Indolyl derivatives and their use as 5-HT.sub.3, receptor antagonists

New pharmacologically active amidino and guanidino derivatives which are 5-HT.sub.3 receptor antagonists useful as antiemetic, gastric prokinetic and antimigrainic agents of the following general formula (I) ##STR1## , wherein the substituents are defined hereinbelow, which compounds are 5-HT.sub.3 receptor antagonists useful as antiemetic gastric prokinetic and antimigraine agents, inter alia.

The present invention relates to novel pharmacologically active amidino and 
guanidino derivatives, to the process for their preparation and to the 
pharmaceutical compositions containing them. The new compounds are 
5-HT.sub.3 receptor antagonists useful as antiemetic, gastric prokinetic 
and antimigraine agents. 
Serotonin (5-HT) is known to play a major role both in the central nervous 
system (CNS) and in peripheral nervous system (PNS). Furthermore it is 
known that there are different subtypes of receptors for 5-HT; the 
receptors which have been emphasized on the nervous terminations are 
called neuronal 5-HT receptors or M-receptors or 5-HT.sub.3 receptors (B. 
P. Richardson, G. Egel "Trends in Neurological Sciences" 1986, 424). 
Compounds acting as 5-HT.sub.3 receptor antagonists may be effectively 
used in the prevention and treatment of migraine, cluster headaches and 
trigeminal neuralgia. Since these compounds may have a beneficial role on 
gastrointestinal motility, a further use of these compounds is in delayed 
gastric emptying, dyspepsia, flatulence, gastroesophageal reflux, peptic 
ulcer, constipation and irritable bowel syndrome. It has been also 
discovered that some 5-HT.sub.3 antagonists may be particularly useful in 
the treatment of chemotherapy or radiation induced nausea and emesis (J. 
R. Fozard "Trends in Pharmacological Sciences" 8, 44 1987). 
The patent applications GB 2,125,398 A, EP 223 385, EP 254 584, EP 067 770 
and U.S. Pat. No. 3,177,252 describe for these uses esters or amides 
derivatives of substituted heterocyclic or arylic acids, having as 
substituent of carboxylic acid a basic chain, generally azabicycloalkanic. 
We have now synthesized, and this is the object of the present invention, a 
novel class of structurally distinct compounds showing specific 5-HT.sub.3 
receptor blocking activity, surprisingly superior to the one of the known 
compounds, object for example of the above mentioned patent applications. 
These new compounds may be useful for the treatment of chemotherapy and 
radiation induced nausea and emesis and/or delayed gastric emptying. They 
may be also of value in the treatment of arrhytmia, motion sickness, 
migraine, cluster headaches, trigeminal neuralgia, anxiety, stress 
psychical illness and psychoses. Moreover they may be used in 
gastrointestinal motility disorders such as dyspepsia, flatulence, 
oesophageal reflux, peptic ulcer, constipation, irritable bowel syndrome 
and ipokinesia, and also in arrhytmia and in rhinitis. 
The compounds object of the present invention have the general formula (I) 
##STR2## 
wherein 
A is a group selected from substituted benzene 
##STR3## 
EQU (R.sub.2).sub.n 
R.sub.2 is H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy optionally substituted by 
halogen , hydroxy, acetyl, or R.sub.2 is C.sub.1-6 alkeniloxy, C.sub.1-6 
alkynyloxy, halogen, amino, C.sub.1-6 alkylamino, nitro, sulphonylamino 
and n is 0-4 or 
mono- or bicyclic heterocycle selected from 
##STR4## 
wherein 
R.sub.3 is H, halogen, C.sub.1-6 alkoxy 
R.sub.4 is H, C.sub.1-6 alkyl 
X represents --O-- or --NH-- 
B is a group selected from 
##STR5## 
wherein 
m is 1, 2 
p is 0, 1, 2, 
q is 0, 1, 2, 3 
R.sub.5 is H, C.sub.1-6 alkyl 
R represents H, C.sub.1-6 alkyl optionally substituted by halogen, NR.sub.6 
R.sub.7 in which R.sub.6 is H, C.sub.1-6 alkyl, NO.sub.2, CN and R.sub.7 
is H, C.sub.1-6 alkyl; and 
R.sub.1 represents H, C.sub.1-6 alkyl optionally substituted by halogen, or 
CN. 
For the pharmaceutical use the compounds of general formula (I) are used as 
such or under the form of physiologically compatible acid addition salts. 
The term "acid addition salts" includes salts with inorganic or organic 
acids. Physiologically compatible acids used for the salification, 
include, for example, maleic, citric, tartaric, fumaric, methansulphonic, 
hydrochloric, hydrobromic, sulphuric, nitric, acetic, benzoic, ascorbic 
and phosphoric acids. The compounds of general formula (I) and their 
physiological acceptable salts may also exist as physiological acceptable 
solvates, such as hydrates, which constitute a further feature of the 
present invention. Although the double bond in the amidine radical is 
indicated in general formula (I) as present in a particular position, 
other tautomeric forms are also possible. The present invention includes 
therefore such tautomeric forms as regards both the compounds and the 
processes of their preparation. 
Some of the compounds of formula (I), according to the present invention, 
contain chiral or prochiral centers and thus they may exist in different 
stereoisomeric forms including enantiomers of (+) and (-) type, 
diastereoisomers or mixture of them. The present invention includes 
therefore both the individual isomers and the mixture thereof. It has to 
be understood that, when mixtures of optical isomers are present, they may 
be separated according to the classic resolution methods based on their 
different physicochemical properties, e.g. by fractional crystallization 
of their acid addition salts with a suitable optically active acid or by 
the chromotographic separation with a suitable mixture of solvents. 
In the present invention the term A of formula (a) means preferably 
2-alkoxy-4-amino-5-halobenzene, 2-alkoxy-5-sulphonamidobenzene, 
2-alkoxy-4-amino-5-nitro-benzene or 2-metoxy-4-alkylamine-5-halobenzene. 
The term halogen means fluorine, chlorine, bromine or iodine. The &term A 
of formula (b) means 3-linked indole, the one of formula (c) means 
3-linked indazole, the one of formula (d) means 3-linked pyridine, the one 
of formula (e) means 3-linked quinoline, the one of formula (f) means 
3-linked 2-methylbenzothiophene, the one of formula (g) means 5-linked 
6-methoxy-1H-benzotriazole and the one of formula (h) means 3-linked 
indolizine. The group B of formula (b) means 3-linked 
8-azabicyclo[3.2.1]octane, 3-linked 9-azabicyclo[3.3.1]nonane, 2-linked 
7-azabicyclo[2.2.1]eptane or 4-linked piperidine. It has to be understood 
that in the compounds of general formula (I) the azabicyclic moieties of 
the group B of formula (b) may be endo or exo substituted. Compounds of 
general formula (I) containing the pure endo or exo moieties may be 
prepared starting from the appropriate precursors or by separating the 
mixtures of the endo or exo isomers not stereospecifically synthesized by 
conventional methods, such as e.g. chromatography. The endo substitution 
is preferred. 
The compounds of general formula (I) may be prepared by reacting a compound 
of general formula (II) 
##STR6## 
wherein X, B, R and R.sub.1 are as hereinbefore defined, optionally in the 
form of its acid addition salts, with a reactive compound of formula (III) 
EQU A--CO Y (III) 
wherein A is as hereinbefore defined and Y is a leaving group such as 
chlorine, imidazolyl, OCOAlk (where Alk is methyl optionally substituted 
by fluorine or ethyl), or OH. When Y is OH the reaction is carried out in 
the presence of suitable condensing agents such as 
dicyclo-hexylcarbodiimide (DCC). The reaction may be conveniently carried 
out in aprotic solvents such as methylene dichloride, chloroform, 
dimethylformamide, tetrahydrofurane, dioxane, toluene at a temperature 
ranging from 0.degree. to 130.degree. C., preferably for 0.degree. to 
60.degree. C. The presence of an acid acceptor, such as triethylamine or 
pyridine may be beneficial in some cases. In other cases the presence of a 
strong base such as sodium hydride or 1,8-diazabicyclo[5.4.0]undec-7-ene 
(DBU) may be advantageous. 
Compounds of general formula (II), used as starting material in the above 
process, may be obtained by reacting compounds of formula (IV) 
EQU P--X--B--H (IV) 
wherein X and B are as hereinbefore defined, and P is hydrogen or 
protecting group, with compounds of formula (V) 
##STR7## 
wherein R and R.sub.1 are as hereinbefore defined, and Z is leaving group 
such as C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, halogen, phenoxy. The 
compounds of formula (V) may be in the form of addition salts with organic 
or mineral acids such as hydrochloric, hydrobromic, idroiodic, sulphuric, 
nitric, tetrafluoboric, alklsulphonic, arylsulphonic, thiocianic acid, 
preferably hydrochloric and sulphuric acid. The reaction may be 
conveniently carried out in a polar solvent such as methanol, ethanol, 
acetonitrile, acetone, ethylacetate, dimethylformamide, 
dimethylsolphoxide, water or mixtures of them at a temperature ranging 
from 10.degree. to 120.degree. C., preferably from 25.degree. to 
80.degree. C. The protecting groups P may be, for example, acetyl, 
benzoyl, carbobenzyloxy, p-nitrocarbobenzyloxy, benzyl, 
2,4-dimetoxybenzyl, benzhydryl, trityl, and they may be removed by 
conventional methods, for example by catalytic or transfer hydrogenation, 
acid or basic hydrolysis. The compounds of formula (II) in which X and B 
are as hereinbefore defined, R is NH.sub.2 and R.sub.1 is H, may be 
obtained by reacting compounds of formula (IV) with cyanamide. 
The reaction may be carried out without solvent or in water, ethanol, at a 
temperature ranging from 70.degree. C. to melting temperature of the 
mixture. 
The compounds of formula (II) in which X, B and R are as hereinbefore 
defined, and R is H, may be obtained by reacting compounds of formula (VI) 
##STR8## 
wherein P, X, B, Alk are as hereinbefore defined, with amines of formula 
(VII) 
EQU H.sub.2 N--R.sub.1 (VII) 
wherein R.sub.1 is as hereinbefore defined. The reaction may be 
conveniently carried out in an inert solvent such as methylene dichloride, 
chloroform, benzene, toluene, acetonitrile, diethyl ether, dioxane, 
tetrahydrofurane or without solvent, at a temperature ranging from: 
-10.degree. to 80.degree. C., preferably from 0.degree. to 40.degree. C. 
The intermediates of formula (VI) may be prepared by reacting compounds of 
formula (IV) and dimethylformamide dialkylacetale. The reaction may be 
conveniently carried out in an inert solvent, such as methylene 
dichloride, diethyl ether, tetrahydrofurane, dioxane, benzene, toluene, 
acetonitrile chloroform or without solvent at a temperature ranging from 
0.degree. to 110.degree. C., preferably from 20.degree. to 60.degree. C. 
The compounds of formula (II) in which X, B and R are as hereinbefore 
defined and R is H may also be prepared by desulphurizing thioureas of 
formula (VIII) 
##STR9## 
The reaction may be carried by Nickel Raney or by H.sub.2 O.sub.2 in an 
appropriate solvent such as methylene dichloride, chloroform, methanol, 
ethanol, water or mixtures of them, at a temperature ranging from 
10.degree. to 70.degree. C., preferably at room temperature. The thioureas 
of formula (VIII) may be obtained by reacting a compound of formula (IV) 
with ammonium thiocyanate or with an isothiocyanate of formula (IX) 
EQU R.sub.1 --N.dbd.C.dbd.S (IX) 
wherein R.sub.1 is as hereinbefore defined. The reaction may be 
conveniently carried out in solvents such as water, methanol, ethanol, 
tetrahydrofurane, acetone or benzenene at a temperature from 25.degree. to 
100.degree. C., preferably from 40.degree. to 80.degree. C. 
The compounds of general formula (II) in which X, B and R.sub.1 are as 
hereinbefore defined, and R is NR.sub.6 R.sub.7 may be prepared by 
reacting compounds of formula (X) 
##STR10## 
wherein X, B, Alk and R.sub.1 are as hereinbefore defined, with an amine 
of formula (XI) 
EQU HNR.sub.6 R.sub.7 (XI) 
wherein R.sub.6 and R.sub.7 are hereinbefore defined. The reaction may be 
carried out in polar solvents such as methanol, ethanol, isopropanol, 
water, dimethylformamide or mixtures of them at a temperature ranging from 
0.degree. and 100.degree. C., preferably at room temperature. The 
compounds of formula (X) may be obtained from the compounds of formula 
(IV) and dithioalkylamido carbonates of formula (XII) 
##STR11## 
The reaction may be carried out in polar solvents such as methanol, 
ethanol, isopropanol, water, dimethylformamide or mixtures of them at a 
temperature from 0.degree. to 100.degree. C., preferably at room 
temperature. 
The compounds of general formula (I) may be also prepared by reacting a 
reactive compound of general formula (V) with a compound of general 
formula (XIII) 
EQU A--CO--X--B--H (XIII) 
wherein A, X and B are as hereinbefore defined, in a polar solvent, such as 
methanol, ethanol, acetonitrile, acetone, ethylacetate, dimethylformamide, 
dimethylsulfoxide, water or mixtures of them at a temperature ranging from 
10.degree. to 120.degree. C., preferably from 25.degree. to 80.degree. C. 
The compounds of formula (V) may be in the form of addition salts with 
organic or mineral acids. The case in which R is NH.sub.2 and R.sub.1 is 
H, the same compounds may be obtained by reacting compounds of formula 
(XIII) with cyanamide in the presence of water, ethanol or without solvent 
at a temperature ranging from 70.degree. to the melting temperature of the 
mixture. 
The intermediates of formula (XIII) may be obtained by reacting a compound 
of formula (III) with a compound of formula (XIV) optionally as acid 
addition salt, 
EQU H--X--B--Q (XIV) 
wherein X and B are as hereinbefore defined, and Q is H or a protecting 
group. 
The protecting group Q may be benzyl, benzhydryl, vinyloxy carbonyl, 
benzyloxy carbonyl and it may be removed by conventional methods, such as 
catalytic or transfer hydrogenation, treatment with acids or bases. The 
reaction may be performed in solvents, such as methylene dichloride, 
chloroform, dimethylformamide, tetrahydrofurane, dioxane, toluene at a 
temperature ranging from 0.degree. to 130.degree. , preferably from 
0.degree. to 60.degree. C. The presence of an acid acceptor such as 
triethylamine or pyridine may be advantageous in some cases as well as the 
presence of a strong base such as NaH or DBU. 
The compounds of general formula (I), in which R is H, may be prepared by 
reacting an amine of formula (VII) with a compound of general formula (XV) 
##STR12## 
wherein A, X, B and Alk are as hereinbefore defined, in inert solvents, 
such as methylene dichloride, chloroform, benzene, toluene, acetonitrile, 
diethyl ether, dioxane, tetrahydrofurane or without solvents at a 
temperature ranging from -10.degree. to 80.degree. C., preferably from 
0.degree. to 40.degree. C. 
The intermediates of formula (XV) are obtained by reacting a compound of 
formula (XIII) with dimethylformamide dialkylacetale in an inert solvent 
such as methylene dichloride, chloroform, diethyl ether, tetrahydrofurane, 
dioxane, benzene, toluene, acetonitrile or without solvent at a 
temperature ranging from 0.degree. to 110.degree. C., preferably from 
20.degree. to 60.degree. C. 
The compounds of general formula (I) in which R is H, may be also prepared 
by desulphurizing thioureas of formula (XVI) 
##STR13## 
by Nickel Raney or by H.sub.2 O.sub.2 in an appropriate solvent such as 
methylene dichloride, chloroform, methanol, ethanol, water or mixtures of 
them at a temperature ranging from 10.degree. to 70.degree. C., preferably 
at room temperature. 
The intermediates of formula (XVI) may be obtained by reacting compounds of 
formula (XIII) with ammonium thiocyanate or with isothiocyanates of 
formula (IX) in solvents, such as water, methanol, ethanol, 
tetrahydrofuran, acetone at a temperature ranging from 25.degree. to 
100.degree. C., preferably from 40.degree. to 80.degree. C. 
The compounds of general formula (I) in which R is NR.sub.6 R.sub.7 may be 
also prepared by reacting an amine of formula (XI) with a compound of 
formula (XVII) 
##STR14## 
wherein A, X, B, Alk and R.sub.1 are as hereinbefore defined. The reaction 
may be performed in polar solvents such as methanol, ethanol, isopropanol, 
water, dimethylformamide or mixtures of them at a temperature ranging from 
0.degree. and 100.degree. C., preferably at room temperature. The 
compounds of formula (XVII) may be obtained by reacting the intermediates 
of formula (XII) and XIII) in polar solvents such as methanol, ethanol, 
isopropanol, water, dimethylformamide or mixtures of them at a temperature 
ranging from 0.degree. and 100.degree. C., preferably at room temperature. 
It has to be understood that compounds of general formula (I) containing an 
A, R and R group which may give rise to another A, R and R' group are 
useful novel intermediates. Some of these transformations may also occur 
in the intermediates for compounds of general formula (I). Some examples 
of such conversion, which obviously do not include all possibilities, are: 
1) A N-nitroguanidine may be transformed into a guanidine by reduction. 
2) A heterocyclic N-H may be transformed into a N-alkyl group by 
alkylation. 
3) A N-cyanoformamidinic group may be transformed into a 
N-alkylformamidinic group by reaction with an alkylamine. 
4) N-cyanoguanidinic group may be transformed in guanidinic group by 
treatment with acids. 
These transformations are well known to any chemist skilled in the art. 
The compounds of formula (I) prepared according to the processes as above 
described may be optionally converted with inorganic or organic acids into 
the corresponding physiologically compatible acid addition salts for 
example by reacting with conventional methods the compounds as bases with 
a solution of the corresponding acid in a suitable solvent. Particularly 
preferred acids include for example hydrochloric, sulphuric, hydrobromic, 
acetic, citric, tartaric acids. 
Preferred groups of compounds according to the present invention for their 
better activity as 5-HT.sub.3 receptor blocking agents are those formed by 
the compounds of general formula (I) in which: 
--A is 2-methoxy-4-amino-5-chlorophenyl, B is the group (a), X is NH, R and 
R.sub.1 are as above defined 
--A is 3-linked 1H-indol, 3-linked 1-methylindazol, 3,5-dimethylphenyl or 
3,5-dichlorophenyl, B is the group (b), and X, R and R.sub.1 are as above 
defined. 
--A is 2-methoxy-4-amino-5-chlorophenyl, B is the group (c), X is NH, R and 
R.sub.1 are as above defined. 
As already mentioned hereinbefore the new compounds of formula (I), 
according to the present invention, have interesting pharmacological 
properties owing to their ability to antagonize the physiological 5-HT 
effects at 5-HT.sub.3 receptors in warm-blooded animals. Therefore the new 
compounds are commercially useful in the prevention and in the treatment 
of disorders wherein 5-HT.sub.3 receptors are involved, such as 
chemotherapy or radiation induced nausea and emesis, migraine, delayed 
gastric emptying, stress-induced psychological disorders, irritable bowel 
syndrome, arrhytmia and rhinitis. 
The following test shows that the compounds, object of the present 
invention, have favorable characteristics in this respect. 
PHARMACOLOGY 
Bezold-Jarish reflex in anesthetized rats 
Rats (250-275 g) were anesthetized with urethane (1.25 g/kg ip.). The blood 
pressure and the heart rate were recorded from the left femoral artery by 
means of a pressure transducer (Statham) connected with a 
cardiotachometer. The Bezold-Jarish reflex was elicited by rapid 
intravenous injection of serotonin (20 .mu.g/kg). 
Increasing doses of antagonists were injected 5 min. before serotonin to 
evaluate their effect on the initial bradycardia and associated fall in 
blood pressure resulting from the reflex vagal stimulation. In other 
experiments, the right vagus nerve was stimulated with platinum electrodes 
at 10 V, 10Hz, 2 msec, (Grass 248 stimulator), to evoke bradycardia. 
ED.sub.50 values were calculated by linear regression analysis of the data 
expressed as percentage inhibition. The obtained potency of three 
compounds object of the present invention is shown below: 
______________________________________ 
Bradycardia Hypotension 
ED.sub.50 (.mu.g/kg.sup.-1, i.v.) 
ED.sub.50 (.mu.g/kg.sup.-1, i.v.) 
______________________________________ 
Compound 7 
0.04 0.06 
Compound 15 
0.2 0.5 
Compound 16 
0.01 0.3 
______________________________________ 
According to a further feature of the present invention there are provided 
pharmaceutical compositions comprising as active ingredient at least one 
compound of formula (I), as hereinbefore defined, or a physiologically 
compatible acid addition salt thereof in association with pharmaceutical 
carriers or excipients. For pharmaceutical administration the compounds of 
general formula (I) and their physiologically compatible acid addition 
salts may be incorporated into the conventional pharmaceutical 
preparations in either sold or liquid form. The compositions may, for 
example, be presented in a form suitable for oral, rectal or parenteral 
administration. Preferred forms include, for example, capsules, tablets, 
coated tablets, ampoules, suppositories and oral drops. 
The active ingredient may be incorporated in excipients or carriers 
conventionally used in pharmaceutical compositions such as, for example, 
talc, gum arabic, lactose, gelatin, magnesium stearate, corn starch, 
aqueous or non-aqueous vehicles, polyvinylpyrrolidone, mannitol, 
semisynthetic glycerides of fatty acids, sorbitol, propylene glycol, 
citric acid, sodium citrate. 
The compositions are advantageously formulated as dosage units, each dosage 
unit being adapted to supply a single dose of the active ingredient. Each 
dosage unit may conveniently contain from 5 mg to 100 mg and preferably 
from 10 mg to 50 mg of the above ingredient. 
The following examples illustrate some of the new compounds according to 
the present invention, but they are not to be considered in any way 
limiting of the scope of the invention itself:

EXAMPLE 1 
S-Methyl-N-cyano-(4-hydroxy)-piperidin-1-thiocarboxymidate 
A solution of 4-hydroxypiperidine (3 g) in ethanol (10 ml) was added 
dropwise to a suspension of dithiomethylcyanoimidocarbonate (4.3 g) in 
ethanol (20 ml). The reaction mixture was stirred at room temperature for 
24 hours, then the solvent was evaporated under nitrogen. Crystallization 
of the residue from ethyl acetate afforded the title compound (3.9 g). 
M.p. 90.degree.-92.degree. C. 
Analogously the following intermediate was obtained: 
S-Methyl-N-cyano-endo-(3-hydroxy)-8-azabicyclo[3.2.1]octan-8-thiocarboxymid 
ate 
M.p. 103.degree.-105.degree. C. 
EXAMPLE 2 
1-(N-Cyano-N',N'-dimethyl)guanyl-4-hydroxypiperidine 
Dimethylamine (19 g) was added dropwise to a solution of 
S-methyl-N-cyano-(4-hydroxy)-piperidin-1-thiocarboxymidate (4 g) in 
ethanol (250 ml). The reaction mixture was stirred at room temperature for 
4 days, then the solvent was degased by nitrogen and evaporated under 
vacuum. The residue was chromotographed on silica (eluent CH.sub.2 
Cl.sub.2 /CH.sub.3 OH 95:5). Thus the title compound was obtained (2.15 
g). M.p. 103.degree.-105.degree. C. 
Analogously the following intermediates can be obtained: 
1-(N-Cyano-N'-methyl)guanyl-4-hydroxypiperidine M.p. 120.degree. C. 
endo-8-(n-Cyano-N'-methyl)guanyl-8-azabicyclo[3.2.1]octan-3-ol. M.p. 
130.degree.-132.degree. C. 
EXAMPLE 3 
endo-8-(N-Cyanoguanyl)-8-azabicyclo3.2.11octan-3-ol 
A suspension of endo-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (2.0 g) 
and sodium dicyanamide (1.2 g) in n-butanol (6.25 ml) was heated at 
140.degree. C. for 2.5 hours. The reaction mixture was concentrated to 
dryness, the solid residue was taken up with water and the insoluble solid 
was collected by filtration. After washing accurately with water and after 
drying under vacuum 1.25 g of the desired product sufficiently pure were 
obtained. M.p. 197.degree.-200.degree. C. 
EXAMPLE 4 
N-Nitro-N'-aminoethylguanidine hydrochloride 
To a solution of N-triphenylmethyl-1,2-diamino ethane (2 g) in methylene 
chloride/methanol 1:1 (40 ml) a suspension of 
2-methyl-1(3)-nitro-2-pseudo-thiourea (0.9 g) in methylene 
chloride/methanol 1:1 (40 ml) was added. The resulting solution was 
stirred at room temperature for 24 hours. 
N-Nitro-N'-(2-triphenylmethylaminoethyl)guanidine, m.p. 
229.degree.-230.degree. C. was obtained by filtration. The triphenylmethyl 
protection was removed by hydrolysis with hydrochloric acid in 
ethanol/water, yielding the desired compound (0.5 g), M.p. 
217.degree.-219.degree. C. 
EXAMPLE 5 
1-(N',N'-Dimethylguanyl)-4-hydroxypiperidine hydrochloride 
A solution of 1-(N-cyano-N',N'-dimethyl)guanyl-4-hydroxypiperidine (2.7 g) 
in 50% HCl (30 ml) was heated at 100.degree. C. for 1 hour. The water was 
evaporated and the residue was freeze-dried obtaining the title compound 
which was used as such in the following reaction. M.p. 
60.degree.-65.degree. C. 
Similarly the following intermediates can be obtained: 
1-(N-Methylguanyl)-4-hydroxypyrimidine, hydrochloride. M.p. 
55.degree.-60.degree. C. 
endo-8-(N-Methylguanyl)-8-azabicyclo[3.2.1]octan-3-ol hydrochloride. M.p. 
244.degree.-245.degree. C. 
EXAMPLE 6 
endo-8-guanyl-8-azabicyclo3.2.11octan-3-ol hydrochloride 
A mixture of endo-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (10.0 g) and 
cyanamide (5.14 g) was heated with stirring for 3 hours at 120.degree. C. 
and then allowed to cool. It was taken up with 30 ml of warm absolute 
ethanol, acidified with alcoholic HCl and the insoluble solid was 
collected by filtration. The desired product was crystalized from absolute 
ethanol. M.p.&gt;270.degree. C. 
Analysis; 
Found % C 46.72, H 7.86, N 20.601, 
C.sub.8 H.sub.15 N.sub.3 O.multidot.HCl; 
Calc. % C 46.71, H 7.84.1, N 20.43. 
Analogously the following intermediates can be obtained: 
endo-9-Guanyl-9-azabicyclo[3.3.1]nonan-3-ol hydrochloride. M.p. 
186.degree.-189.degree. C. 2-Aminomethyl-1-guanylpyrrolidine 
hydrochloride. 
EXAMPLE 7 
endo-8-Imino methyl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride 
Ethyl formimidate hydrochloride (1.9 g), newly prepared, was added to a 
solution of endo-8-azabicyclo[3.2.1]octan-3-ol (2.0 g) in absolute ethanol 
(60 ml). The reaction mixture was stirred for 3 hours at room temperature, 
then some more ethyl formimidate were added (0.86 g) and stirring was 
continued for 3 hours. The reaction mixture was then allowed to stand at 
room temperature (r.t.) overnight. After concentration to dryness the 
obtained residue was chromatographed on Silicagel (eluent CH.sub.2 
Cl.sub.2 /CH.sub.3 OH/CH.sub.3 COOH/H.sub.2 O 80:20:10:2). After 
crystallization from a mixture of absolute ethanol and acetone 0.5 g of 
the desired product were obtained. A further crystallization gave a 
product with M.p. 177.degree.-178.degree. C. 
EXAMPLE 8 
1-(1'-Iminoethyl)-4-hydroxypiperidine hydrochloride 
1.46 g of ethyl acetoimidate hydrochloride was added to a solution of 
4-hydroxy-piperidine (1.0 g) in 10 ml of absolute ethanol. The resulting 
mixture was stirred at room temperature for 6 hours and then allowed to 
stand for 7 days. After concentration to dryness the obtained oil 
spontaneously solidified. After crystallization from acetone 0.7 g of the 
desired product were obtained. 
M.p. 78.degree.-80.degree. C. 
Analogously the following intermediate can be obtained: 
1-(1'-Iminoethyl)-2-aminomethyl)-pyrrolidine hydrochloride. 
EXAMPLE 9 
endo-8-(N-Methylthiocarbamoyl)-8-azabicyclo[3.2.1]octan-3amine 
hydrochloride 
a) 1.5 g of endo-3-acetylamino-8-azabicyclo[3.2.1]octane hydrochloride was 
dissolved in methanol and passed through an IRA 400 resin column (OH 
form). After concentration of the fractions containing the desired 
product, 1.1 g of endo-3-acetylamino-8-azabicyclo[3.2.1]octane as a free 
base was collected and used directly for the following step. 
b) 0.5 g of methylisothiocyanate in 50 ml ol tetrahydrofurane (THF) were 
added to a solution of endo-3-acetylamino-8-azabicyclo[3.2.1]octane (1.1 
g) in THF (100 ml). After a few minutes of stirring the precipitation of 
white solid was noted. The stirring was kept on for 2 hours and then the 
solid was collected by filtration. 1.25 g of 
endo-3-acetylamino-8-(N-methyl thiocarbamoyl)-8-azabicyclo[3.2.1]octane 
obtained. M.p. 259.degree.-260.degree. C. 
c) 1.2 g of endo-3-acetylamino-8-(N-methyl 
thiocarbamoyl)-8-azabicyclo[3.2.1]octane were hydrolized in 100 ml of 17% 
HCl at 100.degree.-110.degree. C. for 24 hours. The concentration to 
dryness of the reaction mixture gave 1.02 g of the desired product. M.p. 
244.degree.-245.degree. C. The base can be obtained by conventional 
methods. 
EXAMPLE 10 
endo-(8-Azabicyclo[3.2.1]oct-3-yl)-3,5-dichlorobenzoate 
a) A solution of 3,5-dichlorobenzoylchlpride (11.8 g) and of 
endo-8-vinyloxy-carbonyl-8-azabicyclo[3.2.1]octan-3-ol (11.1 g) in 
pyridine (200 ml) was stirred at room temperature for 5 hours and then 
concentrated to dryness. The residue was taken up with ethyl acetate and 
the organic layer was washed with diluted HCl, with diluted NaOH and with 
water until neutrality. The raw product, so obtained, was crystallized 
from diisopropyl ether and then from acetonitrile. 11.4 g of 
endo-[8-vinyloxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-3,5dichlorobenzoate 
were obtained. M.p. 137.degree.-138.degree. C. 
b) A solution of bromine (5.2 g) in methylene chloride (40 ml) was added 
dropwise, under stirring, to a solution of 
endo-[8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-3,5-dichlorobenzoa 
te (12.0 g) in the same solvent (200 ml) until the reddish-yellow color 
remained visible for some seconds. The reaction mixture was concentrated 
to dryness, taken up with methanol and refluxed for 30 minutes. After 
cooling the hydrobromide of the desired product was separated. M.p. 
249.degree.-250.degree. C. (dec.). The base was obtained by conventional 
methods. 7.0 g M.p. 182.degree.-184.degree. C. 
Analogously the following intermediate was obtained: 
endo-N-(9-Azabicyclo[3.2.1]non-3-yl)-1-methylindazol3-carboxamide 
hydrochloride. M.p. 151.degree.-155.degree. C. 
EXAMPLE 11 
endo-(8-Azabicyclo3.2.11oct-3-yl)-3,5-dimethylbenzoate 
A suspension of endo-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (3.5 g) 
and 3,5-dimethylbenzoylchloride (4.8 g) in 0-dichloro benzene was heated 
at 150.degree.-160.degree. C. for 3 hours until the stirring stuck. After 
cooling the residue was taken up with water and the acid aqueous layer was 
washed with ethyl acetate. After alkalization with 10% NaOH, the desired 
product was extracted with ethyl acetate. 2.7 g were obtained. M.p. 
137.degree.-138.degree. C. 
Analogously the following intermediates were obtained: 
endo-(9-Azabicyclo[3.3.1]non-3-yl)-1H-indol-3-carboxylate. 
M.p. 230.degree. C. (dec.) 
endo-(8-Azabicyclo[3.2.1]oct-3-yl)-3-quinolinecarboxylate. 
M.p. 199.degree.-200.degree. C 
(Piperidin-4-yl)-3,5-dimethylbenzoate hydrochloride. 
M.p. 214.degree.-215.degree. C. 
EXAMPLE 12 
endo-N-(8-Azabicyclo3.2.11oct-3-yl)-3,5-dimethylbenzoate 
a) 1.36 g of vinylchloroformate dissolved in benzene (20 ml) were added to 
a solution of 
endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-3,5-dimethylbenzamide (3.5 
g) in benzene (100 ml) cooled at 10.degree. C. and under stirring. A white 
solid precipitated and the reaction mixture was heated at 60.degree. C. 
for 20 hours and then allowed to cool. The reaction mixture was washed 
with diluted HCl and then the organic layer was acidified and concentrated 
to dryness. 1.9 g of 
endo-N-(8-vinyloxycarbonyl-8-azabicyclo[3.2.1]oct-3-yl)-3,5-dimethylbenzam 
ide were obtained. M.p. 219.degree.-220.degree. C. 
b) The desired product was prepared starting from 
endo-N-(8-vinyloxycarbonyl-8-azabicyclo[3.2.1]oct-3-yl)3,5-dimethylbenzami 
de in an analogous manner as described in example 10. M.p. 
119.degree.-120.degree. C. 
EXAMPLE 13 
[1,(N-Cyano-N',N'-dimethyl)guanylpiperidin-4-yl]-3,5-dimethylbenzoate 
(Compound 1) 
A solution of 3,5-dimethylbenzoic acid chloride (1.7 g) in CH.sub.2 
Cl.sub.2 (10 ml) was added dropwise to a solution of 1-(N-cyano, N', 
N'-dimethyl)guanyl-4-hydroxypiperidine (2 g) in CH.sub.2 Cl.sub.2 (20 ml) 
and pyridine (1.2 ml). The reaction mixture was stirred at room 
temperature overnight. The solvent was evaporated and the residue, after 
taking up with ethyl acetate, was washed with acidic and basic water. 
After drying and evaporation the residue was chromotographed on silica 
(eluent CH.sub.2 Cl.sub.2 /ethyl acetate 8:2). Thus the title compound was 
obtained (0.8 g). M.p. 134.degree. C. 
Analysis; 
Found % C 65.68, H 7.39, N 17.00, 
C.sub.18 H.sub.24 N.sub.402 ; 
Calc. % C 65.83, H 7.37, N 17.06. 
EXAMPLE 14 
4-Amino-5-chloro-2-methoxy-N-(N'-nitro-N"-aminoethylguanidino)benzamide 
(Compound 2) 
A solution of 4-amino-5-chloro-2-methoxy benzoic acid (0.6 g) and 
N,N'-carbonyldiimidazole (0.49 g) in anhydrous dimethylformamide (DMF) (15 
ml) was stirred at room temperature for 30 minutes, then a solution of 
N-nitro-N'-aminoethylguanidine hydrochloride (0.55 g) and 
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in DMF was added. The mixture was 
stirred for 4 hours at 50.degree. C., then was cooled, poured into water 
and extracted with methylene chloride. The organic layer was washed with 
sodium carbonate solution and dried. After cooling, the title compound was 
collected as a solid, M.p. 226.degree.-227.degree. C. (dec.) 
Analysis; 
Found % C 40.02, H 4.55. N 25.39, 
C.sub.11 H.sub.15 ClN.sub.6 O.sub.4 ; 
Calc. % C 39.951, H 4.5, N 25.41. 
EXAMPLE 15 
endo 8-(N-Cyanoguanyl)-8-azabicyclo3.2.1]oct-3-yl]-1H-indol-3-carboxylate 
(Compound 3) 
Trifluoroacetic anhydride (0.26 g) was added, under stirring and at room 
temperature, to a solution of indole-3carboxylic acid (0.165 g) in 10 ml 
of THF and the reaction mixture was stirred for 10 minutes. 
endo-8-(N-Cyanoguanyl)8-azabicyclo[3.2.1]octan-3-ol (0.2 g) dissolved in 
THF (15 ml was then added. The reaction mixture was stirred at the same 
temperature for 2 hours, then was concentrated to dryness and taken up 
with ethyl acetate; after washing with a solution of sodium carbonate and 
water the organic layer was concentrated to dryness again. The residue was 
chromatographed on Silicagel (eluent CH.sub.2 Cl.sub.2 /CH.sub.3 OH 93:7). 
0.027 g of the desired compound were obtained. M.p. 145.degree. C. 
Analysis; 
Found % C 63.814, H 5.5, N 19.91, 
C.sub.18 H.sub.19 N.sub.5 O.sub.2 ; 
Calc. % C 64.08, H 5.67, N 20.76. 
EXAMPLE 16 
endo-[8-(N-Methylguanyl)-8-azabicyclo3.2.1]oct-3-yl]-1H-indole-3-carboxylat 
e (Compound 4) 
A suspension of 3-indolecarbonylchloride (0.6 g) and 
endo-8-(N-methylguanyl)-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (0.5 
g) in 0-dichlorobenzene (4 ml) was heated at 150.degree.-160.degree. C. 
for 1 hour. After cooling the obtained solid was collected by filtration 
and dichlorobenzene was removed. The solid was taken up with diluted HCl 
and washed with ethyl acetate; the aqueous layer was filtrated in the 
presence of carbon and concentrated to dryness again. After triturating 
with diethyl ether and freeze-drying 0.15 g of the desired product were 
obtained. M.p. 159.degree.-160.degree. C. 
Analysis; 
Found % C 58.83, H 6.52, N 15.49, 
C.sub.18 H.sub.22 N.sub.4 O.sub.2 .multidot.HCl; 
Calc. % C 59.58, H 6.39, N 15.44. 
Analogously the following compound were obtained: 
endo-(8-Guanyl-8-azabicyclo3.2.1]oct-3-yl)quinoline-3-carboxylate 
dihydrochloride (Compound 5) 
M.p. 224.degree.-225.degree. C. (EtOH) 
Analysis; 
Found % C 53.40, H 5.78, N 13.90, 
C.sub.18 H.sub.20 N.sub.4 O.sub.2 .multidot.HCl; 
Calc. % C 54.4, H 5.58, N 14.10. 
EXAMPLE 17 
endo-(8-Guanyl-8-azabicyclo3.2.1]oct-3-yl)-3,5dichlorobenzoate 
hydrochloride (Compound 7) 
A mixture of endo-(8-azabicyclo[3.2.1]oct-3-yl)-3,5-dichlorobenzoate (1 g), 
cyanamide (0.25 g) and H.sub.2 O 50.1 ml) was heated at 
110.degree.-120.degree. C. until melting. After heating for three hours 
and after a night at room temperature, the glassy mass was taken up with 
warm absolute ethanol obtaining a solid which was treated with alcoholic 
hydrochloric acid. After crystallization from isopropanol the title 
compound, as hydrochloride, was obtained (0.2 g). M.p.&gt;260.degree. C. 
Analysis; 
Found % C 47.42, H 4.75, N 11.41, 
C.sub.15 H.sub.17 Cl.sub.2 N.sub.3 O.sub.2 .multidot.HCl; 
Calc. % C 47.57, H 4.79, N 11.09. 
Analogously the following compounds can be obtained: 
endo-(9-Guanyl-9-azabicyclo3.3.1]non-3-yl)-3,5-dimethylbenzoate 
hydrochloride (Compound 6) 
M.p. 249.degree.-250.degree. (CH.sub.3 CN) 
Analysis; 
Found % C 60.82, H 7.45, N 11.84, 
C.sub.18 H.sub.25 N.sub.3 O.sub.2 .multidot.HCl; 
Calc. % C 61.44, H 7.45, N 11.94. 
endo-N-(9-Guanyl-9-azabicyclo[3.2.1]non-3-yl)-1-methylindazol-3-carboxamide 
hydrochloride (Compound 8) 
4-Amino-5-chloro-2-methoxy-N-(2-guanidinoethyl)benzamide hydrochloride 
(Compound 9) 
4-Amino-5-chloro-2-methoxy-N-[2-(N-guanyl)-N-ethylamino]ethylbenzamide 
hydrochloride (Compound 10) 
M.p. 186.degree.-191.degree. C. 
4-Amino-5-chloro-2-methoxy-N-(1-guanylpyrrolidin-2-yl)methylbenzamide 
hydrochloride (Compound 11) 
6-Methoxy-1H-benzotriazol-N-(2-guanidinoethyl)-5-carboxamide hydrochloride 
(Compound 12) 
endo-(8-Guanyl-8-azabicyclo3.2.1]oct-3-yl)-3,5dimethylbenzoate 
hydrochloride (Compound 13) 
M.p. 258.degree.-260.degree. C. (CH.sub.3 CN) 
Analysis; 
Found % C 59.71, H 7.07, N 12.03, 
C.sub.17 H.sub.23 N.sub.3 O.sub.2 .multidot.HCl; 
Calc. % C 60.43, H 7.16, N 12.44. 
endo-(8-Guanyl-8-azabicyclo3.2.1]oct-3-yl)-1H-indol-3carboxylate 
hydrochloride (Compound 14) 
M.p.&gt;270.degree. C. 
Analysis; 
Found % C 58.18, H 6.03, N 16.08, 
C.sub.17 H.sub.2 ON.sub.4 O.sub.2 .multidot.HCl; 
Calc. % C 58.53, H 6.07, N 16.06. 
endo-8-(Iminomethyl-8-azabicyclo3.2.1]oct-3-yl)-1H-indol-3carboxylate 
hydrochloride (Compound 16) 
M.p. 260.degree. C. (dec) [EtOH/(iPr).sub.2 O] 
Analysis; 
Found % C 60.87, H 5.98, N 12.53, 
C.sub.17 H.sub.19 N.sub.2 O.sub.2 .multidot.HCl; 
Clac. % C 61.16, H 6.04, N 12.59. 
EXAMPLE 18 
endo-(8-Iminomethyl-8-azabicyclo[3.2.1]oct-3-yl)-3,5-dichlorobenzoate 
hydrochloride (Compound 15) 
Ethyl formimidate hydrochloride (0.43 g) was added portion wise to a 
suspension of endo-(8-azabicyclo-[3.2.1]oct-3-yl)-3,5-dichlorobenzoate (1 
g) in ethanol (10 ml). The reaction mixture was stirred at room 
temperature for 2 hours, filtered and dried. The residue treated with warm 
CH.sub.2 Cl.sub.2, gave the title product (0.45 g). M.p.&gt;250.degree. C. 
Analysis; 
Found % C 45.71, H 4.70, N 7.78, 
C.sub.15 H.sub.16 Cl.sub.2 N.sub.2 Cl.sub.2 .multidot.HCl; 
Calc. % C 45.94, H 4.71, N 7.70. 
4-Amino-5-chloro-2-methoxy-N-2-(N-iminomethyl)-N-ethylamino]ethyl benzamide 
hydrochloride (Compound 17) 
endo-8-(N-Cyanoimino)methyl-8-azabicyclo-[3.2.1]oct-3-yl]-1-indazole-3-carb 
oxylate (Compound 18) 
endo-N-8-(N-Cyanoimino)methyl-8-azabicyclo-3.2.1]oct-3-yl]-1 
indole-3-carboxamide (Compound 19) 
endo-[8-(N-n.Butilimino)methyl-8-azabicyclo-[3.2.1]oct-3-yl]1-indazole-3-ca 
rboxylate hydrochloride (Compound 20) 
endo-N-(9-Iminomethyl-9-azabicyclo[3.3.1]non-3-yl)-1-methylindazole-3-carbo 
xamide hydrochloride (Compound 21) 
4-Amino-5-chloro-2-methoxy-N-[2-(N'-cyanoimino)methyl]ethylamino benzamide 
(Compound 22) 
M.p. 212.degree.-217.degree. C. 
Analysis; 
Found % C 48.61, H 4.80, N 23.70, 
C.sub.12 H.sub.14 ClN.sub.5 O.sub.2 ; 
Calc. % C 48.74, H 4.77, N 23.68. 
endo-(9-Iminomethyl-9-azabicyclo[3.3.1]non-3-yl)pyridine-3-carboxylate 
hydrochloride (Compound 23) 
endo-(8-Iminomethyl-8-azabicyclo-[3.2.1]oct-3-yl)-2methylbenzo[b]thiophene- 
3-carboxylate hydrochloride (Compound 24) 
endo-(8-Iminomethyl-8-azabicyclo-[3.2.1]oct-3-yl)-3,5-dimethylbenzoate 
hydrochloride (Compound 25) 
M.p. 252.degree.-253.degree. C. (Acetone/EtOH) 
Analysis; 
Found % C 62.86, H 7.03, N 8.54, 
C.sub.17 H.sub.22 N.sub.2 O.sub.2 .multidot.HCl; 
Calc. % C 63.24, H 7.18N 8.68. 
endo-N-(8-Iminomethyl-8-azabicyclo-[3.2.1]oct-3-yl)-3,5-dimethylbenzamide 
hydrochloride (Compound 26) 
M.p. 80.degree.-82.degree. C. 
Analysis; 
Found % C 63.01, H 7.48, N 12.97, 
C.sub.17 H.sub.23 N.sub.3 O.multidot.HCl; 
Calc. % C 63.44, H 7.52, N 13.05. 
endo-(9-Iminomethyl-9-azabicyclo[3.3.1]non-3-yl)-1H-indole3-carboxylate 
hydrochloride (Compound 27) 
M.p.&gt;270.degree. C. 
Analysis; 
Found % C 61.73, H 6.31, N 11.84, 
C.sub.18 H.sub.21 N.sub.3 O.sub.2 .multidot.HCl; 
Calc. % C 62.16, H 6.37, N 12.08. 
endo-(8-Iminomethyl-8-azabicyclo-[3.2.1]oct-3-yl)quinoline3-carboxylate 
dihydrochloride (Compound 28) 
M.p. 261.degree.-262.degree. C. (EtOH) 
Analysis; 
Found % C 56.01, H 5.61, N 10.89, 
C.sub.18 H.sub.19 N.sub.3 O.sub.2 .multidot.HCl; 
Calc. % C 56.55, H 5.54, N 10.99. 
endo-[8-(N-Ethylimino)methyl-8-azabicyclo-[3.2.1]oct-3-yl]1H-indole-3-carbo 
xylate hydrochloride (Compound 29) 
a) Ethylisothiocyanate (0.46 g) dissolved in THF (5 ml) was added to a 
suspension of endo-(8-azabicyclo[3.2 1 ]oct-3-yl)-1H-indole-3-carboxylate 
(1.3 g) in THF (30 ml). The reaction mixture was stirred for 4 hours and a 
clear solution was obtained. 1.4 g of endo-[8-(N-ethyl 
thiocarbamoyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H-indole-3-carboxylate were 
obtained M.p. 230.degree.-232.degree. C. 
Analogously the following intermediates were obtained: 
4-Amino-5-chloro-2-methoxy-N-[N'-(N"ethylthiocarbamoyl)-2-aminoethyl]benza 
mide. M.p. 168.degree.-170.degree. C. 
endo-N-[9-(N'-Methilthiocarbamoyl)-9-azabicyclo[3.3.1]non-3-yl]-1-methyl-i 
ndazole-3carboxamide. M.p. 190.degree. C. 
endo-N-[8-(N'-Methilthiocarbamoyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H-indol-3 
-carboxamide. M.p.&gt;270.degree. C. 
The same product was also prepared by reacting 1H-indol-3-carbonylchloride 
with endo-8-(N-methyl thiocarbamoyl)-8-azabicyclo-[3.2.1]octan-3-amine in 
THF in the presence of triethylamine. 
b) 0.8 g of endo-[8-(N-ethyl 
thiocarbamoyl)-8-azabicyclo-[3.2.1]oct-3-yl]-1H-indol-3-carboxylate were 
dissolved in a mixture of absolute ethanol (10 ml) and CH.sub.2 Cl.sub.2 
(100 ml). Ni/Raney (4.0 g) was added to the resulting solution, under 
stirring and at room temperature, and stirring was kept on for 5 hours. 
After filtering the clear solution was concentrated to dryness and the raw 
product was crystallized from acetonitrile. 0.17 g of the desired product 
were obtained. M.p.&gt;270.degree. C. 
Analysis; 
Found % C 62.71, H 6.73, N 11.51, 
C.sub.19 H.sub.23 N.sub.3 O.sub.2 .multidot.HCl; 
Calc. % C 63.06, H 6.68, N 11.61. 
Analogously the following compounds can be obtained: 
endo-[8-(N-Methylimino)methyl-8--azabicyclo-[3.2.1]oct-3-yl]indazole-carbox 
ylate hydrochloride (Compound 30) 
endo-N-[8-(N'-Methylimino)methyl-8-azabicyclo-[3.2.1]oct-3-yl]-1H-indol-3-c 
arboxamide hydrochloride (Compound 31) 
M.p. 126.degree.-129.degree. C. (acetone) 
Analysis; 
Found % C 61.86, H 6.80, N 15.93, 
C.sub.18 H.sub.22 N.sub.4 O.multidot.HCl; 
Calc. % C 62.32, H 6.68, N 16.15. 
4-Amino-5-chloro-2-methoxy-N-[N'-(N"-ethyliminomethyl)2-aminoethyl]benzamid 
e hydrochloride (Compound 32) 
M.p. 165.degree.-170.degree. C. (dec) 
Analysis; 
Found % C 45.97, H 6.09, N 16.01, 
C.sub.13 H.sub.19 ClN.sub.4 O.sub.2 .multidot.HCl; 
Calc. % C 46.58, H 6.01, N 16.71. 
EXAMPLE 19 
[1-(1'-Iminoethyl)-piperidin-4-yl]-1H-indol-3-carboxylate hydrochloride 
(Compound 33) 
Ethyl acetoimidate hydrochloride (1.2 g) was added portionwise to a 
solution of (piperidine-4-yl)-1H-indole-3-carboxylate (2 g) in ethanol 
(300 ml). The reaction mixture was stirred at room temperature for 3 
hours. After evaporation of the solvent the residue was chromatographed on 
silica (eluent n.propanol, acetic acid, H.sub.2 O 90:10:10). After 
treatment of the base with HCl the title compound, as hydrochloride, was 
obtained (0.4 g). M.p. 240.degree. C. 
Analysis; 
Found % C 59.60, H 6.28, N 12.97, 
C.sub.16 H.sub.19 N.sub.3 O.sub.2 .multidot.HCl; 
Calc. % C 59.71, H 6.26, N 13.06. 
Analogously the following compounds can be obtained: 
endo-[8-(1-Iminoethyl)-8-azabicyclo-[3.2.1]oct-3-yl]-3,5-dichlorobenzoate 
hydrochloride (Compound 34) 
4-Amino-5-chloro-2-methoxy-N-[1-(1'-iminoethyl)pyrrolidin-2-yl-methyl]benza 
mide hydrochloride (Compound 35) 
endo-8-(1'-Iminoethyl)-8-azabicyclo-[3.2.1]oct-3-yl]-1H-indol-3-carboxylate 
hydrochloride (Compound 36) 
1-(1'-Imino-n-propyl)-piperidin-4-yl]-1H-indole-3-carboxylate hydrochloride 
(Compound 37) 
This compound was prepared analogously to compound 33 using 
(piperidin-4-yl)-3,5-dimethylbenzoate and ethyl propionimidate 
hydrochloride in absolute ethanol. After chromatographing on Silicagel 
(eluent CH.sub.2 Cl.sub.2 /methanol/acetic acid 80:15:15) the title 
compound was obtained. 
M.p. 70.degree.-75.degree. C. (Freeze-dried). 
Analysis; 
Found % C 60.04, H 6.56, N 12.36, 
C.sub.17 H.sub.21 N.sub.3 O.sub.2 .multidot.HCl; 
Calc. % C 60.80, H 6.60, N 12.51. 
EXAMPLE 20 
[1-[1'-(N-Methylimino)ethyl]piperidin-4-yl -3,5-dimethylbenzoate 
hydrochloride (Compound 38) 
Phenyl-N-methylacetimidate (0.6 g) was added to a solution of 
(piperidin-4-yl)-3,5-dimethylbenzoate hydrochloride (1.0 g) in absolute 
ethanol (10 ml) and the solution was stirred at room temperature for 4 
hours. After concentrating to dryness the product was chromatographed on 
Silicagel (eluent methylene dichloride/methanol/acetic acid 7:2:1). Yield 
0.35 g 
M.p. 68.degree.-72.degree. C. (Freeze-dried) 
Analysis; 
Found % C 62.31, H 7.81 , N 8.63, 
C.sub.17 H.sub.24 N.sub.2 O.sub.2 .multidot.HCl; 
Calc. % C 62.85, H 7.76, N 8.62. 
The following not limitative examples of pharmaceutical compositions 
according to the invention are reported: 
EXAMPLE 21 
Tablets 
active ingredient 25 mg 
lactose 311 mg 
corn starch 60 mg 
magnesium stearate 4 mg 
Method of preparation: The active ingredient, lactose and corn starch were 
mixed and homogeneously moistened with water. After screening of the moist 
mass and drying in a tray drier, the mixture was again passed through a 
screen and magnesium stearate was added. Then the mixture was pressed into 
tablets weighing 400 mg each. Each tablet contains 25 mg of active 
ingredient. 
EXAMPLE 22 
Capsules 
active ingredient 25 mg 
lactose 223 mg 
magnesium stearate 2 mg 
Method of preparation: The active ingredient was mixed with auxiliary 
products, and the mixture was passed through a screen and mixed 
homogeneously in a suitable device. The resulting mixture was filled into 
hard gelatine capsules (250 mg per capsule); each capsule contains 25 mg 
of active ingredient. 
EXAMPLE 23 
Ampoules 
Active ingredient 5 mg 
sodium chloride 9 mg 
Method of preparation: The active ingredient and sodium chloride were 
dissolved in an appropriate amount of water for injection. The resulting 
solution was filtered and filled into ampoules under sterile conditions. 
Each ampoule contains 5 mg of active ingredient. 
EXAMPLE 24 
Suppositories 
active ingredient 25 mg 
semisynthetic glicerides of fatty acids 925 mg 
Method of preparation: The semisynthetic glycerides of fatty acids were 
melted and the active ingredient was added while stirring homogeneously. 
After cooling at a proper temperature the mass was poured into preformed 
moulds for suppositories weighing 950 mg each. Each suppository contains 
25 mg of active ingredient. 
EXAMPLE 25 
Oral drops 
active ingredient 5 mg 
sorbitol 350 mg 
propylene glycol 100 mg 
citric acid 1 mg 
sodium citrate 3 mg 
demineralized water q.s. 1 ml 
Method of preparation: The active ingredient, citric acid and sodium 
citrate were dissolved in a mixture of a proper amount of water and 
propylene glycol. Then sorbitol was added and the final solution was 
filtered. The solution contains 0.5% of active ingredient and is 
administered by using a proper dropper.