Amine derivatives, processes for their production and their use

Compounds of formula I ##STR1## wherein R.sub.1 represents a group of formula ##STR2## and R.sub.2 represents hydrogen or lower alkyl, or PA0 R.sub.1 and R.sub.2 together with the carbon atom to which they are attached represent a group of formula IIg ##STR3## R.sub.4 and R.sub.5 represent independently hydrogen or lower alkyl, R.sub.3 represents hydrogen, alkyl, cycloalkyl or halogenalkyl and PA0 R.sub.6 represents a group of formula ##STR4## R.sub.1 represents a group of formula IIa to IIf as defined above, R.sub.2 and R.sub.3 together form a --(CH.sub.2)--.sub.u group wherein u stands for a whole number from 1 to 8 and R.sub.4, R.sub.5 and R.sub.6 have the meanings given above. which compounds are indicated for use as pharmaceuticals and agrochemicals.

The present invention concerns the use of amine derivatives as antimycotics 
and agro fungicides as well as certain amine derivatives as such, 
pharmaceutical and agrochemical compositions containing them and processes 
for their production. 
In particular the invention concerns the use of compounds of formula I as 
antimycotics and agro fungicides 
##STR5## 
wherein R.sub.1 represents a group of formula 
##STR6## 
and R.sub.2 represents hydrogen or lower alkyl, or 
R.sub.1 and R.sub.2 together with the carbon atom to which they are 
attached represent a group of formula IIg 
##STR7## 
whereby in formulae IIa to IIg R.sub.7 and R.sub.8 represent 
independently hydrogen, halogen, trifluoromethyl, lower alkyl or lower 
alkoxy, 
R.sub.9 represents hydrogen, halogen, lower alkyl or lower alkoxy, 
R.sub.10 and R.sub.11 represent independently hydrogen, halogen, 
trifluoromethyl, lower alkyl, lower alkoxy or lower alkylthio, whereby 
when one of R.sub.10 and R.sub.11 represents hydrogen, halogen or lower 
alkoxy the other is other than hydrogen, 
X represents oxygen, sulphur, imino, lower alkylimino, --O--CH.sub.2 -- or 
--CH.sub.2 --, 
p stands for 1, 2 or 3, 
s stands for 3, 4 or 5, 
v stands for 3, 4, 5 or 6 
whereby one or two of the --CH.sub.2 -- groups in formula IId may be 
replaced by oxygen or sulphur, 
R.sub.4 and R.sub.5 represent independently hydrogen or lower alkyl, 
R.sub.3 represents hydrogen, alkyl, cycloalkyl or halogenalkyl and 
R.sub.6 represents a group of formula 
##STR8## 
whereby in the formulae IIIa to IIIe R.sub.7 and R.sub.8 have the 
meanings given above, 
w stands for 2,3,4,5 or 6, 
Z represents oxygen, sulphur or NR.sub.3 wherein R.sub.3 has the meaning 
given above and 
R.sub.12 represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, 
lower alkoxy, lower alkoxycarbonyl, lower alkylthio, phenyl, phenalkyl, 
trialkylsilyl, dialkylphenylsilyl or halogen, whereby alkyl, alkenyl, 
alkynyl, cycloalkyl, cycloalkylalkyl, phenyl or phenalkyl may be 
substituted by phenyl, lower alkoxy, lower alkylthio, phenalkoxy, lower 
alkoxyphenyl, lower alkylphenyl, halogenphenyl, halogen or an optionally 
substituted heterocycle; optionally interrupted by carbonyl; or 
R.sub.1 represents a group of formula IIa to IIf as defined above, 
R.sub.2 and R.sub.3 together form a --(CH.sub.2)--.sub.u group wherein u 
stands for a whole number from 1 to 8 and R.sub.4, R.sub.5 and R.sub.6 
have the meanings given above, in free form or in pharmaceutically 
acceptable acid addition salt form. 
Each lower alkyl moiety preferably contains 1 to 4, especially 2 or 1 
carbon atoms. Alkyl moieties contain in particular 1 to 12, especially 2 
to 8, more particularly 2 to 6 and preferably 2to 4 carbon atoms. Each 
alkenyl or alkynyl contains in particular 3 to 6, especially 3 or 4 carbon 
atoms e.g. allyl, propenyl or propynyl. Such groups as mentioned above can 
be straight chained or branched. A preferred cycloalkylidene is 
cyclohexylidene. Cycloalkyl is to be understood as embracing polycycles 
such as bornyl or adamantyl but is preferably cyclohexyl, cyclopentyl or 
cyclopropyl. Conveniently R.sub.7, R.sub.8 and R.sub.9 are independently 
hydrogen or halogen. X is conveniently sulphur, imino or lower alkylimino. 
Examples of heterocycles are saturated or unsaturated 5 or 6 membered rings 
containing one or more heteroatoms selected from nitrogen, oxygen or 
sulphur--e.g. thiophene. These can contain one or more substituents such 
as defined for R.sub.7. 
R.sub.1 is preferably a group of formula IIc or IId in particular IIa or 
IIb. R.sub.2 is preferably hydrogen and R.sub.3 conveniently lower alkyl. 
R.sub.6 is preferably IIIa 
Values for p, s, u, v and w are conveniently chosen such that seven- or 
preferably six- or five-membered rings are formed. Halogen stands for 
fluorine, chlorine or bromine. 
The compounds of the present invention may be prepared by 
(a) reacting a compound of formula IV 
##STR9## 
with a compound of formula V 
##STR10## 
(b) for preparing a compound of formula Ia 
##STR11## 
introducing a R'.sub.3 group into a compound of formula Ib 
##STR12## 
(c)(i) for preparing a compound of formula Ic 
##STR13## 
reacting a compound of formula VI 
##STR14## 
with a compound of formula VII 
EQU R.sub.6 --Me VII 
or 
(ii) for preparing a compound of formula Id 
##STR15## 
reacting a compound of formula VIa 
##STR16## 
with a compound of formula VIIa 
EQU R.sub.1 --Me VIIa 
(d) for preparing a compound of formula Ie 
##STR17## 
reacting a compound of formula VIb 
##STR18## 
with a Wittig reagent of formula IVb or IVc 
##STR19## 
(e) for preparing a compound of formula If and Ig 
##STR20## 
reducing a Schiff's base of formula Ih, Ii 
##STR21## 
whereby in the above formulae R, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and 
R.sub.6 are as defined for formula I, one Y represents a leaving group and 
the other --NH--R.sub.3, R'.sub.3 represents cycloalkyl, halogenalkyl or 
lower alkyl, R represents lower alkyl, Me represents a metal equivalent, 
R'.sub.6 represents a group of formula IIIf 
##STR22## 
wherein R.sub.13, R.sub.14 and R.sub.15 represent independently hydrogen, 
lower alkyl, lower alkoxy, phenyl, phenalkoxy, lower alkoxyphenyl, lower 
alkylphenyl, halogenphenyl, halogen or an optionally substituted 
heterocycle, 
and recovering the compound obtained in free form or acid addition salt 
form. 
Process (a) is carried out in a manner conventional for the preparation of 
tertiary amines by condensation. The process can be carried out in an 
inert solvent such as a lower alkanol e.g. ethanol, optionally mixed with 
water, an aromatic hydrocarbon e.g. benzene or toluene, a cyclic ether 
e.g. dioxane, or a carboxylic acid dialkylamide e.g. dimethylformamide. 
The reaction temperature conveniently lies between room temperature and 
the boiling point of the reaction mixture, preferably room temperature. 
The process is conveniently carried out in the presence of an acid binding 
agent e.g. an alkali metal carbonate such as sodium carbonate. The leaving 
group is conveniently iodine or preferably bromine or chlorine or an 
organic sulphonyloxy with 1 to 10 carbon atoms e.g. an alkylsulphonyloxy, 
preferably with 1 to 4 carbon atoms such as mesyloxy or an 
alkylphenylsulphonyloxy, preferably with 7 to 10 carbon atoms such as 
tosyloxy. 
Process (b) is carried out in a manner conventional for the alkylation of 
secondary amines e.g. by direct alkylation with an alkylating agent e.g. 
with a halogenide or a sulphate or by reductive alkylation, especially by 
reaction with a suitable aldehyde and subsequent or simultaneous 
reduction. Reductive alkylation can conveniently be carried out by 
reacting a compound of formula Ib in an inert solvent e.g. in a lower 
alkanol such as methanol, with a corresponding aldehyde. Reduction can be 
carried out for example with a complex metal hydride such as NaBH.sub.4 or 
NaCNBH.sub.3 as reducing agent. It can also be carried out using aqueous 
NaH.sub.2 PO.sub.3 -solution (H. Loibner et.al. Tetrahedron Letters 
1984/2535) or formic acid which can serve simultaneously as reducing agent 
and reaction medium. 
Process (c) can be carried out in a manner conventional for reactions 
involving organometal compounds. It is preferably carried out in an inert 
solvent e.g. in an ether between -20.degree. C. and +50.degree. C. 
Process (d) can be carried out in a manner conventional for Wittig 
reactions preferably in an aprotic solvent such as a cyclic ether e.g. 
tetrahydrofuran or an aromatic hydrocarbon e.g. toluene between 20.degree. 
C. and the boiling point of the reaction mixture. 
Reduction according to process (e) can be carried out for example with a 
complex hydride such as NaBH.sub.4. It is preferably carried out in an 
inert solvent e.g. in a lower alkanol such as methanol at room 
temperature. 
The final products can be isolated and purified in conventional manner. 
Free bases of the compounds of formula I can be converted into salt forms 
and vice versa. Suitable acid addition salts are the hydrochloride, 
hydrogen fumarate or naphthalin-1,5-disulphonate. 
The starting materials of formulae VI and VIa can be prepared by reaction 
of the corresponding amine of formula IV or V with formaldehyde and a 
lower alcohol of formula ROH. 
The compounds of formula Ih can be prepared by reaction of a compound of 
formula IVd 
##STR23## 
with a compound of formula VIII 
##STR24## 
wherein R.sub.1, R.sub.2, R.sub.4 and R.sub.6 are as defined above. 
Starting materials of formula Ii can be prepared by reacting a compound of 
formula IVe 
##STR25## 
with a compound of formula IX 
##STR26## 
The remaining intermediates are either known or can be prepared analogously 
to known processes or e.g. as described in the examples. 
Some of compounds of formula I are new and also form part of the invention. 
These are the compounds of formula Ij 
##STR27## 
wherein R.sub.4 and R.sub.5 are as defined above and R".sub.1, R".sub.2, 
R".sub.3 and R".sub.6 have the same meanings as R.sub.1, R.sub.2, R.sub.3 
and R.sub.6 respectively with the proviso that 
(a) when R".sub.1 stands for naphthyl, R".sub.2, R".sub.3, R.sub.4 and 
R.sub.5 stand for hydrogen and R".sub.6 stands for a group IIIa wherein 
R.sub.8 is hydrogen then R.sub.12 and R.sub.7 are not both halogen and 
R.sub.12 is not halogen or methyl when R.sub.7 is hydrogen. 
(b) when R".sub.1 stands for a group 
##STR28## 
wherein R'.sub.7 and R'.sub.9 represent independently hydrogen, lower 
alkyl, lower alkoxy or halogen and s stands for 3, 4 or 5, R".sub.2 
represents hydrogen or lower alkyl, X represents oxygen, sulphur or 
nitrogen and R.sub.4 and R.sub.5 represent hydrogen then R".sub.6 does not 
stand for a group 
##STR29## 
wherein Z' represents oxygen or sulphur, R".sub.7 represents hydrogen, 
R'.sub.8 represents hydrogen, halogen or lower alkyl and R'.sub.12 
represents hydrogen, alkyl, cycloalkyl, halogenalkyl or alkyl; in free 
form or in acid addition salt form. 
A preferred group of compounds for use as antimycotics and agro fungicides 
are those of formula Ij as defined above. 
A further preferred group of compounds of formula I are those wherein 
(a) R.sub.1 represents a group of formula IIa to IIf and R.sub.2 represents 
hydrogen or lower alkyl or R.sub.1 and R.sub.2 together represent a group 
of formula IIg whereby in the formulae IIa to IIg R.sub.7 and R.sub.8 
represent independently hydrogen, halogen, trifluoromethyl, lower alkyl or 
lower alkoxy and R.sub.9 represents hydrogen, halogen, lower alkyl or 
lower alkoxy, R.sub.10 and R.sub.11 represent independently hydrogen, 
lower alkyl, halogen, trifluoromethyl, lower alkoxy or lower alkylthio, 
whereby when one of R.sub.10 or R.sub.11 represents hydrogen, halogen or 
lower alkoxy the other is not hydrogen, X represents oxygen, sulphur, 
imino, lower alkylamino or --CH.sub.2 --, p stands for 1, 2, or 3, u 
stands for 3, 4 or 5 and v stands for 3, 4, 5 or 6 and in the group of 
formula IId one or two of the CH.sub.2 groups may be replaced by oxygen or 
sulphur, R.sub.4 and R.sub.5 represent independently hydrogen or lower 
alkyl, R.sub.3 represents hydrogen, cycloalkyl, halogenalkyl or alkyl and 
R.sub.6 represents a group of formula IIIa to IIIe, whereby R.sub.7 and 
R.sub.8 are as hereindefined, w stands for 2, 3, 4, 5 or 6, z stands for 
oxygen, sulphur or N--R.sub.3 wherein R.sub.3 is as herein defined and 
R.sub.12 represents alkyl, alkenyl, alkynyl, cycloalkylalkyl, lower 
alkoxy, lower alkylthio, phenyl, phenalkyl, trialkylsilyl, 
dialkylphenylsilyl or halogen, whereby alkyl, alkenyl, alkynyl, 
cycloalkylalkyl, phenyl and phenalkyl can be substituted by lower alkoxy; 
optionally interrupted by carbonyl or 
(b) R.sub.1 represents a group of formula IIa to IIf as defined under (a), 
R.sub.2 and R.sub.3 represent together --(CH.sub.2).sub.u -- whereby u 
stands for a whole number from 1 to 8 and R.sub.4, R.sub.5 and R.sub.6 are 
as herein defined. 
A further preferred group of compounds of formula I are those wherein 
(a) R.sub.1 represents a group of formula IIa or IIb 
(b) R.sub.2 represents hydrogen or lower alkyl in particular hydrogen, 
(c) R.sub.3 represents hydrogen or alkyl in particular lower alkyl and 
(d) R.sub.6 represents a group of formula IIIa 
whereby R.sub.7 and R.sub.8 represent independently, hydrogen, halogen or 
lower alkoxy in particular hydrogen, X represents --O--CH.sub.2 --, oxygen 
or sulphur in particular sulphur, R.sub.4 and R.sub.5 represent 
independently hydrogen or lower alkyl in particular hydrogen and R.sub.12 
represents alkyl, alkenyl, alkynyl, cycloalkylalkyl, lower alkoxy, lower 
alkoxycarbonyl, lower alkylthio, phenyl, phenalkyl, trialkylsilyl, 
dialkylphenylsilyl or halogen whereby alkyl, alkenyl, alkynyl, 
cycloalkylalkyl, phenyl or phenylalkyl can be substituted by phenyl, lower 
alkoxy, lower alkylthio, phenalkoxy, lower alkoxyphenyl, lower 
alkylphenyl, halogenphenyl, halogen or an optionally substituted 
heterocycle; optionally interrupted by carbonyl. 
A further preferred group of compounds of formula I are those wherein 
R.sub.1 represents a group of formula IIa, IIb, IIc, IId or IIe and 
R.sub.2 represent hydrogen or lower alkyl or R.sub.1 and R.sub.2 together 
represent a group of formula IIg whereby R.sub.7 and R.sub.8 represent 
independently hydrogen, halogen, trifluoromethyl, lower alkyl, lower 
alkoxy and R.sub.9 represents hydrogen, halogen, lower alkyl or lower 
alkoxy, R.sub.10 and R.sub.11 represent independently hydrogen, lower 
alkyl, halogen, trifluoromethyl, lower alkoxy or lower alkylthio whereby 
when one of R.sub.10 or R.sub.11 is hydrogen, halogen or lower alkoxy the 
other is not hydrogen, X represents oxygen, sulphur, imino, lower 
alkylimino, --O--CH.sub.2 -- or --CH.sub.2 --, p stands for 1, 2 or 3, s 
stands for 3, 4 or 6 and v stands for 3, 4, 5 or 6 and one or two CH.sub.2 
groups in formula IId may be replaced by oxygen or sulphur, R.sub.4 and 
R.sub.5 represent independently hydrogen or lower alkyl, R.sub.3 
represents hydrogen, cycloalkyl, halogenalkyl or alkyl and R.sub.6 
represents a group of formula IIIa, IIIb, IIIc, IIId or IIIe, whereby 
R.sub.7 and R.sub.8 are as herein defined, w stands for 2, 3, 4, 5 or 6, Z 
stands for oxygen, sulphur or N--R.sub.3 wherein R.sub.3 is as defined 
above and R.sub.12 is as defined under formula I or R.sub.1 represents a 
group of formula IIa to IIe, R.sub.2 and R.sub.3 together represent 
--(CH.sub.2).sub.u -- wherein u is a whole number from 1 to 8 and R.sub.4, 
R.sub.5 and R.sub.6 are as defined above. 
The compounds of formula I possess advantageous chemotherapeutical 
properties and in particular exhibit on local or oral application an 
antimycotic activity and are thus indicated for use as pharmaceuticals in 
particular as antimycotics. This activity can be established on various 
families and species of mycetes e.g. Trichophyton spp., Aspergillus spp., 
Microsporum spp., Sporothrix schenckii and Candida spp. both in vitro 
dilution tests at concentrations of from 0.003 to 50 ug/ml and in vivo in 
the experimental skin mycosis test on guinea pigs and in 
intravaginal-intrauterine or disseminated infections. In the skin mycosis 
model the test substance is taken up in polyethyleneglycol and rubbed 
daily for 7 days on the infected skin surface. The antimycotic activity 
could be observed at concentrations of 0.1 to 2%. The oral activity can be 
demonstrated in vivo in the guinea pig trichophytosis model in a dosage 
range of ca. 2 to 70 mg/kg of body weight. 
For the above-mentioned use, the dose administered will, of course, vary 
depending on the compound employed, mode of administration and treatment 
desired. However, in general, satisfactory results are obtained when 
administered at a daily dosage of from 1 to 30 mg/kg of animal body 
weight, conveniently given in divided doses two to four times daily, or in 
controlled release form. For larger mammals having an approximate body 
weight of 70 kg the corresponding daily dosage is for example in the range 
of from 70 to 2000 mg; dosage forms suitable for e.g. oral administration 
comprise from 17.5 to 1000 mg of active ingredient. 
The compounds of the invention may be administered in similar manner to 
known standards for use in such indications. 
A suitable daily dosage will depend on a number of factors such as relative 
potency of activity. It has for example been determined in the 
experimental skin mycosis model that the preferred compound according to 
the invention 
N-Methyl-N-(1-naphthylmethyl)-4-(2-phenyl-2-propyl)benzylamine exhibited a 
curative dosage (i.e. dosage at which all guinea pigs infected with 
Trichlophyton mentagrophytes var. quinckeanum 158 are mycologically cured) 
of 9.times.6 mg/kg in Miglyol compared with 9.times.60 mg/kg for 
Griseofulvin. 
It is therefore indicated that the compounds be administered at similar or 
lower dosages than conventionally employed for Griseofulvin. 
The compounds of the invention may be employed in the free base form or in 
the form of pharmaceutically acceptable acid addition salts. In general 
these forms exhibit the same order of activity as the free base forms. 
Examples of such acid addition salts include the hydrochloride, hydrogen 
fumarate and naphthaline-1,5-disulfonate. 
The compounds may be admixed with conventional pharmaceutically acceptable 
diluents and carriers, and, optionally other excipients and administered 
orally, topi ally, i.v. or parenterally in such forms as tablets, 
capsules, creams, tinctures or injectable preparations. 
Such compositions also form part of the invention. 
The invention also concerns a method of combatting infections and diseases 
caused by mycetes comprising administering to a subject in need of such 
treatment an effective amount of a compound of formula I in free base form 
or in the form of a pharmaceutically acceptable salt thereof and such 
compounds for use as pharmaceuticals, in particular as anti-mycotic 
agents. 
The compounds of the invention in free form or in agriculturally acceptable 
salt or metal complex form are also suitable for combatting 
phytopathogenic fungi. This fungicidal activity can be demonstrated i.a. 
in in vivo tests against Uromyces appendiculatus (bean rust) on runner 
beans as well as against other rust fungi (e.g. Hemileia, Puccinia), on 
coffee, wheat, flax and ornamentals (e.g. pelargonium, snapdragon); and 
against Erysiphe cichoracearum on cucumber as well as against other 
powdery mildews (e.g. E. Graminis f. sp. tritici. E. gram. f. sp. hordei, 
Podosphaera leucotricha, Uncinula recator) on wheat, barley, apple and 
vines.