Imidazole derivatives, their preparation and their use as S-adenosylmethionine decarboxylase (=SAMDC) inhibitors

Described are compounds of formula I ##STR1## wherein R.sub.1 is hydrogen or hydroxy; PA1 R.sub.2, R.sub.2 ' and R.sub.2 " are each independently of the others hydrogen or a substituent other than hydrogen; either PA1 R.sub.3 is hydrogen or a substituent other than hydrogen and PA1 R.sub.4 is hydrogen or lower alkyl, or PA1 R.sub.3 and R.sub.4 together form a divalent radical of the formula --(CH.sub.2).sub.n -- wherein n is 2 or 3; PA1 R.sub.5 and R.sub.6 are each independently of the other hydrogen, alkyl or aryl; and PA1 either R.sub.7 and R.sub.8 are each hydrogen, or R.sub.7 and R.sub.8 together form a bond; tautomers thereof, provided that at least one tautomerisable group is present; and salts thereof. The compounds inhibit the enzyme S-adenosylmethionine decarboxylase and are suitable, for example, for the treatment of tumours and protozoal infections.

This application has been filed under 35 USC 371 as a National Stage 
application of PCT/EP 96/00143, filed Jan. 15, 1996. 
BRIEF DESCRIPTION OF THE INVENTION 
The invention relates to novel imidazole derivatives, to tautomers thereof 
and/or to salts thereof, to a process for the preparation of those 
compounds, to pharmaceutical compositions comprising those compounds, and 
to 
a) those compounds for use in, or 
b) the use of those compounds for, the therapeutic treatment of the human 
or animal body; and/or to the use of those compounds in the preparation of 
pharmaceutical compositions. 
BACKGROUND OF THE INVENTION 
It is known that inhibition of S-adenosylmethionine decarboxylase can be 
used for therapeutic purposes. Surprisingly, a novel class of compounds 
having valuable pharmacological properties has now been found. 
COMPLETE DESCRIPTION OF THE INVENTION 
An imidazole derivative according to the invention is especially a compound 
of formula I 
##STR2## 
wherein 
R.sub.1 is hydrogen or hydroxy; 
R.sub.2, R.sub.2 ' and R.sub.2 " are each independently of the others 
hydrogen or a substituent other than hydrogen; 
either 
R.sub.3 is hydrogen or a substituent other than hydrogen and 
R.sub.4 is hydrogen or lower alkyl, 
or 
R.sub.3 and R.sub.4 together form a divalent radical of the formula 
--(CH.sub.2),-- wherein n is 2 or 3; 
R.sub.5 and R.sub.6 are each independently of the other hydrogen, alkyl or 
aryl; and either R.sub.7 and R.sub.8 are each hydrogen, or R.sub.7 and 
R.sub.8 together form a bond; a tautomer thereof, provided that at least 
one tautomerisable group is present; or a salt thereof. 
Within the scope of the present Application, the general terms used 
hereinbefore and hereinafter have preferably the following meanings 
(unless indicated otherwise): 
The term "lower" denotes a radical having up to and including a maximum of 
7 carbon atoms, preferably up to and including a maximum of 4 carbon 
atoms. 
Lower alkyl is, for example, n-propyl, isopropyl, n-butyl, isobutyl, 
sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, or, 
preferably, ethyl or, especially, methyl. 
A substituent other than hydrogen is especially lower alkyl, halo-lower 
alkyl having one or more, preferably up to three, halogen atoms, 
cycloalkyl, aryl-lower alkyl, hydroxy, lower alkoxy, aryl-lower alkoxy, 
aryloxy, acyloxy, such as lower alkanoyloxy or arylcarbonyl-oxy, halogen, 
amino, N-lower alkylamino, N,N-di(lower alkyl)amino, acylamino, such as 
lower alkanoylamino or arylcarbonylamino, nitro, lower alkanoyl, 
arylcarbonyl, carboxy, lower alkoxycarbonyl, aryl-lower alkoxycarbonyl, 
such as 1-aryl-lower alkoxycarbonyl, for example benzyloxycarbonyl, 
carbamoyl (--CONH.sub.2), N-lower alkylcarbamoyl, N,N-di-(lower 
alkyl)carbamoyl, N-arylcarbamoyl, cyano, mercapto, lower alkylthio, lower 
alkanesulfonyl, sulfamoyl (--SO.sub.2 NH.sub.2), N-lower alkylsulfamoyl or 
N,N-di(lower alkyl)sulfamoyl. 
Halo-lower alkyl is especially mono-, di- or tri-(halo)-lower alkyl, such 
as trifluoromethyl. 
Halogen is, for example, iodine or, preferably, bromine or, especially, 
fluorine or chlorine. 
Cycloalkyl is preferably C.sub.3 -C.sub.8 cycloalkyl (having from 3 to 8 
ring carbon atoms) and especially C.sub.5 -C.sub.6 cycloalkyl (having 5 or 
6 ring carbon atoms), it being possible for cycloalkyl to be unsubstituted 
or substituted by lower alkyl. 
Aryl is preferably an aromatic ring system having from 6 to 12 ring carbon 
atoms that is unsubstituted or substituted by one or more substituents of 
any kind selected independently of one another, and is bi- or, preferably, 
mono-cyclic; especially unsubstituted or substituted phenyl or naphthyl, 
such as 1- or 2-naphthyl; suitable substituents being preferably one or 
more, especially from one to three, more especially one or two, radicals 
selected independently of one another from the group consisting of lower 
alkyl, phenyl, naphthyl, such as 1- or 2-naphthyl, lower alkoxy, hydroxy, 
lower alkanoyloxy, nitro, amino, halogen, halo-lower alkyl, such as 
trifluoromethyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower 
alkylcarbamoyl, N,N-di(lower alkyl)carbamoyl, cyano, lower alkanoyl, 
phenyl- or naphthyl-carbonyl, lower alkanesulfonyl, sulfamoyl, N-lower 
alkylsulfamoyl and N,N-di-lower alkylsulfamoyl. Aryl is especially 1- or 
2-naphthyl; or phenyl that is unsubstituted or substituted by one or two 
radicals selected independently of one another from halogen, such as 
fluorine or chlorine (in each case especially in the p-position), lower 
alkyl, such as methyl or tert-butyl (in each case especially in the 
p-position), lower alkoxy, such as methoxy, and phenyl. 
Aryl-lower alkyl preferably contains an aryl radical as defined above and 
is preferably phenyl-lower alkyl and, especially, benzyl. 
Aryl-lower alkoxy preferably contains an aryl radical as defined above and 
is especially phenyl-lower alkoxy, such as benzyloxy. 
Lower alkanoyl is especially foiinyl or, more especially, acetyl, propionyl 
or pivaloyl. 
Lower alkanoyloxy is especially acetoxy, propionyloxy or pivaloyloxy. 
Arylcarbonyl preferably contains an aryl radical as defined above and is, 
for example, benzoyl or 1- or 2-naphthoyl, each of which is unsubstituted 
or substituted by lower alkyl, lower alkoxy, hydroxy, halogen or by 
halo-lower alkyl, such as trifluoromethyl. 
Lower alkanesulfonyl (lower alkyl--SO.sub.2 --) is preferably methane- or 
ethane-sulfonyl. 
Alkyl is a hydrocarbon radical having preferably up to a maximum of 20 
carbon atoms that is unbranched or has one or more branches, such as 
dodecyl, for example 1-(n-dodecyl), decyl, for example 1-(n-decyl), nonyl, 
for example 1-(n-nonyl), octyl, for example 1-(n-octyl), or, preferably, 
lower alkyl, such as, especially, methyl or, more especially, ethyl. 
While the other radicals have the meanings given at each of the definition 
levels mentioned hereinbefore and hereinafter (generally defined compounds 
of formula I and preferred compounds of formula I), the following 
compounds are especially preferred: 
a) compounds of formula I wherein RI is hydrogen are preferred to those 
wherein R.sub.1 is hydroxy; 
b) when R.sub.7 and R.sub.8 are each hydrogen, in preferred compounds of 
formula I R.sub.5 and R.sub.6 are likewise each hydrogen; 
c) compounds of formula I wherein R.sub.3 and R.sub.4 together are 
--(CH.sub.2).sub.3 -- or, especially, --(CH.sub.2).sub.2 -- are preferred 
to those wherein R.sub.3 is hydrogen or a substituent other than hydrogen 
and R.sub.4 is hydrogen or lower alkyl. 
When tautomerisable groups are present in the compounds of formula I, it is 
possible (for example depending upon the solvent, pH value or aggregate 
state) for compounds of formula I (and some precursors thereof) to be in 
the form of tautomers. For example, in compounds of formula I wherein 
R.sub.7 and Rs are each hydrogen and the other radicals are as defined, 
the 4,5-dihydroimidazolyl radical may be in the following tautomeric 
forms: 
##STR3## 
The person skilled in the art is familiar with the occurrence of such 
tautomers and of similar tautomers and can therefore easily infer the 
corresponding compounds and tautomers. The present invention relates also 
to such tautomers. 
If cis/trans-isomerismn is possible and/or centres of asymmetry are 
present, compounds of formula I can be in the form of isomers or mixtures 
of isomers, for example in the form of mixtures of diastereoisomers, 
enantiomeric mixtures or pure isomers. 
On account of their basic properties, salts of compounds of formula I are 
especially acid addition salts and, where one or more acid groups (such as 
--COOH) are present, also internal salts; mixed salts are also possible. 
Salts are especially the pharmaceutically acceptable, that is to say 
non-toxic, salts of compounds of formula I, that is to say especially the 
corresponding acid addition salts with acid anions that are 
toxicologically tolerable (at the dose in question). 
Such salts are formed, for example, by compounds of formula I with 
inorganic acids, for example hydrohalic acids, such as hydrochloric acid 
or hydrobromic acid, sulfuric acid or phosphoric acid, or with organic 
carboxylic, sulfonic, sulfo or phosphonic acids or N-substituted sulfamic 
acids, for example acetic acid, propionic acid, glycolic acid, succinic 
acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, 
lactic acid, malic acid, tartaric acid, gluconic acid, glucaric acid, 
glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, 
salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 
2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, 
also with amino acids, such as the 20 a-amino acids involved in the 
synthesis of proteins in nature, for example glutamic acid or aspartic 
acid, and with methanesulfonic acid, ethanesulfonic acid, 
2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic 
acid, 4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, 
naphthalene-1,5-disulfonic acid, 2- or 3-phosphoglycerate, 
glucose-6-phosphate, N-cyclohexylsulfamic acid (with the formation of 
cyclamates), or with other acidic organic compounds, such as ascorbic 
acid. Carbonates or hydrogen carbonates are also possible. 
The mixed salts include, for example, salts of compounds of formula I with 
di- or trivalent acids that have acidic radicals with different 
dissociation constants, such as citric acid or phosphoric acid, one or two 
protons of those acids, for example, being replaced by cations, such as 
alkali metal cations, for example Na.sup.+ or K.sup.+, so that the 
corresponding salts contain, in addition to the compound of formula I and 
the corresponding acid anions, also the corresponding cations. 
Internal salts also may be in the form of mixed salts. 
The terms "compounds" and "salts" expressly include also individual 
compounds or individual salts. 
For isolation or purification it is also possible to use pharmaceutically 
unacceptable salts, for example picrates or perchlorates. Only the 
pharmaceutically acceptable, non-toxic salts are used therapeutically, and 
those salts are therefore preferred. 
The compounds according to the invention have valuable, especially 
pharmacologically useful, properties. In particular, they have a 
pronounced, specific inhibitory action on the enzyme S-adenosylmethionine 
decarboxylase (SAMDC). SAMDC, as a key enzyme, plays an important role in 
polyamine synthesis, which takes place in virtually all mammalian cells, 
including human cells. SAMDC regulates the concentration of polyamines in 
the cell. Inhibition of the enzyme SAMDC results in a reduction in the 
polyamine concentration. Since a reduction in the polyamine concentration 
causes inhibition of cell growth, it is possible by administering 
SAMDC-inhibiting substances to inhibit the growth of both eukaryotic and 
prokaryotic cells and even to kill cells or inhibit the onset of cell 
differentiation. For example, it is possible to control tumors, for 
example in models, such as tumors produced by syngenic transplantation of 
tumor cells. Syngenic transplantation means transplantation within a 
strain of individuals that are genetically virtually identical. 
Inhibition of the enzyme SAMDC can be demonstrated by conventional methods 
(for example by the method of H. G. Williams-Ashmann and A. Schenone, see 
Biochem. Biophys. Res. Communs. 46, 288 (1972), or preferably by the 
method of A. E. Pegg and H. S. Poso, see Methods Enzymol. 94, 234-239 
(1983)). The compounds of the invention have IC.sub.50 values in the range 
of from 10.sup.-9 to 10.sup.-4 M, especially from 2.times.10.sup.-9 to 
10.sup.-7 M. 
A further advantage of the compounds according to the invention is that 
they inhibit diamine oxidase only to a small extent as compared with their 
pronounced inhibitory action on SAMDC and are well tolerated. Inhibition 
of diamine oxidase is disadvantageous since it can lead to the 
accumulation of putrescine and hence to indirect activation of SAMDC (see 
J. Jaenne and D. R. Morris, Biochem. J. 218, 974 (1984)). The low degree 
of diamine oxidase inhibition can be determined by known methods (see, for 
example, P. Seppanen, L. Alhonen-Hongistu, K. Kapyaho and J. Janne, 
Methods Enzymol. 94, 247-253 (1983)). 
As polyamine antimetabolites, the compounds of formula I have 
antiproliferative properties which can be demonstrated, for example, by 
identifying the inhibitory action on the growth of human T24 bladder cell 
carcinomas. This is demonstrated by incubating the cells in "Eagle's 
Minimal Essential Medium" (see Eagle, H., Science 130, c1432-1437 (1959)), 
to which 5% (v/v) fetal calf serum is added, in a humidified incubator at 
37.degree. C. and 5% by volume CO.sub.2 in the air. The carcinoma cells 
(1000-1500; ATCC HB 4) are transferred to 96-well microtitre plates and 
are incubated overnight under the said conditions. The test compound is 
added in serial dilutions on day 1. The plates are incubated under the 
said conditions for 5 days. During that period, control cultures undergo 
at least 4 cell divisions. After the incubation, the cells are fixed with 
3.3% (weight/volume=w/v) aqueous glutaraldehyde solution, washed with 
water and stained with 0.05% (w/v) aqueous methylene blue solution. After 
washing, the dye is eluted with 3% (w/v) aqueous hydrochloric acid. The 
optical density (OD) per well, which is directly proportional to the 
number of cells, is then measured by means of a photometer (Titertek 
multiskan) at 665 nm. The IC.sub.50 values are calculated by means of a 
computer system using the formula 
##EQU1## 
The IC.sub.50 value is defined as the concentration of active ingredient 
at which the number of cells per well at the end of the incubation period 
is only 50% of the number of cells in the control cultures. 
For compounds of formula I, IC.sub.50 values in the range of from 10.sup.-4 
to 5.times.10.sup.-7 M, especially in the range of from 10.sup.-5 to 
10.sup.-6 M, are obtained. 
The tolerability and anti-tumor activity of the compounds of formula I in 
vivo can be demonstrated by known methods, for example using the method of 
U. Regenass, H. Mett, J. Stanek, M. Muller, D. Kramer and C. W. Porter 
(see Cancer Res. 54, 3210-3217 (1994)). Briefly, the procedure is as 
follows: To determine the maximum tolerable dose (MTD), the compounds 
according to the invention (for example dissolved in distilled water/0.9% 
NaCl) are injected i.p. into three mice per group. The dose is increased 
until the first animals die within a period of 10 days. To determine the 
anti-tumor activity, for example, small pieces of human T-24 bladder 
carcinoma cells (ATCC HTB 4) are cultured and transplanted as xenogenic 
transplants ("xenografts") into female BALB/c nude mice (Bomholtgarden, 
Copenhagen, Denmark). The anti-tumor treatment using compounds of formula 
I is started after at least three successive transplants. Tumor fragments 
weighing approximately 25 mg are transplanted into the left flank of the 
mouse (n=6 per group). Treatment is started as soon as the tumors have an 
average tumor volume of from 150 to 200 mm.sup.3. The growth of the tumors 
is determined twice weekly by measuring mutually perpendicular tumor 
diameters. The tumor volumes are determined in the manner described by U. 
Regenass, H. Mett, J. Stanek, M. Muller, D. Kramer and C. W. Porter (see 
Cancer Res. 54 3210-3217 (1994)) and are given as relative tumor size 
(i.e. increase in tumor volume relative to the tumor volume at the 
beginning of treatment) in T/C % (percent treated/control). The test 
compounds are dissolved in distilled water and diluted with 3 volumes of 
0.9% (w/v) NaCl in water. 
Values found for MTD are especially in the region of more than 200 mg/kg 
p.o. for example more than 500 mg/kg p.o.; or more than 50 mg/kg i.p., for 
example approximately 125 mg/kg i.p.. In the determination of the activity 
against tumors, dose-dependent inhibition of tumor growth on 
administration of compounds of formula I is found; in particular, in the 
case of p.o. administration marked reductions in tumor growth are found at 
a dose of as little as approximately 5 mg/kg, and in the case of i.p. 
administration very marked reductions in tumor growth are found at the 
lowest dose used (3.13 mg/kg), with preferred T/C values of less than 60%. 
It is also possible to demonstrate the effectiveness of the compounds of 
formula I against trypanosomes using test systems known per se (see, for 
example, Brun, R. and Kunz, C., Acta Tropica 46 361-368 (1989)). 
The compounds also exhibit good to very good plasma levels when 
administered p.o. (for example to mice). 
When partitioned between octanol and water (log P determination), the 
compounds of formula I exhibit good lipophilicity. 
Accordingly, the compounds of formula I can be used, for example, in the 
treatment of benign and malignant tumors. They are able to bring about the 
regression of tumors and also to prevent the spread of tumor cells and the 
growth of micrometastases. Moreover, they are beneficial, for example, in 
the treatment of protozoal infections, such as trypanosomiasis, malaria, 
or pulmonary inflammation caused by Pneumocystis carinii. 
The corresponding diseases, especially tumor diseases, in warm-blooded 
animals, especially in mammalian domestic animals and in humans, can be 
treated. 
As selective SAMDC inhibitors, the compounds of formula I can be used 
either on their own or in combination with other substances having 
pharmacological activity, for example in combination with (a) inhibitors 
of other enzymes of polyamine biosynthesis, for example ornithine 
decarboxylase inhibitors, (b) inhibitors of protein kinase C, (c) 
inhibitors of tyrosine protein kinase, (d) cytokines, (e) negative growth 
regulators, (f) aromatase inhibitors, (g) anti-oestrogens or (h) 
conventional cytostatic or also cytotoxic active ingredients. 
Preference is given to a compound of formula I wherein 
R.sub.1 is hydroxy or, especially, hydrogen; the radicals R.sub.2, R.sub.2 
' and R.sub.2 " are each independently of the others hydrogen or a 
substituent selected from lower alkyl, halo-lower alkyl having one or 
more, preferably up to three, halogen atoms, such as trifluoromethyl, 
C.sub.3 -C.sub.8 cycloalkyl, phenyl-lower alkyl, hydroxy, lower alkoxy, 
phenyl-lower alkoxy, phenyloxy, lower alkanoyloxy or benzoyloxy, halogen, 
amino, N-lower alkylamino, N,N-di(lower alkyl)amino, lower alkanoylamino, 
benzoylamino, nitro, lower alkanoyl, benzoyl, carboxy, lower 
alkoxycarbonyl, 1-phenyl-lower alkoxycarbonyl, for example 
benzyloxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di(lower 
alkyl)carbamoyl, N-phenylcarbamoyl, cyano, mercapto, lower alkylthio, 
lower alkanesulfonyl, sulfamoyl, N-lower alkylsulfamoyl and N,N-di-(lower 
alkyl)sulfamoyl; 
either 
R.sub.3 is hydrogen and 
R.sub.4 is hydrogen or lower alkyl 
or 
R.sub.3 and R.sub.4 together form a divalent radical of the formula 
--(CH.sub.2)n-- wherein n is 2 or 3; 
R.sub.5 and R.sub.6 are each independently of the other hydrogen, lower 
alkyl, such as methyl or ethyl; or phenyl or naphthyl each of which is 
unsubstituted or mono- to tri-substituted, especially mono- or 
di-substituted, such as 1- or 2-naphthyl, wherein the substituents are 
selected independently of one another from the group consisting of lower 
alkyl, phenyl, naphthyl, lower alkoxy, hydroxy, lower alkanoyloxy, nitro, 
amino, halogen, halo-lower alkyl, such as trifluoromethyl, carboxy, lower 
alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di(lower 
alkyl)carbamoyl, cyano, lower alkanoyl, phenyl- or naphthylcarbonyl, lower 
alkanesulfonyl, sulfamoyl, N-lower alkylsulfamoyl and N,N-di-lower 
alkylsulfamoyl; R.sub.5 preferably being hydrogen; and 
either R.sub.7 and R.sub.8 are each hydrogen, or R.sub.7 and R.sub.8 
together form a bond; a tautomer thereof, provided that at least one 
tautomerisable group is present; or a salt thereof. 
Special preference is given to a compound of formula I wherein R.sub.1 is 
hydroxy or, especially, hydrogen; 
R.sub.2, R.sub.2 ' and R.sub.2 " are each hydrogen; 
either 
R.sub.3 is hydrogen and 
R.sub.4 is hydrogen or lower alkyl, or 
R.sub.3 and R.sub.4 together are --(CH.sub.2).sub.2 -- or 
--(CH.sub.2).sub.3 --; 
R.sub.5 is hydrogen, lower alkyl, such as methyl or ethyl; or naphthyl or 
phenyl each of which is unsubstituted or substituted by from one to three, 
especially one or two, radicals selected from lower alkoxy, such as 
methoxy, halogen, such as bromine or, especially, chlorine or fluorine, 
lower alkyl, such as methyl or also tert-butyl, and phenyl; 
R.sub.6 is hydrogen; and 
either R.sub.7 and R.sub.8 are each hydrogen, or R.sub.7 and R.sub.8 
together form a bond; a tautomer thereof, provided that at least one 
tautomerisable group is present; or a salt thereof. 
Greater preference is given to a compound of formula I wherein 
R.sub.1 is hydroxy or, especially, hydrogen; 
the radicals R.sub.2, R.sub.2 ' and R.sub.2 " are each hydrogen; 
either 
R.sub.3 is hydrogen and 
R.sub.4 is hydrogen or lower alkyl, or 
R.sub.3 and R.sub.4 together are --(CH.sub.2).sub.2 -- or 
--(CH.sub.2).sub.3 --; 
R.sub.5 is hydrogen, lower alkyl, phenyl, 2-, 3- or 4-lower alkoxyphenyl, 
2,5-di-lower alkoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-lower 
alkylphenyl, 4-biphenylyl, or 1- or 2-naphthyl; 
R.sub.6 is hydrogen; and 
either R.sub.7 and R.sub.8 are each hydrogen, or R.sub.7 and R.sub.8 
together form a bond; or a salt thereof; 
lower alkyl in the mentioned radicals being in each case especially methyl 
or ethyl. 
Very great preference is given to a compound of formula I wherein R.sub.1, 
R.sub.2, R.sub.2 ' and R.sub.2 " are each hydrogen; 
either 
R.sub.3 is hydrogen and 
R.sub.4 is hydrogen or methyl, or 
R.sub.3 and R.sub.4 together are --(CH.sub.2).sub.2 -- or 
--(CH.sub.2).sub.3 --; 
R.sub.5 is hydrogen, ethyl, phenyl, 2-, 3- or 4-methoxyphenyl, 
2,5-dimethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 
4-biphenylyl or 2-naphthyl; 
R.sub.6 is hydrogen; and 
either R.sub.7 and R.sub.8 are each hydrogen, or R.sub.7 and R.sub.8 
together form a bond; or a salt thereof. 
Very great preference is given also to a compound of formula I wherein 
R.sub.1, R.sub.2, R.sub.2 ' and R.sub.2 " are each hydrogen; 
R.sub.3 and R.sub.4 together are --(CH.sub.2).sub.2 -- or 
--(CH.sub.2).sub.3 --; 
R.sub.5 is 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 
3,5-dimethoxyphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 
2,4-dimethylphenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 
2,4-dichlorophenyl or 3,5-di(tert-butyl)phenyl; 
R.sub.6 is hydrogen; and 
R.sub.7 and R.sub.8 together form a bond; or a salt thereof. 
The invention relates especially to the specific compounds described in the 
Examples, or salts thereof. 
The compounds of formula I can be prepared in accordance with methods known 
per se, for example by 
a) reacting a compound of formula II 
##STR4## 
wherein W.sub.1 is functionally modified carboxy and the other radicals 
are as defined for compounds of formula I, or a salt thereof, with 
hydroxylamine or ammonia of formula III 
EQU R.sub.1 --NH.sub.2 (III), 
wherein R.sub.1 is hydrogen or hydroxy, or with a salt thereof, functional 
groups in the starting materials that are not intended to participate in 
the reaction being, if necessary, in protected form, and removing any 
protecting groups that are present; or 
b) reacting a hydroxyimino compound of formula IV 
##STR5## 
wherein the radicals are as defined for compounds of formula I, or a salt 
thereof, with an aminoimidazole of formula V 
##STR6## 
wherein the radicals are as defined for compounds of formula I, or with a 
salt thereof, functional groups in the starting materials that are not 
intended to participate in the reaction being, if necessary, in protected 
form, and removing any protecting groups that are present; or 
c) for the preparation of a compound of formula I wherein R.sub.1 is 
hydrogen and the other radicals are as defined, reacting an oxo compound 
of formula VI 
##STR7## 
or a reactive derivative thereof, wherein the radicals are as defined for 
compounds of formula I, or a salt thereof, with an aminoimidazole of 
formula V 
##STR8## 
wherein the radicals are as defined for compounds of formula I, or with a 
salt thereof, functional groups in the starting materials that are not 
intended to participate in the reaction being, if necessary, in protected 
form, and removing any protecting groups that are present; 
and, if desired, converting a compound of formula I obtained according to 
one of processes a), b) or c) into a different compound of formula I, if 
desired converting a resulting salt of a compound of formula I into the 
free compound, if desired converting into a salt a free compound of 
formula I having salt-forming properties that has been obtained directly 
or according to the last-mentioned step from a different salt, and/or, if 
desired, separating a resulting mixture of isomers of compounds of formula 
I into individual isomers. 
DETAILED DESCRIPTION OF THE PROCESS 
In the following detailed description of the preferred process conditions, 
the radicals R.sub.1, R.sub.2, R.sub.2 ', R.sub.2 ", R.sub.3, R.sub.4, 
R.sub.5, R.sub.6, R.sub.7 and R.sub.8 in starting materials, intermediates 
and end products are each as defined for compounds of formula I, unless 
indicated otherwise. 
Process a): Conversion of a cyano group into a hydroxyamidino or amidino 
group 
In an intermediate of formula II, WI is functionally modified carboxy, 
preferably imino-alkoxycarbonyl, imino-alkanethiolcarbonyl (both 
especially in salt form) or, especially, cyano. 
In the preparation of amidines of formula I (R.sub.1 =H or OH), the group 
W.sub.1 in a compound of formula II may be, for example: an acid addition 
salt of an imino-lower alkyl ester (which corresponds to an imino-lower 
alkyl ether) or of an imino-lower alkanethiol ester, for example having 
the radical --C(.dbd.NH)--OCH.sub.5.HCl or --C(.dbd.NH)--SC.sub.2 
H.sub.5.HCl. Cyano is, however, preferred. 
Reaction of an imino-(lower)alkyl ester or imino-(lower)alkanethiol ester 
of formula II (in the form of a salt) with ammonia yields a compound of 
formula I that contains an amidino group (R.sub.1 =H). Preferably, cyano 
compounds of formula II are converted, for example, by reaction with an 
alkali metal amide, such as KNH.sub.2, into the corresponding amidino 
compounds of formula I (R.sub.1 =H). 
N-Hydroxyamidino compounds of formula I (R.sub.1 =OH) can be prepared in an 
analogous manner, for example by reacting an imino-(lower)alkyl ester or 
imino-(lower)alkanethiol ester of formula II (in the form of a salt) with 
hydroxylamine or a salt thereof. 
Preferably, cyano compounds of formula II are converted into the 
corresponding amidino (R.sub.1 =H) or, especially, N-hydroxyamidino 
compounds (R.sub.1 =OH) of formula I with ammonia or, especially, 
hydroxylamine of formula III, or salts thereof, for example by reaction in 
the presence of a base, such as a metal alcoholate, for example the metal 
alcoholate of a lower alkanol, such as methanol or ethanol, or a metal 
hydrogen carbonate or, especially, a metal carbonate, preferably a salt of 
that kind, "metal" denoting an alkali metal, such as sodium or potassium, 
such as sodium or potassium methanolate or sodium or potassium carbonate. 
The reaction takes place (i) in the case of metal alcoholates, preferably 
in the alcohol that matches the metal alcoholate, such as methanol or 
ethanol, at preferred temperatures of from 0.degree. to 50.degree. C., 
especially at room temperature; or (ii) in the case of metal carbonates 
(or also metal hydrogen carbonates), in alcohols, such as methanol or 
ethanol, N,N-di-lower alkyl-alkanoylamides, such as N,N-dimethylformamide, 
or water, or mixtures thereof, at preferred temperatures of from 
50.degree. C. to the reflux temperature, especially from 75.degree. C. to 
the reflux temperature. 
Starting materials of formula II wherein WI is imino-(lower)alkoxycarbonyl 
are prepared, for example, by acid-catalyzed reaction of compounds of 
formula II wherein W.sub.1 is cyano with alkanols, especially lower 
alkanols, for example by reaction with ethanol and hydrochloric acid in, 
for example, chloroform or diethyl ether. Starting materials of formula II 
wherein W.sub.1 is imino-(lower)alkanethiolcarbonyl are obtained, for 
example, by first of all converting a compound of formula II wherein WI is 
cyano into the corresponding thiocarboxamide (in which 
--C(.dbd.S)--NH.sub.2 is present instead of W.sub.1) by treatment with 
hydrogen sulfide (for example in pyridine in the presence of a tertiary 
nitrogen base, such as triethylamine, at temperatures of from 0.degree. to 
50.degree. C., for example at approximately 40.degree. C). The 
thiocarboxamide can then be S-alkylated, for example with the 
corresponding (lower) alkyl iodide or, preferably, tri(lower) alkyloxonium 
tetrafluoroborate, preferably under a protective gas, such as argon, in an 
inert polar solvent, such as a chlorinated hydrocarbon, for example 
methylene chloride, at preferred temperatures of from 0.degree. to 
50.degree. C., especially at approximately room temperature, and thus 
converted into the imino-(lower) alkanethiol ester hydroiodide 
(--C(.dbd.NH)--S--alkyl--HI) or imino-(lower) alkanethiol ester 
tetrafluoroborate, respectively. 
Compounds of formula II wherein W.sub.1 is cyano can be prepared, for 
example, by reacting a compound of formula VII 
##STR9## 
wherein CW.sub.2 W.sub.3 is free or functionally modified or protected 
carbonyl, with an aminoimidazole of formula V 
##STR10## 
wherein the radicals are as defined above (under processes b) and c)). 
Functionally modified or protected carbonyl is, for example: di-lower 
alkoxymethylene (W.sub.2 and W.sub.3 are each lower alkoxy), C.sub.1 
-C.sub.2 alkylenedioxymethylene (W.sub.2 and W.sub.3 together are C.sub.1 
-C.sub.2 alkylenedioxy), di-lower alkylthiomethylene (W.sub.2 and W.sub.3 
are each lower alkylthio), C.sub.1 -C.sub.2 alkylenedithiomethylene 
(W.sub.2 and W.sub.3 together are C.sub.1 -C.sub.2 alkylenedithio) or, 
especially, hydroxyiminomethylene. (W.sub.2 and W.sub.3 together are 
.dbd.N--OH). 
In free carbonyl, which (together with hydroxyiminomethylene) is preferred, 
W.sub.2 and W.sub.3 together are oxo (.dbd.O). 
The reaction takes place under the conditions known per se for the reaction 
of carbonyl derivatives with amino compounds, especially with acid 
catalysis, preferably analogously to the conditions mentioned under 
processes b) and c) for the reaction of compounds of formula IV and VI, 
respectively, with compounds of formula V. 
Compounds of formula VII are known or can be prepared in accordance with 
processes known per se (see, for example, Coll. Czechoslov. Chem. Commun. 
43, 3227 (1978)). 
For example, compounds of formula VII wherein CW.sub.2 W.sub.3 is carbonyl 
and the other radicals are as defined for compounds of formula I can be 
obtained from compounds of formula VIII 
##STR11## 
wherein W.sub.2 and W.sub.3 together are carbonyl and W.sub.4 is halogen, 
especially bromine, or protected amino, for example acetylamino, for 
example by reaction with copper(I) cyanide (in the case of bromo) or by 
removal of the acetyl protecting group, diazotisation and reaction with 
copper(I) cyanide (in the case of acetylamino). 
Compounds of formula VII wherein the group CW.sub.2 W.sub.3 is carbonyl can 
also be prepared by oxidation, for example with chromium trioxide 
(CrO.sub.3), from the corresponding compounds of formula VIIIa 
##STR12## 
wherein W.sub.4 ' is cyano or halogen, especially bromine, or protected 
amino, for example acetylamino, and when W.sub.4 ' is not cyano but one of 
the other radicals mentioned above, the conversion into a cyano group is 
carried out analogously to the procedure described above when using 
compounds of formula VIII. 
The corresponding hydroxyimino compounds of formula VII (W.sub.2 and 
W.sub.3 together are .dbd.N--OH) can then be prepared therefrom by 
subsequent reaction with hydroxylamine (in free form or in the form of a 
salt) under customary conditions for the reaction of carbonyl groups with 
nitrogen bases. In the reaction, an oxo compound of formula VII (W.sub.2 
and W.sub.3 =oxo) is reacted with hydroxylamine, which is preferably 
introduced in an equimolar amount or in an excess, preferably an up to 
ten-fold excess, relative to the starting material of formula VII, or with 
a salt thereof, preferably a salt with an inorganic acid, for example a 
hydrohalic acid, such as hydrofluoric acid, hydrogen chloride, hydrogen 
bromide or hydrogen iodide, especially hydrogen chloride, with sulfuric 
acid or a hydrogen sulfate, such as an alkali metal hydrogen sulfate, for 
example sodium hydrogen sulfate, with phosphoric acid, a hydrogen 
phosphate or a dihydrogen phosphate, for example an alkali metal hydrogen 
phosphate or dihydrogen phosphate, such as sodium hydrogen phosphate, 
disodium hydrogen phosphate, potassium hydrogen phosphate or dipotassium 
hydrogen phosphate, or a salt with an organic acid, for example with a 
carboxylic acid, such as a lower alkanecarboxylic acid that is 
unsubstituted or substituted in the lower alkyl moiety, preferably by 
halogen, such as fluorine, chlorine or iodine, for example acetic acid, 
chloroacetic acid, dichloroacetic acid or trifluoro- or trichloro-acetic 
acid, or with a sulfonic acid, such as a lower alkanesulfonic acid, for 
example methanesulfonic acid, ethanesulfonic acid or ethanedisulfonic 
acid, or with an arylsulfonic acid, such as benzene- or 
naphthalene-sulfonic acid or naphthalene-1,5-disulfonic acid, or a double 
salt, such as Zn(NH.sub.2 OH).sub.2 Cl.sub.2 (Crismer's reagent); or is 
reacted with hydroxylamine prepared in situ, for example from an alcoholic 
solution of nitric oxide and a tin(II) salt, such as Sn(II)Cl.sub.2, in 
the presence of copper salts, or from the potassium salt of 
N,O-bistrimethyl-silyl!hydroxylamine (prepared from (H.sub.3 C).sub.3 
Si--NH--O--Si(CH.sub.3).sub.3 and potassium hydride in tetrahydrofuran, 
with subsequent freeing of the potassium salt of the compound of formula 
VII with an acid, for example ammonium chloride); the reaction being 
carried out in water (in the presence or absence of surfactants), in an 
aqueous solvent mixture, such as a mixture of water with one or more 
alcohols, for example methanol or ethanol, di-lower alkyl sulfoxides, such 
as dimethyl sulfoxide, or di-lower alkyl-lower alkanoylamides, such as 
dimethylformamide; in organic solvents, such as alcohols, for example 
methanol or ethanol, di-lower alkyl sulfoxides, such as dimethyl 
sulfoxide, di-lower alkyl-lower alkanoylamides, such as dimethylformamide, 
or in sufficiently inert nitrites, such as acetonitrile; a mixture of such 
organic solvents; or in liquid ammonia, preferably in an aqueous-alcoholic 
solution, such as methanol/water or ethanol/water; at temperatures of from 
-78.degree. C. to the reflux temperature of the corresponding reaction 
mixture, preferably from -30.degree. to 100.degree. C., especially from 
5.degree. to 90.degree. C., for example at approximately from 75.degree. 
to 80.degree. C.; under pressures of approximately from 1 to 10000 bar, 
preferably, where hydroxylamine salts are used, under normal pressure; in 
the absence of a base or preferably, where acid salts of hydroxylamine are 
used, with neutralization of the acid with a base, especially with a 
hydroxide, such as an alkali metal hydroxide, for example sodium or 
potassium hydroxide, with a carbonate or hydrogen carbonate, especially an 
alkali metal or alkaline earth metal carbonate or hydrogen carbonate, for 
example sodium carbonate, potassium carbonate, sodium hydrogen carbonate, 
potassium hydrogen carbonate or barium carbonate, with a salt of a weak 
organic acid, especially an alkali metal or alkaline earth metal salt of a 
lower alkanecarboxylic acid, for example sodium acetate or potassium 
acetate, with organic nitrogen bases, especially a secondary or tertiary 
amine, for example a cyclic 5- or 6-membered secondary or tertiary amine, 
such as pyrrolidine or pyridine, or with alcoholates, for example alkali 
metal lower alkyl alcoholates, such as sodium or potassium methanolate, 
ethanolate or tert-butanolate, or with an anion exchanger, the presence of 
an alkali metal carbonate being especially preferred; the compound of 
formula VII wherein W.sub.2 and W.sub.3 together are hydroxyimino being 
obtained, preferably directly in crystalline form and, where appropriate, 
after recrystallization from solvents or solvent mixtures. Preferably, one 
of the mentioned salts of hydroxylamine, especially the salt of a 
hydrohalic acid, such as the hydrochloride salt, is reacted in the 
mentioned organic solvents, especially in an alcohol, such as methanol or 
ethanol, at the mentioned temperatures, especially at approximately from 
75.degree. to 80.degree. C., to yield the corresponding oxime of formula 
VII, which can be purified or is used further directly. 
The other compounds of formula VII, wherein W.sub.2 and W.sub.3 have one of 
the meanings mentioned above other than oxo or hydroxyimino, can be 
prepared from the oxo or hydroxyimino compounds under customary conditions 
for the preparation of ketals, acetals, thioketals or thioacetals. 
Compounds of formula VIII and VIIIa are known or can be prepared in 
accordance with processes known per se (see, for example, J. Org. Chem. 
49, 4226 (1984)). 
A further, preferred method for the preparation of a compound of formula II 
wherein W.sub.1 is cyano, R.sub.7 and R.sub.8 together form a bond and the 
other radicals are as defined uses as starting material a guanylhydrazone 
derivative of formula IX 
##STR13## 
wherein R.sub.2, R.sub.2 ', R.sub.2 ", R.sub.3 and R.sub.4 are as defined 
for compounds of formula I, which is reacted with a compound of formula X 
##STR14## 
wherein W.sub.5 is a nucleofugal leaving group and R.sub.5 and R.sub.6 are 
as defined for compounds of formula I, or with a reactive derivative 
thereof, to form the corresponding compound of formula II. 
A nucleofugal leaving group W.sub.5 is especially a leaving group selected 
from hydroxy esterified by a strong inorganic or organic acid, especially 
hydroxy esterified by a mineral acid, for example a hydrohalic acid, such 
as hydrochloric, hydrobromic or also hydriodic acid, or also by a strong 
organic sulfonic acid, such as a lower alkanesulfonic acid that is 
unsubstituted or substituted by, for example, halogen, such as fluorine, 
or an aromatic sulfonic acid, for example a benzenesulfonic acid that is 
unsubstituted or substituted by lower alkyl, such as methyl, halogen, such 
as bromine, and/or by nitro, such as a methanesulfonic, 
p-bromotoluenesulfonic or p-toluenesulfonic acid, or hydroxy esterified by 
hydrazoic acid. The compound in question can also be prepared in situ by 
replacement of a radical W.sub.5, for example chlorine, by another radical 
W.sub.5, for example iodine (preferably using an alkali metal iodide, such 
as NaI), followed by further reaction in the resulting reaction mixture. 
A reactive derivative of a compound of formula X is especially a 
corresponding acetal or ketal, especially with lower alkanols, such as 
methanol or ethanol. The carbonyl group in formula X is in that case in 
the form of a di-lower alkoxymethylene group. 
In the case of free compounds of formula X, the reaction preferably takes 
place in a suitable polar solvent, such as an alcohol, for example 
methanol or, especially, ethanol, at temperatures of from -10.degree. C. 
to the reflux temperature, preferably from 0.degree. to 25.degree. C. or 
at the reflux temperature. If desired or necessary, a tertiary nitrogen 
base, for example a tri-lower alkylamine, such as triethylamine, is added 
(especially when the compound of formula IX is not used in a molar excess, 
for example a two-fold molar excess, relative to the compound of formula X 
and therefore protons that are released in the reaction can no longer be 
bound by the excess of the compound of formula IX). Where a reactive 
derivative of a compound of formula X is used (which is preferred when 
R.sub.5 is hydrogen), the reaction takes place especially in an aprotic 
solvent, for example an N,N-di-lower alkyl-lower alkanoylamide, such as 
N,N-dimethylformamide or N,N-dimethylacetamide, in the presence of a 
strong base, especially an alkali metal hydride, such as potassium hydride 
or, especially, sodium hydride, at preferred temperatures of from 
0.degree. to 100.degree. C., especially from 18.degree. to 60.degree. C., 
preferably using a protective gas, such as nitrogen or argon, the radical 
W.sub.5 being nucleophilically substituted by the 2'-imino nitrogen of the 
compound of formula IX (indicated by an arrow in formula IX). The 
resulting intermediate (containing a reactively derivatized carbonyl 
group) is then reacted by treatment with an acid, such as a mineral acid, 
for example a hydrohalic acid, such as HCl, in aqueous solution at 
preferred temperatures of from 60.degree. C. to the reflux temperature, 
the corresponding compound of formula II being obtained. 
Compounds of formula IX can be prepared in accordance with processes known 
per se, especially from compounds of formula VII, as defined above, by 
reaction with aminoguanidine, which is preferably used in approximately 
equimolar amount or in excess relative to the molar amount of the compound 
of formula I, especially in an amount that is from 1 to 2 times the molar 
amount. The reaction takes place under conditions that are customary per 
se for the reaction of carbonyl groups with nitrogen bases, aminoguanidine 
preferably being used in the form of the salt of an acid, for example of a 
hydrohalic acid, such as hydrogen fluoride, hydrogen chloride, hydrogen 
bromide or hydrogen iodide, especially hydrogen chloride, of sulfuric acid 
or a hydrogen sulfate, such as an alkali metal hydrogen sulfate, for 
example sodium hydrogen sulfate, of phosphoric acid, a hydrogen phosphate 
or a dihydrogen phosphate, for example an alkali metal hydrogen phosphate 
or dihydrogen phosphate, such as sodium hydrogen phosphate, disodium 
hydrogen phosphate, potassium hydrogen phosphate or dipotassium hydrogen 
phosphate, or in the form of a salt with an organic acid, especially with 
a carboxylic acid, such as a lower alkanecarboxylic acid that is 
unsubstituted or substituted in the lower alkyl moiety, preferably by 
halogen, such as fluorine, chlorine or iodine, for example acetic acid, 
chloroacetic acid, dichloroacetic acid, or trifluoro- or trichloro-acetic 
acid, with lactic acid or with a sulfonic acid, such as a lower 
alkanesulfonic acid, for example methanesulfonic acid, ethanesulfonic acid 
or ethanedisulfonic acid, or an arylsulfonic acid, such as benzene- or 
naphthalene-sulfonic acid or naphthalene-1,5-disulfonic acid; a salt of a 
strong acid of the compound of formula III especially being formed in 
situ, especially from the corresponding salt of a readily volatile weak 
acid that is capable of being liberated by a strong acid, such as sulfuric 
acid or, more especially, one of the mentioned hydrohalic acids or 
methanesulfonic acid, such as a lower alkanecarboxylic acid, for example 
acetic acid, or especially carbonic acid or hydrogen carbonate, by 
liberating the weak acid; in water (in the presence or absence of 
surfactants), in an aqueous solvent mixture, such as a mixture of water 
with one or more alcohols, for example methanol, ethanol or isopropanol, 
di-lower alkyl sulfoxides, such as dimethyl sulfoxide, or di-lower 
alkyl-lower alkanoylamides, such as dimethylformamide, organic solvents, 
such as one or more alcohols, for example methanol or ethanol, di-lower 
alkyl sulfoxides, such as dimethyl sulfoxide, di-lower alkyl-lower 
alkanoylamides, such as dimethylformamide, or sufficiently inert nitrites, 
such as acetonitrile, or a mixture of such organic solvents, preferably in 
an aqueous-alcoholic solution, such as in water/methanol, water/ethanol or 
water/isopropanol; preferably at temperatures of from -20.degree. C. to 
the reflux temperature of the reaction mixture, especially at temperatures 
of from room temperature to the reflux temperature of the reaction 
mixture, more especially at approximately the reflux temperature; the 
compound of formula VII being obtained directly in free form or, 
especially, in the form of a salt, preferably of the acid present in the 
reaction, for example in crystalline form. 
Compounds of formula X are known, can be prepared in accordance with 
processes known per se, or are available commercially. 
Corresponding reactive derivatives of compounds of formula X are known, are 
available commercially or can be prepared in accordance with processes 
known per se, for example by reaction of a compound of formula X with the 
corresponding alcohol, if necessary in the presence of dehydrating agents, 
such as dimethyl sulfide. 
Compounds of formula V are known, can be prepared in accordance with 
processes known per se, or are available commercially. They are prepared, 
for example, as follows: 
Compounds of formula V wherein R.sub.7 and R.sub.8 together form a bond are 
prepared from guanidino compounds of formula XI 
##STR15## 
wherein Q is an aryl-1-alkylidene radical used as a protecting group, 
especially benzylidene or also phenyl-1-ethylidene, by reaction with 
compounds of formula X 
##STR16## 
wherein W.sub.5 is a nucleofugal leaving group and R.sub.5 and R.sub.6 are 
as defined for compounds of formula I, or with a reactive derivative 
thereof. 
A nucleofugal leaving group W.sub.5 is especially a leaving group selected 
from hydroxy esterified by a strong inorganic or organic acid, especially 
hydroxy esterified by a mineral acid, for example a hydrohalic acid, such 
as hydrochloric, hydrobromic or also hydriodic acid, or also by a strong 
organic sulfonic acid, such as a lower alkanesulfonic acid that is 
unsubstituted or substituted by, for example, halogen, such as fluorine, 
or an aromatic sulfonic acid, for example a benzenesulfonic acid that is 
unsubstituted or substituted by lower alkyl, such as methyl, halogen, such 
as bromine, and/or by nitro, such as methanesulfonic acid, 
p-bromotoluenesulfonic acid or p-toluenesulfonic acid, or hydroxy 
esterified by hydrazoic acid. The compound in question can also be 
prepared in situ by replacement of a radical W.sub.5, for example 
chlorine, by a different radical W.sub.5, for example iodine (preferably 
using an alkali metal iodide, such as NaI), followed by further reaction 
in the resulting reaction mixture. 
A reactive derivative of a compound of formula X is especially a 
corresponding acetal or ketal, especially with lower alkanols, such as 
methanol or ethanol. The carbonyl group in formula X is in that case in 
the form of, for example, a di-lower alkoxymethylene group. 
In the case of free compounds of formula X, the reaction is preferably 
carried out in a suitable polar solvent, such as an alcohol, for example 
methanol or, especially, ethanol, at temperatures in the range of from 
-10.degree. C. to the reflux temperature, preferably from 0.degree. to 
20.degree. C. or from 20.degree. C. to the reflux temperature. If desired 
or necessary, a tertiary nitrogen base, for example a tri-lower 
alkylamine, such as triethylamine, is added (especially when the compound 
of formula XI is not used in a molar excess, for example a two-fold molar 
excess, relative to the compound of formula X and therefore the protons 
that are released in the reaction cannot be bound by the excess of the 
compound of formula XI) (see Chem. Ber. 101, 3151-3162 (1968) or J. Het. 
Chem. 11(3), 327-329 (1974)). In order to obtain a free compound of 
formula V, the protecting group Q (especially benzylidene) is then 
removed, preferably either with hydrazine (for example in the form of 
hydrazine hydrate) in a high-boiling alcohol, such as a di-lower 
alkylene-di-lower alkanol, such as diethylene glycol, at temperatures of 
from 100.degree. C. to the reflux temperature, for example from 
140.degree. to 170.degree. C., or in the presence of an acid, such as a 
mineral acid, for example sulfuric acid, phosphoric acid or, especially, a 
hydrohalic acid, such as HCl or HBr, in aqueous solution at temperatures 
of from 50.degree. C. to the boiling temperature, especially from 
100.degree. to 120.degree. C., preferably with the simultaneous removal by 
distillation (for example by azeotropic distillation or steam 
distillation) of the freed compound of the formula Q.dbd.O, wherein Q is 
as defined for compounds of formula XI. 
Where a reactive derivative of a compound of formula X is used (which is 
preferred when R.sub.5 is hydrogen), the reaction is preferably carried 
out in an aprotic solvent, such as an N,N-di-lower alkyl-lower 
alkanoylamide, for example N,N-dimethylformamide or N,N-dimethylacetamide, 
in the presence of a strong base, especially an alkali metal hydride, such 
as potassium hydride or, especially, sodium hydride, at preferred 
temperatures of from 0.degree. to 100.degree. C., especially from 
18.degree. to 60.degree. C., preferably using a protective gas, such as 
nitrogen or argon, the radical W.sub.5 being replaced by the 2'-imino 
nitrogen of the compound of formula XI (indicated by an arrow in formula 
XI). The resulting intermediate (containing a reactively derivatized 
carbonyl group) is then heated by treatment with an acid, such as a 
mineral acid, for example a hydrogen halide, such as HCl, in aqueous 
solution at preferred temperatures of from 60.degree. C. to the reflux 
temperature (for example from 60.degree. C. at the start of the reaction, 
with heating to 120.degree. C. by the end of the reaction), the compound 
of formula II being obtained and, where appropriate, the arylalkyl-1-oxo 
compound Q.dbd.O (for example be:nzaldehyde) that is formed simultaneously 
during the reaction by the removal of protecting groups being removed by 
azeotropic distillation. 
Compounds of formula V wherein R.sub.5 is aryl, R.sub.6 is hydrogen and 
R.sub.7 and R.sub.8 together form a bond can also be prepared from 
corresponding 2-amino-3-aroylalkyl-5-lower alkyl-1,2,3-oxazolidine 
bromides with NH.sub.3 (at room temperature or with heating) to yield 
2-amino-4-aryl-1-lower alkylcarbonyl-imidazoles, hydrolysis of which (for 
example with water/mineral acid, such as HCl, in the presence.or absence 
of an alcohol, such as ethanol), with removal of the lower 
alkanecarboxylic acid, yields a compound of formula V as last defined (see 
Hetzheim et al., Chem. Ber. 100, 3418-3426 (1967)). 
Compounds of formula V wherein R.sub.5 and R.sub.6 are as defined, and are 
each especially hydrogen, and wherein R.sub.7 and R.sub.8 are each 
hydrogen are prepared especially from imidazolyl ketones or (preferably) 
imidazolyl thiones of formula XII 
##STR17## 
wherein Z is oxygen or, preferably, sulfur, R.sub.5 and R.sub.6 are as 
defined for compounds of formula I, and are each especially hydrogen, and 
R.sub.7 and R.sub.8 are each hydrogen, by reaction with a compound of 
formula XII 
EQU Y--W.sub.6 (XIII), 
wherein Y is lower alkyl, especially methyl, and W.sub.6 is a nucleofugal 
leaving group, especially a leaving group selected from hydroxy esterified 
by a strong inorganic or organic acid, especially hydroxy esterified by a 
mineral acid, for example a hydrohalic acid, such as hydrochloric, 
hydrobromic or also hydriodic acid, or preferably by a strong organic 
sulfonic acid, such as a lower alkanesulfonic acid that is unsubstituted 
or substituted, for example, by halogen, such as fluorine, or especially 
an aromatic sulfonic acid, for example a benzenesulfonic acid that is 
unsubstituted or substituted by lower alkyl, such as methyl, halogen, such 
as bromine, and/or by nitro, such as methanesulfonic acid, 
p-bromotoluenesulfonic acid or, especially, p-toluenesulfonic acid, or 
hydroxy esterified by hydrazoic acid. 
The reaction is carried out in suitable solvents or solvent mixtures, such 
as alcohols, for example a lower alkanol, such as methanol or ethanol, at 
elevated temperature, for example at the reflux temperature, and yields a 
compound of formula XIV 
##STR18## 
wherein Y is lower alkyl and the other radicals are as defined for 
compounds of formula XII. The latter is then converted into a compound of 
formula Va in the form of an acid addition salt 
##STR19## 
wherein Y and R.sub.5 and R.sub.6 are as defined for compounds of formula 
XIV, by reaction with ammonia in aqueous solution, if desired in the 
presence of a polar organic solvent, such as an alcohol, for example 
methanol, ethanol, isopropanol or a mixture thereof, at preferred 
temperatures of from 0.degree. C. to the reflux temperature, especially 
from room temperature to the reflux temperature (see EP 0 327 919). The 
compound of formula Va corresponds to a compound of formula V wherein 
R.sub.5 and R.sub.6 are as defined, and are each especially hydrogen, and 
R.sub.7 and R.sub.8 are each hydrogen. The corresponding free compound of 
formula V can then be obtained from that compound by converting the salt 
into the free base or into a different salt, analogously to the method 
described below for compounds of formula I under "Additional process 
measures", for example by ion exchange on an anion exchanger in the form 
of the salt of the anion of the acid HY to be introduced (for example 
anion exchanger based on a styrene/divinylbenzene polymer with quaternary 
ammonium groups, with the anion Y.sup.- as the counter-ion that is to be 
introduced). 
Other starting materials are known, can be prepared in accordance with 
processes known per se, or are available commercially. 
In all starting materials (for example those of formula II and also III), 
functional groups that are not intended to participate in the reaction 
may, independently of one another, be in protected form. If necessary, 
protecting groups can be removed at suitable stages or not until the stage 
of the protected precursors of the end products of formula I. 
Where specific protecting groups have already been mentioned, those groups 
are preferred. 
The protecting groups for functional groups in starting materials the 
reaction of which is to be avoided, especially carboxy, amino, hvdroxy and 
mercapto groups, include especially those protecting groups (conventional 
protecting groups) that are conventionally employed in the synthesis of 
peptide compounds, and also in the synthesis of cephalosporins and 
penicillins as well as nucleic acid derivatives and sugars. Those 
protecting groups may already be present in the precursors and are 
intended to protect the functional groups in question against undesired 
secondary reactions, such as acylation, etherification, esterification, 
oxidation, solvolysis, etc.. In some cases the protecting groups may 
additionally cause the reactions to proceed selectively, for example 
stereoselectively. It is characteristic of protecting groups that they can 
be removed easily, that is to say without undesired secondary reactions 
taking place, for example by solvolysis, reduction, photolysis, and also 
enzymatically, for example under physiological conditions, and that they 
are not present in the end products. 
The protection of functional groups by such protecting groups, the 
protecting groups themselves and the reactions for their removal are 
described, for example, in standard works, such as J.F.W. McOmie, 
"Protective Groups in Organic Chemistry", Plenum Press, London and New 
York 1973, in Th. W. Greene, "Protective Groups in Organic Synthesis", 
Wiley, New York 1981, in "The Peptides"; Vol. 3 (E. Gross and J. 
Meienhofer, eds.), Academic Press, London and New York 1981, in "Methoden 
der organischen Chemie", Houben-Weyl, 4th edition, Vol. 15/I, Georg Thieme 
Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Aminosauren, 
Peptide, Proteine", Verlag Chemie, Weinheim, Deerfield Beach and Basle 
1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und 
Derivate", Georg Thieme Verlag, Stuttgart 1974. 
A carboxy group is protected, for example, in the form of an ester group 
which is selectively removable under mild conditions. A carboxy group 
protected in esterified form is esterified especially by a lower alkyl 
group, which is preferably branched in the 1-position of the lower alkyl 
group or substituted by suitable substituents in the 1- or 2-position of 
the lower alkyl group. 
A protected carboxy group esterified by a lower alkyl group is, for 
example, methoxycarbonyl or ethoxycarbonyl. 
A protected carboxy group esterified by a lower alkyl group that is 
branched in the 1-position of the lower alkyl group is, for example, 
tert-lower alkoxycarbonyl, e.g. tertbutoxycarbonyl. 
A protected carboxy group esterified by a lower alkyl group that is 
substituted by suitable substituents in the 1- or 2-position of the lower 
alkyl group is, for example, 1-aryl-lower alkoxycarbonyl, such as 
arylmethoxycarbonyl, having one or two aryl radicals, wherein aryl is 
phenyl that is unsubstituted or mono-, di- or tri-substituted, for 
example, by lower alkyl, e.g. tert-lower alkyl, such as tert-butyl, lower 
alkoxy, e.g. methoxy, hydroxy, halogen, e.g. chlorine, and/or by nitro, 
for example benzyloxycarbonyl, benzyloxycarbonyl substituted by the 
mentioned substituents, for example 4-nitrobenzyloxycarbonyl or 
4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or 
diphenylmethoxycarbonyl, substituted by the mentioned substituents, e.g. 
di(4-methoxyphenyl)methoxycarbonyl, also carboxy esterified by a lower 
alkyl group, the lower alkyl group being substituted in the 1-or 
2-position by suitable substituents, such as 1-lower alkoxy-lower 
alkoxycarbonyl, for example methoxymethoxycarbonyl, 
1-methoxyethoxycarbonyl or 1-ethoxyethoxy-carbonyl, 1-lower 
alkylthio-lower alkoxycarbonyl, for example 1-methylthiomethoxy-carbonyl 
or 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl wherein the aroyl group 
is benzoyl that is unsubstituted or substituted, for example, by halogen, 
such as bromine, e.g. phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, 
e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 
2-iodoethoxycarbonyl, as well as 2-(trisubstituted silyl)-lower 
alkoxycarbonyl wherein the substituents are each independently of the 
others an aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon 
radical that is unsubstituted or substituted, for example, by lower alkyl, 
lower alkoxy, aryl, halogen and/or by nitro, for example lower alkyl, 
phenyl-lower alkyl, cycloalkyl or phenyl, each of which is unsubstituted 
or substituted as above, for example 2-tri-lower alkylsilyl-lower 
alkoxycarbonyl, such as 2-tri-lower alkylsilylethoxycarbonyl, e.g. 
2-trimethylsilylethoxycarbonyl or 
2-(di-n-butylmethylsilyl)-ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, 
such as triphenylsilylethoxycarbonyl. 
A carboxy group can also be protected in the form of an organic 
silyloxycarbonyl group. An organic silyloxycarbonyl group is, for example, 
a tri-lower alkylsilyloxycarbonyl group, for example 
trimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group 
can also be substituted by two lower alkyl groups, e.g. methyl groups, and 
an amino or carboxy group of a second molecule of the compound to be 
protected. Compounds having such protecting groups can be prepared, for 
example, using corresponding tri-lower alkylhalosilanes, such as 
tert-butyl-dimethylchlorosilane, as silylating agent. 
A carboxy group is also protected in the form of an internal ester with a 
hydroxy group present at a suitable distance, for example in the 
.gamma.-position, with respect to the carboxy group, that is to say in the 
form of a lactone, preferably a .gamma.-lactone. 
A protected carboxy group is preferably tert-lower alkoxycarbonyl, for 
example tertbutoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 
9-fluorenylmethoxy-carbonyl or diphenylmethoxycarbonyl, or a carboxy group 
protected in the form of a lactone, especially a .gamma.-lactone. 
A protected amino group is protected by an amino-protecting group, for 
example in the form of an acylamino, arylmethylamino, etherified 
mercaptoamino, 2-acyl-lower alk-1-enylamino or silylamino group, or in the 
form of an azido group. 
In an acylamino group acyl is, for example, the acyl radical of an organic 
carboxylic acid having, for example, up to 18 carbon atoms, especially of 
a lower alkanecarboxylic acid that is unsubstituted or substituted by, for 
example, halogen or aryl, or of a benzoic acid that is unsubstituted or 
substituted by, for example, halogen, lower alkoxy or nitro, or preferably 
of a carbonic acid semiester. Such acyl groups are preferably lower 
alkanoyl, such as formyl, acetyl, propionyl or pivaloyl, halo-lower 
alkanoyl, for example 2-halo-acetyl, such as 2-chloro-, 2-bromo-, 2-iodo-, 
2,2,2-trifluoro- or 2,2,2-trichloro-acetyl, benzoyl that is unsubstituted 
or substituted by, for example, halogen, lower alkoxy or nitro, such as 
benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, lower 
alkoxycarbonyl, lower alkoxycarbonyl that is preferably branched at the 
1-position of the lower alkyl radical or suitably substituted at the 1- or 
2-position, for example tert-lower alkoxycarbonyl, such as 
tert-butoxycarbonyl, 1-aryl-lower alkoxycarbonyl, such as 
aryl-methoxycarbonyl, having one, two or three aryl radicals which are 
phenyl that is unsubstituted or mono- or poly-substituted, for example, by 
lower alkyl, especially tert-lower alkyl, such as tert-butyl, lower 
alkoxy, such as methoxy, hydroxy, halogen, such as chlorine, and/or by 
nitro, for example benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 
di-phenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl or 
di(4-methoxyphenyl)methoxy-carbonyl, aroylmethoxycarbonyl wherein the 
aroyl group is preferably benzoyl that is unsubstituted or substituted by, 
for example, halogen, such as bromine, for example phenacyloxycarbonyl, 
2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxy-carbonyl, 
2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, 2-(trisubstituted 
silyl)-lower alkoxycarbonyl, for example 2-tri-lower alkylsilyl-lower 
alkoxycarbonyl, such as 2-tri-methylsilylethoxycarbonyl or 
2-(di-n-butylmethylsilyl)ethoxycarbonyl, or triarylsilyl-lower 
alkoxycarbonyl, for example 2-triphenylsilylethoxycarbonyl. 
In an arylmethylamino group, for example a mono-, di- or, especially, 
tri-arylmethylamino group, the aryl radicals are especially unsubstituted 
or substituted phenyl radicals. Such groups are, for example, benzyl-, 
diphenylmethyl- or, especially, trityl-amino. 
In an etherified mercaptoamino group, the mercapto group is especially in 
the form of substituted arylthio or aryl-lower alkylthio wherein aryl is, 
for example, phenyl that is unsubstituted or substituted, for example, by 
lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, 
halogen, such as chlorine, and/or by nitro, for example 4-nitrophenylthio. 
In a 2-acyl-lower alk-1-enyl radical that may be used as an 
amino-protecting group, acyl is, for example, the corresponding radical of 
a lower alkanecarboxylic acid, of a benzoic acid that is unsubstituted or 
substituted, for example, by lower alkyl, such as methyl or tert-butyl, 
lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro, 
or especially of a carbonic acid semiester, such as a carbonic acid lower 
alkyl semiester. Corresponding protecting groups are especially 1-lower 
alkanoyl-lower alk-1-en-2-yl, for example 1-lower alkanoyl-prop-1-en-2-yl, 
such as 1-acetyl-prop-1-en-2-yl, or lower alkoxycarbonyl-lower 
alk-1-en-2-yl, for example lower alkoxycarbonyl-prop-1-en-2-yl, such as 
1-ethoxycarbonyl-prop-1-en-2-yl. 
A silylamino group is, for example, a tri-lower alkylsilylamino group, for 
example tri-methylsilylamino or tert-butyl-dimethylsilylamino. It is also 
possible for the silicon atom of the silylamino group to be substituted by 
only two lower alkyl groups, for example methyl groups, and by the amino 
group or carboxy group of a second molecule of formula I. Compounds having 
such protecting groups may be prepared, for example, using the 
corresponding chlorosilanes, such as tert-butyl-dimethylchlorosilane, as 
silylating agent. 
An amino group can also be protected by conversion into the protonated 
form; suitable anions are especially anions of strong inorganic acids, 
such as sulfuric acid, phosphoric acid or hydrohalic acids, for example 
the chlorine or bromine anion, or of organic sulfonic acids, such as 
p-toluenesulfonic acid. 
Preferred amino-protecting groups are lower alkoxycarbonyl, phenyl-lower 
alkoxycarbonyl, fluorenyl-lower alkoxycarbonyl, 2-lower alkanoyl-lower 
alk-l-en-2-yl or lower alkoxycarbonyl-lower alk-1-en-2-yl, especially 
tert-butoxycarbonyl or benzyloxycarbonyl. 
A hydroxy group can be protected, for example, by an acyl group, for 
example lower alkanoyl that is unsubstituted or substituted by halogen, 
such as chlorine, such as acetyl or 2,2-dichloroacetyl, or especially by 
an acyl radical of a carbonic acid semiester mentioned for protected amino 
groups. A hydroxy group can be protected also by tri-lower alkylsilyl, for 
example trimethylsilyl, triisopropylsilyl or tert-butyl-dimethylsilyl, a 
readily removable etherifying group, for example an alkyl group, such as 
tert-lower alkyl, for example tert-butyl, an oxa- or a thia-aliphatic or 
-cycloaliphatic, especially 2-oxa- or 2-thia-aliphatic or -cycloaliphatic, 
hydrocarbon radical, for example 1-lower alkoxy-lower alkyl or 1-lower 
alkylthio-lower alkyl, such as methoxymethyl, 1-methoxyethyl, 
1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 
2-oxa- or 2-thiacycloalkyl having from 5 to 7 ring atoms, such as 
2-tetrahydrofuryl or 2-tetrahydropyranyl, or a corresponding thia 
analogue, as well as by 1-phenyl-lower alkyl, such as benzyl, 
diphenylmethyl or trityl, it being possible for the phenyl radicals to be 
substituted, for example, by halogen, e.g. chlorine, lower alkoxy, e.g. 
methoxy, and/or by nitro. A preferred hydroxy-protecting group is, for 
example, 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxy-carbonyl, 
diphenylmethoxycarbonyl, benzyl or trityl. 
Two hydroxy groups occurring in a molecule, especially adjacent hydroxy 
groups, or adjacent hydroxy and amino groups can be protected, for 
example, by divalent protecting groups, such as a methylene group that is 
preferably substituted, for example by one or two lower alkyl radicals or 
by oxo, for example by unsubstituted or substituted alkylidene, e.g. lower 
alkylidene, such as isopropylidene, cycloalkylidene, such as 
cyclohexylidene, a carbonyl group or benzylidene. 
A hydroxy group that is adjacent to a carboxy group can be protected by the 
formation of an internal ester (lactone), especially a .gamma.-lactone. 
A protected hydroxy group is preferably protected by tri-lower alkylsilyl 
or in the form of a lactone, especially by tert-butyl-dimethylsilyl or in 
the form of a .gamma.-lactone. 
A mercapto group, for example in cysteine, can be protected especially by 
S-alkylation with unsubstituted or substituted alkyl radicals, silylation, 
thioacetal formation, S-acylation or by the formation of asymmetrical 
disulfide groupings. Preferred mercapto-protecting groups are, for 
example, benzyl that is unsubstituted or substituted in the phenyl moiety, 
for example by methoxy or by nitro, such as 4-methoxybenzyl, 
diphenylmethyl that is unsubstituted or substituted in the phenyl moiety, 
for example by methoxy, such as di(4-methoxyphenyl)methyl, 
triphenylmethyl, pyridyldiphenylmethyl, trimethylsilyl, benzylthiomethyl, 
tetrahydropyranyl, acylaminomethyl, such as acetamidomethyl, 
iso-butyrylacetamidomethyl or 2-chloroacetamidomethyl, benzoyl, 
benzyloxycarbonyl or alkylaminocarbonyl, especially lower 
alkylaminocarbonyl, such as ethylaminocarbonyl, as well as lower 
alkylthio, such as S-ethylthio or S-tert-butylthio, or S-sulfo. 
The person skilled in the art is familiar with protecting groups that are 
suitable for the reaction conditions in question and can therefore select 
them without difficulty. 
For the removal of protecting groups, the reaction conditions already 
mentioned specifically are preferably employed. 
The removal of protecting groups that are not constituents of the desired 
intermediate or, especially, of the end product of formula I is effected 
in a manner known per se, for example by means of solvolysis, especially 
hydrolysis, alcoholysis or acidolysis, or by means of reduction, 
especially hydrogenolysis or by means of other reducing agents, as well as 
photolysis, as appropriate stepwise or simultaneously, it being possible 
also to use enzymatic methods. The removal of the protecting groups is 
described, for example, in the standard works mentioned hereinabove in the 
section relating to protecting groups. 
For example, protected carboxy, for example lower alkoxycarbonyl 
(preferably branched in the 1-position), such as tert-lower 
alkoxycarbonyl, lower alkoxycarbonyl substituted at the 2-position by a 
trisubstituted silyl group or at the 1-position by lower alkoxy or by 
lower alkylthio, or unsubstituted or substituted diphenylmethoxycarbonyl 
can be converted into free carboxy by treatment with a suitable acid, such 
as formic acid, acetic acid, hydrochloric acid or trifluoroacetic acid, 
where appropriate with the addition of a nucleophilic compound, such as 
phenol or anisole. Unsubstituted or substituted benzyloxycarbonyl can be 
freed, for example, by means of hydrogenolysis, that is to say by 
treatment with hydrogen in the presence of a metallic hydrogenation 
catalyst, such as a palladium catalyst. Moreover, suitably substituted 
benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, can be converted into 
free carboxy also by reduction, for example by treatment with an alkali 
metal dithionite, such as sodium dithionite, or with a reducing metal, for 
example zinc, or with a reducing metal salt, such as a chromium(II) salt, 
for example chromium(II) chloride, customarily in the presence of a 
hydrogen-yielding agent that, together with the metal, is capable of 
producing nascent hydrogen, such as an acid, especially a suitable 
carboxylic acid, such as an unsubstituted or substituted, for example 
hydroxy-substituted, lower alkanecarboxylic acid, for example acetic acid, 
formic acid, glycolic acid, diphenylglycolic acid, lactic acid, mandelic 
acid, 4-chloromandelic acid or tartaric acid, or in the presence of an 
alcohol or thiol, water preferably being added. By treatment with a 
reducing metal or metal salt, as described above, 2-halo-lower 
alkoxycarbonyl (where appropriate after conversion of a 2-bromo-lower 
alkoxycarbonyl group into a corresponding 2-iodo-lower alkoxycarbonyl 
group) or aroylmethoxycarbonyl can also be converted into free carboxy. 
Aroylmethoxycarbonyl can be cleaved also by treatment with a nucleophilic, 
preferably salt-forming, reagent, such as sodium thiophenolate or sodium 
iodide. The carboxy group can be freed from 1-aryl-lower alkoxycarbonyl, 
for example arylmethoxycarbonyl, such as benzyloxycarbonyl, also by 
hydrolysis in the presence of a base, such as an alkali metal hydroxide, 
for example sodium or potassium hydroxide. 2-(Trisubstituted silyl)-lower 
alkoxycarbonyl, such as 2-tri-lower alkylsilyl-lower alkoxycarbonyl, can 
also be converted into free carboxy by treatment with a salt of 
hydrofluoric acid that yields the fluoride anion, such as an alkali metal 
fluoride, for example sodium or potassium fluoride, where appropriate in 
the presence of a macrocyclic polyether ("crown ether"), or with a 
fluoride of an organic quaternary base, such as a tetra-lower 
alkylammonium fluoride or tri-lower alkylaryl-lower alkylammonium 
fluoride, for example tetraethylammonium fluoride or tetrabutylammonium 
fluoride, in the presence of an aprotic, polar solvent, such as dimethyl 
sulfoxide, N,N-dirnethylformamide or N,N-dimethylacetamide. Carboxy 
protected in the form of organic silyloxycarbonyl, such as tri-lower 
alkylsilyloxycarbonyl, for example trimethylsilyloxycarbonyl, can be freed 
in customary manner by solvolysis, for example by treatment with water, an 
alcohol or an acid, or, furthermore, a fluoride, as described above. 
Esterified carboxy can also be freed enzymatically, for example by means 
of esterases or suitable peptidases, for example esterified arginine or 
lysine, such as lysine methyl ester, by using trypsin. Carboxy protected 
in the form of an internal ester, such as in the form of the 
.gamma.-lactone, can be freed by hydrolysis in the presence of a 
hydroxide-containing base, such as an alkaline earth metal hydroxide or, 
especially, an alkali metal hydroxide, for example NaOH, KOH or LiOH, more 
especially LiOH, the correspondingly protected hydroxy group being freed 
at the same time. 
A protected amino group is freed in a manner known per se and, according to 
the nature of the protecting groups, in various ways, preferably by means 
of solvolysis or reduction. Lower alkoxycarbonylamino, such as 
tert-butoxycarbonylamino can be cleaved in the presence of acids, for 
example mineral acids, e.g. a hydrogen halide, such as hydrogen chloride 
or hydrogen bromide, especially hydrogen bromide, or sulfuric or 
phosphoric acid, preferably hydrogen chloride, or in the presence of 
relatively strong organic acids, such as formic acid, trichloroacetic acid 
or trifluoroacetic acid, in polar solvents, for example water or a 
carboxylic acid, such as acetic acid or formic acid, halogenated 
hydrocarbons, such as chlorinated lower alkanes, for example 
dichloromethane or chloroform, or ethers, preferably cyclic ethers, such 
as dioxane, or in organic carboxylic acids that are liquid at the reaction 
temperature, without solvents, for example in formic acid. 2-Halo-lower 
alkoxycarbonylamino (where appropriate after conversion of a 2-bromo-lower 
alkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylamino group), 
aroyl-methoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be 
cleaved, for example, by treatment with a suitable reducing agent, such as 
zinc in the presence of a suitable carboxylic acid, such as aqueous acetic 
acid. Aroylmethoxycarbonylamino can be cleaved also by treatment with a 
nucleophilic, preferably salt-forming, reagent, such as sodium 
thiophenolate, and 4-nitrobenzyloxycarbonylamino can be cleaved also by 
treatment with an alkali metal dithionite, for example sodium dithionite. 
Unsubstituted or substituted diphenylmethoxycarbonylamino, tert-lower 
alkoxycarbonylamino or 2-(trisubstituted silyl)-lower alkoxycarbonylamino, 
such as 2-tri-lower alkylsilyl-lower alkoxycarbonylamino, can be cleaved 
by treatment with a suitable acid, for example formic acid or 
tri-fluoroacetic acid, for example in a halogenated hydrocarbon, such as 
methylene chloride or chloroform (especially when hydroxy protected by 
benzyl is not to be freed at the same time), 1-aryl-lower 
alkoxycarbonylamino, such as unsubstituted or substituted 
benzyloxycarbonylamino, can be cleaved, for example, by means of 
hydrogenolysis, that is to say by treatment with hydrogen in the presence 
of a suitable hydrogenation catalyst, such as a palladium catalyst, for 
example bonded to a carrier, such as carbon, preferably in polar solvents, 
such as di-lower alkyl-lower alkanoylamides, for example 
dimethylformamide, ethers, such as cyclic ethers, for example dioxane, 
esters, such as lower alkanoic acid lower alkyl esters, for example ethyl 
acetate, or alcohols, such as methanol, ethanol or propanol, methanol 
being especially preferred, preferably approximately at room temperature, 
unsubstituted or substituted triarylmethylamino or formylamino can be 
cleaved, for example, by treatment with an acid, such as a mineral acid, 
for example hydrochloric acid, or an organic acid, for example formic 
acid, acetic acid or trifluoroacetic acid, where appropriate in the 
presence of water, and triphenylaminomethyl can be cleaved especially by 
hydrogenolysis with a noble metal or noble metal oxide as catalyst, such 
as platinum, palladium or, especially, palladium hydroxide, the catalyst 
preferably being bonded to a carrier, such as carbon, silica gel or 
aluminum oxide, in inert solvents, such as an ether, preferably a lower 
alkyl-lower alkanoate, such as ethyl acetate, at temperatures of from 
20.degree. to 80.degree. C., especially from 50.degree. to 70.degree. C., 
if necessary under elevated pressure, for example approximately from 1 to 
10 bar, and an amino group protected in the form of silylamino can be 
freed, for example, by means of hydrolysis or alcoholysis. An amino group 
protected by 2-haloacetyl, for example 2-chloroacetyl, can be freed by 
treatment with thiourea in the presence of a base, or with a thiolate 
salt, such as an alkali metal thiolate of thiourea, and subsequent 
solvolysis, such as alcoholysis or hydrolysis, of the resulting 
substitution product. An amino group protected by 2-(trisubstituted 
silyl)-lower alkoxycarbonyl, such as 2-tri-lower alkylsilyl-lower 
alkoxycarbonyl, can be converted into the free amino group also by 
treatment with a salt of hydrofluoric acid that yields fluoride anions, as 
indicated above in connection with the freeing of a correspondingly 
protected carboxy group. Likewise, silyl, such as trimethylsilyl or 
tert-butyldimethylsilyl, bonded directly to a hetero atom, such as 
nitrogen, can be removed using fluoride ions, preferably with a fluoride 
of an organic quaternary nitrogen base, such as a tetra-lower 
alkylammonium fluoride or tri-lower alkylaryl-lower alkylammonium 
fluoride, for example tetraethylammonium fluoride or tetrabutylammonium 
fluoride, in the presence of an aprotic, polar solvent, such as dimethyl 
sulfoxide or N,N-dimethylacetamide, or especially an ether, such as 
tetrahydrofuran, at temperatures of from 0.degree. to 50.degree. C., 
especially at about room temperature. 
Amino protected in the form of an azido group is converted into free amino, 
for example, by reduction, for example by catalytic hydrogenation with 
hydrogen in the presence of a hydrogenation catalyst, such as platinum 
oxide, palladium or Raney nickel, by reduction using mercapto compounds, 
such as dithiothreitol or mercaptoethanol, or by treatment with zinc in 
the presence of an acid, such as acetic acid. The catalytic hydrogenation 
is preferably carried out in an inert solvent, such as a halogenated 
hydrocarbon, for example methylene chloride, or in water or a mixture of 
water and an organic solvent, such as an alcohol or dioxane, at 
approximately from 20.degree. C. to 25.degree. C., or with cooling or 
heating. 
A hydroxy or mercapto group protected by a suitable acyl group, by a 
tri-lower alkylsilyl group or by unsubstituted or substituted 1-aryl-(such 
as 1-phenyl)-lower alkyl is freed analogously to a correspondingly 
protected amino group. A hydroxy or mercapto group protected by 
2,2-dichloroacetyl is freed, for example, by basic hydrolysis, and a 
hydroxy or mercapto group protected by tert-lower alkyl or by a 2-oxa- or 
2-thia-aliphatic or -cycloaliphatic hydrocarbon radical is freed by 
acidolysis, for example by treatment with a mineral acid or a strong 
carboxylic acid, for example trifluoroacetic acid. A hydroxy group 
protected by benzyloxy is freed, for example, by hydrogenolysis, that is 
to say by treatment with hydrogen in the presence of a suitable 
hydrogenation catalyst, such as a palladium catalyst, for example bonded 
to a carrier, such as carbon, preferably in polar solvents, such as 
di-lower alkyl-lower alkanoylamides, for example dimethylformamide, 
ethers, such as cyclic ethers, for example dioxane, esters, such as lower 
alkylalkanoates, for example ethyl acetate, or alcohols, such as methanol, 
ethanol or propanol, with methanol being especially preferred, preferably 
at about room temperature. Mercapto protected by pyridyldiphenylmethyl can 
be freed, for example, using mercury(II) salts at pH 2-6 or by zinc/acetic 
acid or electrolytic reduction; acetamidomethyl and isobutyrylamidomethyl 
can be removed, for example, by reaction with mercury(II) salts at pH 2-6; 
2-chloroacetamidomethyl can be removed, for example, using 
1-piperidinothiocarboxamide; and S-ethylthio, S-tert-butylthio and S-sulfo 
can be removed, for example, by thiolysis with thiophenol, thioglycolic 
acid, sodium thiophenolate or 1,4-dithiothreitol. Two hydroxy groups or 
adjacent amino and hydroxy groups which are protected together by means of 
a divalent protecting group, preferably, for example, by a methylene group 
mono- or di-substituted by lower alkyl, such as lower alkylidene, for 
example isopropylidene, cycloalkylidene, for example cyclohexylidene, or 
benzylidene, can be freed by acid solvolysis, especially in the presence 
of a mineral acid or a strong organic acid. A tri-lower alkylsilyl group 
is likewise removed by acidolysis, for example by a mineral acid, 
preferably hydrofluoric acid, or a strong carboxylic acid. Hydroxy can be 
freed from tri-lower alkylsilyloxy preferably also by treatment with a 
salt of hydrofluoric acid that yields the fluoride anion, such as an 
alkali metal fluoride, for example sodium or potassium fluoride, where 
appropriate in the presence of a macrocyclic polyether ("crown ether"), or 
with a fluoride of an organic quaternary base, such as a tetra-lower 
alkylammonium fluoride or tri-lower alkylaryl-lower alkylammonium 
fluoride, for example tetraethylammonium fluoride or tetrabutylammonium 
fluoride, in the presence of an aprotic polar solvent, such as dimethyl 
sulfoxide or N,N-dimethylacetamide. 2-Halo-lower alkoxycarbonyl is removed 
using the above-mentioned reducing agents, for example a reducing metal, 
such as zinc, reducing metal salts, such as chromium(II) salts, or using 
sulfur compounds, for example sodium dithionite or, preferably, sodium 
sulfide and carbon disulfide. Esterified hydroxy groups, for example lower 
alkanoyloxy, such as acetyloxy, can also be freed using esterases, and 
acylated amino can be freed, for example, using suitable peptidases. 
The temperatures at which the protected functional groups are freed are 
preferably from -80.degree. C. to the boiling temperature of the reaction 
mixture, especially from -80.degree. to 110.degree. C., more especially 
from -20.degree. to 50.degree. C., for example from 10.degree. to 
35.degree. C., such as approximately room temperature, or at from 
80.degree. C. to the boiling temperature of the reaction mixture in 
question, for example at approximately 100.degree. C. 
When several protected functional groups are present, the protecting groups 
may, if desired, be so selected that it is possible to remove more than 
one such group simultaneously, for example by means of acidolysis, such as 
by treatment with trifluoroacetic acid, or by means of hydrogen and a 
hydrogenation catalyst, such as a palladium-on-carbon catalyst. 
Conversely, the groups may also be so selected that they are not all 
removed simultaneously but can be removed in a desired sequence, in which 
case the corresponding intermediates are obtained. 
Process b) - Formation of a Schiff's base by reaction of a hydroxyimino 
compound with an amino compound 
In compounds of formulae IV and V, functional groups that are not intended 
to participate in the reaction may, if necessary, be in protected form; 
protecting groups, processes for their introduction and processes for 
their removal from resulting protected compounds of formula I are 
analogous to those mentioned in the detailed description of process a). 
In the starting materials of formula IV, and hence in the products of 
formula I, the radical R.sub.1 is preferably hydroxy. 
The reaction between compounds of formula IV (hydroxyimino compound) and 
formula V (aminoimidazole) takes place under conditions that are known per 
se, the aminoimidazole of formula V preferably being used in an 
approximately equimolar amount or in excess relative to the molar amount 
of the compound of formula IV, especially in an amount that is from 0.95 
times to twice the molar amount--in particular, the reaction takes place 
under conditions that are customary for the reaction of carbonyl compounds 
with nitrogen bases; preferably in the presence of acids, for example of a 
hydrohalic acid, such as hydrogen fluoride, hydrogen chloride, hydrogen 
bromide or hydrogen iodide, especially hydrogen chloride, of sulfuric acid 
or a hydrogen sulfate, such as an alkali metal hydrogen sulfate, for 
example sodium hydrogen sulfate, of phosphoric acid, a hydrogen phosphate 
or a dihydrogen phosphate, for example an alkali metal hydrogen phosphate 
or dihydrogen phosphate, such as sodium hydrogen phosphate, disodium 
hydrogen phosphate, potassium hydrogen phosphate or dipotassium hydrogen 
phosphate, or of an organic acid, especially a carboxylic acid, such as a 
lower alkanecarboxylic acid that is unsubstituted or substituted in the 
lower alkyl moiety, preferably by halogen, such as fluorine, chlorine or 
iodine, for example acetic acid, chloroacetic acid, dichloroacetic acid or 
trifluoro- or trichloroacetic acid, of lactic acid or of a sulfonic acid, 
such as a lower alkanesulfonic acid, for example methanesulfonic acid, 
ethanesulfonic acid or ethanedisulfonic acid, or an arylsulfonic acid, 
such as benzene- or naphthalene-sulfonic acid or 
naphthalene-1,5-disulfonic acid; there being used especially a strong 
acid, such as sulfuric acid or, more especially, one of the mentioned 
hydrohalic acids or methanesulfonic acid; in water (in the presence or 
absence of surfactants) or in an aqueous solvent mixture, such as a 
mixture of water with one or more alcohols, for example methanol, ethanol 
or, especially, isopropanol, or also di-lower alkyl sulfoxides, such as 
dimethyl sulfoxide, or di-lower alkyl-lower alkanoylamides, such as 
dimethylformamide, organic solvents, such as one or more alcohols, for 
example methanol or ethanol, di-lower alkyl sulfoxides, such as dimethyl 
sulfoxide, di-lower alkyl-lower alkanoylamides, such as dimethylformamide, 
or in sufficiently inert nitriles, such as acetonitrile, a mixture of such 
organic solvents, preferably in an aqueous-alcoholic solution, such as in 
water/methanol, water/ethanol or, especially, water/isopropanol; 
preferably at temperatures of from -20.degree. C. to the reflux 
temperature of the reaction mixture, especially at temperatures of from 
room temperature to the reflux temperature of the reaction mixture, more 
especially at approximately from 80.degree. C. to the reflux temperature; 
the compound of formula I (where appropriate after customary working up) 
being obtained directly in free form or, especially, in the form of a 
salt, preferably of the acid present in the reaction, for example in 
crystalline form. Special preference is given to the reaction of the 
hydroxyimino compound of formula IV and the aminoimidazole of formula V 
with aqueous HCl in isopropanol at temperatures of from 80.degree. C. to 
the reflux temperature (for example not higher than 120.degree. C.). 
The preparation of the starting materials of formula V has already been 
described in connection with the preparation of starting materials for 
process a). 
Hydroxyimino compounds of formula IV are preferably prepared from compounds 
of formula VII, which are described as starting materials in process a), 
wherein W.sub.2 and W.sub.3 are especially together oxo and the other 
radicals are as defined therein, different procedures being possible. 
For example, compounds of formula IV wherein R.sub.1 is hydrogen and the 
other radicals are as defined can first be converted into compounds of 
formula VI 
##STR20## 
wherein the radicals are as defined for compounds of formula I, by the 
reaction of cyano compounds of formula VII wherein W.sub.2 and W.sub.3 are 
especially together oxo, while R.sub.2, R.sub.2 ', R.sub.2 ", R.sub.3 and 
R.sub.4 are as defined for compounds of formula I, with ammonia or with a 
salt thereof. The reaction is preferably carried out starting from the 
starting materials of formula VII by acid-catalysed reaction of the cyano 
group either 
a) with alkanols, especially lower alkanols, for example by reaction with 
ethanol and hydrochloric acid in, for example, chloroform or diethyl 
ether, via the corresponding compound wherein there is an irnino-(lower) 
alkoxycarbonyl radical (preferably in salt form) instead of the cyano 
group; or 
b) preferably by treatment with hydrogen sulfide (for example in pyridine 
in the presence of a tertiary nitrogen base, such as triethylamine, at 
temperatures of from 0.degree. to 50.degree. C., for example at 
approximately 40.degree. C.) via the corresponding thiocarboxamide (the 
group --C(.dbd.S)--NH.sub.2 is present in formula VII instead of the cyano 
group), which is then converted into the corresponding compound with an 
imino-(lower) alkanethiolcarbonyl group, preferably the corresponding 
imino-(lower) alkanethiol ester salt, for example by S-alkylating the 
thiocarboxamide with the corresponding (lower) alkyl iodide or, 
preferably, tri-(lower) alkyloxonium tetrafluoroborate, preferably under a 
protective gas, such as argon, in an inert polar solvent, such as a 
chlorinated hydrocarbon, for example methylene chloride, at preferred 
temperatures of from 0.degree. to 50.degree. C., especially at 
approximately room temperature, and thus converting it into the 
imino-(lower) alkanethiol ester hydroiodide (--C(.dbd.NH)--S-alkyl.HI) or 
imino-(lower) alkanethiol ester tetrafluoroborate, respectively; 
and then, by reaction of the imino-(lower) alkyl ester derivative or the 
imino-(lower) alkanethiol ester derivative of the compound of formula VII 
(in salt form) with ammonia or salts thereof, the corresponding compound 
of formula VI containing the amidino group (R.sub.1 =H) is obtained. The 
reaction with ammonia--with or without previous isolation of the 
imino-(lower) alkyl ester derivative or imino-(lower) alkanethiol ester 
derivative of the compound of formula VII (in salt form)--is preferably 
carried out in a suitable organic solvent, such as an alcohol, for example 
ethanol, at temperatures of from 40.degree. C. to the reflux temperature, 
preferably at the reflux temperature, in the presence of acids, for 
example a mineral acid, such as sulfuric acid, phosphoric acid or, 
especially, a hydrohalic acid, such as HCl; in an especially preferred 
form of the process, ammonia is added directly in the form of the 
corresponding salt. 
The resulting compound of formula VI is then converted, by conversion of 
the carbonyl group into the hydroxy imino group, into the corresponding 
compound of formula IV wherein R.sub.1 is hydrogen and the other radicals 
are as defined. In the reaction, an oxo compound of formula VI is reacted 
with hydroxylamine, which is preferably introduced in an equimolar amount 
or in an excess, preferably an up to ten-fold excess, relative to the 
starting compound of formula VII, or with a salt thereof, preferably a 
salt with an inorganic acid, for example a hydrohalic acid, such as 
hydrofluoric acid, hydrogen chloride, hydrogen bromide or hydrogen iodide, 
especially hydrogen chloride, with sulfuric acid or a hydrogen sulfate, 
such as an alkali metal hydrogen sulfate, for example sodium hydrogen 
sulfate, with phosphoric acid, a hydrogen phosphate or a dihydrogen 
phosphate, for example an alkali metal hydrogen phosphate or dihydrogen 
phosphate, such as sodium hydrogen phosphate, disodium hydrogen phosphate, 
potassium hydrogen phosphate or dipotassium hydrogen phosphate, or a salt 
with an organic acid, for example with a carboxylic acid, such as a lower 
alkanecarboxylic acid that is unsubstituted or substituted in the lower 
alkyl moiety, preferably by halogen, such as fluorine, chlorine or iodine, 
for example acetic acid, chloroacetic acid, dichloroacetic acid or 
trifluoro- or tri-chloro-acetic acid, or with a sulfonic acid, such as a 
lower alkanesulfonic acid, for example methanesulfonic acid, 
ethanesulfonic acid or ethanedisulfonic acid, or with an arylsulfonic 
acid, such as benzene- or naphthalene-sulfonic acid or 
naphthalene-1,5-di-sulfonic acid, or a double salt, such as Zn(NH.sub.2 
OH).sub.2 Cl.sub.2 (Crismer's reagent); or is reacted with hydroxylamine 
prepared in situ, for example from an alcoholic solution of nitric oxide 
and a tin(II) salt, such as Sn(II)Cl.sub.2, in the presence of copper 
salts, or from the potassium salt of N,O-bistrimethylsilyl!hydroxylamine 
(prepared from (H.sub.3 C).sub.3 Si--NH--O--Si(CH.sub.3).sub.3 and 
potassium hydride in tetrahydrofuran, with subsequent freeing of the 
potassium salt of the compound of formula VI with an acid, for example 
ammonium chloride); the reaction being carried out in water (in the 
presence or absence of surfactants), in an aqueous solvent mixture, such 
as a mixture of water with one or more alcohols, for example methanol or 
ethanol, di-lower alkyl sulfoxides, such as dimethyl sulfoxide, or 
di-lower alkyl-lower alkanoylamides, such as dimethylformamide; in organic 
solvents, such as alcohols, for example methanol or ethanol, di-lower 
alkyl sulfoxides, such as dimethyl sulfoxide, di-lower alkyl-lower 
alkanoylamides, such as dimethylformamide, or in sufficiently inert 
nitriles, such as acetonitrile; a mixture of such organic solvents; or in 
liquid ammonia, preferably in an aqueous-alcoholic solution, such as 
methanol/water or ethanol/water; at temperatures of from -78.degree. C. to 
the reflux temperature of the corresponding reaction mixture, preferably 
from -30.degree. to 100.degree. C., especially from 5.degree. to 
90.degree. C., for example at approximately from 75.degree. to 80.degree. 
C.; under pressures of approximately from 1 to 10000 bar, preferably, 
where hydroxylamine salts are used, under normal pressure; in the absence 
of a base or preferably, where acid salts of hydroxylamine are used, with 
neutralization of the acid with a base, especially with a hydroxide, such 
as an alkali metal hydroxide, for example sodium or potassium hydroxide, 
with a carbonate or hydrogen carbonate, especially an alkali metal or 
alkaline earth metal carbonate or hydrogen carbonate, for example sodium 
carbonate, potassium carbonate, sodium hydrogen carbonate, potassium 
hydrogen carbonate or barium carbonate, with a salt of a weak organic 
acid, especially an alkali metal or alkaline earth metal salt of a lower 
alkane-carboxylic acid, for example sodium acetate or potassium acetate, 
with organic nitrogen bases, especially a secondary or tertiary amine, for 
example a cyclic 5- or 6-membered secondary or tertiary amine, such as 
pyrrolidine or pyridine, or with alcoholates, for example alkali metal 
lower alkyl alcoholates, such as sodium or potassium methanolate, 
ethanolate or tert-butanolate, or with an anion exchanger, the presence of 
an alkali metal carbonate being especially preferred; the corresponding 
compound of formula IV being obtained. Preferably, one of the mentioned 
salts of hydroxylamine, especially the salt of a hydrohalic acid, such as 
the hydrochloride salt, is reacted in the mentioned organic solvents, 
especially in an alcohol, such as methanol or ethanol, at the mentioned 
temperatures, especially at approximately from 75.degree. to 80.degree. 
C., to yield the corresponding oxime of formula IV, which can be purified 
or is used further directly. 
N-Hydroxyamidino compounds of formula IV (R.sub.1 =OH) can be prepared, for 
example, by reaction of an imino-(lower) alkyl ester derivative or an 
imino-(Iower) alkanethiol ester derivative of a compound of formula VII 
(in salt form), wherein W.sub.2 and W.sub.3 together are oxo (preparation 
as described above), or preferably directly by reaction of a compound of 
formula VII with hydroxylamine or with a salt thereof, compounds of 
formula I containing an amidino group (R.sub.1 =H) being obtained--the 
reaction is carried out under conditions analogous to those described 
above for the conversion of compounds of formula VI into compounds of 
formula IV. Both the cyano group and the carbonyl group in the starting 
material of formula VII are reacted. 
Finally, a compound of formula IV wherein R.sub.1 is hydrogen or hydroxy 
and the other radicals are as defined can be obtained from a compound of 
formula VII wherein W.sub.2 and W.sub.3 together are oxo by first reacting 
the carbonyl group with hydroxylamine, or with a salt thereof, under 
conditions analogous to those mentioned above for the reaction of 
compounds of formula VI to form compounds of formula VII, preferably 
omitting the mentioned bases, there being obtained a compound of formula 
VII wherein W.sub.2 and W.sub.3 together are hydroxyimino and the other 
radicals are as defined above for the corresponding starting material 
under process a), and then (if desired after isolating the resulting 
compound of formula VII) reacting the cyano group, under conditions 
analogous to those described for the reaction of cyano compounds of 
formula II (W.sub.1 =cyano) under process a), with ammonia or 
hydroxylamine or a salt thereof, preferably in the presence of 
alcoholates, for example alkali metal lower alkyl alcoholates, such as 
sodium or potassium methanolate, ethanolate or tert-butanolate, in the 
corresponding alcohols, for example methanol, ethanol or tert-butanol, at 
preferred temperatures of from 0.degree. C. to the reflux temperature, 
especially from room temperature to the reflux temperature. 
Process c) - Formation of a Schiff's base by reaction of a carbonyl 
derivative with an amino compound 
In compounds of formulae V and VI, functional groups that are not intended 
to participate in the reaction may, if necessary, be in protected form; 
protecting groups, processes for their introduction and processes for 
their removal from resulting protected compounds of formula I are 
analogous to those mentioned in the detailed description of process a). 
Reactive derivatives of compounds of formula VI are especially compounds in 
which there is present instead of the carbonyl function in formula I 
functionally modified or protected carbonyl in the form of di-lower 
alkoxymethylene, C.sub.1 -C.sub.2 alkylenedioxymethylene, di-lower 
alkylthiomethylene or C.sub.1 -C.sub.2 alkylenedithiomethylene. 
The reaction between compounds of formula VI (oxo compound), or their 
reactive derivatives, and compounds of formula V (aminoimidazole) takes 
place under conditions that are knownper se, the aminoimidazole of formula 
V preferably being used in an approximately equimolar amount or in excess 
relative to the molar amount of the compound of formula VI, especially in 
an amount that is from 0.95 times to twice the molar amount--in 
particular, the reaction takes place under conditions that are customary 
for the reaction of carbonyl compounds with nitrogen bases; preferably in 
the presence of acids, for example of a hydrohalic acid, such as hydrogen 
fluoride, hydrogen chloride, hydrogen bromide or hydrogen iodide, 
especially hydrogen chloride, of sulfuric acid or a hydrogen sulfate, such 
as an alkali metal hydrogen sulfate, for example sodium hydrogen sulfate, 
of phosphoric acid, a hydrogen phosphate or a dihydrogen phosphate, for 
example an alkali metal hydrogen phosphate or dihydrogen phosphate, such 
as sodium hydrogen phosphate, disodium hydrogen phosphate, potassium 
hydrogen phosphate or dipotassium hydrogen phosphate, or of an organic 
acid, especially a carboxylic acid, such as a lower alkanecarboxylic acid 
that is unsubstituted or substituted in the lower alkyl moiety, preferably 
by halogen, such as fluorine, chlorine or iodine, for example acetic acid, 
chloroacetic acid, dichloroacetic acid or trifluoro- or trichloro-acetic 
acid, of lactic acid or of a sulfonic acid, such as a lower alkanesulfonic 
acid, for example methanesulfonic acid, ethanesulfonic acid or 
ethanedisulfonic acid, or an arylsulfonic acid, such as benzene- or 
naphthalene-sulfonic acid or naphthalene-1,5-disulfonic acid; there being 
used especially a strong acid, such as sulfuric acid or, more especially, 
one of the mentioned hydrohalic acids or methanesulfonic acid; in water 
(in the presence or absence of surfactants) or an aqueous solvent mixture, 
such as a mixture of water with one or more alcohols, for example 
methanol, ethanol or, especially, isopropanol, or also di-lower alkyl 
sulfoxides, such as dimethyl sulfoxide, or di-lower alkyl-lower 
alkanoylamides, such as dimethylformamide, organic solvents, such as one 
or more alcohols, for example methanol or ethanol, di-lower alkyl 
sulfoxides, such as dimethyl sulfoxide, di-lower alkyl-lower 
alkanoylamides, such as dimethylformamide, or in sufficiently inert 
nitrites, such as acetonitrile, a mixture of such organic solvents, 
preferably in an aqueous-alcoholic solution, such as in water/methanol, 
water/ethanol or, especially, water/isopropanol; preferably at 
temperatures of from -20.degree. C. to the reflux temperature of the 
reaction mixture, especially at temperatures of from room temperature to 
the reflux temperature of the reaction mixture, more especially at 
approximately from 80.degree. C. to the reflux temperature; the compound 
of formula I (where appropriate after customary working up) being obtained 
directly in free form or, especially, in the form of a salt, preferably of 
the acid present in the reaction, for example in crystalline form. Special 
preference is given to the reaction of the oxo compound of formula VI and 
the aminoimidazole of formula V with aqueous HCl in isopropanol at 
temperatures of from 80.degree. C. to the reflux temperature (for example 
not higher than 120.degree. C.). 
The corresponding reactive derivatives can be prepared from the oxo 
compounds of formula VI under customary conditions for the preparation of 
ketals, acetals, thioketals or thioacetals. 
The preparation of starting materials of formula VI from corresponding 
compounds of formula VII has already been described in connection with the 
preparation of starting materials for process b). 
The preparation of the starting materials of formula V has already been 
described in connection with the preparation of starting materials for 
process a). 
Additional process measures 
In the additional process measures, which are carried out if desired, 
functional groups in the starting materials that are not intended to 
participate in the reaction may be unprotected or in protected form, for 
example protected by one or more of the protecting groups mentioned above 
for process a). Some or all of the protecting groups may be introduced 
and/or removed by one of the methods mentioned for process a). 
The conversion of a compound of formula I wherein R.sub.1 is hydroxy and 
the other radicals each have one of the meanings given, into a different 
compound of formula I wherein R.sub.1 is hydrogen is effected by means of 
reduction, especially by selective hydrogenation. The selective 
hydrogenation takes place in the presence of a catalyst and to acid. There 
are used as catalyst(s) especially cobalt and, more especially, nickel, 
which is/are employed preferably as such or in finely dispersed form on 
carriers, such as argillaceous earth, pumice, aluminum oxide, silica gel 
or activated carbon, with Raney nickel being very especially preferred. 
There are used as acids especially the acids mentioned above in the 
definition of salts, which acids are employed in at least an equimolar 
amount relative to the starting material of formula I in question or in 
excess, especially in the amount that is stoichiometrically necessary for 
salt formation with the basic centers of the compounds of formula I; there 
being used as solvents organic solvents, such as alcohols that are inert 
under the reaction conditions. for example methanol, ethanol or 
isopropanol, ethers, such as diethyl ether, dioxane, tetrahydrofuran or 
anisole, esters, such as ethyl acetate, or, if the acid is an organic acid 
that is liquid under the reaction conditions, that acid itself, for 
example acetic acid, mixtures of those solvents, mixtures of water-soluble 
organic solvents, such as the mentioned alcohols or liquid organic acids, 
with water, or water itself, of which solvents water, methanol or mixtures 
thereof are very especially preferred; the reaction temperature being from 
0.degree. C. to the reflux temperature of the reaction mixture, especially 
from 10.degree. to 70.degree. C., for example from approximately 
20.degree. C. to approximately 55.degree. C., and the reaction being 
carried out under slightly reduced pressure, normal pressure or slightly 
elevated pressure, preferably at from 0.5 to 10 bar, especially the 
prevailing air pressure, with the introduction of hydrogen, preferably 
until the calculated amount of hydrogen has been absorbed, especially 
until the absorption of hydrogen ceases by itself under the reaction 
conditions. Special preference is given to hydrogenation with hydrogen in 
the presence of Raney nickel in methanol, water or mixtures thereof, under 
normal pressure and at temperatures of from 20.degree. to 55.degree. C. 
The hydrogenation can also be carried out continuously, for example by 
allowing solutions of a starting material of formula I wherein R.sub.1 is 
hydroxy to flow over fixed catalysts and bringing those solutions into 
contact with hydrogen flowing the same way or in the opposite direction, 
under the above-mentioned conditions. 
Salts can be converted into the free compounds in customary manner; metal 
salts and ammonium salts are converted, for example, by treatment with 
suitable acids or acid ion exchangers, and acid addition salts are 
converted, for example, by treatment with a suitable basic agent or basic 
ion exchangers. 
Salts of free compounds of formula I having at least one salt-forming group 
can be prepared in a manner known per se. For example, salts of compounds 
of formula I having acidic groups can be formed, for example, by treatment 
with metal compounds, such as alkali metal salts of suitable organic 
carboxylic acids, for example the sodium salt of 2-ethyl-hexanoic acid, 
with inorganic alkali metal or alkaline earth metal compounds, such as the 
corresponding hydroxides, carbonates or hydrogen carbonates, such as 
sodium and potassium hydroxide, carbonate or hydrogen carbonate, with 
corresponding calcium compounds or with ammonia or a suitable organic 
amine, there preferably being used stoichiometric amounts or only a slight 
excess of the salt-forming agent. Acid addition salts of compounds of 
formula I are obtained in customary manner, for example by treatment with 
an acid or with a suitable anion exchange reagent. Internal salts of 
compounds of formula I, which contain acidic and basic salt-forming 
groups, for example a free carboxy group and a free amino group, can be 
formed, for example, by neutralization of salts, such as acid addition 
salts, to the isoelectric point, for example with weak bases, or by 
treatment with ion exchangers. 
Isomeric mixtures of compounds of formula I, that is to say mixtures of 
diastereoisomers and/or enantiomers, for example racemic mixtures, can be 
separated into the corresponding isomers in a manner known per se by 
suitable methods of separation. For example, diastereoisomeric mixtures 
can be separated into the individual diastereoisomers by fractional 
crystallization, chromatography, solvent partitioning or other customary 
methods. Racemates can be separated from one another after conversion of 
the optical antipodes into diastereoisomers, for example by reaction with 
optically active compounds, for example with optically active acids or 
bases by the formation of salts with optically pure salt-forming reagents, 
and separation of the diastereoisomeric mixture so obtainable, for example 
by means of fractional crystallization; by chromatography on column 
materials charged with optically active compounds; or by enzymatic 
methods, for example by selective reaction of only one of the two 
enantiomers. The separation may be effected either at the stage of one of 
the starting materials or with the compounds of formula I themselves. 
General process conditions 
All the above-mentioned process steps can be carried out under reaction 
conditions that are known per se, preferably those mentioned specifically, 
in the absence or, customarily, in the presence of solvents or diluents, 
preferably solvents or diluents that are inert towards the reagents used 
and are solvents therefor, in the absence or presence of catalysts, 
condensation agents or neutralizing agents, for example ion exchangers, 
such as cation exchangers, e.g. in the H.sup.+ form, depending on the 
nature of the reaction and/or of the reactants at reduced, normal or 
elevated temperature, for example in a temperature range of from 
approximately -100.degree. C. to approximately 190.degree. C., preferably 
from approximately -80.degree. C. to approximately 150.degree. C., for 
example at from -80.degree. to -60.degree. C., at from -20.degree. to 
40.degree. C., for example at room temperature, or at the reflux 
temperature, under atmospheric pressure or in a closed vessel, where 
appropriate under reduced or elevated pressure, in an inert atmosphere, 
for example under an argon or nitrogen atmosphere, and/or with the 
exclusion of light. 
At all stages of the reactions, mixtures of isomers that are formed can, if 
desired, be separated into the individual isomers, for example 
diastereoisomers or enantiomers, or into any desired mixtures of isomers, 
for example racemates or mixtures of diastereoisomers, for example 
analogously to the methods described under "Additional process measures". 
The solvents from which those solvents that are suitable for any particular 
reaction may be selected include, for example, water, esters, such as 
lower alkyl lower alkanoates, for example ethyl acetate, ethers, such as 
aliphatic ethers, for example diethyl ether or 1,2-di-methoxyethane, or 
cyclic ethers, for example tetrahydrofuran, liquid aromatic hydrocarbons, 
such as benzene, toluene or o-, m- or p-xylene, liquid acyclic 
hydrocarbons, such as hexane or heptane, alcohols, such as methanol, 
ethanol, 1- or 2-propanol or diethylene glycol, nitrites, such as 
acetonitrile, halogenated hydrocarbons, such as methylene chloride or 
chloroform, acid amides, such as dimethylformamide or dimethylacetamide, 
ketones, such as lower alkanones, for example acetone, heterocyclic 
solvents, for example bases, such as heterocyclic nitrogen bases, for 
example pyridine, or 1,3-dimethyl-3,4,5,6-tetra-hydro-2(1H)-pyrimidone 
(DMPU), carboxylic acids, such as acetic acid or formic acid, carboxylic 
acid anhydrides, such as lower alkanoic acid anhydrides, for example 
acetic anhydride, cyclic, linear or branched hydrocarbons, such as 
cyclohexane, hexane or iso-pentane, or mixtures of those solvents, for 
example aqueous solutions, unless otherwise indicated in the description 
of the processes. Such solvents, or mixtures thereof, may also be used in 
working up, for example by chromatography or partitioning. 
The compounds, including their salts, may also be obtained in the form of 
hydrates, or their crystals may, for example, include the solvent used for 
crystallization. 
Working up after reactions is carried out, if desired, in accordance with 
methods known per se, preferably analogously to the methods described in 
the Examples. 
Many of the starting materials mentioned are already known or can be 
prepared in accordance with processes known per se, for example as 
described in European Patent Application EP 0 538 193 (published on 21st 
Apr. 1993), in European Patent Application EP 0 456 133 (published on 13th 
Nov. 1991) or in Hungarian Patent Application HU 93 02416 (published on 
28th Jun. 1994). 
The invention relates also to those forms of the process in which a 
compound obtainable as intermediate at any stage of the process is used as 
starting material and the remaining process steps are carried out, or in 
which a starting material is formed under the reaction conditions or is 
used in the form of a derivative, for example in protected form or in the 
form of a salt, or a compound obtainable by the process according to the 
invention, or a salt thereof, is produced under the process conditions and 
processed further in situ. In the process of the present invention there 
are preferably used those starting materials which result in the compounds 
described at the beginning as being especially valuable. Special 
preference is given to reaction conditions that are analogous to those 
mentioned in the Examples. 
If necessary or desired, protected starting materials can be used in all 
process steps and the protecting groups can be removed at suitable stages 
of the reaction. 
Protecting groups, the introduction and the freeing thereof are as 
described in process a). 
In view of the close relationship between the compounds of formula I and 
their starting materials in free form and in the form of salts, any 
reference hereinbefore and hereinafter to the free compounds and starting 
materials or their salts is to be understood as meaning also the 
corresponding salts or free compounds and starting materials, 
respectively, where appropriate and expedient. 
Pharmaceutical processes and compositions 
The present invention relates also to pharmaceutical compositions that 
comprise one of the pharmacologically active compounds of formula I as 
active ingredient. Compositions for enteral, especially oral, and 
parenteral administration are especially preferred. The compositions 
comprise the active ingredient on its own or, preferably, together with a 
pharmaceutically acceptable carrier. The dose of active ingredient depends 
upon the disease to be treated, the species, age, weight and individual 
condition of the individual to be treated, and the mode of administration. 
The pharmaceutical compositions comprise from approximately 0.1% to 
approximately 95% active ingredient, dosage forms that are in single dose 
form preferably comprising from approximately 1% to approximately 90% 
active ingredient, and dosage forms that are not in single dose form 
preferably comprising from approximately 0.1% to approximately 20% active 
ingredient. Unit dose forms, such as dragees, tablets or capsules, 
comprise from approximately 1 mg to approximately 500 mg of active 
ingredient. 
The pharmaceutical compositions of the present invention are prepared in a 
manner known per se, for example by means of conventional mixing, 
granulating, confectioning, dissolving or lyophilizing processes. For 
example, pharmaceutical compositions for oral administration can be 
obtained by combining the active ingredient with one or more solid 
carriers, optionally granulating a resulting mixture, and, if desired, 
processing the mixture or granules, if appropriate by the addition of 
additional excipients, to form tablets or dragee cores. 
Suitable carriers are especially fillers, such as sugars, for example 
lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or 
calcium phosphates, for example tri-calcium phosphate or calcium hydrogen 
phosphate, and also binders, such as starches, for example corn, wheat, 
rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, 
sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if 
desired, disintegrators, such as the above-mentioned starches and also 
carboxymethyl starch, cross-linked polyvinylpyrrolidone, or alginic acid 
or a salt thereof, such as sodium alginate. 
Additional excipients are especially flow conditioners and lubricants, for 
example silicic acid, talc, stearic acid or salts thereof, such as 
magnesium or calcium stearate, and/or polyethylene glycol, or derivatives 
thereof. 
Dragee cores can be provided with suitable, optionally enteric, coatings, 
there being used inter alia concentrated sugar solutions, which may 
comprise gum arabic, talc, polyvinyl-pyrrolidone, polyethylene glycol 
and/or titanium dioxide, or coating solutions in suitable organic solvents 
or solvent mixtures or, for the preparation of enteric coatings, solutions 
of suitable cellulose preparations, such as acetylcellulose phthalate or 
hydroxypropylmethylcellulose phthalate. Colorings or pigments may be added 
to the tablets or dragee coatings, for example for identification purposes 
or to indicate different doses of active ingredient. 
Pharmaceutical compositions for oral administration are also hard gelatin 
capsules, and soft sealed capsules consisting of gelatin and a 
plasticizer, such as glycerol or sorbitol. The hard gelatin capsules may 
contain the active ingredient in the form of granules, for example in 
admixture with fillers, such as corn starch, binders and/or glidants, such 
as talc or magnesium stearate, and, where appropriate, stabilizers. In 
soft capsules the active ingredient is preferably dissolved or suspended 
in suitable liquid excipients, for example fatty oils, paraffin oil or 
liquid polyethylene glycols, it likewise being possible to add 
stabilizers. 
Other oral dosage forms are, for example, syrups prepared in customary 
manner which comprise the active ingredient, for example, in dispersed 
form and in a concentration of approximately from 0.1% to 10%, preferably 
approximately 1% or in a similar concentration that provides a suitable 
single dose when administered, for example, in a measure of 5 or 10 ml. 
Also suitable are, for example, powdered or liquid concentrates for the 
preparation of shakes, for example in milk. Such concentrates may also be 
packaged in single dose quantities 
Suitable rectally administrable pharmaceutical compositions are, for 
example, suppositories that consist of a combination of the active 
ingredient with a suppository base. Suitable suppository bases are, for 
example, natural or synthetic triglycerides, paraffin hydrocarbons, 
polyethylene glycols or higher alkanols. 
For parenteral administration there are suitable, especially, aqueous 
solutions (preferably in the presence of sodium chloride) of an active 
ingredient in water-soluble form, for example in the form of a 
water-soluble salt, or aqueous injection suspensions that comprise 
viscosity-increasing substances, for example sodium 
carboxymethylcellulose, sorbitol and/or dextran, and, if desired, 
stabilizers. The active ingredient, where appropriate together with 
excipients, can also be in the form of a lyophilisate and be made into a 
solution prior to parenteral administration by the addition of suitable 
solvents. 
Solutions of the kind used, for example, for parenteral administration can 
also be used as infusion solutions. 
The invention relates also to pharmaceutical compositions and to a method 
for the (therapeutic or prophylactic) treatment of the above-mentioned 
diseases, for example of tumors, metastases or protozoal diseases, an 
amount of a compound of formula I according to the invention that is 
prophylactically, or preferably, therapeutically effective against the 
mentioned diseases being present in a pharmaceutical composition that is 
suitable for administration to a warm-blooded animal, especially a human, 
requiring that treatment for the treatment of one of the mentioned 
diseases; and a therapeutically effective amount of a compound of formula 
I according to the invention being administered in the treatment method to 
a warm-blooded animal, for example a human, requiring such treatment on 
account of one of the mentioned diseases, in an amount that is 
prophylactically or therapeutically effective against that disease. 
The invention relates also to a method of treating the above-mentioned 
pathological conditions. 
Accordingly, the compounds of the present invention can be administered 
prophylactically or therapeutically, preferably in the form of 
pharmaceutical compositions. For a body weight of approximately 70 kg, a 
daily dose of from approximately 1 mg to approximately 1000 mg, preferably 
of approximately from 25 to 100 mg orally. and from 2 to 50 mg 
parenterally, of a compound of the present invention is administered. 
Children usually receive half the adult dose. 
The following Examples serve to illustrate the invention, but do not limit 
the scope thereof in any way. 
Temperatures are given in degrees Celsius. 
The following abbreviations are used: DMF=N,N-dimethylformamide; 
DMSO=dimethyl sulfoxide; MS (FAB)=mass spectrum (fast atom bombardment). 
N-Hydroxyamidino is the group --C(.dbd.NOH)--NH.sub.2.4-Tolyl is the 
p-methylphenyl radical.

EXAMPLE 1 
1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-phen 
yl-imidazole dihydrochloride 
6 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) are added, 
with stirring, to a mixture of 4.1 g (0.02 mol) of 
4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 3.5 g (0.02 mol) of 
1,2-diamino-4-phenyl-imidazole (see Beyer H. et al., Chem. Ber. 101, 3151 
(1968)) and 150 ml of isopropanol, and the mixture is stirred at 
80.degree. C. for 5 hours. During that time, the starting materials 
dissolve and the title compound gradually crystallizes out. At the end of 
the reaction time, the mixture is cooled. The product that has 
crystallized out is filtered off with suction, washed with isopropanol and 
dried. The product crystallizes with one mole of isopropanol, m.p. 
238.degree.-240.degree. C., .sup.1 H-NMR (DMSO/D.sub.2 O): .delta.=8.24 
(d, 1H); 7.88 (s, 1H); 7.73 (d, 1H); 7.55-7.68 (m, 3H); 7.34-7.5 (m, 3H); 
3.26 (s, 4H). 
(For another method of synthesis, see Example 32). 
The starting material is prepared as follows: 
a) 4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime 
Variant 1: 
A mixture of 20.43 g (0.13 mol) of 4-cyano-2,3-dihydro-1H-inden-1-one 
Coll. Czechoslov. Chem. Commun. 43, 3227 (1978)!, 18.07 g (0.26 mol) of 
hydroxylamine hydrochloride, 13.46 g (0.127 mol) of sodium carbonate and 
650 ml of 50% aqueous ethanol is stirred at 800 for 3.5 h6urs. A further 
9.035 g (0.13 mol) of hydroxylamine hydrochloride and 6.73 g (0.0635 mol) 
of sodium carbonate are then added to the reaction mixture, stirring is 
continued at 80.degree. for a further 5 hours, and the reaction mixture is 
allowed to cool slowly to room temperature. The reaction mixture is then 
cooled to 10.degree. and is filtered, and the resulting product is washed 
with 20 ml of 50% aqueous ethanol and a small amount of diethyl ether. The 
crystallizate is then added to 900 ml of methanol, the mixture is stirred 
at room temperature for one hour, insoluble constituents are filtered off, 
and the filtrate is concentrated to a volume of approximately 150 ml. The 
product precipitated on cooling to 5.degree. C. is filtered off, washed 
with a small amount of methanol and diethyl ether, and dried. The title 
compound so obtained melts at 192.degree.-194.degree. (decomp.). 
Variant 2: 
10.4 g (150 mmol) of hydroxylamine hydrochloride and 37.5 ml of 2M Na.sub.2 
CO.sub.3 solution are added, with stirring, to a solution of 7.86 g (50 
mmol) of 4-cyano-2,3-dihydro-1H-inden-1-one Coll. Czechoslov. Chem. 
Commun. 43 3227 (1978)! in 75 ml of N,N-dimethylformamide, and the 
reaction mixture is heated at 75.degree. C. for 3.75 hours. While still 
warm, the reaction mixture is diluted with 25 ml of water and is filtered 
while warm. 88 ml of water are then added to the filtrate, with stirring, 
and the mixture is cooled to 0.degree.-5.degree. C. The product that has 
crystallized out is filtered off with suction, is washed with DMF/water 
1:3 and finally with ethanol, is dried and is recrystallized from three 
times the amount of DMF. In that manner there is obtained the title 
compound, which melts at 192.degree.-194.degree. (decomp.); MS (FAB): 
(M+H).sup.+ =206; .sup.1 H-NMR (DMSO): .delta.=10.87 (s, 1H); 9.64 (s, 
1H); 7.56 (d, 1H); 7.49 (d, 1H); 7.30 (t, 1H); 5.76 (s, 2H); 3.15 (t, 2H); 
2.74 (t, 2H). 
Variant 3: 
A mixture of 157 mg (1.0 mmol) of 4-cyano-2,3-dihydro-1H-inden-1-one Coll. 
Czechoslov. Chem. Commun. 43, 3227 (1978)! and 139 mg (2.0 mmol) of 
hydroxylamine hydrochloride in 4 ml of ethanol is stirred at 80.degree. C. 
for 1.5 hours and cooled in an ice-water bath. The product that has 
crystallized out is filtered off with suction, washed with cold ethanol 
and diethyl ether and dried. In that manner there is obtained the 
intermediate 4-cyano-2,3-dihydro-1H-inden-1-one oxime, which melts at 
200.degree.-202.degree. C. with decomposition; .sup.1 H-NMR (DMSO): 
.delta.=11.22 (s, 1H); 7.84 (d, 1H); 7.81 (d, 1H); 7.45 (t, 1H); 3.15 (t, 
2H); 2.84 (t, 2H). 
920 mg (5.1 mmol) of sodium methanolate are added to a mixture of 360 mg 
(2.06 mmol) of the intermediate 4-cyano-2,3-dihydro-1H-inden-1-one oxime 
and 355 mg (5.1 mmol) of hydroxylamine hydrochloride in 10 ml of methanol, 
and the reaction mixture is stirred at room temperature for 10 minutes. 
The reaction mixture is then filtered and the filtrate is boiled under 
reflux conditions for 2 hours. After cooling, the resulting product is 
filtered off, washed with a small amount of methanol and dried. In that 
manner there is obtained the title compound, which melts at 
192.degree.-194.degree. (decomp.); .sup.1 H-NMR (DMSO): .delta.=10.87 (s, 
1H); 9.64 (s, 1H); 7.56 (d, iH); 7.49 (d, 1H); 7.30 (t, 1H); 5.76 (s, 2H); 
3.15 (t, 2H); 2.74 (t, 2H). 
EXAMPLE 2: 
1-4-(Amidino)-2,3-dihydro-1H-inden-1: 
-ylideneamino!-2-amino-4-phenyl-imidazole dihydrochloride 
0.2 g of Raney nickel is added to a solution of 2.0 g (0.0048 mol) of 
1-4-(N-hydroxy-amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-ph 
enyl-imidazole dihydrochloride in 100 ml of methanol, and hydrogenation is 
carried out at room temperature and under normal pressure until the 
absorption of hydrogen has ceased. The reaction mixture is then filtered 
and the catalyst is washed thoroughly with methanol. The filtrate is 
adjusted to pH 4 with a small amount of 2N alcoholic hydrochloric acid and 
is concentrated. The product that has crystallized out is filtered off 
with suction and recrystallized from 30 ml of methanol, yielding the title 
compound in the form of the trihydrate, m.p. 211.degree.-215.degree. C., 
.sup.1 H-NMR (DMSO): .delta.=9.56 (d, 4H); 8.34 (d, 1H); 8.14 (s, 1H); 
7.97 (s, 2H); 7.82 (m, 3H); 7.67 (t, 1H); 7.3-7.52 (m, 4H); 3.41 (s, 4H). 
EXAMPLE 3 
1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-m 
ethoxvphenyl)-imidazole dihydrochloride 
7.2 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) are 
added, with stirring, to a mixture of 4.92 g (0.024 mol) of 
4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 4.9 g (0.024 mol) 
of 1,2-diamino-4-(4-methoxyphenyl)-imidazole (see Hetzheim A. et al., 
Chem. Ber. 100, 3418 (1967)) and 120 ml of isopropanol, and the reaction 
mixture is stirred at 80.degree. C. for 19 hours. The reaction mixture is 
filtered while hot and the filtrate is cooled. The pale-yellow title 
product that has crystallised out is filtered off with suction and dried. 
It crystallizes in the form of the monohydrate, m.p. &gt;220.degree. C., MS 
(FAB): (M+H).sup.+ =377, .sup.1 H-NMR (DMSO/D.sub.2 O): .delta.=8.23 (d, 
1H); 7.74 (s, 1H); 7.72 (d, 1H); 7.57-7.63 (m, 3H); 7.02 (d, 2H); 3.75 (s, 
3H), 3.26 (s, 4H). 
EXAMPLE 4 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-methoxvphe 
nyl)-imidazole dihydrochloride 
Analogously to Example 2, approximately 2 g of Raney nickel are added to a 
solution of 5.8 g (0.00129 mol) of 
1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4- 
methoxyphenyl)-imidazole dihydrochloride in 600 ml of methanol, and 
hydrogenation is carried out at room temperature and under normal pressure 
until the absorption of hydrogen has ceased. The reaction mixture is then 
filtered and the filtrate is concentrated. The product that has 
crystallised out is filtered off with suction and recrystallized from 
methanol, yielding the title compound in the form of the monohydrate, m.p. 
&gt;220.degree. C., .sup.1 H-NMR (DMSO): .delta.=9.56 (d, 4H); 8.33 (d, 1H); 
7.99 (s, 1H); 7.94 (s, 2H); 7.75-7.84 (m, 3H); 7.64 (t, 1H); 7.04 (d, 2H); 
3.80 (s, 3H), 3.40 (m, 4H). 
EXAMPLE 5 
1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-l1-ylideneamino!-2-amino-4-(2- 
methoxyphenyl)-imidazole dihydrochloride 
0.6 ml of 32 % hydrochloric acid (Merck, Darmstadt, Germany; p.a.) is 
added, with stirring, to a mixture of 0.41 g (0.002 mol) of 
4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 0.408 g (0.002 mol) 
of 1,2-diamino-4-(2-methoxyphenyl)-imidazole and 10 ml of isopropanol, and 
the reaction mixture is stirred at 80.degree. C. for 20 hours. The 
reaction mixture is filtered while hot and the filtration product is 
washed with isopropanol and dried. In that manner there is obtained the 
title compound, m.p. &gt;220.degree. C., .sup.1 H-NMR (DMSO/D.sub.2 O): 
.delta.=8.22 (d, 1H); 7.77 (m, 2H); 7.58 (m, 2H); 7.36 (m, 1H); 7.12 (d, 
1H); 7.05 (t, 1H); 3.88 (s, 3H), 3.24 (s, 4H). 
The starting materials are prepared as follows: 
a) 2-Amino-1-benzylideneamino-4-(2-methoxyphenyl)-imidazole 
A solution of 41.7 g (0.257 mol) of benzaldehyde guanylhydrazone (see 
Thiele, A., Liebigs Annalen der Chemie 270, 35) and 30.12 g of 
2-methoxyphenacyl bromide (Aldrich, Buchs, Switzerland; 98%, Cat. no. 
10,085-4) in 130 ml of ethanol is boiled under reflux for one hour. After 
cooling, the product that has crystallised out is filtered off with 
suction and recrystallized from ethanol. In that manner there is obtained 
the title compound, m.p. 166.degree.-167.degree. C., .sup.1 H-NMR (DMSO): 
.delta.=8.61 (s, 1H); 8.0 (m, 3H); 7.88 (s, 1H); 7.5 (m, 3H); 7.19 (m, 
1H); 7.03 (d, 1H); 6.96 (t, 1H); 6.16 (s, 2H); 3.94 (s, 3H). 
b) 1,2-Diamino-4-(2-methoxyphenyl)-imidazole 
A solution of 23.2 g of 
2-amino-1-benzylideneamino-4-(2-methoxyphenyl)-imidazole and 15.8 ml of 
hydrazine hydrate in 80 ml of diethylene glycol is stirred at 170.degree. 
C. for 7 hours. After cooling, 400 ml of water are added to the reaction 
mixture. The product that has separated out is filtered off with suction, 
washed with water and recrystallized from 200 ml of ethanol. In that 
manner there is obtained the title compound, m.p. 195.degree.-196.degree. 
C., .sup.1 H-NMR (DMSO): .delta.=7.9 (d, 1H); 7.06 (m, 2H); 6.91 (m, 2H); 
5.52 (s, 2H); 5.3 (s, 2H); 3.88 (s, 3H). 
EXAMPLE 6 
1-4-(Armidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2-methoxyph 
enyl)-imidazole dihydrochloride 
Analogously to Example 2, approximately 0.2 g of Raney nickel is added to a 
solution of 0.45 g (0.001 mol) of 
1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2- 
methoxyphenyl)-imidazole dihydrochloride in 50 ml of methanol/water 1:1, 
and hydrogenation is carried out at room temperature and under normal 
pressure until the absorption of hydrogen has ceased. The reaction mixture 
is then diluted with 100 ml of methanol and filtered. The filtrate is 
adjusted to pH 4 with a small amount of 2N alcoholic hydrochloric acid and 
is concentrated to dryness by evaporation. The residue is recrystallized 
from ethyl acetate, yielding the title compound in the form of the 
dihydrate, m.p. &gt;220.degree. C. (decomp.), .sup.1 H-NMR (DMSO/D.sub.2 O): 
.delta.=8.28 (d, 1H); 7.80 (m, 2H); 7.64 (m, 2H); 7.38 (t, 1H); 7.16 (d, 
1H); 7.06 (t, 1H); 3.91 (s, 3H), 3.30 (m, 4H). 
EXAMPLE 7 
1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1 
-ylideneamino!-2-amino-4-(2,5-dimethoxyphenyl)-imidazole dihydrochloride 
0.6 ml of concentrated hydrochloric acid is added, with stirring, to a 
mixture of 0.41 g (0.002 mol) of 
4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 0.47 g (0.002 mol) 
of 1,2-diamino-4-(2,5-dimethoxyphenyl)-imidazole and 10 ml of isopropanol, 
and the reaction mixture is stirred at 80.degree. C. for 3.hours. The 
reaction mixture is filtered while hot and the filtration product is 
washed with isopropanol and dried. In that manner there is obtained the 
title compound, m.p. &gt;220.degree. C., .sup.1 H-NMR (DMSO/D.sub.2 0): 
.delta.=8.23 (d, 1H); 7.75 (m, 2H); 7.61 (t, 1H); 7.17 (d, 1H); 7.07 (d, 
1H); 6.93 (q, 1H); 3.82 (s, 3H), 3.71 (s, 3H); 3.25 (bs, 4H). 
The starting materials are prepared as follows: 
a) 2-Amino-1-benzylideneamino-4-(2,5-dimethoxyphenyl)-imidazole 
A solution of 1.62 g (0.01 mol) of benzaldehyde guanylhydrazone and 1.34 g 
of 2,5-dimethoxyphenacyl bromide (Aldrich, Buchs, Switzerland, 97%, Cat. 
no. 10,458-2) in 5 ml of ethanol is boiled under reflux for 45 minutes. 
After cooling, the product that has crystallized out is filtered off with 
suction and recrystallized from ethanol. In that manner there is obtained 
the title compound, m.p. 180.degree.-181.degree. C., .sup.1 H-NMR (DMSO): 
.delta.=8.62 (s, 1H); 7.97 (m, 2H); 7.90 (s, 1H); 7.42-7.60 (m, 4H); 6.95 
(d, 1H); 6.76 (m, 1H); 6.18 (s, 2H); 3.9 (s, 3H); 3.73 (s, 3H). 
b) 1.2-Diamino-4-(2,5-dimethoxyphenyl)-imidazole 
A solution of 26.1 g of 
2-amino-1-benzylideneamino-4-(2,5-dimethoxyphenyl)-imidazole and 16.2 ml 
of hydrazine hydrate in 80 ml of diethylene glycol is stirred at 
170.degree. C. for 6 hours. After cooling, 400 ml of water are added to 
the reaction mixture. The product that has separated out is filtered off 
with suction, washed with water and recrystallized from 150 ml of ethanol. 
In that manner there is obtained the title compound, m.p. 
159.degree.-160.degree. C., .sup.1 H-NMR (DMSO): .delta.=7.47 (d, 1H); 
7.07 (s, 1H); 6.87 (d, 1H); 6.63 (q, 1H); 5.52 (s, 2H); 5.34 (s, 2H); 3.79 
(s, 3H); 3.69 (s, 3H). 
EXAMPLE 8 
1-4-(Amidino)-213-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2,5-di-metho 
xyphenyl)-imidazole dihydrochloride 
Analogously to Example 2, approximately 0.2 g of Raney nickel is added to a 
solution of 0.48 g (0.001 mol) of 
1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2, 
5-dimethoxyphenyl)-imidazole dihydrochloride in 50 ml of methanol/water 
1:1, and hydrogenation is carried out at room temperature and under normal 
pressure until the absorption of hydrogen has ceased. The reaction mixture 
is then diluted with 100 ml of methanol and filtered. The filtrate is 
adjusted to pH 4 with a small amount of 2N alcoholic hydrochloric acid and 
is concentrated in vacuo to approximately 50 ml. The product that has 
crystallized out, which is filtered off with suction and dried, is the 
title compound in the form of the dihydrate, m.p. 260.degree. C. 
(decomp.), .sup.1 H-NMR (DMSO/D.sub.2 O): .delta.=8.27 (d, 1H); 7.82 (m, 
2H); 7.64 (t, 1H); 7.28 (d, 1H); 7.09 (d, 1H); 6.94 (q, 1H); 3.76 (s, 3H), 
3.30 (m, 4H). 
EXAMPLE 9 
1-4-(N-Hydroxvamidino)-2,3-dihydro-1H-inden-1 
-ylideneamino!-2-amino-4-(3-methoxyphenyl)-imidazole dihydrochloride 
6.0 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) are 
added, with stirring, to a mixture of 4.1 g (0.02 mol) of 
4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 4.08 g (0.02 mol) 
of 1,2-diamino-4-(3-methoxyphenyl)-imidazole and 100 ml of isopropanol, 
and the reaction mixture is stirred at 80.degree. C. for 18 hours. The 
reaction mixture is filtered while hot and the filtration product is 
washed with isopropanol and dried. In that manner there is obtained the 
title compound, m.p. 257.degree.-259.degree. C., .sup.1 H-NMR 
(DMSO/D.sub.2 O): .delta.=8.24 (d, 1H); 7.91 (s, 1H); 7.75 (d, 1H); 7.61 
(t, 1H); 7.38 (t, 1H); 7.25 (m, 2H); 6.95 (m, 1H); 3.76 (s, 3H), 3.27 (s, 
4H). 
The starting materials are prepared as follows: 
a) 2-Amino-1-benzylideneamino-4-(3-methoxyphenyl)-imidazole 
A solution of 16.2 g (0.1 mol) of benzaldehyde guanylhydrazone and 11.8 g 
(0.050 mol) of 3-methoxyphenacyl bromide (Aldrich, Buchs, Switzerland; 98 
%, Cat. no. 11,567-3) in 50 ml of ethanol is stirred at 20.degree. C. for 
3 hours. The product that has crystallized out is filtered off with 
suction and dried. In that manner there is obtained the title compound, 
m.p. 170.degree.-171.degree. C., .sup.1 H-NMR (DMSO): .delta.=8.56 (s, 
1H); 8.03 (s, 1H); 7.92 (m, 2H); 7.5 (m, 3H); 7.26 (m, 3H); 6.76 (m, 1H); 
6.2 (s, 2H); 3.8 (s, 3H). 
b) 1,2-Diamino-4-(3-methoxy-phenyl)-imidazole 
A solution of 8.1 g of 
2-amino-1-benzylideneamino-4-(3-methoxyphenyl)-imidazole and 5.5 ml of 
hydrazine hydrate in 28 ml of diethylene glycol is stirred at 170.degree. 
C. for 7 hours. After cooling, 150 ml of water are added to the reaction 
mixture. The product that has separated out is filtered off with suction, 
washed with water and recrystallized from 100 ml of ethanol. In that 
manner there is obtained the title compound, m.p. 181.degree.-182.degree. 
C., .sup.1 H-NMR (DMSO): .delta.=7.17 (m, 3H); 7.06 (s, 1H); 6.64 (m, 1H); 
5.52 (s, 2H); 5.35 (s, 2H); 3.74 (s, 3H). 
EXAMPLE 10 
1-4-(Amidino)-2,3-dihydro-1 1H-inden- 
1-ylideneamino!-2-amino-4-(3-methoxyphenyl)-imidazole dihydrochloride 
Analogously to Example 2, approximately 2 g of Raney nickel are added to a 
solution of 4.1 g (0.008 mol) of 
1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3- 
methoxyphenyl)-imidazole dihydrochloride in 410 ml of water, and 
hydrogenation is carried out at room temperature and under normal pressure 
until the absorption of hydrogen has ceased. The reaction mixture is then 
diluted with 1.3 liters of methanol and filtered. The filtrate is adjusted 
to pH 4 with a small amount of 2N alcoholic hydrochloric acid and is 
concentrated in vacuo to approximately 200 ml. The product that has 
crystallized out, which is filtered off with suction and dried, is the 
title compound in the form of the monohydrate, m.p. 260.degree. C. 
(decomp.), .sup.1 H-NMR (DMSO/D.sub.2 O): .delta.=8.32 (d, 1H); 8.05 (s, 
1H); 7.83 (d, 1H); 7.65 (t, 1H); 7.3-7.44 (m, 3H); 6.94 (d, 1H); 3.81 (s, 
3H); 3.36 (s, 4H). 
EXAMPLE 11 
1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-c 
hlorophenyl)-imidazole dihydrochloride 
A mixture of 1.026 g (5 mmol) of 
4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 1.043 g (5 mmol) of 
1,2-diamino-4-(4-chlorophenyl)-imidazole (see Beyer H. et al., Chem. Ber. 
101, 3151 (1968)) and 20 ml of 4N hydrochloric acid is heated at 
120.degree. C. for 18 hours, with stirring, and is then concentrated by 
evaporation in vacuo. 25 ml of ethanol are added to the crystalline 
residue, the mixture is cooled to 5.degree. C., with stirring, and is 
filtered, and the crystallizate is washed with a small amount of ethanol 
and diethyl ether. The crude title compound, dried under a high vacuum, 
contains 8.17% water and melts at 226.degree.-228.degree. C. (decomp.), 
.sup.1 H-NMR (D.sub.2 O): .delta.=8.06 (d, 1H); 7.75 (d, 1H); 7.55 (t, 
1H); 7.40 (s, 1H); 7.38 (d, 2H); 7.28 (d, 2H); 3.21-3.27 (m, 2H), 
3.03-3.09 (m, 2H). 
EXAMPLE 12 
1-4-(Amidino)-2,3-dihydro-1H-inden- 
1-ylideneamino!-2-amino-4-(4-chlorophenyl)-imidazole dihydrochloride 
Analogously to Example 2, 0.2 g of Raney nickel is added to a solution of 
1.0 g (2.024 mmol) of 
1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4- 
chlorophenyl)-irnidazole dihydrochloride in 35 ml of methanol and 20 ml of 
water, and hydrogenation is carried out at room temperature and under 
normal pressure until the absorption of hydrogen has ceased. The reaction 
mixture is then diluted with 50 ml of methanol and filtered. The filtrate 
is adjusted to pH 3 with a small amount of 3N methanolic hydrochloric acid 
and is concentrated to a volume of approximately 30 ml. After cooling in 
an ice-bath, the product that has crystallized out is filtered off, washed 
with a small amount of methanol and diethyl ether and dried under a high 
vacuum at 120.degree. C. The title compound is obtained in the form of the 
monohydrate, m.p. 245.degree.-250.degree. C. (decomp.), .sup.1 H-NMR 
(DMSO/D.sub.2 O): .delta.=8.33 (d, 1H); 8.12 (s, 1H); 7.79-7.87 (m, 3H); 
7.67 (t, 1H); 7.57 (d, 2H); 3.38 (s, 4H). 
EXAMPLE 13 
1-4-(N-Hydroxyamidino)-2.3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-t 
olyl)-imidazole dihydrochloride 
A mixture of 1.20 g (5.848 mmol) of 
4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 1.10 g (5.844 mmol) 
of 1,2-diamino-4-(4-tolyl)-imidazole (Beyer H. et al., Chem. Ber. 101, 
3151 (1968)) and 20 ml of 4N hydrochloric acid is heated at 110.degree. C. 
for 22 hours, with stirring, and is then concentrated in vacuo to 
approximately half its original volume. The product that has crystallized 
out is filtered off, washed with isopropanol and recrystallized from a 
mixture of 15 ml of methanol and 30 ml of isopropanol, yielding the title 
compound in the form of the dihydrate, m.p. 225.degree.-232.degree. C. 
(decomp.), .sup.1 H-NMR (D.sub.2 O): .delta.=8.04 (d, 1H); 7.74 (d, 1H); 
7.55 (t, 1H); 7.30 (s, 1H); 7.26 (d, 2H); 7.07 (d, 2H); 3.17-3.23 (m, 2H); 
2.98-3.04 (m, 2H); 2.07 (s, 3H). 
EXAMPLE 14 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-tolyl)-imi 
dazole dihydrochloride 
Analogously to Example 2, 0.2 g of Raney nickel is added to a solution of 
0.9 g (1.917 mmol) of 
1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4- 
tolyl)-imidazole dihydrochloride in 60 ml of methanol/water (1:1), and 
hydrogenation is carried out at room temperature and under normal pressure 
until the absorption of hydrogen has ceased. The reaction mixture is then 
filtered, and the filtrate is acidified to pH 3 with 3N methanolic 
hydrochloric acid and is concentrated to a volume of approximately 20 ml. 
The product that has crystallized out is filtered off and recrystallized 
from ethanol/water, yielding the title compound with a water content of 
11.81%, m.p. 220.degree.-225.degree. C. (decomp.), .sup.1 H-NMR 
(DMSO/D.sub.2 O): .delta.=8.33 (d, 1H); 7.98 (s, 1H); 7.83 (d, 1H); 
7.61-7.71 (m, 3H); 7.29 (d, 2H); 3.37 (s, 4H); 2.34 (s, 3H). 
EXAMPLE 15 
1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-f 
luorophenyl)-imidazole dihydrochloride 
1.91 ml of 37% hydrochloric acid are added, with stirring, to a mixture of 
1.303 g (6.35 mmol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one 
oxime, 1.22 g (6.348 mmol) of 1,2-diamino-4.-(4-fluorophenyl)-imidazole 
and 32 ml of isopropanol, and the reaction mixture is stirred at 
110.degree. C. for 4 hours. Filtration of the hot reaction mixture, 
washing of the crystallizate with isopropanol and drying under a high 
vacuum yield the title compound in the form of the monohydrate with an 
isopropanol content of 4.17%, m.p. 242.degree.-247.degree. C. (decomp.), 
.sup.1 H-NMR (D.sub.2 O): .delta.=8.12 (d, 1H); 7.79 (d, 1H); 7.52-7.63 
(m, 3H); 7.47 (s, 1H); 7.65 (t, 2H); 3.28-3.32 (m, 2H); 3.16-3.20 (m, 2H). 
The starting materials are prepared as follows: 
a) 2-Amino-1-benzylideneamino-4-(4-fluorophenyl)-imnidazole 
7.32 ml (0.0525 mol) of triethyl amine and 8.63 g (0.05 mol) of 
2-chloro-4'-fluoro-aceto-phenone (Aldrich, Buchs, Swilzerland; 99%, Cat. 
no. 13,288-8) are added to a solution of 8.11 g (0.05 mol) of benzaldehyde 
guanylhydrazone in 40 ml of ethanol. The reaction mixture is stirred at 
20.degree. C. for 0.5 hour and is then boiled under reflux for 2.5 hours. 
After cooling to 5.degree. C., the product that has crystallized out is 
filtered off, washed with diethyl ether and dried. In that manner there is 
obtained the title compound, m.p. 207.degree.-210.degree. C., .sup.1 H-NMR 
(DMSO): .delta.=8.55 (s, 1H); 8.00 (s, 1H); 7.90-7.98 (m, 2H); 7.69-7.79 
(m, 2H); 7.45-7.57 (m, 3H); 7.15-7.27 (m, 2H); 6.22 (s, 2H). 
b) 1,2-Diamino-4-(4-fluorophenyl)-imidazole 
A solution of 5.3 g (0.0189 mol) of 
2-amino-1-benzylideneamino-4-(4-fluorophenyl)-imidazole and 12.5 ml of 
hydrazine hydrate in 18.8 ml of diethylene glycol is stirred at 
140.degree. C. for 15 hours. After cooling to 80.degree. C., 70 ml of 
acetonitrile are added to the reaction mixture, which is then cooled 
further to 0.degree. C. The product that has separated out is filtered off 
and washed with acetonitrile and diethyl ether. In that manner there is 
obtained the title compound, m.p. 227.degree.-230.degree. C., .sup.1 H-NMR 
(DMSO): .delta.=7.57-7.68 (m, 2H); 7.06-7.15 (m, 2H); 7.01 (s, 1H); 5.52 
(s, 2H); 5.36 (s, 2H). 
EXAMPLE 16 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-fluoro-phe 
nyl)-imidazole dihydrochloride 
Analogously to Example 2, 0.25 g of Raney nickel is added to a solution of 
1.0 g (2.105 mmol) of 
1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4- 
fluorophenyl)-imidazole dihydrochloride in 70 ml of methanol/water (1:1), 
and hydrogenation is carried out at room temperature and under normal 
pressure until the absorption of hydrogen has ceased. The reaction mixture 
is then filtered, the filtrate is acidified to pH 3 with 3N methanolic 
hydrochloric acid, and concentration is carried out by evaporation in 
vacuo. The crystalline residue is recrystallized from methanol/diethyl 
ether, yielding the title compound with a water content of 4.88%, m.p. 
245.degree.-250.degree. C. (decomp.), .sup.1 H-NMR (D.sub.2 O): 
.delta.=8.09 (d, 1H); 7.81 (d, 1H); 7.44-7.61 (m, 3H); 7.42 (s, 1H); 
7.03-7.15 (m, 2H); 3.27-3.33 (m, 2H); 3.11-3.17 (m, 2H). 
EXAMPLE 17 
1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-ethy 
l-imidazole dihydrochloride 
3.2 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) are 
added, with stirring, to a mixture of 3.28 g (0.016 mol) of 
4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 2.6 g (0.016 mol) 
of 1,2-diamino-4-ethyl-imidazole hydrochloride and 150 ml of isopropanol, 
and the reaction mixture is stirred at 80.degree. C. for 90 hours. The 
reaction mixture is filtered while hot and the filtration product is 
washed with isopropanol and dried. In that manner there is obtained the 
title compound, m.p. 245.degree.-246.degree. C., .sup.1 H-NMR 
(DMSO/D.sub.2 O): .delta.=8.22 (d, 1H); 7.73 (d, 1H); 7.59 (t, 1H); 7.19 
(s, 1H); 3.2 (m, 4H); 2.47 (m, 2H); 1.17 (t, 3H). 
The starting materials are prepared as follows: 
a) 2-Amino-1-benzylideneamino-4-ethyl-imidazole 
A solution of 1.62 g (0.01 mol) of benzaldehyde guanylhydrazone and 0.84 g 
(0.005 mol) of 1-bromo-2-butanone (Aldrich, Buchs, Switzerland; tech. 90%, 
Cat. no. 24,329-9) in 5 ml of ethanol is stirred for one hour in an 
ice-water bath and for 16 hours at 20.degree. C. The reaction mixture is 
then concentrated to dryness by evaporation. The residue is taken up in 
lethyl acetate, washed twice with water and once with dilute sodium 
chloride solution, and dried over MgSO.sub.4. The ethyl acetate solution 
is concentrated, whereupon the title compound crystallizes out, m.p. 
164.degree.-167.degree. C., .sup.1 H-NMR (DMSO): .delta.=8.41 (s, 1H); 
8.89 (m, 2H); 7.46 (m, 3H); 7.13 (s, 1H); 5.9 (s, 2H); 2.34 (q, 2H); 1.13 
(t, 3H). 
b) 1,2-Diamino-4-ethyl-imidazole hydrochloride 
A mixture of 4.29 g (0.02 mol) of 
2-amino-1-benzylideneamino-4-ethyl-imidazole and 25 ml of 2N hydrochloric 
acid is heated to 120.degree. C. and subjected to steam distillation for 
one hour. The distillation residue is cooled and then concentrated to 
dryness by evaporation, and the residue is crystallized from ethanol/ethyl 
acetate. In that manner there is obtained the title compound, m.p. 
124.degree.-125.degree. C., .sup.1 H-NMR (DMSO/D.sub.2 0) .delta.=6.53 (s, 
1H); 2.36 (q, 2H); 1.07 (t, 3H). 
EXAMPLE 18 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-ethyl-imidazo 
le dihydrochloride 
Analogously to Example 2, approximately 0.4 g of Raney nickel is added to a 
solution of 1.0 g (0.0027 mol) of 
1-4-(N-hydroxyamidino)-2,3-dihydro-l1H-inden-1-ylideneamino!-2-amino-4-et 
hyl-imidazole dihydrochloride in 100 ml of methanol, and hydrogenation is 
carried out at room temperature and under normal pressure until the 
absorption of hydrogen has ceased. The reaction mixture is then filtered, 
adjusted to pH 4 with a small amount of 2N alcoholic hydrochloric acid and 
concentrated to dryness by evaporation. The residue is recrystallized from 
ethanol, yielding the title compound in the form of the dihydrate, m.p. 
&gt;240.degree. C. (decomp.), .sup.1 H-NMR (DMSO/D.sub.2 O): .delta.=8.21 (d, 
1H); 7.75 (d, 1H); 7.6 (t, 1H); 7.18 (s, 1H); 3.26 (m, 2H); 3.18 (m, 2H); 
2.46 (q. 2H): 1.15 (t, 3H). 
EXAMPLE 19 
1-4-(N-Hydroxyamidino)-2,3-dihydro- 
1H-inden-1-ylideneamino!-2-amino-4,5-dihydro-imidazole dihydrochloride 
0.5 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) is added, 
with stirring, to a mixture of 0.51 g (0.0025 mol) of 
4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 0.342 g (0.0025 
mol) of 1,2-diamino-4,5-dihydro-imidazole hydrochloride m.p. 
245.degree.-246.degree. C.; prepared from the corresponding 
p-toluenesulfonate salt, see EP 0 327 919, Example 12, by ion exchange on 
.RTM.Amberlite IRA-400 (anion exchanger based on a styrene/divinylbenzene 
polymer with quaternary ammonium groups in the Cl.sup.- form; Fluka, 
Buchs, Switzerland)! and 12 ml of isopropanol, and the reaction mixture is 
stirred at 80.degree.-90.degree. C. for 16 hours. The reaction mixture is 
filtered while hot and the filtration product is washed with isopropanol 
and recrystallized from hot water. In that manner there is obtained the 
title compound, m.p. &gt;245.degree. C., .sup.1 H-NMR (D.sub.2 O): 
.delta.=8.08 (d, 1H); 7.72 (d, 1H); 7.56 (t, 1H); 4.14 (t, 2H); 3.81 (t, 
2H); 3.3 (m, 2H); 3.15 (m, 2H). 
EXAMPLE 20 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4,5-di-hydro-im 
idazole dihydrochloride 
Analogously to Example 2, approximately 2.0 g of Raney nickel are added to 
a solution of 4.75 g (0.0138 mol) of 
1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4,5-d 
ihydro-imidazole dihydrochloride in 240 ml of water, and hydrogenation is 
carried out at room temperature and under normal pressure until the 
absorption of hydrogen has ceased. The reaction mixture is then filtered, 
adjusted to pH 4 with a small amount of 2N alcoholic hydrochloric acid and 
concentrated to dryness by evaporation. The residue is recrystallized from 
water, yielding the title compound in the form of the monohydrate, m.p. 
280.degree. C. (decomp.), .sup.1 H-NMR (DMSO/D.sub.2 O): .delta.=8.17 (d, 
1H); 7.66 (d, 1H); 7.54 (t, 1H); 4.18 (t, 2H); 3.70 (t, 2H); 3.25 (m, 2H); 
3.13 (m, 2H). 
EXAMPLE 21 
1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-b 
iphenylyl)-imidazole dihydrochloride 
20 ml of concentrated hydrochloric acid are added, with stirring, to a 
mixture of 5.09 g (0.0248 mol) of 
4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 6.23 g (0.0248 mol) 
of 1,2-diamino-4-(4-biphenylyl)-imidazole and 70 ml of isopropanol, and 
the mixture is stirred at 120.degree. C. for 28 hours. Cooling to room 
temperature, filtration, washing the crystallizate with isopropanol and 
drying under a high vacuum yield the title compound with a water content 
of 0.9%, m.p. 284.degree.-285.degree. C. (decomp.), .sup.1 H-NMR 
(DMSO/D.sub.2 O): .delta.=8.28 (d, 1H); 7.99 (s, 4H); 7.80 (s, 4H); 
7.60-7.76 (m, 4H); 7.35-7.53 (m, 3H); 3.32 (s, 4H). 
The starting materials are prepared as follows: 
a) 2-Amino-1-benzylideneamino-4-(4-biphenylyl)-imidazole 
7 ml (0.0507 mol) of triethylamine and 13.75 g (0.050 mol) of 
2-bromo-4'-phenylaceto-phenone (Aldrich, Buchs, Switzerland; tech., Cat. 
no. 10,108-7) are added to a solution of 8.11 g (0.05 mol) of benzaldehyde 
guanylhydrazone in 40 ml of ethanol. The reaction mixture is stirred at 
20.degree. C. for 15 hours and is filtered, and the crystallizate is taken 
up in methylene chloride and acidified to pH 1 with 1N hydrochloric acid. 
After filtration, the filtration product is taken up in methanol, and 2N 
sodium hydroxide solution is added until a basic reaction is obtained (pH 
11). Filtration is carried out and the crystalline product is washed with 
methanol/water (1:1). The title compound so obtained melts at 
254.degree.-255.degree. C. (decomp.), .sup.1 H-NMR (DMSO): .delta.=8.60 
(s, 1H); 8.10 (s, 1H); 7.93-7.98 (m, 2H); 7.67-7.83 (m, 6H); 7.32-7.55 (m, 
6H); 6.24 (s, 2H). 
b) 1,2-Diamino-4-(4-biphenylyl)-imidazole 
A solution of 9.2 g (0.0189 mol) of 
2-amino-1-benzylideneamino-4-(4-biphenylyl)-imidazole and 22 ml of 
hydrazine hydrate in 73 ml of diethylene glycol is stirred at 140.degree. 
C. for 48 hours. After cooling to 20.degree. C., 100 ml of acetonitrile 
are added to the reaction mixture, which is then cooled further to 
5.degree. C. The product that has separated out is filtered off and washed 
with acetonitrile and diethyl ether. In that manner there is obtained the 
title compound having a water content of 0.41 %, m.p. &gt;280.degree. C., 
.sup.1 H-NMR (DMSO): .delta.=7.29-7.73 (m, 9H); 7.12 (s, 1H); 5.55 (s, 
2H); 5.39 (s, 2H). 
EXAMPLE 22 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-bi-phenyly 
l)-imidazole dihydrochloride 
Analogously to Example 2, a mixture of 9.27 g (18.54 mmol) of 
1-4-(N-hydroxy-amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4 
-biphenylyl)-imidazole dihydrochloride, 800 ml of water, 820 ml of methanol 
and 7.3 g of Raney nickel is hydrogenated at 25.degree.-51.degree. C. and 
under normal pressure until the absorption of hydrogen has ceased. The 
reaction mixture is then filtered, the filtrate is acidified to pH 1 with 
concentrated hydrochloric acid, and concentration is carried out by 
evaporation in vacuo. Recrystallization of the residue twice from ethanol 
yields the title compound, m.p. 269.degree.-270.degree. C. (decomp.), 
.sup.1 H-NMR (DMSO/D.sub.2 O): .delta.=8.32 (d, 1H); 8.03 (s, 1H); 
7.62-7.83 (m, 8H); 7.35-7.53 (m, 3H); 3.36 (s, 4H). 
EXAMPLE 23 
1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2-n 
aphthyl)-imidazole dihydrochloride 
7 ml of concentrated hydrochloric acid are added, with stirring, to a 
mixture of 2.01 g (9.8 mmol) of 
4-(N-hydroxyarnidino)-2,3-dihydro-1H-inden-1-one oxime, 2.2 g (9.8 mmol) 
of 1,2-diamino-4-(2-naphthyl)-imidazole (see J. Heterocycl. Chem. 11, 
327-329 (1974)) and 25 ml of isopropanol, and the mixture is stirred at 
120.degree. C. for 24 hours. The mixture is cooled to 20.degree. C., 
filtered and washed with isopropanol, and the filtration product is taken 
up in 60 ml of methylene chloride. The suspension is stirred at room 
temperature for 15 hours and is then filtered, and the crystallizate is 
washed with methylene chloride. In that manner there is obtained the title 
compound, m.p. 265.degree.-270.degree. C., .sup.1 H-NMR (DMSO/D.sub.2 O): 
.delta.=8.32 (s, 1H); 8.29 (d, 1H); 8.19 (s, 1H); 8.04 (d, 1H); 7.88-7.98 
(m, 3H); 7.81 (d, 1H); 7.53-7.68 (m, 3H); 3.38 (s, 4H). 
EXAMPLE 24 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2-naphthyl)- 
imidazole dihydrochloride 
Analogously to Example 2, 0.3 g of Raney nickel is added to a mixture of 
1.0 g (2.13 mmol) of 
1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2- 
naphthyl)-imidazole dihydrochloride in 120 ml of methanol/water (1:1), and 
hydrogenation is carried out at room temperature and under normal pressure 
until the absorption of hydrogen has ceased. The reaction mixture is then 
filtered, the filtrate is acidified to pH 3 with 3N methanolic 
hydrochloric acid, and concentration is carried out by evaporation in 
vacuo. Recrystallization of the residue from ethanol with the addition of 
a small amount of methanol yields the title compound, m.p. &gt;280.degree. 
C., .sup.1 H-NMR (DMSO/D.sub.2 O): .delta.=8.31 (d, 1H); 8.18 (s, 1H); 
8.05 (s, 1H); 7.92-8.03 (m, 3H); 7.79-7.86 (m, 2H); 7.52-7.69 (m, 3H); 
3.35 (s, 4H). 
EXAMPLE 25 
1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-imidaz 
ole dihydrochloride 
A mixture of 0.837 g (4.079 mmol) of 
4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 0.40 g (4.077 mmol) 
of 1,2-diamino-imidazole, 23 ml of isopropanol and 1.33 ml of concentrated 
hydrochloric acid is heated under reflux for 22 hours. Filtration of the 
hot reaction mixture, washing of the crystallizate with isopropanol and 
diethyl ether and drying under a high vacuum yield the title compound, 
m.p. 258.degree.-260.degree. C. (decomp.), .sup.1 H-NMR (DMSO/D.sub.2 O): 
.delta.=8.29 (d, 1H); 7.80 (d, 1H); 7.65 (t, 1H); 7.55 (d, 1H); 7.13 (d, 
1H); 3.22-3.32 (m 4H). 
The starting materials are prepared as follows: 
a) N-Benzylidenamino-N'-(2,2-dimethoxy-ethyl)-guanidine 
2.88 g (0.06 mol) of sodium hydride dispersion (approximately 50% in oil; 
Fluka, Buchs, Switzerland) are added in portions over a period of 10 
minutes, with stirring and with the introduction of nitrogen, to a 
solution of 8.1 g (0.05 mol) of benzaldehyde guanylhydrazone in 80 ml of 
DMF. After 25 minutes stirring at room temperature, 7.1 ml (0.06 mol) of 
bromoacetaldehyde dimethylacetal (Aldrich, Buchs, Switzerland; 97%, Cat. 
no. 24,250-0) are added dropwise to the mixture, which has been cooled in 
an ice-bath. The reaction mixture is stirred for one hour at room 
temperature and for 20 hours at 55.degree. C., and then concentration by 
evaporation is carried out in vacuo and the residue is partitioned between 
ethyl acetate and water. The organic phase is washed with water and brine 
and is concentrated by evaporation, and the oily residue is purified by 
flash chromatography on silica gel having a particle size of 0.04-0.063 
mm, using ethyl acetate and ethyl acetate/methanol (9:1). Concentration of 
the product-containing fractions by evaporation yields the title compound 
in the form of an oil, Rf value=0.80 (silica gel/methylene 
chloride:methanol:conc. ammonia (40:10:1)), .sup.1 H-NMR (DMSO): 
.delta.=8.07 (s, 1H); 7.67-7.73 (m, 2H); 7.23-7.40 (m, 3H); 5.93 (bs, 3H); 
4.48 (t, 1H); 3.32 (s, 6H); 3.29 (d, 2H). 
b) 1,2-Diamino-imidazole 
A mixture of 2.5 g (0.01 mol) of 
N-benzylideneamino-N'-(2,2-dimethoxyethyl)guanidine and 50 ml of 2N 
hydrochloric acid is heated slowly from 60.degree. C. to 120.degree. C. 
over a period of 4 hours, with stirring. The benzaldehyde that is 
separated off during the course of the reaction is removed from the 
reaction mixture by azeotropic distillation (approximately 2 hours). After 
making up to the original volume by the addition of water, the reaction 
mixture is heated for a further 8 hours under reflux and is then 
concentrated by evaporation in vacuo. The resinous residue is dissolved in 
a mixture of 3 ml of methanol and 2.5 ml of 30% sodium hydroxide solution 
and is purified by flash chromatography on silica gel having a particle 
size of 0.04-0.063 mm using methylene chloride:methanol (9:1) and 
methylene chloride:methanol:conc. ammonia (90:10:0.5 and 40:10:1). 
Concentration of the product-containing fractions by evaporation yields 
the title compound in the form of an oil, .sup.1 H-NMR (DMSO): 
.delta.=6.60 (s, 1H); 6.38 (s, 1H); 5.67 (bs, 2H); 5.54 (bs 2H). 
EXAMPLE 26 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-imidazole 
dihydrochloride 
0.3 g of Raney nickel is added to a solution of 0.8 g (2.33 mmol) of 
1-4-(N-hydroxy-amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-imid 
azole dihydrochloride in 60 ml of methanol/water (1:1), and hydrogenation 
is carried out at room temperature and under normal pressure until the 
absorption of hydrogen has ceased. The filtrate is adjusted to pH 3 with a 
small amount of 3N methanolic hydrochloric acid and is concentrated by 
evaporation in vacuo. Recrystallization of the residue from methanol/water 
yields the title compound, m.p. &gt;260.degree. C., .sup.1 H-NMR (D.sub.2 O): 
.delta.=8.15 (d, 1H); 7.82 (d, 1H); 7.58 (t, 1H); 7.17 (d, 1H); 6.90 (d, 
1H); 3.29-3.35 (m, 2H); 3.12-3.18 (m, 2H). 
EXAMPLE 27 
1-4-(N-HydroxVamidino)-213-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4-t 
ert-butylphenyl)-imidazole dihydrochloride 
0.45 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) is 
added, with stirring, to a mixture of 0.307 g (0.0015 mol) of 
4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 0.345 g (0.0015 
mol) of 1,2-diamino-4-(4-tert-butylphenyl)-imidazole (see Ivaschenko A. V. 
et aL, Khim. Geterotsikl. Soedin. (2), 236-241 (1982)--English 
translation: Chem. Heterocycl. Compd. 1982, 185-189) and 7.5 ml of 
isopropanol, and the reaction mixture is stirred at 80.degree.-90.degree. 
C. for 16 hours. The reaction mixture is filtered while hot and the 
filtration product is washed with isopropanol and dried. In that manner 
there is obtained the title compound, m.p. &gt;250.degree. C., .sup.1 H-NMR 
(D.sub.2 O): .delta.=8.26 (d, 1H); 7.86 (s, 1H); 7.75 (d, 1H); 7.6 (m, 
3H); 7.47 (d, 2H); 3.28 (s, 4H); 1.27 (s, 9H). 
EXAMPLE 28 
1-4-(Amidino)-2,3-dihydro- 
1H-inden-1-ylideneaminol-2-amino-4-(4-tert-butylphenyl)-imidazole 
dihydrochloride 
Analogously to Example 2, approximately 2.0 g of Raney nickel are added to 
a solution of 3.9 g (0.0082 mol) of 
1-4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(4- 
tert-butylphenyl)-imidazole dihydrochloride in 400 ml of methanol, and 
hydrogenation is carried out at room temperature and under normal pressure 
until the absorption of hydrogen has ceased. The reaction mixture is then 
filtered, adjusted to pH 4 with a small amount of 2N alcoholic 
hydrochloric acid and concentrated to dryness by evaporation. The residue 
is recrystallized from ethanol, yielding the title compound in the form of 
the trihydrate, m.p. 250.degree. C. (decomp.), .sup.1 H-NMR (DMSO/D.sub.2 
O): .delta.=8.27 (d, 1H); 7.75-7.92 (m, 2H); 7.6 (m, 3H); 7.46 (m, 2H); 
3.32 (bs, 4H); 1.27 (s, 9H). 
EXAMPLE 29 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4,5-di-hydro-im 
idazole dihydrochloride 
A solution of 0.24 g (0.001 mol) of 4-amidino-2,3-dihydro-1H-inden-1-one 
hydrochloride and 0.136 g (0.001 mol) of 1,2-diamino-4,5-dihydro-imidazole 
hydrochloride m.p. 245.degree.-246.degree. C., prepared from the 
corresponding p-toluenesulfonate salt, see EP 0 327 919, Example 12, by 
ion exchange on .RTM.Amberlite IRA-400 (anion exchanger based on a 
styrene/divinylbenzene polymer with quaternary ammonium groups in the 
Cl.sup.- form; Fluka, Buchs, Switzerland)! in 3 ml of water is left to 
stand at room temperature for 18 hours. The product that has crystallized 
out is filtered off with suction and recrystallized from water, yielding 
the title compound (monohydrate), m.p. 280.degree. C. (decomp.), .sup.1 
H-NMR (DMSO/D.sub.2 O): .delta.=8.17 (d, 1H); 7.66 (d, 1H); 7.54 (t, 1H); 
4.18 (t, 2H); 3.70 (t, 2H); 3.25 (m, 2H); 3.13 (m, 2H). 
The starting materials are prepared as follows: 
a) 4-Thiocarbamoyl-2,3-dihydro-1H-inden-1-one 
A solution of 12.1 g (77 mmol) of 4-cyano-2,3-dihydro-1H-inden-1-one see 
Coll. Czechoslov. Chem. Commun. 4, 3227 (1978)! in 220 ml of pyridine and 
10.6 ml (77 mmol) of triethylamine is saturated with hydrogen sulfide for 
3 hours at 40.degree. and is then stirred at the same temperature for 16 
hours. The reaction mixture is cooled and then concentrated to dryness by 
evaporation, and 300 ml of water are added to the residue. The yellow 
product that has crystallized out is filtered off with suction, washed 
with water, dried and recrystallized from ethyl acetate. In that manner 
there is obtained the title compound, m.p. 197.degree. (decomp.). 
b) 4-Amidino-2,3-dihydro-1H-inden-1-one hydrochloride 
10.8 g (54 mmol) of triethyloxonium tetrafluoroborate are added at room 
temperature, under argon, to a solution of 9.8 g (51.3 mmol) of 
4-thiocarbamoyl-2,3-dihydro-1H-inden-1-one in 500 ml of absolute methylene 
chloride. After 16 hours, a mixture of 4.2 g of potassium carbonate and 
4.2 ml of water is added to the reaction solution. The mixture is then 
stirred briefly and is filtered, and the filtrate is washed with water. 
The organic phase is dried over magnesium sulfate, filtered and 
concentrated by evaporation. The crude ethylthio-imino ether so obtained 
is dissolved in 160 ml of absolute ethanol; 3.3 g (60 mmol) of ammonium 
chloride are added and the reaction mixture is heated at reflux for 20 
hours. After cooling, the reaction mixture is concentrated to dryness by 
evaporation. The title compound is purified by chromatography on 1000 ml 
of .RTM.Amberlite ER-180 (Rohm & Haas, Darmstadt, Germany; ER-180 is a 
polystyrene-based adsorbate resin which is used for separating off 
lipophilic impurities and for decoloring; water as eluant) and is 
recrystallized from ethanol/diethyl ether, m.p. 215.degree.-218.degree. 
(decomp.). 
EXAMPLE 30 
1-5-(Amidino)-tetralin-1-ylideneamino!-2-amino-4,5-dihydro-imidazole 
dihydrochloride 
0.2 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) is added, 
with stirring, to a solution of 0.25 g (0.001 mol) of 
5-(amidino)-1-tetralone hydrochloride and 0.136 g (0.001 mol) of 
1,2-diamino-4,5-dihydro-imidazole hydrochloride in 5 ml of iso-propanol, 
and the mixture is stirred at 80.degree.-90.degree. C. for 16 hours. The 
reaction mixture is filtered while hot and the filtration product is 
washed with isopropanol and dried, yielding the title compound, m.p. 
&gt;220.degree. C. (decomp.), .sup.1 H-NMR (DMSO/D.sub.2 O): .delta.=8.15 (d, 
1H); 7.67 (d, 1H); 7.55 (t, 1H); 4.17 (t, 2H); 3.68 (t, 2H); 3.23 (m, 2H); 
3.15 (m, 2H); 1.9 (m, 2H). 
The starting materials are prepared as follows: 
a) 5-Cyano-1-tetralone 
0.41 g (4.5 mmol) of copper(I) cyanide is added to a solution of 1.0 g (4.4 
mmol) of 5-bromo-1-tetralone see J. Org. Chem. 49, 4226 (1984)! in 1.3 ml 
of DMF, and the reaction mixture is stirred at 160.degree. for 6 hours. 
The reaction mixture is then cooled to 80.degree., and a solution of 1.6 g 
of iron(III) chloride hexahydrate in 2.5 ml of water and 0.44 ml of 
concentrated hydrochloric acid is added. Stirring is continued for 45 
minutes, the reaction mixture is cooled and diluted with water, and 
extraction is carried out with toluene. The organic phase is washed with 
water, dried over magnesium sulfate, filtered and concentrated by 
evaporation. In that manner there is obtained the title compound in the 
form of yellow-orange crystals, IR (CH.sub.2 Cl.sub.2): 2220, 1690 
cm.sup.-1 ; .sup.1 H-NMR (CDCl.sub.3): .delta.=8.26 (q,1H); 7.81 (q,1H); 
7.43 (t,1H); 3.21 (t,2H); 2.72 (t,2H); 2.23 (m,2H). 
b) 5-Thiocarbamoyl-1-tetralone 
Analogously to Example 29a), 10.6 g (62 mmol) of 5-cyano-l-tetralone in 200 
ml of pyridine and 8.6 ml of triethylamine are treated with hydrogen 
sulfide and worked up. There is thus obtained the title compound in the 
form of yellow crystals, m.p. 200.degree.-205.degree.. 
c) 5-Amidino-1-tetralone hydrochloride 
Analogously to Example 29b), 8.6 g (42 mmol) of 5-thiocarbamoyl-1-tetralone 
are treated with 8.8 g (44 mmol) of triethyloxonium tetrafluoroborate and 
2.6 g (49 mmol) of ammonium chloride. There is thus obtained the title 
compound in the form of slightly pink-colored crystals, MS (FAB): 
(M+H).sup.+ =189. 
EXAMPLE 31 
1-5-(Amidino)-tetralin-1-ylideneamino!-2-amino-4-phenyl-imidazole 
di-hydrochloride 
Analogously to Example 3, 5-(amnidino)-1-tetralone hydrochloride is reacted 
with 1,2-di-amino-4-phenyl-imidazole, yielding the title compound. M.p. 
&gt;240.degree. C. (decomp.), .sup.1 H-NMR (DMSO/D.sub.2 O) .delta.=8.54 (d, 
1H); 7.6-7.8 (m, 4H); 7.3-7.58 (M, 5H); 2.96 (m, 2H); 2.88 (m, 2H); 1.9 
(m, 2H). 
EXAMPLE 32 
1-4-(N-Hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-phen 
yl-imidazole dihydrochloride 
A mixture of 0.406 g (0.0019 mol) of 4-cyano-2,3-dihydro-1H-inden-1-one 
2'-amidino-hydrazone (prepared from the HCl salt in aqueous solution with 
NaOH) and 0.19 g (0.0009 mol) of phenacyl bromide (Aldrich, Buchs, 
Switzerland; Cat. No. 11,583-5) in 40 ml of ethanol is boiled under reflux 
for 4 hours. The reaction mixture is filtered while hot and the filtration 
product is washed with ethanol and dried, yielding 
1-4-cyano-2,3-di-hydro-1H-inden-1-ylideneamino!-2-amino-4-phenyl-imidazol 
e, MS (FAB): (M+H).sup.+ =314, .sup.1 H-NMR (DMSO): .delta.=8.32 (d, 1H); 
7.94 (d, 1H); 7.76 (m, 3H); 7.56 (t, 1H); 7.32 (m, 2H); 7.16 (t, 1H); 6.12 
(s, 2H); 3.35 (bs, 4H). 
That intermediate is maintained under reflux in ethanol for 4 hours with 
equivalent amounts of hydroxylamine hydrochloride and sodium carbonate, 
the title compound being obtained after working up with hydrochloric acid 
(for physical data see Example 1). 
The starting material is prepared as follows: 
a) 4-Cyano-2,3-dihydro-1H-inden-1-one 2-amidinohydrazone hydrochloride 
314 mg (2 mmol) of 4-cyano-2,3-dihydro-1H-inden-1-one are dissolved in 20 
ml of methanol, a solution of 272 mg (2 mmol) of aminoguanidine hydrogen 
carbonate in 9 ml of water and 1 ml of 2N hydrochloric acid are added 
thereto and the mixture is stirred at reflux for 4 days. After cooling, 
the reaction mixture is concentrated to dryness by evaporation and the 
residue is crystallized from water. There is thus obtained the title 
compound, m.p. &gt;230.degree. C.; .sup.1 H-NMR (DMSO-d.sub.6 /D.sub.2 O): 
.delta.=8.16 (d,1H); 7.9 (d,1H); 7.55 (t,1H); 3.28 (m,2H); 2.9 (m,2H); 
IR(Nujol): 2190 cm.sup.-1 (CN). 
EXAMPLE 33 
1-(3-Amidinobenzylideneamino)-2-amino-4-phenyl-imidazole dihydrochloride 
Analogously to Example 31, 3-amidinobenzaldehyde hydrochloride is reacted 
with 1,2-di-amino-4-phenyl-imidazole, yielding the title compound. 
The starting material is prepared as follows: 
a) Ethyl-3-formylbenzimidate hydrochloride (3-formyl-benzimide acid ethyl 
ester chloride): 
59.7 ml (1.025 mol) of absolute ethanol are added to a solution of 86.7 g 
(0.662 mol) of 3-cyanobenzaldehyde (Aldrich, Buchs, Switzerland, Cat. No. 
14,625-0) in 530 ml of absolute diethyl ether and the reaction solution is 
cooled to 0.degree. C. The reaction solution is saturated with dry 
hydrochloric acid gas and then left to stand at 0.degree. C. for 6 days. 
When a fine precipitate has been filtered off, 1 liter of diethyl ether is 
added to the reaction solution. The title compound crystallizes out, m.p. 
126.degree.-128.degree. C. (with foaming). 
b) 3-Amidinobenzaldehyde hydrochloride 
250 ml of absolute ethanol and 250 ml of saturated ethanolic ammonia 
solution are added to 21.3 g (0.1 mol) of the imino ether from Example 
33a) and the mixture is heated at 70.degree. C. for 3 hours. After 
cooling, the ethanol is evaporated off and the residue, which corresponds 
to the title compound in crude form, is reacted further directly. 
EXAMPLE 34 
1-(.alpha.-Methyl-3-amidinobenzylideneamino)-2-amino-4-phenyl-imidazole 
di-hydrochloride 
Analogously to Example 3, 3-amidinoacetophenone hydrochloride is reacted 
with 1,2-di-amino-4-phenyl-imidazole, yielding the title compound. 
The starting material is prepared as follows: 
a) Ethyl-3-acetylbenzimidate hydrochloride (3-acetyl-benzimide acid ethyl 
ester hydrochloride) 
A solution of 7.25 g (0.05 mol) of 3-acetylbenzonitrile (Aldrich, Buchs, 
Switzerland; Cat. No. 29,221-4) in 150 ml of diethyl ether and 4.5 ml of 
ethanol is saturated at 0.degree. C. with dry hydrochloric acid gas and 
then left to stand at 0.degree. C. for 2 days. The product that has 
crystallized out is filtered off and the title compound is obtained after 
recrystallization from ethanol/diethyl ether, m.p. 110.degree. C. 
(decomp.). 
b) 3-Amidinoacetophenone hydrochloride 
11.4 g of the title compound from Example 34a), 200 ml of ethanol and 125 
ml of saturated ethanolic ammonia solution are boiled at reflux for 6 
hours. After cooling, the reaction mixture is concentrated by evaporation, 
and the residue is dissolved in 4N hydrochloric acid, washed with diethyl 
ether and concentrated to dryness by evaporation. The resulting crude 
product (title compound) is used further directly. 
The following compounds are prepared analogously to one of the methods 
described in this Application (Examples 35 to 44) 
EXAMPLE 35 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,4-di-metho 
xyphenyl)-imidazole dihydrochloride 
EXAMPLE 36 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,4,5-tri-me 
thoxyphenyl)-imidazole dihydrochloride 
EXAMPLE 37 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,5-di-metho 
xyphenyl)-imidazole dihydrochloride 
EXAMPLE 38 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,4-di-methy 
lphenyl)-imidazole dihydrochloride 
EXAMPLE 39 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,5-di-methy 
lphenyl)-imidazole dihydrochloride 
EXAMPLE 40 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2,4-di-methy 
lphenyl)-imidazole dihydrochloride 
EXAMPLE 41 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,4-di-chlor 
ophenyl)-imidazole dihydrochloride 
EXAMPLE 42 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,5-di-chlor 
ophenyl)-imidazole dihydrochloride 
EXAMPLE 43 
1-4-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(2,4-di-chlor 
ophenyl)-imidazole dihydrochloride 
EXAMPLE 44 
1-14-(Amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-(3,5-di-(tert 
-butyl)phenyl)-imidazole dihydrochloride 
EXAMPLE 45 
Capsules 
Capsules containing 1 g of active ingredient, i.e. a compound of formula I 
according to any one of Examples 1 to 34, are prepared as follows: 
______________________________________ 
Composition (for 1250 capsules): 
______________________________________ 
active ingredient 1250 g 
talc 180 g 
wheat starch 120 g 
magnesium stearate 80 g 
lactose 20 g 
______________________________________ 
The pulverulent substances are forced through a sieve of 0.6 mm mesh size 
and mixed. 1.32 g portions of the mixture are introduced into gelatin 
capsules using a capsule-filling machine. 
EXAMPLE 46 
Tablets 
10000 tablets, each comprising 5 mg of active ingredient, i.e. one of the 
compounds of formula I prepared in Examples 1 to 34, are prepared: 
______________________________________ 
Composition: 
______________________________________ 
active ingredient 50.00 g 
lactose 2535.00 g 
corn starch 125.00 g 
polyethylene glycol 6.000 
150.00 g 
magnesium stearate 40.00 g 
purified water quantum satis 
______________________________________ 
Method: All the pulverulent constituents are forced through a sieve of 0.6 
mm mesh size. Then the active ingredient, the lactose, the magnesium 
stearate and half the starch are mixed in a suitable mixer. The other half 
of the starch is suspended in 65 ml of water and the resulting suspension 
is added to a boiling solution of the polyethylene glycol in 260 ml of 
water. The paste that is formed is added to the powder mixture and 
granulated, if necessary with the addition of more water. The granules are 
dried overnight at 35.degree. C., forced through a sieve of 1.2 mm mesh 
size and compressed to form tablets having a breaking notch. 
EXAMPLE 47 
Infusion or injection solutions 
Infusion or injection solutions comprising 100 mg of active ingredient 
dissolved in 5 ml of aqueous 5% D-glucose solution are prepared. The 
active ingredient used is one of the compounds from Examples 1 to 34. The 
solutions are introduced into vials. 
EXAMPLE 48 
Dry vials 
Dry vials are parepared by lyophilising solutions prepared in Example 37 of 
one of the active ingredients mentioned therein. 
EXAMPLE 49 
Inhibition of S-adenosylmethionine decarboxylase (SAMDC) 
Using the method of A. E. Pegg and H. S. Poso (see Methods Enzymol. 94, 
234-239 (1983)) mentioned hereinbefore, the following IC.sub.50 values are 
obtained for the inhibition of the enzyme SAMDC for the compounds of 
formula I mentioned below: 
______________________________________ 
Title compound of formula I 
from Example IC.sub.50 (mM) 
______________________________________ 
2 2 
4 3.6 
6 8.4 
8 8.9 
10 4.2 
12 6.7 
14 3.4 
16 4.0 
18 6.1 
20 3.4 
22 11 
24 7.5 
28 5.4 
______________________________________ 
EXAMPLE 50 
Inhibition of the growth of human T24 bladder carcinoma cells: 
The inhibition of the growth of human T24 bladder carcinoma cells is 
measured using the method mentioned hereinbefore. The following IC.sub.50 
values (concentration of the test compound at half the maximum inhibition) 
are determined using the following Examples: 
______________________________________ 
Title compound of formula I 
from Example IC.sub.50 (mM) 
______________________________________ 
2 1.16 
4 2 
6 1.2 
8 1.6 
10 2.6 
12 1.55 
14 1.12 
16 2.70 
18 1.5 
20 0.28 
22 0.44 
24 2.46 
26 2.15 
28 0.23 
______________________________________ 
EXAMPLE 51 
Inhibition of the growth of T24 bladder carcinoma cells in vivo (nude 
mouse) 
Using the method mentioned hereinbefore (see also Regenass et al., Cancer 
Res. 54, 3210-3217 (1974)), the compound of Example 2 of the present 
Application is administered in accordance with the following treatment 
scheme to BALB/c nude mice with transplanted human T24 bladder cell 
carcinomas: The compound is administered p.o. (50, 25 and 12.5 mg/kg) or 
i.p. (12.5, 6.25 and 3.13 mg/kg). The compound is dissolved in distilled 
water and diluted with 3 volumes of 0.9% NaCl (w/v) in water. 
As shown in the following Table, 
1-4-(amidino)-2,3-dihydro-1H-inden-1-ylideneamino!-2-amino-4-phenyl-imida 
zole dihydrochloride inhibits the growth of T24 bladder carcinoma cells 
both on oral and on intraperitoneal administration. The dose-dependence of 
the action is observed. The maximum tolerated dose is &gt;500 mg/kg in the 
case of p.o. administration and 125 mg/kg in the case of i.p. 
administration. 
Inhibition of T24 tumor growth: 
______________________________________ 
T/C (%)* on 
Title compound from Example 2 
administration 
(mg/kg) i.p. p.o. 
______________________________________ 
0 (control) 100 100 
3.13 34 n.d. 
6.25 22 n.d. 
12.5 16 68 
25 n.d. 47 
50 n.d. 31 
______________________________________ 
(n.d. = not determined) 
*average for 6 animals