This invention relates to new isoprenylamine derivatives and acid addition salts thereof, which are useful for controlling virus infection of vertebrate animals.

There are known heretofore various substances, which have been decided to 
have preventive or alleviative effects on diseases caused by virus whose 
host is a vertebrate animal, or which have been recognized to be capable 
of alleviating symptoms of the diseases by significantly enhancing 
antibody activity in the animal. Antivirotics reported so far include 
interferon, substances capable of inducing interferon, i.e. inducers 
(interferon inducers), and synthetic substances, such as amantadine 
hydrochloride or methisazone, which directly exert inhibitory effect on 
virus propagation. Interferon is glycoprotein having antiviral and 
antitumor activities, said glycoprotein being produced in situ by cells of 
a vertebrate animal when the cells are infected with virus, and has been 
known to be effective in therapy of infectious viral disease. Known 
inducers, which induce interferon in vertebrate animals through a process 
other than virus infection, include natural high molecular substances such 
as double strand ribonucleic acid of bacteriophage of a certain species, 
or synthetic high molecular substances such as double strand ribonucleic 
acid, typical of which is polyinosinic acid-polycytidylic acid, or low 
molecular inducers such as tirolone. 
In the production of interferon, however, there is involved a problem how 
to carry out purification thereof, and in fact, no economical process for 
the production thereof has not been established yet. On the other hand, 
conventional interferon inducers have not been put to practical use mainly 
because of toxicity thereof. Synthetic antiviral agents which directly 
exert inhibitory effect on virus propagation, which are commercially 
available at present, have a rather narrow range of virus-infected 
diseases which are curable by administration of said agents, and thus the 
advent of novel synthetic activiral agents is earnestly desired. Taking 
such circumstances into consideration, the present inventors extensively 
conducted studies in finding compounds capable of producing interferon of 
high potency and, moreover, having antiviral activity on the biological 
level, and as the result they have eventually found that compounds 
represented by the general formula (I) and acid addition salts thereof 
show excellent interferon-inducing ability and, at the same time, 
demonstrate excellent antiviral activity even in the biological test. 
Thus, the present invention is to provide a new class of an isoprenylamine 
derivative represented by the following general formula 
##STR1## 
wherein n is 2 to 10, A and B are individually hydrogen atom or A and B 
may jointly form a single bond, and when n is 4, A and B may be a 
combination of the aforesaid two cases, m is 0 or an integer of 1 to 4 and 
when m.noteq.0, there may be hydroxy- or phenyl-substituent on the carbons 
of methylene groups, and X signifies phenyl, naphthyl or diphenylmethyl, 
which may optionally have a nucleic substituent, and acid addition salts 
thereof. For the production of isoprenylamine represented by the general 
formula (I) and acid addition salts thereof, there may be adopted the 
known procedure in which isoprenyl alcohol (e.g. decaprenol, solanesol, 
geraniol or phytol) represented by the general formula 
##STR2## 
wherein n, A and B are as defined above, is first converted into a 
corresponding halide (e.g. decaprenyl bromide, solanesyl bromide, phytyl 
bromide or geranyl bromide) or arylsulfonic acid ester (e.g. decaprenyl 
tosylate, solanesyl tosylate, phytyl tosylate or geranyl tosylate) and the 
resulting halide or ester is then allowed to react in the presence or 
absence of a base with an amino compound represented by the general 
formula 
EQU H.sub.2 N--(CH.sub.2).sub.m --X (III) 
wherein m and X are as defined above. This reaction is usually carried out 
in an organic solvent. Preferably usable as organic solvents in the 
reaction are common solvents such as methanol, ethanol, chloroform, 
isopropyl ether, ethyl acetate and the like. The reaction is carried out 
suitably at a temperature ranging from room temperature up to 100.degree. 
C. After the completion of the reaction, a desired isoprenylamine can be 
produced by treating the resultant reaction liquid according to usual 
isolation and purification procedures such as extraction, concentration, 
column chromatography, crystallization and the like. 
For the production of compounds of the general formula (I), there may be 
adopted another process in which the aforementioned halide or arylsulfonic 
acid ester is allowed to react with a compound represented by the general 
formula 
##STR3## 
wherein M represents an alkali metal atom, and m and X are as defined 
above, followed by saponification. 
This reaction is usually carried out in non-protonic polar solvents. 
Preferably usable as the solvents in the reaction are tetrahydrofuran, 
N,N-dimethylformamide and the like. The reaction temperature to be 
employed is suitably from room temperature up to 100.degree. C. The 
saponification is suitably carried out by heating the reaction liquid 
using an alcohol type solvent (e.g. methanol or ethanol) at a temperature 
ranging from room temperature up to 100.degree. C. in the presence of 
alkali (e.g. potassium or sodium hydroxide or ammonia). After the 
completion of the reaction, a desired isoprenylamine can be produced by 
treating the reaction liquid according to usual isolation and purification 
procedures such as extraction, concentration, column chromatography, 
crystallization and the like. 
An acid addition salt of the thus produced isoprenylamine derivative can be 
obtained by mixing said derivative in an appropriate solvent (e.g. acetone 
or ethyl acetate) with a desired acid to form a salt and applying such 
means as concentration or crystallization to the salt. The acid addition 
salts suitable for use as medicines include, for example, those with 
hydrochloric acid, acetic acid, citric, acid, fumaric acid, lactic acid 
and the like.

Illustrated below are preparative examples of isoprenylamine derivatives of 
the present invention. 
PREATIVE EXAMPLE 1 
N-(p-methoxybenzyl)decaprenylamine hydrochloride 
To an ethanol solution (100 ml) containing p-methoxybenzylamine (25 g) was 
added dropwise with stirring an isopropyl ether solution (100 ml) 
containing decaprenyl bromide (30 g) at room temperature over a period of 
1 hour. After the completion of the dropwise addition, the mixture was 
stirred at room temperature for 3 hours and then heated under reflux for 1 
hour with stirring. The reaction liquid was cooled, charged with a 5% 
aqueous sodium hydroxide solution (100 ml) and then extracted with 
isopropyl ether. The extract was washed with water and saturated saline, 
dried over anhydrous sodium sulfate and then concentrated under reduced 
pressure. The concentrate (26.5 g) was treated by chromatography with a 
chloroform-ethyl acetate mixture over a column packed with silica gel (300 
g) to obtain N-(p-methoxybenzyl)didecaprenylamine (5.3 g) from the 
initially eluted fraction and N-(p-methoxybenzyl)decaprenylamine (10.5 g) 
from the secondly eluted fraction. The oily product thus obtained was 
dissolved in acetone (50 ml), charged with a hydrogen chloride-ether 
solution to weakly acidic, and then allowed to stand in a refrigerator 
overnight. The crystallized mass was separated by filtration and then 
dried to obtain N-(p-methoxybenzyl)decaprenylamine hydrochloride (7.1 g) 
represented by the following formula, the measured values of physical 
properties of which were as shown below. 
##STR4## 
Melting point: 101.8.degree. C. 
N.M.R. (.delta.value in CDCl.sub.3) (Free base): 7.22 (2H,d J=8 Hz), 6.80 
(2H,d J=8 Hz), 4.9-5.3 (10H,br), 3.75 (3H,s), 3.68 (2H,s), 3.18 (2H,d J=7 
Hz), 2.02 (36H,br), 1.60 (33H,s). 
Elementary analysis (as C.sub.58 H.sub.91 NO.HCl): 
______________________________________ 
Calcd. 
Found 
______________________________________ 
C (%) 81.49 81.45 
H (%) 10.85 10.91 
N (%) 1.64 1.62 
______________________________________ 
PREATIVE EXAMPLE 2 
N-(2,4-dimethylbenzyl)solanesylamine hydrochloride 
To an ethanol solution (50 ml) containing 2,4-dimethylbenzylamine (10 g) 
was added dropwise with stirring an isopropyl ether solution (50 ml) 
containing solanesyl bromide (15 g) at room temperature over a period of 1 
hour. After the completion of the dropwise addition, the mixture was 
further stirred at room temperature for 3 hours. The reaction liquid was 
cooled, charged with a 5% aqueous sodium hydroxide solution (100 ml) and 
then extracted with isopropyl ether. The extract was washed with water and 
saturated saline, dried over anhydrous sodium sulfate and then 
concentrated under reduced pressure. The concentrate (18.1 g) was treated 
by chromatography with a chloroformethyl acetate mixture over a column 
packed with silica gel (18.1 g). From the initially eluted faction, 
N-(2,4-dimethylbenzyl)disolanesylamine was obtained, and the secondly 
eluted fraction, N-(2,4-dimethylbenzyl)solanesylamine (7.5 g). The thus 
obtained N-(2,4-dimethylbenzyl)solanesylamine was dissolved in acetone (40 
ml), charged with a hydrogen chloride-ether solution to weakly acidic, and 
then allowed to stand in a refrigerator overnight. The crystallized mass 
was separated by filtration and then dried to obtain 
N-(2,4-dimethylbenzyl)solanesylamine hydrochloride (3.9 g) represented by 
the following formula, the measured values of physical properties of which 
were as shown below. 
##STR5## 
Melting point: 38.4.degree.-40.2.degree. C. 
N.M.R. (.delta.value in CDCl.sub.3) (Free base): 6.71-7.55 (3H,m), 4.9-5.3 
(9H,br), 3.58 (2H,s), 3.16 (2H,d J=7 Hz), 2.26 (6H,s), 2.02 (32H,br), 1.60 
(30H,s). 
Elementary analysis (as C.sub.54 H.sub.85 N.HCl.H.sub.2 O): 
______________________________________ 
Calcd. 
Found 
______________________________________ 
C (%) 80.80 80.91 
H (%) 11.05 10.95 
N (%) 1.74 1.71 
______________________________________ 
PREATIVE EXAMPLE 3 
N-(1-naphthylmethyl)decaprenylamine hydrochloride 
To a pyridine solution (30 ml) containing 1-naphthylmethylamine (5.0 g) 
cooled on an ice bath was added dropwise with stirring trifluoroacetic 
anhydride (7.0 ml) over a period of 30 minutes. After the completion of 
the dropwise addition, the mixture was stirred while cooling for 1 hour 
and further stirred at room temperature overnight (about 16 hours). The 
reaction liquid was poured in water (200 ml) and then extracted with ethyl 
acetate. The extract was washed with water, 5% hydrochloric acid, 3% 
sodium hydrogen carbonate, water and saturated saline in that order, dried 
over anhydrous sodium sulfate and then concentrated under reduced pressure 
to obtain crude N-trifluoroacetyl-1-naphthylmethylamine (8.2 g) as yellow 
crystal. 
To an anhydrous tetrahydrofuran solution (150 ml) containing the thus 
obtained crude N-trifluoroacetyl-1-naphtylmethylamine (8.2 g) while 
cooling with stirring was added in small portions 60% sodium hydride (1.3 
g) and stirred at room temperature for 3 hours. The reaction liquid was 
poured in water (1 l) and then extracted with isopropyl ether. The extract 
was washed with water and saturated saline, dried over anhydrous sodium 
sulfate and then concentrated under reduced pressure. The concentrate 
(25.6 g) was treated by chromatography with a hexane-ethyl acetate mixture 
over a column packed with silica gel (300 g) to obtain 
N-decaprenyl-N-trifluoroacetyl-1-naphthylmethylamine (21.6 g). A mixture 
of an isopropyl ether solution (50 ml) containing the thus obtained 
N-decaprenyl-N-trifluoroacetyl-1-naphthylmethylamine (21.6 g) and a 
methanol solution (200 ml) containing 5% potassium hydroxide was heated at 
60.degree. C., with stirring. The reaction liquid was poured in water (1 
l) and then extracted with isopropyl ether. The extract was washed with 
water and saturated saline, dried over anhydrous sodium sulfate and then 
concentrated under reduced pressure. The concentrate (19.8 g) was treated 
by column chromatography with chloroform-ethyl acetate mixture over a 
column packed with silica gel (200 g) to obtain an oily 
N-(1-naphthylmethyl)decaprenylamine (15.3 g). The thus obtained 
N-(1-naphthylmethyl)decaprenylamine was dissolved in acetone (80 ml), 
charged with a hydrogen chloride-ether solution to weakly acidic, and then 
allowed to stand at room temperature overnight. The crystallized mass was 
separated by filtration and then dried to obtain 
N-(1-naphthylmethyl)decaprenylamine hydrochloride (13.1 g) represented by 
the following formula, the measured values of physical properties of which 
were as shown below. 
##STR6## 
Melting point: 56.6.degree.-61.3.degree. C. 
N.M.R. (.delta.value in CDCl.sub.3) (Free base): 8.28-7.28 (7H,m), 
4.85-5.27 (10H,br), 4.18 (2H,s), 3.33 (2H,d J=7 Hz), 2.02 (36H,br), 1.58 
(33H,s). 
Elementary analysis (as C.sub.61 H.sub.91 N.HCl.H.sub.2 O): 
______________________________________ 
Calcd. 
Found 
______________________________________ 
C (%) 82.80 82.77 
H (%) 10.71 10.53 
N (%) 1.58 1.60 
______________________________________ 
PREATIVE EXAMPLE 4 
The same procedures as in Preparative Example 1 were carried out for the 
reaction of a halide selected from decaprenyl bromide, solanesyl bromide, 
geranyl bromide and phytyl bromide with an amino compound selected from 
p-aminobenzoic acid, p-aminosalicyclic acid, 3-phenyl-1-propylamine, 
p-nitrobenzylamine, p-methylbenzylamine, p-chlorobenzylamine, 
3,4-dimethoxybenzylamine, amino-diphenylmethane, p-aminobenzylamine, 
4-phenyl-1-butylamine, 3,4-dimethoxyphenethylamine, 
4-hydroxy-3-methoxybenzylamine, m-xylenediamine, 2,3-dimethoxybenzylamine 
and 2-amino-1-phenylethanol, thereby to produce the below-indicated 
compounds, the measured values of physical properties of which were as 
shown in Table 1. 
In the chemical structural formulas indicated hereinafter, D represents 
decaprenyl, S represents solanesyl, Phy represents phytyl and Ger 
represents geranyl. 
TABLE 1 
__________________________________________________________________________ 
N.M.R. (.delta. value 
Elementary analysis 
.sup.n D/Melt- 
in CDCl.sub.3) Free 
Calcd. (%) 
Found (%) 
Structural formula 
Molecular formula 
ing point 
base C H N C H N 
__________________________________________________________________________ 
##STR7## C.sub.57 H.sub.87 NO.sub.2 
59.6- 62.2.degree. C. 
7.86(2H,d J=8Hz), 6.43(2H,d J=8Hz), 
4.9-5.3(10H,br), 3.70(2H,d J=7Hz), 
1.98(36H,br), 1.58(33H,s) 
83.66 
10.72 
1.71 
83.71 
10.64 
1.67 
##STR8## C.sub.57 H.sub.87 NO.sub.3 
54.6- 56.2.degree. C. 
7.12-7.46(3H,m), 4.9-5.3(10H,br), 
3.73(2H,d J=7Hz), 2.02(36H,br), 1.60(33H, 
s) 82.06 
10.51 
1.68 
82.98 
10.55 
1.65 
##STR9## C.sub.59 H.sub.93 N.HCl.2H.sub.2 O 
56.0- 59.4.degree. C. 
7.18(5H,s), 4.9-5.3(10H,br), 3.27(2H,d 
J=7Hz), 2.63(4H,t J=7Hz), 2.02(36H,br), 
1.60(35H,s) 79.72 
11.11 
1.58 
79.40 
10.78 
1.55 
##STR10## C.sub.57 H.sub.88 N.sub.2 O.sub.2.HCl 
88.5- 89.7.degree. C. 
7.81(4H,dd), 5.22- 4.82(10H,br), 3.87 
(2H,s), 3.22(2H,d J=7Hz), 2.00(36H, 
br-s), 1.59(33H,s) 
78.71 
10.31 
3.22 
78.73 
10.42 
3.10 
##STR11## C.sub.58 H.sub.91 N.HCl. 1/2H.sub.2 O 
98.4- 101.0.degree. C. 
7.13(4H,s), 4.9- 5.3(10H,br), 3.73 
(2H,s), 3.22(2H,d J=7Hz), 2.33(3H,s) 
2.01(36H,br), 1.60(33H,s) 
82.22 
11.00 
1.65 
82.49 
10.95 
1.59 
##STR12## C.sub.57 H.sub.88 NCl.HCl .1/2H.sub.2 O 
116- 119.degree. C. 
7.22(4H,s), 4.9- 5.3(10H,br), 3.75 
(2H,s), 3.20(2H,d J=7Hz), 1.98(36H,br- 
s), 1.58(33H,s) 
78.85 
10.45 
1.61 
78.77 
10.25 
1.57 
##STR13## C.sub.59 H.sub.93 NO.sub.2.HCl.H.sub.2 O 
44.7- 45.4.degree. C. 
6.73-6.96(3H,m), 4.9-5.3(10H,br), 
3.85(6H,s), 3.72(2H, s), 3.21(2H,d 
J=7Hz), 1.99(36H,br), 1.58 (33H,br-s) 
78.49 
10.72 
1.55 
78.67 
10.56 
1.47 
##STR14## C.sub.63 H.sub.93 N.HCl.1/2H.sub.2 O 
50.3- 50.8.degree. C. 
7.53-7.00(10H,m), 5.45-4.86(10H,br), 
4.80(1H,s), 3.12(2H,d J=7Hz), 
1.96(36H,br-s), 1.58(33H,s) 
83.16 
10.52 
1.54 
83.17 
10.50 
1.52 
##STR15## C.sub.58 H.sub.92 N.sub.2.2HCl 
148.1.degree. C. 
6.95(2H,d J=8Hz), 6.55(2H,d J=8Hz), 
4.9-5.3(10H,br), 3.20 (2H, d J=7Hz), 
2.6-2.85 (4H,m), 2.00(36H,br), 1.59(33H,s 
) 78.25 
10.64 
3.15 
78.03 
10.60 
3.16 
##STR16## C.sub.60 H.sub.95 N.HCl .1/2H.sub.2 O 
53.5- 55.2.degree. C. 
7.10-7.30(5H,m), 4.9-5.3(10H,br), 
3,18(2H,d J=7Hz), 2.46- 2.80(4H,m), 
2.02(36H, br), 1.60(37H,s) 
82.27 
11.16 
1.60 
82.37 
11.13 
1.69 
##STR17## C.sub.60 H.sub.95 NO.sub.2.HCl .1/2H.sub.2 O 
69.2- 72.1.degree. C. 
6.73(3H,s), 4.9- 5.3(10H,br), 3.83 
(6H,s), 3.22(2H,d J=7Hz), 2.53-2.90(4H, 
m), 1.98(36H,br), 1.58(33H,s) 
79.37 
10.77 
1.54 
79.39 
10.79 
1.50 
##STR18## C.sub.58 H.sub.91 NO.sub.2.HCl .3/2H.sub.2 O 
41.7- 43.1.degree. C. 
6.75-7.30(3H,m), 4.9-5.3(10H,br), 
3.83(5H,br-s), 3.40 2H,d J=7Hz), 2.00 
(36H,br), 1.60(33H,s) 
77.59 
10.66 
1.56 
77.28 
10.38 
1.52 
##STR19## C.sub.54 H.sub.85 NO.sub.2.HCl.H.sub.2 O 
57.0- 64.9.degree. C. 
6.70-6.90(3H,m), 4.9-5.3(9H,br), 
3.90(6H,br-s), 3.75 (2H,s), 3.23(2H,d 
J=7Hz), 1.98(32H, br), 
77.7030H,s) 
10.62 
1.68 
77.55 
10.50 
1.63 
##STR20## C.sub.58 H.sub.92 N.sub.2 
30.2- 31.2.degree. C. 
7.21(4H,m), 4.9- 5.3(10H,br), 3.75 
(2H,s), 3.83(2H,s), 3.23(2H,d J=7Hz), 
1.98 (36H,br), 1.58(33H,s) 
85.23 
11.34 
3.43 
85.34 
11.33 
3.23 
##STR21## C.sub.59 H.sub.93 NO.sub.2.HCl.H.sub.2 O 
50.4- 52.6.degree. C. 
6.71-6.90(3H,m), 4.9-5.3(10H,br), 
3.80(8H,s), 3.20 (2H,d J=7Hz), 2.02 
(36H,br), 1.61(33H,s) 
79.37 
9.71 
1.56 
79.48 
9.75 
1.48 
##STR22## C.sub.58 H.sub.91 NO.HCl.H.sub.2 O 
46.3- 48.9.degree. C. 
7.30(5H,s), 4.9- 5.3(10H,br), 4.68 (1H,t 
J=6Hz), 3.20 (2H,d J=7Hz), 2.66(2H, t 
J=6Hz), 1.98(36H,br), 1.58(33H,br-s) 
79.81 
10.85 
1.60 
80.03 
10.79 
1.49 
##STR23## C.sub.19 H.sub.29 NO.sub.2.HCl .1/2H.sub.2 O 
Caramel- like 
6.71-6.96(3H,m), 5.00-5.45(2H,m), 
3.83(6H,s), 3.70(2H, s), 3.23(2H,d 
J=7Hz), 2.03(4H,br-s), 
65.41(9H,br-s) 
8.95 
4.01 
65.38 
8.82 
3.93 
##STR24## C.sub.29 H.sub.51 NO.sub.2.HCl .H.sub.2 O 
80.0- 82.6.degree. C. 
6.70-7.00(3H,m), 5.26(1H,t J=7Hz), 
3.85(6H,s), 3.70(2H, s), 3.22(2H, d 
J=7Hz), 0.70-2.20(36H,m) 
69.64 
10.88 
2.80 
69.53 
10.11 
2.69 
##STR25## C.sub.55 H.sub.87 NO.sub.3.HCl .H.sub.2 O 
42.5- 45.8.degree. C. 
6.56(2H,s), 5.50- 4.85(9H,br), 3.84 
(9H,s), 3.71(2H,s J= 7Hz), 3.24(2H,d), 
1.99 (32H,br-s), 1.58(30H,s) 
76.39 
10.49 
1.62 
76.44 
10.29 
1.54 
__________________________________________________________________________ 
Physiological effects of the compounds of the present invention are 
illustrated below in detail. 
(1) Effect on mice infected with vaccinia virus 
Groups, each consisting of 10 ICR female mice weighing about 15 g, were 
intravenously injected a dilute solution (0.1 ml) of vaccinia virus at a 
portion 2 cm from the base of a tail. On the 8th day after the 
inoculation, the number of lesions in the form of small pocks on the tail 
surface was counted after dyeing the tail with an ethanol solution of 1% 
fluorescein and 0.5% methylene blue. Each test compound suspended in a 
surfactant solution was administered intraperitoneally at a rate of 50 
mg/kg to the mice 24 hours before inoculation of the virus, whereby 
antivirus activity of the test compound was evaluated in terms of 
inhibition of tail lesions as calculated in each test group against a 
group to which only the surfactant solution had been administered. The 
rate of tail lesion inhibition of each test compound is shown in Table 2. 
TABLE 2 
______________________________________ 
Prevention from 
vaccinia infection 
Test compound (Pock inhibition 
(Structural formula) rate %) 
______________________________________ 
##STR26## 15.0 
##STR27## 42.9 
##STR28## 68.1 
##STR29## 47.7 
##STR30## 21.6 
##STR31## 44.8 
##STR32## 34.0 
##STR33## 35.4 
##STR34## 14.8 
##STR35## 64.4 
##STR36## 40.3 
##STR37## 68.1 
##STR38## 67.1 
##STR39## 58.8 
##STR40## 54.1 
##STR41## 91.4 
##STR42## 32.5 
##STR43## 64.4 
##STR44## 10.0 
______________________________________ 
(2) Effect on mice infected with influenza virus 
Groups, each consisting of 10 ICR female mice weighing about 25 g were 
challenged by nasal inhalation of influenza virus (PR-8). Each test 
compound suspended in a surfactant solution was intraperitoneally 
administered at a rate of 50 mg/kg to the mice 24 hours before the virus 
infection, and 5 times every other day from the second day after the 
infection. The mice that survived 21 days or more after the challenge were 
regarded as survivors, and survival rate was obtained according to the 
following equation, as shown in Table 3. 
##EQU1## 
TABLE 3 
______________________________________ 
Prevention from 
Test compound influenza infection 
(Structural formula) (Survival rate %) 
______________________________________ 
10 
##STR45## 50 
##STR46## 40 
##STR47## 50 
##STR48## 55 
##STR49## 60 
##STR50## 70 
##STR51## 30 
##STR52## 30 
##STR53## 60 
##STR54## 10 
##STR55## 70 
##STR56## 60 
##STR57## 30 
______________________________________ 
(3) Anti-tumor activity 
Groups, each consisting of 6 Balb/c male mice weighing about 20 g, were 
intraperitoneally administered 5.times.10.sup.5 of tumor cells KN.sub.7 
-8. A test compound suspended in a surfactant solution was 
intraperitoneally administered (each time at a rate of 30 mg/kg) to the 
mice 24 hours before inoculation of the tumor cells, and on the second day 
and the fifth day after the inoculation, totalling 3 times, and the 
anti-tumor activity was evaluated in terms of number of survivors on the 
30th day after the inoculation. The number of survivors relative to the 
test compound is shown in Table 4. 
TABLE 4 
______________________________________ 
Test compound Anti-tumor activity 
(Structural formula) 
(Survivor on the 30th day) 
______________________________________ 
##STR58## 1/6 
______________________________________ 
(4) Toxicity 
Using ddY male mice weighing 20-25 g, 50% lethal dose of each test compound 
when intravenously administered was obtained, the results of which are 
shown in Table 5. 
TABLE 5 
______________________________________ 
LD.sub.50 
Test compound (Intravenously admini- 
(Structural formula) 
stered mg/kg) 
______________________________________ 
##STR59## 27.7 
##STR60## 45 
##STR61## &gt;268.9 
##STR62## 207.3 
##STR63## 122.8 
##STR64## 371.3 
##STR65## 56.8 
##STR66## 1178.7 
##STR67## 28 
##STR68## 68 
##STR69## 26 
##STR70## 30 
______________________________________ 
(5) Human interferon-inducing activity (in vitro) 
Interferon was induced according to the method of Edward A. Havell et al. 
by treating normal diploid cells (fibroblast) originated from human being 
with each test compound in the form of ethanol solution diluted with PBS 
(-) (25 n molar suspension). Using the radioisotope microassay method of 
H. Ishitsuka et al., interferon was measured in terms of 3H-uridine-uptake 
inhibition rate. The rate of 3H-uridine-uptake inhibition of each test 
compound as measured is shown in Table 6. 
TABLE 6 
______________________________________ 
Human interferon 
Test compound 3Huridine-uptake 
(Structural formula) inhibition rate % 
______________________________________ 
##STR71## 12.7 
##STR72## 39.8 
##STR73## 17.7 
##STR74## 23.6 
##STR75## 13.7 
##STR76## 91.1 
##STR77## 75.7 
##STR78## 77.8 
##STR79## 67.2 
##STR80## 32.5 
##STR81## 41.9 
##STR82## 61.4 
##STR83## 86.9 
##STR84## 20.2 
##STR85## 26.6 
##STR86## 37.6 
##STR87## 1.8 
##STR88## 21.5 
______________________________________ 
(6) Anti-vaccinia virus activity (in vitro) 
Virus plaque-formation inhibition rate of each test compound was obtained 
by treating Vero cells originated from the kidney of African green monkey 
with the test compound suspension (the compound in the form of ethanol 
solution was suspended in Hanks culture liquid, 50 n molar concentration) 
and the virus diluted solution. The inhibition rate of each test compound 
as measured is shown in Table 7. 
TABLE 7 
______________________________________ 
Anti-vaccinia virus 
activity 
Test compound Plaque inhibition 
(Structural formula) rate % 
______________________________________ 
##STR89## 9.8 
##STR90## 22.0 
______________________________________ 
As is clear from the foregoing test results, the active ingredients of the 
present invention have interferon-inducing activity in vivo and, at the 
same time, are low in toxicity with showing excellent antiviral activity. 
In the light of the fact that the strict correlation of interferon 
activity with the individual antivirus activities is not always observed 
for the present ingredients, there is considered also a possibility that 
the antivirus activities of said ingredients at biological level are 
concerned not only in interferon but also in other defensive mechanism of 
host. As diseases of human being caused by virus, there are known a number 
of symptoms, for example, herpes-infected diseases such as herpes simplex, 
influenza, measles, etc. Accordingly, when the active ingredients of the 
present invention are used for prevention from virus infection and for the 
treatment of virus-infected diseases, they are administered to patients by 
such technique involving oral, inhalant, or the like administration as 
well as subcutaneous, intramuscular and intravenous injection. According 
to the condition of patient such as age, symptom and route by which the 
ingredient is administered, the active ingredient of the present invention 
is used in a dose of 0.5-20 mg/kg, preferably 3-5 mg/kg several times (2-4 
times) per day. 
The active ingredients of the present invention can be formulated into 
compositions for medication, for example, tablets, capsules, granules, 
powder, liquid preparation for oral use, eye lotions, suppositories, 
ointments, injections and the like. 
When the present active ingredients are orally administered, they may be 
formulated into tablets, capsules, granules or powder. These solid 
preparations for oral use may contain commonly used excipients, for 
example, silicic anhydride, metasilicic acid, magnesium alginate, 
synthetic aluminum silicate, lactose, cane sugar, corn starch, 
microcrystalline cellulose, hydroxypropylated starch or glycine and the 
like; and binders, for example, gum arabic, gelatin, tragacanth, 
hydroxypropyl cellulose, or polyvinyl pyrrolidone; lubricants, for 
example, magnesium stearate, talc or silica; disintegrating agents, for 
example, potato starch and carboxymethyl cellulose calcium; or wetting 
agents, for example, polyethylene glycol, sorbitan monooleate, 
polyoxyethylene hydrogenated castor oil, sodium laurylsulfate and the 
like. In preparing soft capsules, in particular, the present active 
ingredients may be formulated by dissolving or suspending them in 
polyethylene glycol or commonly used oily substrates such as sesame oil, 
peanut oil, germ oil, fractionated coconut oil such as Miglyol.RTM., or 
the like. Tablet or granule preparations may be coated according to the 
usual method. 
Liquid preparation for oral use may be in the form of aqueous or oily 
emulsion or syrup, or alternatively in the form of dry product which can 
be re-dissolved before use by means of a suitable vehicle. To these liquid 
preparations, there may be added commonly used additives, for example, 
emulsifying aids such as sorbitol syrup, methyl cellulose, gelatin 
hydroxyethyl cellulose and the like; or emulsifiers, for example, 
lecithin, sorbitan monooleate, polyoxyethylene hydrogenated castor oil, 
non-aqueous vehicles, for example, fractionated coconut oil, almond oil, 
peanut oil and the like; or antiseptics, for example, methyl 
p-hydroxybenzoate, propyl p-hydroxybenzoate, or sorbic acid. Further, 
these preparations for oral use may contain, if necessary, preservatives, 
stabilizers and the like additives. 
In case where the present active ingredients are administered in the form 
of non-oral suppository, they may be formulated according to the ordinary 
method using oleophilic substrates such as cacao oil or Witepsol.RTM., or 
may be used in the form of rectum capsule obtained by wrapping a mixture 
of polyethylene glycol, sesame oil, peanut oil germ oil, fractionated 
coconut oil and the like in a gelatin sheet. The rectum capsule may be 
coated, if necessary, with waxy materials. 
When the present active ingredients are used in the form of injection, they 
may be formulated into preparations of oil solution, emulsified solution 
or aqueous solution, and they may contain commonly used emulsifiers, 
stabilizers or the like additives. 
According to the method of administration, the above-mentioned compositions 
can contain the present active ingredients in an amount of at least 1%, 
preferably 5 to 50%. 
The procedure of formulating the present active ingredients into various 
preparations is illustrated below with reference to pharmaceutical 
examples. 
PHARMACEUTICAL EXAMPLE 1 
Hard capsule preparations for oral use 
A mixture of 25 g of N-(3,4-dimethoxybenzyl)decaprenylamine hydrochloride 
and 7.5 g of polyoxyethylene castor oil in acetone was mixed with 25 g of 
silicic anhydride. After evaporation of the acetone, the mixture was mixed 
further with 5 g of calcium carboxymethylcellulose, 5 g of corn starch, 
7.5 g of hydroxypropylcellulose and 20 g of microcrystalline cellulose, 
and 30 ml of water was added thereto and kneaded to give a granular mass. 
The mass was pelletized by means of a pelletizer (ECK pelletizer of Fuji 
Paudal Co., Japan) equipped with No. 24 mesh (B.S.) screen to obtain 
granules. The granules were dried to less than 5% moisture content and 
screened with No. 16 mesh (B.S.) screen. The screened granules were 
capsuled by means of a capsule filling machine so as to be contained in an 
amount of 190 mg per capsule. 
PHARMACEUTICAL EXAMPLE 2 
Soft capsule preparation for oral use 
A homogeneous solution was prepared by mixing 50 g of 
N-1-(naphthylmethyl)decaprenylamine hydrochloride with 130 g of 
polyethylene glycol (Macrogel 400). Separately, a gelatin solution was 
prepared which contained 93 g of gelatin, 19 g of glycerin, 10 g of 
D-sorbitol, 0.4 g of ethyl p-hydroxybenzoate, 0.2 g of propyl 
p-hydroxybenzoate and 0.4 g of titanium oxide and which was used as a 
capsule film-forming agent. The previously obtained solution, together 
with the capsule film forming agent, was treated with a manual type flat 
punching machine to obtain capsules each having the contents of 180 mg. 
PHARMACEUTICAL EXAMPLE 3 
Injections 
A mixture of 5 g of N-(3,4,5-trimethoxybenzyl)solanesylamine hydrochloride, 
an appropriate amount of peanut oil and 1 g of benzyl alcohol was made a 
total volume of 100 cc by addition of peanut oil. The solution was 
portionwise poured in an amount of 1 cc under asepsis operation into an 
ampule which was then sealed 
PHARMACEUTICAL EXAMPLE 4 
Injections 
A mixture of 1.0 g of N-(3,4-dimethoxybenzyl)solanesylamine hydrochloride, 
5.0 g of Nikkol HCO-60 (a trade name) (hydrogenated castor oil 
polyoxyethylene-60 moles-ether), 20 g of propylene glycol, 10 g of 
glycerol and 5.0 g of ethyl alcohol was mixed with 100 ml of distilled 
water and stirred. Under asepsis operation, the solution was portionwise 
poured in an amount of 1.4 ml into an ampule which was then sealed.