There are disclosed novel compounds described as aminoalkyl benzofuran derivatives in which the aminoalkyl benzofuran is connected to a guanidine moiety or functional equivalent thereof through a linear connecting group. Processes for the preparation of such compounds are also disclosed. The compounds are useful for the suppression of gastric acid secretions in mammals and compositions for such uses are also disclosed.

BACKGROUND OF THE INVENTION 
Imidazolylcyanoguanidines in which the imidazole and cyanoguanidine are 
joined through a linear connecting group are known as H-2 receptor 
inhibitors. See U.S. Pat. No. 3,950,333 to Durant et al. In addition, 
compounds have been prepared similar to those of Durant et al in which the 
imidazole moiety has been replaced by an alkylaminoalkylfuran moiety. See 
U.S. Pat. No. 4,128,658 to Price et al. The instant compounds differ in 
utilizing the aminoalkyl benzofuran moiety. 
SUMMARY OF THE INVENTION 
This invention is concerned with aminoalkyl benzofuran compounds wherein 
the aminoalkyl benzofuran is connected to a guanidine or guanidine-like 
moiety through a linear connecting group. Thus, it is an object of this 
invention to describe such compounds. A further object of this invention 
is to descrbe processes for the preparation of such compounds. A still 
further object is to describe the use of such compounds as gastric acid 
secretion inhibitors in mammals. Further objects will become apparent from 
a reading of the following description. 
DESCRIPTION OF THE INVENTION 
The compounds of this invention are best realized in the following 
structural formula: 
##STR1## 
wherein R.sub.1 and R.sub.2 are independently loweralkyl of from 1-3 
carbons and R.sub.1 and R.sub.2 may be joined to form together with the 
nitrogen atom to which they are attached, a 5- or 6-membered heterocyclic 
ring, which may optionally contain another hetero atom selected from 
oxygen or N-R.sub.4 wherein R.sub.4 is hydrogen or loweralkyl; 
X is sulfur or a methylene group; 
n is 2,3 or 4; 
R.sub.3 is hydrogen loweralkyl, cycloloweralkyl, cycloloweralkylloweralkyl, 
loweralkenyl, loweralkynyl, phenylloweralkyl, hydroxyloweralkyl, 
loweralkoxyloweralkyl and di(loweralkyl)aminoloweralkyl; and 
Y is sulfur, .dbd.CHNO.sub.2 or .dbd.NR.sub.4 where 
R.sub.4 is nitro, cyano or loweralkylsulfonyl. 
In the instant invention, the term "loweralkyl" unless otherwise defined is 
intended to include those alkyl groups, of either a straight or branched 
configuration, which contain from 1-5 carbon atoms. Exemplary of such 
alkyl groups are methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, 
pentyl and the like. 
The term "loweralkoxy" is intended to include those alkoxy groups of either 
straight or branched configuration, which contain from 1-5 carbon atoms. 
Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, 
butoxy, pentoxy and the like. 
The term "loweralkenyl" is intended to include those alkenyl groups, of 
either a straight or branched configuration, which contain from 2-5 carbon 
atoms. Exemplary of such alkenyl groups are vinyl, allyl, butenyl, 
1-methyl-2-butenyl, pentenyl, and the like. 
The term "loweralkynyl" is intended to include those alkynyl groups of 
either straight or branched configuration which contain from 2-5 carbon 
atoms. Exemplary of such alkynyl groups are ethynyl, propargyl, butynyl, 
pentynyl and the like. The heterocycle formed when R.sub.1 and R.sub.2 are 
joined may be piperidine, or pyrrolidine and the like. 
The term "cycloloweralkyl" is intended to include those cycloalkyl groups 
which contain from 3-6 carbon atoms. Exemplary of such groups are 
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 
The heterocycle formed by joining R.sub.1 and R.sub.2 may be piperidine, 
pyrrolidine, morpholine, piperazine, N-methyl piperazine and the like. 
The preferred compounds of the instant invention are realized in the above 
structural formula when: R.sub.1 and R.sub.2 are the same and are 
loweralkyl of from 1-3 carbon atoms; 
X is sulfur; 
n is 2; 
R.sub.3 is hydrogen, loweralkyl or loweralkynyl and 
Y is .dbd.CHNO.sub.2, or .dbd.N--CN; 
Further preferred compounds are realized when; 
R.sub.1 and R.sub.2 are methyl; 
X is sulfur; 
n is 2; 
R.sub.3 is hydrogen, methyl, ethyl, or propargyl; and 
Y is .dbd.CH--NO.sub.2 or .dbd.N--CN. 
The most preferred compounds are those wherein: 
R.sub.1 and R.sub.2 are methyl; 
X is sulfur; 
n is 2; 
R.sub.3 is hydrogen or methyl; and 
Y is .dbd.CH--NO.sub.2 or .dbd.N--CN. 
The compounds according to the invention readily form physiologically 
acceptable salts. Such salts include salts with inorganic and organic 
acids such as hydrochlorides, hydrobromides and sulphates. Particularly 
useful salts of organic acids are formed with aliphatic mono- or 
di-carboxylic acids. Examples of such salts are acetates, maleates and 
fumarates. The compounds may also form hydrates. 
The compounds according to the invention can be administered orally, 
topically or parenterally or by suppository, of which the preferred route 
is the oral route. They may be used in the form of the base or as a 
physiologically acceptable salt. They will be in general be associated 
with a pharmaceutically acceptable carrier or diluent, to provide a 
pharmaceutical composition. 
The compounds according to the invention can be administered in combination 
with other active ingredients, e.g. conventional antihistamines if 
required. For oral administration the pharmaceutical composition can most 
conveniently be in the form of capsules or tablets, which may be slow 
release tablets. The composition may also take the form of a dragee or may 
be in syrup form. Suitable topical preparation include ointments, lotions, 
creams, powders and sprays. 
A convenient daily dose by the oral route would be of the order of 100 mg. 
to 1.2 g. per day, in the form of dosage units containing from 20 to 200 
mg. per dosage unit. A convenient regimen in the case of a slow release 
tablet would be twice or three times a day. 
Parenteral administration may be by injection at intervals or as a 
continuous infusion. Injection solutions may contain from 10 to 100 
mg./ml. of active ingredient. 
For topical application a spray, ointment, cream or lotion may be used. 
These compositions may contain an effective amount of the active 
ingredient, for example of the order of 11/2 to 2% by weight of the total 
composition. 
The compounds of the present invention may be made by reacting a primary 
amine of the formula: 
##STR2## 
in which R.sub.1, R.sub.2, n, and X have the meanings given herein with a 
compound capable of introducing directly or indirectly the group: 
##STR3## 
in which R.sub.3 and Y have the meanings given herein. Compounds which are 
capable of directly introducing the group: 
##STR4## 
are, isothiocyanates R.sub.3 NCS, or compounds of the formula: 
##STR5## 
wherein P is a leaving group. The reaction with the isothiocyanate may be 
carried out by allowing the amine and isothiocyanate to stand in a solvent 
such as acetonitrile. The reaction between the amine (II) and: 
##STR6## 
may be carried out in a solvent e.g. ethanol or acetonitrile at ambient or 
elevated temperatures in the presence of silver nitrate as required. The 
amine (II) and the compound. 
##STR7## 
may be stirred in solvents such as ethanol and acetonitrile at ambient or 
elevated temperatures. Where R.sub.3 represents hydrogen, alkali metal 
cyanates and thiocyanates are used. Examples of leaving groups are 
halogen, methylthio or alkoxy, preferably methylthio. The introduction of 
the group: 
##STR8## 
may also be effected indirectly by first reacting the amine (II) with a 
compound of the formula: 
##STR9## 
in which P is a leaving group as defined above. This reaction may be 
effected in a solvent, e.g. ether or acetonitrile at a temperature from 
ambient to reflux. Treatment of the resulting compound of formula (III): 
##STR10## 
where Y represents .dbd.NR.sub.4 or .dbd.CH--NO.sub.2 with a primary amine 
R.sub.3 NH.sub.2 at a temperature from ambient to reflux gives the desired 
end product. 
The preferred compounds of this invention wherein Y is a nitromethylene 
group (.dbd.CHNO.sub.2) or a cyanoimino group (.dbd.N--CN) are prepared 
according to the following reaction scheme: 
##STR11## 
wherein R.sub.1, R.sub.2, R.sub.3, n and X are as defined above. 
In the first step of the reaction for the preparation of the nitromethylene 
compound (I-A), the amine starting material (II) is treated with 
1,1-bis-methylthio-2-nitroethene in a suitable solvent, preferably 
acetonitrile or a lower alcohol, such as ethanol. The reaction may be 
carried out at about 20.degree. C. to the reflux temperature of the 
reaction mixture. The reaction is substantially complete in about 8 hours 
to several days. It is preferred to stir the reaction mixture overnight at 
about 55.degree.-60.degree. C. 
In the first step of the reaction for the preparation of cyanoimino 
compound (I-B) the amine starting material (II) is reacted with dimethyl 
cyanodithioimidocarbonate in a suitable solvent, preferably acetonitrile 
or a lower alcohol, such as ethanol. The reaction may be carried out at 
about 20.degree. C. to the reflux temperature of the reaction mixture. The 
reaction is substantially complete in about 1 hour to several days. It is 
preferred to stir the reaction mixture overnight at about room 
temperature. 
The next step of this reaction sequence is the same for Compounds IVA and 
IVB and involves the displacement of the methylthio group of Compound IVA 
and IVB by a loweralkylamino group. A loweralkyl amine is employed and the 
reaction is carried out by dissolving the amine in a solvent, such as a 
lower alcohol, preferably ethanol. The reaction is carried out at from 
0.degree. C. to the reflux temperature of the reaction mixture. However, 
where volatile amines are employed the reaction mixture must either be 
maintained at from 0.degree. C. to room temperature or, if heating is 
required, the reaction must be placed in a sealed reaction vessel. It is 
preferred to use atmospheric pressure for the reaction, and to keep the 
temperature at about room temperature or less. The reaction is complete in 
about 1 hour to several days, with most reactions requiring stirring 
overnight. The products (I-A and I-B) are isolated using techniques known 
to those skilled in this art. 
The starting materials (II) wherein X is sulfur are prepared according to 
the following reaction scheme: 
##STR12## 
In the above reaction scheme, methylbenzofuran-2-carboxylic acid is 
esterified using ethanol in the presence of acid to prepare the ethyl 
ester derivative thereof. The preferred acid is a mineral acid such as 
sulfuric. The reaction is carried out generally at reflux for from 12 to 
36 hours, using ethanol as the solvent. 
The methyl group is brominated with a brominating agent, preferably a free 
radical brominating agent such as N-bromosuccinimide in the presence of a 
free radical initiator such as .alpha.,.alpha.'-azobisisobutyronitrile 
used in catalytic amounts. The reaction is carried out at from 35.degree. 
C. to the reflux temperature of the reaction mixture and is generally 
complete in from 2 to 8 hours. An inert solvent, immune to bromination, 
such as carbon tetrachloride, is employed. 
The brominated compound is then treated with an amine to produce the 
aminomethyl side chain. The reaction is carried out in an inert solvent 
such as ether, tetrahydrofuran, and the like. The amine reagent is 
employed in excess, or a separate non-reactive base such as a tertiary 
amine, is employed to neutralize the liberated hydrogen bromide. The 
reaction is carried out at from 0.degree. to 30.degree. C. and is 
generally complete in from 0.5 to 3 hours. 
The 2-position ester is then reduced to the hydroxymethyl group using a 
reducing agent, such as lithium aluminum hydride, lithium borohydride and 
the like. The reaction is carried out in a solvent immune to reduction 
such as ether, tetrahydrofuran, and the like. The reaction is carried out 
at about 5.degree. to 37.degree. C. and generally is complete in from 1 to 
3 hours. 
The 2-hydroxymethyl benzofuran is then treated with an amino alkyl 
mercaptan. The reaction is carried out in the presence of acid, generally 
mineral acid such as concentrated hydrochloric acid at from 5.degree. to 
30.degree. C., and is complete in from 20 to 64 hours. The product is 
isolated using techniques known to those skilled in the art. 
The compounds (II) wherein X is a methylene group are prepared according to 
the following reaction scheme wherein Z is the substituent on the benzo 
portion of the molecule which may be undergoing reactions simultaneously 
with the instant synthetic scheme: 
##STR13## 
wherein m is 4,5 or 6. 
In the foregoing reaction scheme an appropriately substituted benzofuran is 
lithiated and then treated with a compound Br(CH.sub.2).sub.m Br where m 
is as defined above. The reaction is carried out in an inert solvent such 
as ether, tetrahydrofuran and the like. The benzofuran is added to a 
solution of lithium diisopropylamide in the solvent in order to prepare 
the 2-lithium benzofuran intermediate which is then reacted with the 
dibromo compound. A reaction promoter such as hexamethylphosphoramide is 
usually present. The reaction is generally carried out at from -20.degree. 
to 20.degree. C., preferably at about 0.degree. C. and is complete in 
about 3 to 10 hours. 
The bromo compound is then converted to the phthalimide with an alkali 
metal salt of phthalimide in a solvent such as dimethylformamide at from 
20.degree. to 60.degree. C. preferably at room temperature, and is 
complete in about 12 to 30 hours. 
The phthalimido derivative is then cleaved with hydrazine to prepare the 
amino group. The reaction is carried out at from 25.degree. to 100.degree. 
C. preferably from about 50.degree. to 75.degree. C., and is complete in 
about 2 to 24 hours. A solvent such a loweralkanol, preferably ethanol, is 
employed, and the product is isolated using techniques known to those 
skilled in the art. 
An alternate procedure for the preparation of the alkylaminomethyl 
substituent on the benzofuran is outlined in the following reaction scheme 
where Z' is the 2-position substituent which may also be undergoing 
synthetic reactions simultaneously with the instant synthetic scheme: 
##STR14## 
wherein R.sub.1 and R.sub.2 are as previously defined and R.sub.5 is 
loweralkyl. 
In the instant reaction the starting group is the carboxylic acid which may 
esterified and then converted to the amide, or the amide may be prepared 
directly if the substituents on the remainder of the molecule would allow. 
The ester is prepared with ethanol in the presence of an acid as described 
in the esterification previously described. 
The amide is prepared with an appropriately substituted amine and a 
catalytic amount of a base such as an alkali metal alkoxide. The reaction 
is carried out in a solvent such as a lower alkanol at from 25.degree. to 
80.degree. C. If temperatures higher than the boiling point of the 
reaction mixture are called for, a pressurized vessel may be employed. The 
reaction is generally complete in from 12 to 36 hours. 
The amide is then reduced to prepare the substituted amino methyl group. 
The reducing agent may be lithium aluminum hydride, borane, and the like 
and is carried out in a solvent such as ether, tetrahydrofuran, and the 
like and is generally complete in from 2 to 6 hours. The products are 
isolated using techniques known to those skilled in the art.

EXAMPLE 1 
N-Cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N"-met 
hylguanidine 
A. Ethyl 6-Methylbenzofuran-2-carboxylate 
A solution of 6-methylbenzofuran-2-carboxylic acid (111.0 g., 0.636 mole) 
and concentrated sulfuric acid (4 ml.) in ethanol (1 l.) is boiled under 
reflux for 16 hours. About 2/3 of the solvent is removed by distillation 
at reduced pressure. The residue is poured into 1 l. of ice water. The 
oily ester is taken up in ether, washed with saturated sodium bicarbonate 
solution and water and dried over sodium sulfate. Distillation at reduced 
pressure affords 90.5 g. (70%) of ethyl 6-methylbenzofuran-2-carboxylate, 
b.p. 174.degree.-176.degree. C. (17 mm.). The product crystallizes in the 
receiver, m.p. 35.degree.-42.degree. C. 
B. Ethyl 6-(bromomethyl)benzofuran-2-carboxylate 
N-Bromosuccinimide (37.4 g., 0.21 mole) is added to a solution of 
ethyl-6-methylbenzofuran-2-carboxylate (40.8 g., 0.2 mole) and 
.alpha.,.alpha.'-azobisisobutyronitrile (500 mg.) in carbon tetrachloride 
(300 ml.). The suspension is boiled under reflux for 3 hours. It is then 
cooled and the succinimide removed by filtration. The carbon tetrachloride 
solution is washed with water and dried over sodium sulfate. The solution 
is then evaporated at reduced pressure. The solid residue is 
recrystallized from hexane to yield 47.4 g. (69%) of crystalline ethyl 
6-(bromomethyl)benzofuran-2-carboxylate, m.p. 95.degree.-102.degree. C. 
NMR (CDCl.sub.3): .delta.1.40 (3H,t,CH.sub.3), 4.40(2H,q,CH.sub.2 O), 4.58 
(2H, s,CH.sub.2 Br). 
C. Ethyl 6-(dimethylaminomethyl)benzofuran-2-carboxylate 
A solution of ethyl 6-(bromomethyl)benzofuran-2-carboxylate (47.0 g., 0.166 
mole) in ether (75 ml.) is added during 30 minutes to a stirred solution 
of dimethylamine (18.9 g., 0.42 mole) in ether (100 ml.). The temperature 
is kept at 0.degree.-5.degree. C. during the addition by means of an ice 
bath. The mixture is then stirred for 30 minutes without being cooled. The 
precipitated dimethylamine hydrobromide is removed by filtration. The 
ether solution is extracted with 400 ml. of 5% hydrochloric acid. The 
aqueous solution is made basic by the addition of 40% sodium hydroxide 
solution. The liberated amine is taken up in ether and dried over sodium 
sulfate. Evaporation of the solvent leaves as an oily residue 36.2 g. 
(88%) of ethyl 6-(dimethylaminomethyl)benzofuran-2-carboxylate. NMR 
(CDCl.sub.3): .delta.1.40 (3H, t,CH.sub.3 CH.sub.2),2.26(6H,s,CH.sub.3 
N),3.53(2H,s,CH.sub.2 N), 4.43(2H, q, CH.sub.2 O). 
D. 6-(Dimethylaminomethyl)-2-benzofuranmethanol 
Ethyl 6-(dimethylaminomethyl)benzofuran-2-carboxylate (36.1 g., 0.146 mole) 
in ether (150 ml.) is added dropwise during 1 hour to a stirred suspension 
of lithium aluminum hydride (5.5 g., 0.146 mole) in ether (150 ml.). The 
mixture is then cooled in an ice bath and treated successively with 5.7 
ml. of water, 5.7 ml. of 15% sodium hydroxide solution and 17 ml. of 
water. The precipitated white solid is removed by filtration. The ether 
solution is evaporated to give 29.6 g. of a crystalline residue of 
6-(dimethylaminomethyl)-2-benzofuranmethanol, m.p. 78.5.degree.-80.degree. 
C. 
E. 2-(2-Aminoethylthiomethyl)-6-(dimethylaminomethyl)-benzofuran 
6-(Dimethylaminomethyl)-2-benzofuranmethanol (28.3 g., 0.138 mole) is added 
to an ice-cold solution of cysteamine hydrochloride (17.2 g., 0.151 mole) 
in concentrated hydrochloric acid (70 ml.). The resulting solution is 
allowed to stand at room temperature for 45 hours. It is then cooled in an 
ice bath and made strongly basic by the addition of 10 N sodium hydroxide 
solution. The product is extracted with five portions of methylene 
chloride. The extracts are combined, washed with water and dried over 
Na.sub.2 SO.sub.4. Evaporation of the solvent leaves 29.8 g. (82%) of 
2-(2-aminoethylthiomethyl)-6-(dimethylaminomethyl)-benzofuran as an orange 
viscous oil. NMR (CDCl.sub.3): .delta.1.70 (2H, br s, NH.sub.2), 2.22 (6H, 
s, CH.sub.3 N), 2.65-2.9 (4H, m, SCH.sub.2 CH.sub.2 N), 3.44 (2H, s, 
PhCH.sub.2 N), 3.75 (2H, s, PhCH.sub.2 S), 6.45 (1H, s, furan H). 
F. N-Cyano-N'-[ 
2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-S-methylisothiour 
ea 
A solution of 2-(2-aminoethylthiomethyl)-6-(dimethylaminomethyl)benzofuran 
(12.0 g, 0.0454 mole) and dimethyl cyanodithioimidocarbonate (7.0 g., 
0.048 mole) in acetonitrile (48 ml.) is allowed to stand 2 hours at room 
temperature. The solvent is evaporated at reduced pressure and the viscous 
oily residue is chromatographed on a column of 250 g. of silica gel. 
Elution with 8% methanol in chloroform removes the product. There is 
obtained 14.6 g. (89%) of 
N-cyano-N'-[2-(6-dimethylaminomethyl-2-(benzofuranylmethylthio)ethyl]-S-me 
thylisothiourea as a yellow oil which gradually crystallizes, m.p. 
98.degree.-100.degree. C. 
G. 
N-Cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N"-me 
thylguanidine 
A solution of 
N-cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-S-met 
hylisothiourea (8.8 g., 0.024 mole) and methylamine (31 g.) in ethanol (90 
ml.) is allowed to stand at room temperature for 3 hours. The solvent is 
evaporated at reduced pressure. The residual oil gradually crystallizes, 
m.p. 62.degree.-65.degree. C. Two crystallizations of this product from 
acetonitrile-ether gives 7.0 g, (84%) of 
N-cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N"-me 
thylguanidine as white needles, m.p. 115.5.degree.-117.5.degree. C. 
EXAMPLE 2 
N-Cyano-N'-[2-(7-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N"-met 
hylguanidine 
This compound is prepared by the series of reactions described in Example I 
except that in Step A 7-methylbenzofuran-2-carboxylic acid is substituted 
for the 6-methylbenzofuran-2-carboxylic acid used in Example 1. The 
compounds thus obtained are: 
Step A--Ethyl 7-methylbenzofuran-2-carboxylate, b.p. 164.degree. C./18 mm. 
Hg. 
Step B--Ethyl 7-bromomethyl)benzofuran-2-carboxylate, m.p. 
81.degree.-83.degree. C. 
Step C--Ethyl 7-(dimethylaminomethyl)benzofuran-2-carboxylate 
Step D--7-(Dimethylaminomethyl)-2-benzofuranmethanol 
Step E--2-(2-Aminoethylthiomethyl)-7-(dimethylaminomethyl)benzofuran 
Step 
F--N-Cyano-N'-[2-(7-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-S- 
methylisothiourea 
Step 
G--N-Cyano-N'-[2-(7-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N" 
-methylguanidine, m.p. 103.5.degree.-105.5.degree. C. 
EXAMPLE 3 
N-Cyano-N'-[2-(5-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N"-met 
hylguanidine 
This compound is prepared by the series of reactions described in Example 1 
except that in Step A 5-methylbenzofuran-2-carboxylic acid is substituted 
for the 6-methylbenzofuran-2-carboxylic acid used in Example 1. The 
compounds thus obtained are: 
Step A--Ethyl 5-methylbenzofuran-2-carboxylate 
Step B--Ethyl 5-(bromomethyl)benzofuran-2-carboxylate 
Step C--Ethyl 5-(dimethylaminomethyl)benzofuran-2-carboxylate 
Step D--5-(Dimethylaminomethyl)-2-benzofuranmethanol 
Step E--2-(2-Aminoethylthiomethyl)-5l -(dimethylaminomethyl)benzofuran 
Step 
F--N-Cyano-N'-[2-(5-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-S- 
methylisothiourea 
Step 
G--N-Cyano-N'-[2-(5-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N" 
-methylguanidine 
EXAMPLE 4 
N-Cyano-N'-[2-(4-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N"-met 
hylguanidine 
This compound is prepared by the series of reactions described in Example 1 
except that in Step A 4-methylbenzofuran-2-carboxylic acid is substituted 
for the 6-methylbenzofuran-2-carboxylic acid used in Example 1. The 
compounds thus obtained are: 
Step A--Ethyl 4-methylbenzofuran-2-carboxylate 
Step B--Ethyl 4-(bromomethyl) benzofuran-2-carboxylate 
Step C--Ethyl 4-(dimethylaminomethyl)benzofuran-2-carboxylate 
Step D--4-(Dimethylaminomethyl)-2-benzofuranmethanol 
Step E--2-(2-Aminoethylthiomethyl)-4-(dimethylaminomethyl)benzofuran 
Step 
F--N-Cyano-N'-[2-(4-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-S- 
methylisothiourea 
Step 
G--N-Cyano-N'-[2-(4-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N" 
-methylguanidinee 
EXAMPLE 5 
N-Cyano-N'-[4-(6-dimethylaminomethyl-2-benzofuranyl)-butyl]-N"-methylguanid 
ine 
A. 2-(4-Bromobutyl)benzofuran-6-carboxylic acid 
n-Butyllithium solution (2.29 M in hexane, 44 ml., 0.1 mole) is added to a 
solution of diisopropylamine (10.1 g., 0.1 mole) in tetrahydrofuran (150 
ml.) and hexamethylphosphoramide (15 ml.). The resulting solution is 
treated with benzofuran-6-carboxylic acid (8.1 g., 0.05 mole) and then 
with 1,4-dibromobutane (10.8 g., 0.05 mole) at 0.degree. C. The mixture is 
stirred at 0.degree. C. for 6 hours. It is then quenched with water, 
acidified with hydrochloric acid and extracted with ethyl acetate. 
Evaporation of the solvent gives 2-(4-bromobutyl)benzofuran-6-carboxylic 
acid. 
B. Ethyl 2-(4-bromobutyl)benzofuran-6-carboxylate 
A solution of 2-(4-bromobutyl)benzofuran-6-carboxylic acid (29.7 g., 0.1 
mole) and sulfuric acid (0.5 ml.) in ethanol (200 ml.) is boiled under 
reflux. The solution is concentrated to 7/8 volume at reduced pressure. 
The residue is poured into water. The oily ester is extracted with ether. 
Evaporation of the solvent provides ethyl 
2-(4-bromobutyl)benzofuran-6-carboxylate. 
C. Ethyl 2-(4-phthalimidobutyl)benzofuran-6-carboxylate 
A solution of ethyl 2-(4-bromobutyl)benzofuran-6-carboxylate (3.25 g., 0.01 
mole) and potassium phthalimide (2.04 g., 0.011 mole) in dimethylformamide 
(25 ml.) is stirred at 25.degree.-27.degree. C. for 18 hours. The solution 
is poured into water. The precipitated ethyl 
2-(4-phthalimidobutyl)benzofuran-6-carboxylate is collected by filtration. 
D. Ethyl 2-(4-aminobutyl)benzofuran-6-carboxylate 
A solution of ethyl 2-(4-phthalimidobutyl)-benzofuran-6-carboxylate (3.9 
g., 0.01 mole) and hydrazine hydrate (0.55 g., 0.011 mole) in ethanol (20 
ml.) is heated at 60.degree. C. for 8 hours. The solvent is evaporated at 
reduced pressure. The solid residue is treated with water and 5 N sodium 
hydroxide solution and then is extracted with chloroform. The evaporation 
of the solvent from the organic extract provides ethyl 
2-(4-aminobutyl)benzofuran-6-carboxylate. 
E. N,N-Dimethyl-2-(4-aminobutyl)benzofuran-6-carboxamide 
A solution of ethyl 2-(4-aminobutyl)benzofuran-6-carboxylate (13.0 g., 0.05 
mole), dimethylamine (35 g.), and a catalytic amount of sodium ethoxide 
(approximately 100 mg.) in ethanol (100 ml.) is heated in a sealed 
pressure bottle at 65.degree. C. for 18 hours. Evaporation of the solvent 
provides N,N-dimethyl-2-(4-aminobutyl)benzofuran-6-carboxamide. 
F. 2-(4-Aminobutyl)-6-(dimethylaminomethyl)benzofuran 
N,N-dimethyl-2-(4-aminobutyl)benzofuran-6-carboxamide (13.0 g., 0.05 mole) 
in tetrahydrofuran (60 ml.) is added dropwise with stirring to lithium 
aluminum hydride (3.0 g., 0.08 mole) in tetrahydrofuran (60 ml.) at 
25.degree.-30.degree. C. The mixture is stirred for 2 hours at 
25.degree.-30.degree. C. and then is treated successively with 3 g. of 
water, 3 g. of 15% sodium hydroxide solution and 9 g. of water. The solid 
precipitate is removed by filtration. The tetrahydrofuran solution is 
evaporated at reduced pressure to provide 
2-(4-aminobutyl)-6-dimethylaminomethyl)benzofuran. 
G. 
N-Cyano-N'-[4-(6-dimethylaminomethyl-2-benzofuranyl)-butyl]-S-methylisothi 
ourea 
This compound is obtained by the reaction of 
2-(4-aminobutyl)-6-(dimethylaminomethyl)benzofuran with dimethyl 
cyanodithioimidocarbonate following the procedure described in Example 1, 
Step F. 
H. 
N-Cyano-N'-[4-(6-dimethylaminomethyl-2-benzofuranyl)butyl]-N"-methylquanid 
ine 
This compound is obtained by the reaction of 
N-cyano-N'-[4-(6-dimethylaminomethyl-2-benzofuranyl)butyl]-S-methylisothio 
urea with methylamine following the procedure described in Example 1, Step 
G. 
EXAMPLE 6 
N-Cyano-N'-[2-(6-diethylaminomethyl)-2-benzofuranylmethylthio)ethyl]-N"-met 
hylguanidine 
This compound is prepared by the series of reactions described in Example 2 
except that in Step C diethylamine is substituted for the dimethylamine 
used in Example 2, Step C. The subsequent compounds thus obtained are: 
Step C--Ethyl 6-(diethylaminomethyl)benzofuran-2-carboxylate 
Step D--6-(Diethylaminomethyl)-2-benzofuranmethanol 
step E--2-(2-Aminoethylthiomethyl)-6-(diethylaminomethyl)benzofuran 
Step 
F--N-Cyano-N'-[2-(6-diethylaminomethyl-2-benzofuranylmethylthio)ethyl]-S-m 
ethylisothiourea 
Step 
G--N-Cyano-N'-[2-(6-diethylaminomethyl)-2-benzofuranylmethylthio)ethyl]-N" 
-methylguanidine 
EXAMPLE 7 
N-Cyano-N'-[2-(6-(1-piperidinyl)methyl-2-benzofuranylmethylthio)ethyl]-N"-m 
ethylguanidine 
This compound is prepared by the series of reactions described in Example 1 
except that in Step C an equivalent quantity of piperidine is substituted 
for the dimethylamine in Example 1, Step C. The subsequent compounds thus 
obtained are: 
Step C--Ethyl 6-[(1-piperidinyl)methyl]benzofuran-2-carboxylate 
Step D--6-[(1-Piperidinyl)methyl]-2-benzofuranmethanol 
Step E--2-(2-Aminoethylthiomethyl)-6-[(1-piperidinyl)-methyl]benzofuran 
Step 
F--N-Cyano-N'-[2-(6-(1-piperidinyl)methyl-2-benzofuranylmethylthio)ethyl]- 
S-methylisothiourea 
Step 
G--N-Cyano-N'-[2-(6-(1-piperidinyl)methyl-2-benzofuranylmethylthio)ethyl]- 
N"-methylguanidine 
EXAMPLE 8 
N-[2-(6-Dimethylaminomethyl-2-benzofuranylmethylthio)-ethyl]-N'-methyl-2-ni 
tro-1,1-ethenediamine 
A. 
N-[2-(6-Dimethylaminomethyl-2-benzofuranylmethylthio)-ethyl]-1-methylthio- 
2-nitroetheneamine 
A solution of 2-(2-aminoethylthiomethyl)-6-(dimethylaminomethyl)benzofuran 
(Example 1, Step E) (8.0 g., 0.0303 mole) and 
1,1-bismethylthio-2-nitroethene (5.25 g., 0.0318 mole) in acetonitrile (80 
ml.) is heated at 55.degree. C. for 16 hours. The solvent is evaporated at 
reduced pressure. The residue is chromatographed on a column containing 
175 g. of silica gel made up in chloroform. The product is eluted with 5% 
methanol in chloroform and is obtained as a light orange viscous oil 
weighing 6.1 g. (53%). 
B. 
N-[2-(6-Dimethylaminomethyl-2-benzofuranylmethylthio)-ethyl]-N'-methyl-2-n 
itro-1,1-ethenediamine 
A solution of 
N-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-1-methylthio-2 
-nitroetheneamine (6.0 g., 0.0157 mole) and methylamine (20 g.) in ethanol 
(60 ml.) is allowed to stand 2 hours at 27.degree. C. The solvent was 
evaporated at reduced pressure. The solid residue is recrystallized from 
acetonitrile-ether to yield 3.1 g. (54%) of 
N-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N'-methyl-2-ni 
tro-1,1-ethenediamine, m.p. 113.degree.-114.degree. C. 
The products in the following table are prepared by the method of Step B of 
this Example except that methylamine is replaced by the appropriate amine 
R.sub.3 NH.sub.2 in the threefold or greater molar excess: 
______________________________________ 
##STR15## 
R.sub.3 M.P. .degree.C. 
______________________________________ 
CH.sub.2 CCH 155-156 
CH.sub.2 CHCH.sub.2 105-107 
##STR16## 148-149 
##STR17## 114-116 
CH.sub.2 CH.sub.2 OH 
125-128 
CH.sub.2 CH.sub.2OCH.sub.3 
115-116 
CH.sub.2 CH.sub.2N(CH.sub.3).sub.2 
89-90 
##STR18## 
##STR19## 109-112 
______________________________________ 
EXAMPLE 9 
N-Cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]guanidi 
ne 
A solution of 
N-cyano-N'-[2-(6-dimethylaminomethyl)-2-benzofuranylmethylthio)ethyl]-S-me 
thylisothiourea (Example 1, Step F) (6.27 g., 0.0173 mole) and ammonia (12 
g.) in ethanol (65 ml.) is heated in a sealed vessel for 36 hours at 
55.degree.-60.degree. C. Volatile materials are then removed by 
distillation at reduced pressure. The residual oil consisting of the 
nearly pure product is purified by column chromatography on 85 g. of 
silica gel with elution by a 10% solution of methanol in chloroform 
affording 
N-cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]guanid 
ine. 
EXAMPLE 10 
N-Cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N"-(2- 
propynyl)guanidine 
A solutiion of 
N-cyano-N'-[2-(6-dimethylaminomethyl)-2-benzofuranylmethylthio)ethyl]-S-me 
thylisothiourea (Example 1, Step F) (6.55 g., 0.018 mole) and 
propargylamine (4.0 g., 0.073 mole) in acetonitrile (100 ml.) is heated in 
a sealed pressure vessel at 110.degree.-120.degree. C. for 36 hours. The 
reaction solution is then evaporated at reduced pressure. 
N-cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N"-(2 
-propynyl)guanidine is obtained when the residual oil is chromatographed on 
silica gel with elution by an 8% solution of methanol in chloroform. 
EXAMPLE 11 
N-Benzyl-N'-cyano-N"-[2-(6-dimethylaminomethyl-2-benzofuranylthio)ethyl[gua 
nidine 
This compound is prepared by the procedure described in Example 10 except 
that an equivalent quantity of benzylamine is substituted for the 
proparglyamine used in Example 10. 
EXAMPLE 12 
N-[2-(6-Dimethylaminomethyl-2-benzofuranylmethylthio)-ethyl]-N'-(2-propenyl 
)thiourea 
A solution of 2-(2-aminoethylthiomethyl)-6-(dimethylaminomethyl)benzofuran 
(Example 1, Step E) (2.6 g., 0.01 mole) and allyl isothiocyanate (1.1 g., 
0.011 mole) in acetonitrile (15 ml.) is kept at 25.degree.-27.degree. C. 
for 16 hours. The solvent is evaporated and the residual oil 
chromatographed (silica gel/5% methanol in chloroform) to yield 
N-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N'-(2-propenyl 
)thiourea. 
EXAMPLE 13 
N-[2-(6-Dimethylaminomethyl-2-benzofuranylmethylthio)-ethyl]-N'-nitroguanid 
ine 
A solution of 2-(2-aminoethylthiomethyl)-6-(dimethylaminomethyl)benzofuran 
(Example 1, Step E) (2.6 g., 0.01 mole) and S-methyl-N-nitroisothiourea 
(1.4 g., 0.01 mole) in acetonitrile (15 ml.) is kept at 
25.degree.-27.degree. C. for 4 hours. The solvent is evaporated and the 
residue chromatographed on silica gel (5% methanol in chloroform elution) 
to yield 
N-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N'-nitroguanid 
ine. 
EXAMPLE 14 
N-[2-(6-Dimethylaminomethyl-2-benzofuranylmethylthio)-ethyl]-N'-methanesulf 
onyl-N"-methylguanidine 
A solution of 2-(2-aminoethylthiomethyl)-6-(dimethylaminomethyl)benzofuran 
(Example 1, Step E) (2.6 g., 0.01 mole) and 
methanesulfonyliminodithiocarbonic acid dimethyl ester (2.0 g., 0.01 mole) 
in methanol (15 ml.) is kept at 25.degree.-27.degree. C. for 4 hours. A 
solution of 10 g. of methylamine in 35 ml. of methanol is added and the 
resulting solution is kept at 25.degree.-27.degree. C. for 16 hours. The 
solvent is evaporated to leave 
N-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)-ethyl]-N'-methanesul 
fonyl-N"-methylguanidine as a residual oil which is purified by column 
chromatography (silica gel/5% methanol in chloroform). 
EXAMPLE 15 
N-Cyano-N'-[3-(6-dimethylaminomethyl-2-benzofuranylmethylthio)propyl]-N"-me 
thylguanidine 
This compound is prepared by the series of reactions described in Example 1 
except that in Step E an equivalent amount of 3-amino-1-propanethiol 
hydrochloride is substituted for the cysteamine hydrochloride employed in 
Example 1, Step E. The subsequent compounds thus obtained are: 
Step E-2-(3-Aminopropylthiomethyl)-6-(dimethylaminomethyl)benzofuran 
Step 
F--N-Cyano-N'-[3-(6-dimethylaminomethyl-2-benzofuranylmethylthio)propyl]-S 
-methylisothiourea 
Step 
G--N-Cyano-N'-[3-(6-dimethylaminomethyl-2-benzofuranylmethylthio)propyl]-N 
"-methylguanidine