the preparation may be in the form of a syrup,
emulsion, soft gelatin capsule, sterile solution for injection,
or an aqueous or nonaqueous liquid suspension. The pharma-
ceutical compositions are pxepared by conventional techniques
appropriate to the desired preparation.
Preferably, each dosage unit will contain the active
ingredient in an amount of from about 50 mg. to about 250 mg.,
and most preferably from about 100 mg. to about 200 mg.. The
activP ingredient will preferably be administered in equal doses
from two to four times a day. The daily dosage regimen will
preEerably be from 250 mg. to about 1000 mg., and most prefer-
ably from about 500 mg. to about 750 mg
-18-
~.
~31~30~
~2st~ne H~ece~t~ anta~Qnist~ hAve been ~hown
to be ef~ect~e ~nhib~tors of gastric secretion in anLmals
and man, Bri~lecombe et al., ~. Int. Med. Res., 3, 86
(1975). Clinical evaluation of the his~amine H2-receptor
antagonist cimetidine has shown it to be an effective thera-
peutic agent in the treatment of peptic ulcer disease, Gray
et al., Lancet, 1 (8001), 4 (1977~. The compound prepared
in Examples 1 and 2 below (hereinafter referred to as BL-5641)
has been compared with c~metidine in various tests and has been
shown to be more potent than cimetidine both as a histamine
H2-receptor antagonist in isolated guinea pig atria and as an
inhibitor or gastric secretion in rats and dogs. Furthermore,
the gastric secretion studies in dogs indicate that BL-5641 has
a longer duration of activity than cimetidine at equal doses.
Histamine H2-Receptor Antagonism-
Isolated Guinea_Pig Atria Assay
Histamine produces concentration-related increases in
the contractile rate of isolated, spontaneously beating
guinea pig right atria. Black et al., Nature, 236, 385
(1972), described the receptors involved in this effect of
histamine as histamine H2-receptors when they reported the
properties of burimamide, a competitive antagonist of these
receptors. Subsequent investigations by Hughes and Coret,
Proc. Soc. Exp. Biol. Med~, 148, 127 ~1975)
--19--
~:13V306
and ~e~m~ ~na ~cNeill~ 3~ Rh~xm~cQl. Exp. Ther., 200, 352
(1~77~ support the conclusion o~ Black ~nd coworkers that
the positive chronotropic e~fect of histamine in isolated
guinea pig right atria is mediated via histamine H2-
receptors. Black et al., Agents and Actions, 3, 133 (1973)
and Bri~blecombe et al., ~ed. Proc., 35, 1931 (1976) have
utilized isolated guinea pig right atria as a means for compar-
ing the activities of histamine H2-receptor antagonists. The
present comparative studies were carried ou~ using a modifica-
tion of the procedure reported by Reinhardt et al., Agents and
Actions, 4, 217 (1974].
Male Hartley strain guinea pigs (350-450 gm.) were
sacrificed by a blow on the head. ~he heart was excised
and placed in a Petri dish of oxygenated (95~ 2~ 5% C2)
modified Krebs solution (g./liter: NaCl 6.6, KCl 0.35,
MgSO4.7 H2O 0.295, KH2PO4 0.162, CaC12 0~238, NaHC03 201
and dextrose 2.09). The spontaneously beating right
atrium was dissected free from other tissues and a silk
thread (4-0) attached to each end. The atrium was sus-
pended in a 20 ml. muscle chamber containing oxygenated
modified Krebs solution maintained at 32C. Atrial
contractions were recorded isometrically by means of a
Grass FT 0.03 force displacement transducer and recordings
of contractile force and rate were made with a Beckman RP
Dynograph.
A resting tension of 1 g. was applied to the atrium
and it was allowed to equilibrate for 1 hour. At the end
of the equilibration period a submaximal concentration of
histamine dihydrochloride (3 x 10-6M) was added to the
bath and washed out to prime the tissue. Histamine was
then added to the bath in a cumulative fashion using
~3~)3~)6
1/2 log lQ ~hte~yals to giVe final mo~ar bath concentrations
o~ 1 x 10 7 to 3 x 10 5. The hista~ine-induced increase in
atrial rate was allowed to plateau before the next succes-
sive concentration was added. The maximal response invariably
occurred at the 3 x 10 5M concentra~ion. The histamine was
washed out several tLmes and the atrium allowed to return
to control rate. The test compound ~1 x 10 5M) was then
added and a~ter a 30 minute incubation the histamine
concentration-response was repeated adding higher concen~
trations as needed.
The histamine ED50 values (concentration of histamine
which increased contractile rate 50% of maximum) and 95%
confidence limits before and after the test compound were
obtained by regression analysis as described by Finney,
Prohit Analysis, 3rd ed., Cambridge (1971). Concentration-
response curve displacement factors were calculated as
~ollows:
ED50 Histamine~Compound
Displacement Factor=
ED50 Histamine Alone
The factor o~tained for BL-~641 ~as then expressed as a
ratio of the factvr obtained f~r cimetidine.
BL-5461 Displacement Factor - 1
Activity Ratio =
Cimetidine Displacement Factor - 1
The results o~tained from these studies are summarized
in ~able 1. Cimetidine and BL-5641 displaced the histamine
concentration-response curve to the right by a factor of
6.6 ana 32.7, respectively. Based on the concentration-
response curve displacemen~ fac~ors, BL-5641 was about
-21_
1~3~)3(~6
5.7 times more actlve than cimetidine as a histzmine ~ -
receptor ant~30nis~ in ~sola~ed guine~ pi~ righ~ ætria.
T_ble 1
Relati~e Acti~ity o~ Cimet~dlne Pnd BL-5641 in Isola~ed -
Guine? Pig Right Atria
_ _ ~istam1ne ~D50 Concen~ration--
: Wi~ 95~ Response Curve
Conf~dence Displa~ement AC~ v
: Co~ound N Concer.tra~ion Limits ~ 1.) _ Factor R~,ic
. _ . _ _ _ . _
Histamine 0.21
Control ¦3 (0- 8 - 25)
Cimetidine 3 1 x 10 5M(1.08 - 1.85) 6.6 1.0
__________ _ _________.~ _ ______________ ______________. . ______.
Histamine o .38
Control 121 1'- 7 ~ 53l ¦
12.44
6~l 2 ~ lC-5~ (7,81 - 20.28l 3~.7 5.7
.
N = n~mba~ o~ e.~Deriments.
1~30306
' De'te'rmination'of Gastric Antisectory Acti'vity
in the ~wo Hour Pylorous Ligated (Shay~ Rat
The pyloric li~ation procedure in the rat was designed
by Shay et al., Gastroenterology, 5,53 (1945) for the study
of perforating gastric ulcers; however, as the method
became known, it was also employed as a means of studyLng
rat gastric secretion, Shay et al., Gastroenterology ! -26~
906 (1954~, Brodie, D. A., Am. J. Dig~ Dis " 11, 231 (1966~.
A modification of this procedure is presently used to eval-
uate compounds for gastr;c antisecretory activity.
Male Long Evans rats, 280-300 gn~, are used~ The
animals are placed in individual cages and fasted for 24
hours with free acess to water. Under ether anesthesia,
the stomach is reached through a midline incision, and a
cotton-thread ligature is placed around the pylorus~ After
wound closure, ether administration is stopped and either
BL-5641, cimetidine or vehicle are administared intra-
peritoneally in a volume of 1 mg./kg, BL-5641 and cimetidine
are solubilized with one equivalent of HCl and brou~ht to
the proper volume with water. The animals are returned to
their cages from which the water bottles have been removed
and two hours later are sacrificed with ether. The stomach
is removed and the two hour gastric collection is drained
into a graduated test tube for volume determination.
Titratable acidity is measured by titrating a one ml.
sample to pH 7.0 with 0.02N NaOH, using an Autoburet and
an electrometric pH meter (Radiometerl. Titratable acid
output is calculated in microequivalents by multiplying
the volume in milliliters by the acid concentration in
millie~uivalents per liter. The percent inhibition of
acid output is calculated as follows
-23-
" ~L3~306
~o Ir~ibition 4cid autput =
Acid Output-Control - Acid Output-Drua
- - X lC~
Acid Output-Cor.trol
The results o~tained ~Jith BL,5641 and ci~etidin~ ~re
presented ;n Tzble 2.
Thes~ res~lts indicate ~hat~ in the two hou~ pylo~us
ligæted rat: ~rep~r?t~.on5 BL-5641 i~ at leas~ as potent as
c~m~tidine wit~ respect to t~le inh~ibiticn o~ g~stric acid
outpu~.
Tablc 2
Ef~e~t o~ 5641 ard Ci~e~i.dine cn C~stric .4c~d Out~u~
~ . . ..
' the ~o Ho~r ~ylorus T igated Ra~ -
.
Co~pound ¦ Dose (ip~a ¦ ~ Inhibition ED50
~ ole/k~ ./k~.¦ of Acid Out~u~ ~Mole/kg,
. =~. _ . - ....
BL-5641 40 11.1 80
5.~3 61 ~ 1
2~76 37
_____.____~_________________ ________________.. __________
C~ id~-lo !~o lO 66
20 5 6~ ~ 14
10 2.5 ~0
5 1.25 34
leas~ 5 ani~.? lS .~r~re emplo~ed at each dose.
-24-
~3~130~ii
Determination of Gastric Antisecretory Acti~ity
'in th'e 'G'astric'Fistula Dog
Thomas type [Thomas, J. E., Proc. Soc. exp. Biol. Med.,
46, 260 (1941~ stainless steel cannulae are inserted into
the stomachs of beagle dogs (10-12 kg.~ just orad to the
pyloric gland area near the greater curvature to provide
a chronic gastric fistula. Animals are allowed to recover
for at least two months before any testing is done. Dogs
are fasted overnight ~18 hours~ with water'ad-lib pr~or
to each experiment. The dogs are placed in a sling and an
eight inch inside needle catheter (C. R. Baird, Inc.~ with a
two inch 17 gauge needle is inserted in~o a leg vsin for
purposes of drug administration. Gastric secretions are
collected every 15 minutes by gravity drainage from the opened
cannula. Basal secretions are collected for two consecutive
15 minute periods and if these prove to be excessive (>4 ml./
15 min.; pH <5.0) the animal is not used. A modification of
the procedure described by Grossman and Konturek~ Gastroenterolo- -
gy, 66, 517 (1974) was followed. Immediately after the second
basal collection, histamine ~100 ~g.~kg./hr.1 is infused for
90 minutes with a Harvard Infusion Pump in a volume of 6 ml./hr.
At this time either ~L-5641, cimetidine (solubilized with one
equivalent of HCl and brought a proper volume with normal
saliné) or normal saline is injected rapidly (within 30 seconds~
in a volume of 0.1 ml./~g. and then infusion of histamine con-
tinues for an additonal 150 minutes (total time of infusion
is 4 hours). Each 15 minute sample of gastric juice is
measured to the nearest 0.5 ml. and titratable acidity against
0.02N NaOH (endpoint pH 7.0~ is measured with an Autoburet
and pH meter (radiometer). The percent inhibition of acid
-25-
13L3~306
output is c~lculated as described in the Pylorus ligated rat
procedure.
Equimolar doses of BL-5641 and cimetidine were administered
to five different dogs and the results obtained are presented
in Table 3.
Both BL-5641 and cimetidine produced an immediate in-
hibitory effect on gastric acid output. However, the degree
of inhibition at equimolar doses was consistently greater and
of longer duration with BL-5641 than with cimetidine. These
results indicate that as an inhibitor of histamine-induced
gastric acid output in the dog, BL-5641 is more potent and/or
longer acting than cimetidine.
The invention is illustrated but in no way limited by the
following Examples.
~13~306
o
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o I ~ o ~ 0 o o c~
h 11 r-j~ ~tIr~ ~ ~1 ~ CU
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Ll ~ J ~ ~ O r~
o ¢ t~
' ~i ~
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I C~ N N --I
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t.~ ~ ~ '"1 ~ G~ O t~
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o o~ ~ 0 o
G~ L'~ N ~ L~
~ ~1 ~ ~ o ~ c~ 1 o
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5,
'~
a~ ~D t~ ~~1 ~1 0 0 ~ C~ L'~
~ O O
'fi ~ Z ~ ~ N N ~t~
V C~ J ~ N N CJ C`J C\l cu N
_
l~ N ^~
O
u~ ~ V ~1 ~ O
~ ~o
. ~ ~ ~ ~ ~1 ~ rt
C~ Y ~ ~ ~O ~ ~O' ~ ~ ~ ~D ~
3 :~: ~ E ~ I fi ,~ F
h :~ . rl rJ ~ ~1 ~ .,1
~1 ~ _ cq, c; a2 c) P:~ u ,~ c.~
~,. .
'I 9 3C~31)~
Example 1
N-Cvano-N ' -{ 2- [ ~Y-m2thvl-S-imidazolvl ) methvlthio] eth~1 } -
.. .
N"-prooargylsuanidine
~ca3
CH2scH2c~l2l`~Lc-scH3 ~ C'~2C--C~
\ /
~CH3
~( NCN
H CH25CH2C}I2NHCNHCH2C----CH
A mixture of N-cyano~ {2-~ (4 methyl-5-imidazolyl)-
methy7 thio] ethyl}-S~methyl isothiourea ~3 . ~0 y, 0 . 011!
mole) and propargyl æ~ine t2.50 g, 0.0~5 mole) in acetonit-
rile (60 ml~ was stirred at reflux for 65 hours j and tne~
~as ~.eate~ in a st2inl esa steel pressure vessel at 120~
13~ ~or 38 hou~s. The reaction mixture was coQle~, de-
c3~ted from ~ ta_, and then evaporated to leave a ~Jum
(3 . ;7 g) . Tnis material was placed on silica gel ~100-2CG
~csh) and el uted with a mixture o methylene chloride (3 /
par~s) a..d meth-nol ~3 parts). The product: ob~ained from
a micdle ~^-action was crystallized by tritura~ion unde_
acetonitrile, and then was recrystallized ~rom ace~onitrile
--2~--
~3~3~:36
to yield the title co:n~oun;l (û..236 cJ; 7.7%); mp 146-149.5.
A~lal. Calc'd ~or C12E~16~6
Four.d: C, 51.86; H, 5.81; ~J, 30.70.
Example 2
N-Cyano-N ' -{ 2- [ (~-methyl-; im dazolyl ) methvltnio] etavl } -
N"-~ro3argvlg,~anidine
(CH3S) 2C-NCN ~ Y.2NC~2C--CH
'.
~JC21
CH3 SCNHCH2C _ CH
A
~3
N~;;~
El CH2SC C}12NH2 ~ A
N C 3
I~N~\ NCN
H CH2scEl2cH22lHe~lHc}~2c ---CEI
2 9
~L3~30
~,
. a. NCyar.o-N'-~ro~argyl-S-methyl isothiour~a (A).
A solution of dimethyl cyanod1thioiminocarbonate
tl6.00 g, 0.109 mole) and propargyl amine (6.03 g, 0.109
mole) in ace~onitrile (320 ml) was stirred at reflux for
4 hours, and .hen at 25 for 12 hours. Workup gave the
title compound A ~13.52 g, 81%), mp 160~164o
b. N-Cyano-~'-{2-[(4-methyl-5-imi~a~olyl)methvlthio]ethyl~- -
N"-propargylguanidine
A solution of A ~11.71 g, 0.0765 mole) ar~d 2-[(4-
methyl-5-imida~olyl)me.hylthio] ethylamine (13.10 g, 0.0765
mole) in metha~.ol (250 ml) ~as heated at reflux for 64 ho~rs.
The solvent was removed by evapo_ation, the residue,'placed
on silica gel (100-200 mesh) and chromatogr~phed by gradien~
elution using methylene chloride/methar.ol; the latter f~act-
ions yielded 4.0 g of the ~itle compound. Rec-ystalli~a~ion
from acetonitrile ~ave purified product mp 150-152.5~ ident-
ical (ir~ ~mr, tlc) with the product prepared in Exam~le 1.
Exa~ple 3
: N-Cva~o ~'-{ -1(4-methY1~5 imidazolyl)methylthio]ethyl}-
N~-~2-butyn-1-yl~guanidine
.
(CH3S)2C--NCN ~ ~ NC~ C-CCH3
~1 C~
CH3SCNHCH2C-- CC~3
-30-
,~, .
1~;~3~6
CH3
H CH2scH2c~2~H2 ~ B
.
N~
N ~ ICN
H ~H2scH2cH2N~cNHcH2c aCC~3
a. N-(2-Butvn-l-yl)-~ cyano-S-meth~lisot~iourea (B)
: A solution of dL~ethyl cyanodithioiminocar~onate
(lO.C0 g, 0.0684 mole) and 2-butyn-1-amine (4.73 g,
0~068~ mole) in acetonitrile (200 ml) was s~irred at
25 for 0.5 hour, anZ then at reflux for 2.5 hours.
~he mixtu~e was cooled, then filtered to yield t:~ title
compound ~, m? 180-183.
b. N-Cva~o-N'-{2-~(4 methvl-5-imidazolyl)me~hvlthio]-
e~:n~l}~N"-(2-butyn-1-yl)guanidine
------..
A solution or B (6~82 g~ 0~0407 mole) ~nd 2-[(4-
~,~thyl-~-Lmidazolyl)methylthio] ethylamine (6.g8 g, 0.0407
mole) in metha~.ol (140 ml) was heated at reflux for 40
hours. Workup and chromatography as described a~ove for
Example 2 yieided the title compound. When the title
compound was prepared according to the general proceduxe o_
Example 1, it melted at l28-130.
-31-
Example 4
N-Cvano-N'-{2-[~4-methyl-5-imidazolyl)methv~lthio]ethyl}-
N"-(3-butvn-1-yl)guanidine
The general procedure of ~xample 1 is repeated e~cept
that the propargyl zmine utilized ther2in is replaced ~y
an e~ui~.olar ~ount of 3-butyn-1-amine, and the title
product is th~reby produced.
Exam~le 5
N-Cyano-N'-{2-~4-methyl-S-imidazolyl)methylthio]eth~l}-
N"-~4-pentyn-1-vl)guanidine
The gen~ral procedure of Example 1 is repeated except
that the proparsyl amine utilized therein is replaced by
an equimolar amount of 4-pentyn~l-a~ine, and the title
product is tnereby produced; m.p. 99-103.
Example 6
N-Cyano-~'-{2-[t4 methyl-S-imidazolyl)methylthio]ethvl~-
Nn-(2-metnyl-3-butyn~2-yl)guanidine
_ _
The general procedure ~f Example 3 is repeated e~cept
that tne 2-butyn-1-amine utilized therei~ is replaced by
: an equimola~ ~mount of l,l-dimethylpropargylaminer and
t*.e ~itie procuct is tnereby produced.
~32-
3.~3~30~
ExamD~e 7
N-Cyano-N'-~2-~(4-methyl-5-imidazolyl)methylthio]ethyl}-
N"-(3-butyn-2-yl)guanidine
The general procedure of Example 3 is repeated except
that the 2-butyn-1-æmine utilized therein is replaced by
an equimola. æmount of l-methylpropargylamine, and the
title produce is thereby produced.
Example 8
N-Cyano-N'-~2-tt4~methyl-5 imidazol~l)methylthio]ethyl}-
N"-~2-butyn-1-yl)gu~nidine
A mixture o N-cyano-N'-{2-[(4-methyl-5-Lmidazolyl)-
methylthio~ethyl~-S-methyliso.hiourea (3.00 g. 0. a 11 1 mole~
and 2-~utyne-l-amin3 ~3.07 g,,0.0445 mole) in 60 ml. of
propionit-ile was stirred at reflux for 4~ hou~s. TLC
assay of an a1iquot of the reaction mix~ure sho-~ed 2 trac~
of the isothiourea startiny material, so the mi:;ture was
refluxed for an additionzl 6 hours and then stirred ~t rocm
temperature fo~ 64 hours. The solvent (along with e~cess
æ~ine) W25 removed at reduced pressure and the r~sidual gum
was placed on silic~ gel (100-200 mesh~ and eluted with a
mix'ure of methylene chloride ~97 parts3 and methar.ol (3 parts~
The mlddle frac'ion.s we~e combined and e~aporated ~o give 1,81
g. of yellow 5~. The gum was dissolved in 20 ml. of ethyl
acetate and crystallized at -15C. The resulting pale yellow
solld (1.2 g.) was dissolved in 11 ml. of hot acetonitrile and
recrys'allized a~ -15C; yield 1.072 g., m.p. 128-130C.
-33-
1~3~3(~6
Anal. Calc'd ~or C13H18N6S: C, 53.77; ~I, 6.25; N, 28.94;
S, 11.08
Found: C, 53.7~; H, 6.29; N, 29.62;
S, 11.~4
Example 9
N-Cvano-N'-r2-[(4-methyl-5-imidazolyl)methylthio~e~hyl~-~i"-
l3-~utyn~ l)guanidir.e
A mixture of N-cyzno-N'-{2-~(4-methyl-S-i~idazolyl)-
methylthio]ethyl}-S-methylisothiourea t3.00 g., 0.0111 mol~)
and 3-butyn-l;amine (3~13 g., 0.0~53 mole) in 60 ml. o~
propionitril~ was stirred at reflux for 4~ nours. The solver.t
was evaporated to give 5.40 g. o~ a syrup which was placed
on 70 g. of 100-200 mesh silica gel and chromatographed b~
gradient elution using me hylene c~loride~methanol.
Fraction Eluan~ Volume
_.
199 CH2C12/1 MeO~ 100 ml.
2 70 ml.
; 3 a ~0 ml. 0.l17 g.
4 ~ 30 ml~ -
$ ~ 75 mlO 0.067 g.
6 " 750 ml. 0.080 g.
; 7 n 32~ ml. 0.168 g.
898 CU2Cl2~2 MeOH 50 ml.
g n 15~ ml. 00125 y.
~ 250 ml. 0.811 g.
11 ~ 250 ml. 0.72 y.
3~-
~1303~
12 ~7 C~2C12!3 ~leOH 175 ml. 0.125 g.
13 n 225 ml~ 0.133 g.
14 ll ~ 0 ~ 027 g .
" 225 ml.
~ 0.002 g.
16 n 200 ml.J
1795 CH2C12/5 MeOH 250 ml. 0.035 g.
18 " 250 ml. 0,236 g.
TLC ~silica gel, 90 CH~C12/10 ~leOH) indicated fractio~s
9-1~ were pur~ and should be com~ined. Fractions 1-8 showed
fzst moving im~urities. Frac~ions 13 and 14 s~.owed scme
trailing impurities. Frac~ions 9-12 were combined and
e~aporated to 1.72 g. of a yellow gum. The gu~ was dissolved
in 11 ml. o nitromethane and crystallized at -15C (pale
yellow solid, 1.18 g.), which was recrystallized fro~ 9 ml.
of nitromethane to give 0.~87 gm.; m.p. 86-89C (softens at
8~C~. Infrared and N~R ~100 ~Y.Z) were clean ar;d consistent
wit~ ,ne desired structure. N~L~ showe~ ~hat the ~roduct was
solvat~d with approxLmately 0.08 mole of nitromethane~
:',~ .,
_13 18N6S-0.08~C~3NO2): C, 53021; ~, 6.22;
:~ N, 28.84; S, 10.86
Found: C, 52.68, 52~87; ~., 6.28, 6.02, N, 29.39,
29.50; Sr 11022
-35-
~"~
3L~3~306
Example 10
N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethvl}-
Nn-~4-pentyn-l~yl)guanidine
A mixture of N-cyano-N'-{2-[(4-methyl-5.~ida7O1yl)-
methylthio~e~hyl}-S-methylisothiourea (3.00 g., 0.0111 mole)
ar.d 4-per.tyn-~-amine (3.69 g.,0.0445 mole) in 60 ml. of
zcetonitrile was stirred at reîlux for 24 hours, and then
allowed to stand at room temperature for 96 hours. The
solvent and excess amine were removed under reduce~ pressure
and the residual yellow gum was purified by chromatography
on 50 g. of 100-200 mesh silica gel, using sradient elution
with methylene chloride/~ethanol ~99:1-96:4). The middle
fractions indicated by TLC to be pure were combined and
evaporated to give 1.91 gO of yellow gum which ~as crystallized
at -15C from 18 ml. of ethyl ace~ate. The resultins white
solid (1.25 g.) ~as recrystallized at -1;C fro~ 10 ml. of
aceto~itrile to glve 1.063 g. of product; m.p. 99 103C.
Anal. Calc'd for C14~0N65: C, 55.24; ~, 6.52, ~, 27~61; S,
10.53
Fou~d. C, 55.43; H, 6.58, N, 28.26; S,
10.97
.
-36-
~13~:)30~
EXamD1e 11
N-Cvano~ t2-~(4-methvl-5-imidazolvl)methvlthio]ethyl}-t~"-
propar~lguanidine
The mixture of l~-cyano~ 2-~(4-methyl-5-imidazolyl)-
methylthio]ethyl~-S-methylisothiourea (10.0 g; 0.0371 mole)
and distilled propargylamine t20 ml; 0.3~5 mole) in ~ethanol
tS0 ~1) was stirred at reflux, under a positive pressure
nitrogen at~osphere (nitrogen sweep~, for 20~5 hours. ~he
solvent and excess amine were then rer.loved by evaporation to
leave a yellow-brown oil that rea~ily crys~alliz~d.
Trituration of the crude product under isopropanol ~30 ml)
gave the title compound as an off-white, friable solid (8.11
g, 79~); m.p..l46-148.5.
Example 12
N-Cyano~ t2-t[4-methyl-5-imidazolvl~meth~lthio]ethvl~-
Nn-proeargvlsuanidin
A mi~ure of N-cyano-N'-{2-lt4 me_hyl-5-imidazolyl~-
m~thylthio3e~hyl}-S-methylisothiourea ~100 g; 0.371 mole)
and ~ist~lled propargylamine ~1~0 ml; 2.~4 moles) in methanol
~500 ml) was s.irred at reflux under a positive pressure
nitrog~n at~osphere ~nitrogen sweep~ for 22 hours. ~he
r~ac _on ~ixtu-e was oooled, and the solvent and excess amine
were removPd by e.vaporation to leave an amber oil that readily
crys~alliz2d. The crude product was triturated under
isopropanol (250 ml), cooled at O for 2 hours and collected
by filtration. The fil~er cake was washed with cold isopropanol
and dried in vacuo over P2O5 for 16 hours~ The dried title
__ __
--37--
~3~306
product was a near-white dense solid; yield 73.5 gm ~71.73)
m.p. 147-149.
Exam~le 13
Recrvstalli~ation of ~I-CYano-N'-t2-[(4-meth~1-5-i~idazolvl)-
methylthiolethyl}-~ln-pro~ar ~ lguanidine
The final products obtained in Ex~ples 11 and 12 were
combined (total 81.3 gl~ dissolved in hot isopropznol (1000
ml), filte_ed through"Super-Cel" and allowed to cool at room
temperature for ca. 68 hours. The resultins crystalline
product was recovered by filtr3tion, washed with cold
isopropanol, pulverized and dried in a heate~ d~sicca~or
under high vacuum for ca. 45 hours. Yield 72.4 g (89~
recovery); m.p. 149-151o IiPLC assay showed the purity ~o
be ca. 99.5~. The N~I~ (100 MI~z) spectrum was clean and
consiste~t.
An 1- Calc'd for C12~16N6S~ 2.15; II, 5-8~; ~l, 30~4~;
~, 11.60
Found: C, 52~4~; ~I, 5.9~; N, 30.51;
S, 11.35
-38-
1~3~;3C)~;
Exa'mp'le''14
N-Cyano'-N'-'~'2-[~('4'-methy'1-'5'-imi'd'a'zo`lyl'~methyl'thio]ethyl~-N"-
propargylguanidine
A. N-Cy'ano-N'-prop'a'rgy'l-'S-me'thylisothiourea
A solution of dimethyl cyanodithioiminocarbonate (16.00
g, 0.109 mole) and propargylamine ~6.03 g, 0.109 mole) in
acetonitrile (320 ml) was stirred at reflux for 4 hours,
and then at 25 for 12 hours. The mixture was cooled and
filtered to yield the title compound (13~58 g, 81%~, mp
160-164.
B. N-Cyano-N'-propargyl-N"-(2-mercaptoethyl~guanidine
A mixture of 1.136 g (10 m moles) of cysteamine hydro-
chloride, 1.53 g (10 m moles) of the product of step A, above,
and 0.055 g of hydroquinone in 10 ml DMF was slightly warmed
to dissolve. To this solution was added 10 ml of lN aqueous
sodium hydroxide and nitrogen was bubbled through the solution~
After standing at room temperature for 17 hours, the reaction
mixture was evaporated to dryness to give a mixture of the
title product and sodium chloride. The title product w~s
extracted from this mixture with 10 ml of ethanol and the
ethanolic solution was used in step C, below.
C. N-Cyano-N'-{2-[(4-met~y__5-'imidazolyl~methy_thio]-
ethyl}-N"-proparg~guanidine
The ethanol solution of the product of step B, above,
(about 10 m moles) was added to a solution of 0.46 g sodium
(0.02 g-atoms) in 10 ml ethanol at 4C under nitrogen. After
5 minutes, a solution of 1.67 g (10 m moles~ of 4-methyl~5-
chloromethylimidazole-HCl in 14 ml eth~nol was added and the
-39-
~3~:306
mixture was stirred at room temperature under nitrogen
~or 70 minutes. The reaction mixture was filtered through
a bed of celite filter aid to r~move the inorganic salts
and the celite was washed with ethanol. The filtrate was
evaporated to dryness a~d the product was purified by chroma-
tography on a silica gel colu~n (20 g silica, 3.2 x 4.5 cm
bed) with ethanol-chloroform mixtures as the sol~ent. The
ethanol content was gradually increased fro~ 2 to 15~. The
eluant was evaporated to dryness to give 1.906 g of crystal'ine
prod-~ct. Recrystallization from 2-prop~no~ gave 1.49 g ~54~)
of ~he title product, m.p. 144 - 145C.
Exam?le 1~
N-Cyano-~J'-{2-~(4-methyl-5-imidazolyl)methylthio]eth~l}-Nn-
butyn-l-yl)guanidine
A ~J-Cvano-?J'-~2-butvn-l-vl)-S-meth~lisothiourea
A solution o~ dime'hyl cya~odithioiminocarbonate (lO.00
g, 0.0684 ~ole) and 2-butyn-1-amir.e (4.73 5, 000684 mole) in
acetonitrile (~00 ml) was stirred at 25 for 0.5 hour, and
then at reflux ~or 2.5 hours. The mixt~re W2S cooled, then
fil~ered to yield the title compou~d, mp 180-183.
B. N-Cyano~ (2-butvn-1-yl~-~ln-(2-merca~toethvl)-
...
guanidi~e
The general procedu-e of Exa~ple~B is repeated ~cept
that the N-cyano-N'-propargyl-S-methylisotniourea utilized
-40-
1~ 3~ 3~
therein is replaced by an equimolar umoun~ of ~-cyano-~J'-
~2-butyn-1-yl)-S-methyl~sothiourea, an~ the ~itle pr~duct
ls thereby produced.
C N-Cyano-N'-{2-~4-methYl-5-imidazolyl)~ethylthioJ-
l}-N~-(2-butvn-1-yl)guanidine
~ he general procedure of Examplel~c is repeated except
~hat the N-cyano-N'-propargyl-~t"-(2-me~capto~thyl)guanidine
utilized therein is ~eplaced by an equ~molar ~r.ount of N-
cyano-N'-(2-butyn-1-yl)-N~-~(2-mercap~oethyl)guanidine, and
the title product is thereby produced.
Exam~lel5
~-CY~nO-N '-{ 2-~4-methyl-S~imiaazolyl~methvlthio]etny
~3-butvn~ gua~idine
A. N-C~ano-~J'~3-butYn-l-Yl)-N"-(2-merca~toethvl)g~ar.i~ine
The general procedures of Exa~ple 14 steps A and B, are
repeated except that th propargylamine utilized in step ~
thereof is rep~aced ~y an ecuimolar 2mount of 3-butyn-1-a~ine,
ar.d the title product is thereby produced.
N-Cyano-N'-{2-[(4-metnY1 5-imidazolyl)methvlthio]-
ethvl}-Nn-(3-butyn-1-yl)~uan~dine
The gPneral procedure of Examplel~C is repea.ed except
that the N-cyano-N'-propargyl-N~-~2-mercaptoethyl)guanidine
-41-
~ 3~ 3~
utilized therein ~ replaced by ~n equimolar amount of N-
cyano-N'-~3-butyn-1-yl~-N~-(2-mercap~oethyl)guanidine,
and the title product is thereby produced.
~Z
~J-Cvano-N'~{2-r(4-met~yl 5-i~idazolYl)me~h~lthio~ethyl}-?l"-
(4-pentyn-l~yl~suanidine
A. N-CYano~ (4-pentyn-1-yl)-N~-~2-me-~aptoethyl)-
guanidine
The ge~eral procedures o~ Example14, steps A and B, axe
repeated e~cept that the proparsylamine utilized in ~tep
: thereo~ is replaced by ~n equimolar ~ount of 4-pentyn-1-
amine, and the title product is thereby produced.
. N-Cyano~ {2-~(4-methvl-5-imiaazolyl)methylth~oi-
The ge~eral procedura o ~xamplel~C is repe~t~d except
that the ~-cyano-N'-propargyl-Nn-l2-mercaptoethyl3guar.idine
utilized therei~ is ~eplaced by a~ e~uLmolar amoun~ of N-
cyano-N~-(4-pentyn-l-yl)-N~2-mercaptoethyl)gu2~id~ne,
and the title product is thereby produced.
~xam~
-Cyano-N'-{2-t(4-methyl-5-imidazolyl)methvlthio~eth~l}-N"-
l2 methyl-3~butvn-2-yl~guanidine
A. N-Cvano-N' (2-methyl-3-butyn~2-yl)-N" (2-me~caDto-
ethyl)guanidine
-42-
,,,;~
~L3(~306
~ he general procedures of Exzmpl~14, steps A and B,
are repeated except that the propargyla~ine utilized in
step A thereof is replaced by an equimolar amount of 1,
l-dimethylpropaxgylEmine, and the tit~e product is thereby
produced.
B. N-C~ano-N'-{2-[(4-methyl-5-imidazolyl~methylthio~-
ethvl}-Nn-(2-meth~ 3-butyn-2-y~uanidi~e
.
~ he general procedu~e of Example14c is repe3ted except
that the ~-cyano-N'-propargyl-Nn-~2-mercaptoethyl)suanidine
utilized therein is replaced ~y an equimolar amount of N-
; cyano-N'-~2-methyl-3-butyn-2-yl)-N~-~2-mer-aptoethyl)guznidine, nd the title product is thereby produce
ExamDle 19
N-Cvano-N ' -~ 2- ~ (4-meth~1-5-i~nidazolyl)methylthio; ethvl}-~ln-
t3-butvn-2-yl)suanidine
A N-Cyar.o-~'-(3-butYn-2 yl)-M"-(2 mercaptoeth~l)guan~dine
The general procedures of Exælnple 14 steps A and B, are
~epeated except that the propargylamine utilized in step A
thereof is replaced by an equimolar amount o~ l-methyl
propargylamine, znd the title product is thereby produced.
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.~
~13(~306
B. N-Cyano-N'-{2-~4 methvl-5 imidazolvl)methvlthiol-
eth~l}-N~-(3-butyn-2-yl)guanidine
The general procedure of Examplel4 is repeated except
that the N-cyano~N'-propargyl-N"-~2-mercaptoethyl)guanidine
utill2ed therein is replaced by an e~ui~olar amoun~ of N-
cyano-Nl-(3-butyn-2-yl)-N~-(2-mercaptoethyl)guaniaineJ ar.d
the title product is thereby produced.
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