U.S. patent application number 09/738105 was filed with the patent office on 2001-06-14 for composition for keeping away vermin.
Invention is credited to Bouvier, Jacques, Christinaz, Catherine, Criscio, Nicola Di, Froelich, Olivier.
Application Number | 20010003646 09/738105 |
Document ID | / |
Family ID | 4207641 |
Filed Date | 2001-06-14 |
United States Patent
Application |
20010003646 |
Kind Code |
A1 |
Froelich, Olivier ; et
al. |
June 14, 2001 |
Composition for keeping away vermin
Abstract
1 The invention describes essentially a non-therapeutical
process for deterring vermin, which is based on the usage of the
largely known compounds of formula (I), as defined herein before.
Furthermore, it describes the corresponding vermin-deterring
compositions which contain these substances as the active
ingredient, compounds of formula (I) for the preparation of
vermin-deterring compositions, and the use of compounds of formula
(I) in the defence against vermin. Thus, the invention describes
how and in which form the compounds of formula (I) or their acid
addition salts are used to deter vermin from materials, places or
warm-blooded animals.
Inventors: |
Froelich, Olivier; (Kembs,
FR) ; Bouvier, Jacques; (Neuchatel, CH) ;
Christinaz, Catherine; (Gletterens, CH) ; Criscio,
Nicola Di; (Basel, CH) |
Correspondence
Address: |
Thomas Hoxie
Novartis Pharmaceuticals Corporation
Patent and Trademark Dept.
564 Morris Avenue
Summit
NJ
07901-1027
US
|
Family ID: |
4207641 |
Appl. No.: |
09/738105 |
Filed: |
December 15, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09738105 |
Dec 15, 2000 |
|
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PCT/EP99/04172 |
Jun 16, 1999 |
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Current U.S.
Class: |
435/1.1 ;
424/405; 514/315 |
Current CPC
Class: |
C07D 211/22 20130101;
A01N 47/16 20130101; A01N 47/24 20130101; A01N 47/38 20130101; A61P
33/00 20180101; Y10S 514/919 20130101; A01N 43/42 20130101; A01N
43/40 20130101; A01N 43/40 20130101; A01N 25/02 20130101; A01N
25/06 20130101; A01N 43/42 20130101; A01N 25/02 20130101; A01N
25/06 20130101; A01N 47/16 20130101; A01N 25/02 20130101; A01N
25/06 20130101; A01N 47/24 20130101; A01N 25/02 20130101; A01N
25/06 20130101; A01N 47/38 20130101; A01N 25/02 20130101; A01N
25/06 20130101 |
Class at
Publication: |
435/1.1 ;
424/405; 514/315 |
International
Class: |
A01N 001/00; A01N
001/02; A61K 031/445; A01N 043/40 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 18, 1998 |
CH |
1318/98 |
Claims
What is claimed is:
1. A non-therapeutical process for deterring vermin from
warm-blooded animals, whereby a compound of formula (I) 4or one of
its acid addition salts, wherein R is hydrogen,
C.sub.1-C.sub.20-alkyl or --C(O)--R.sub.8; whereby R.sub.8 is
C.sub.1-C.sub.20-alkyl, C.sub.1-C.sub.20-alkoxy, unsubstituted
phenyl or phenyl which is substituted once or many times by
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalk- oxy, halogen, cyano, hydroxyl, alkoxy,
amino or nitro; R.sub.1 is hydrogen, C.sub.1-C.sub.20-alkyl,
--C(O)--R.sub.3, --C(S)--R.sub.4, C(O)--O--R.sub.5,
--C(O)--NH--R.sub.6 or --C(S)--NH--R.sub.7; whereby R.sub.3,
R.sub.4, R.sub.5, R.sub.6 and R.sub.7, independently of one
another, signify C.sub.1-C.sub.10-alkyl, acetoxy,
C.sub.1-C.sub.10-haloal- kyl, C.sub.1-C.sub.10-alkoxy or
C.sub.1-C.sub.10-haloalkoxy, or independently of one another,
denote unsubstituted phenyl or phenyl which is substituted once or
many times by C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, halogen, cyano, hydroxyl,
C.sub.1-C.sub.3-alkoxy, amino, CHO or nitro; R.sub.2 and R.sub.3,
independently of one another, are hydrogen, C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalk- oxy, halogen,
cyano, hydroxyl, amino, aryl or nitro; R.sub.a denotes hydrogen,
unsubstituted C.sub.1-C.sub.20-alkyl or C.sub.1-C.sub.20-alkyl
which is substituted once or many times by halogen, cyano,
hydroxyl, alkoxy, nitro, phenyl, biphenyl, benzyloxy or
phenoxyphenyl, whereby each phenyl, biphenyl, benzyloxy or
phenoxyphenyl in turn is unsubstituted or substituted once or many
times by C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, C.sub.1-C.sub.3-alkoxy, halogen, cyano,
hydroxyl, amino or nitro; or it denotes C.sub.3-C.sub.8-cycloalkyl,
phenyl, biphenyl, phenoxyphenyl or heterocyclyl, whereby each of
these cyclic radicals is unsubstituted or substituted once or many
times by C.sub.1-C.sub.3-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy,
C.sub.1-C.sub.3-alkoxy, halogen, cyano, hydroxyl, amino,
(C.sub.1-C.sub.3-alkyl).sub.2N, acetyl or nitro; or it denotes
C.sub.1-C.sub.6-alkylene-aryl , whereby the aryl radical is
unsubstituted or substituted once or many times by
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, halogen, cyano, hydroxyl or nitro; or
it denotes C.sub.1-C.sub.20-alkyl which, depending on the number of
carbon atoms, is interrupted by oxygen at one or several positions;
and R.sub.b signifies hydrogen, C.sub.1-C.sub.20-alkyl,
heterocyclyl or aryl, whereby each of the cyclic radicals is
unsubstituted or substituted once or many times by
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, C.sub.2-C.sub.6-alkenyl, halogen,
cyano, hydroxyl, C.sub.1-C.sub.3-alkoxy,
amino,(C.sub.1-C.sub.3-alkyl).sub.2N, or nitro; is applied
topically, together with a spreading additive, to the skin, the
pelt or the plumage of the warm-blooded animal.
2. Process according to claim 1, whereby a compound of formula (I)
or one of its acid addition salts is applied, wherein R is hydrogen
or C.sub.1-C.sub.6alkyl; R.sub.1 is hydrogen,
C.sub.1-C.sub.6-alkyl, --C(O)--R.sub.3 or --C(S)--R.sub.4; whereby
R.sub.3 and R.sub.4 independently of one another, are
C.sub.1-C.sub.3-alkyl, acetoxy, C.sub.1-C.sub.3-haloalkyl, or
independently of one another, are unsubstituted phenyl or phenyl
which is substituted once or many times by C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl or halogen; R.sub.2 and R.sub.3
independently of one another, are hydrogen or
C.sub.1-C.sub.3-alkyl; R.sub.a is hydrogen, C.sub.5-C.sub.20-alkyl,
C.sub.3-C.sub.8-cycloalkyl or phenyl, whereby each of the cyclic
radicals is unsubstituted or is substituted once or many times by
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-alkoxy, halogen, amino,
(C.sub.1-C.sub.3-alkyl).sub.2N, or acetyl; and R.sub.b is hydrogen,
unsubstituted phenyl or phenyl which is substituted once or many
times by C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-alkoxy, halogen, amino or
(C.sub.1-C.sub.3-alkyl).sub.2N; including the acid addition salts
thereof.
3. Process according to one of claims 1 or 2, whereby a compound of
formula (I) or one of its acid addition salts is applied, wherein R
is hydrogen and the remaining substituents are defined as under
formula (I).
4. Process according to one of claims 1 to 3, whereby a compound of
formula (I) or one of its acid addition salts is applied, wherein
R.sub.1 is --C(O)--R.sub.3, whereby R.sub.3 represents
unsubstituted phenyl or phenyl which is substituted once or many
times by C.sub.1-C.sub.3-alkyl, especially methyl, ethyl or
isopropyl, and the remaining substituents are defined as in formula
(I).
5. Process according to one of claims 1 to 4, whereby a compound of
formula (I) or one of its acid addition salts is applied, wherein
R.sub.2 and R.sub.3, independently of each other, are hydrogen or
methyl and the remaining substituents are defined as under formula
(I).
6. Process according to one of claims 1 to 5, whereby a compound of
formula (I) or one of its acid addition salts is applied, wherein
R.sub.a is C.sub.5-C.sub.20-alkyl, benzoyloxymethyl,
2,3-dihydro-benzo(b)furryl-2- , unsubstituted phenyl or phenyl
which is substituted once or many times by C.sub.1-C.sub.3-alkyl,
methoxy or chlorine.
7. Process according to one of claims 1 to 6, whereby a compound of
formula (I) or one of its acid addition salts is applied, wherein
R.sub.a is a straight-chained C.sub.7-C.sub.20-alkyl.
8. Process according to claim 1, whereby the active ingredient
employed is one of the following named substances or one of their
acid addition salts. 2-[n-(1-hydroxyhexyl)]piperidine,
2-[n-(1-hydroxyheptyl)]piperidin- e, 2-[n-(1-hydroxyoctyl)]
-piperidine, 2-[n-(1-hydroxynonyl)]piperidine,
2-[n-(1-hydroxydecyl)]piperidine,
2-[n-(1-hydroxyundecyl)]piperidine,
2-[n-(1-hydroxydodecyl)]piperidine, 2-[n-(1-hydroxytridecyl)]
piperidine, 2-[n-(1-hydroxytetradecyl)]piperidine,
2-[n-(1-hydroxypentadecyl)]piperid- ine, 2-[
n-(1-hydroxyhexadecyl)]piperidine, 2-[n-(1-hydroxyheptadecyl)]pip-
eridine, 2-[n-(1-hydroxyoctadecyl)]piperidine,
2-[n-(1-hydroxynonadecyl)]p- iperidine, 2-[n-(1-hydroxyeicosyl)]
-piperidine, 2-[n-(1-hydroxyeneicosyl)- ]piperidine,
2-[(1-cyclopentyl)(1-hydroxy)methyl] piperidine,
2-[(1-phenyl)(1-hydroxy)methyl]-4-tert.butyl-piperidine,
2-[(-phenyl)(1-hydroxy)methyl]pipeidine,
N-methyl-2-[(1-phenyl)(1-hydroxy- )methyl]piperidine,
2-[(1-diphenyl)(1-hydroxy)methyl]piperidine,
2-[(1-phenyl)(1-[2,3-dihydrobenzo(b)furryl](1-hydroxy)methyl]
piperidine, N-methyl-2-[(1-[4-
methylphenyl])(1-hydroxy)methyl]piperidine,
2-[(1-[4-methylphenyl])(1-hydroxy)methyl]piperidine,
2-[(1-[4-isopropylphenyl])(1-hydroxy)methyl]piperidine,
N-methyl-2-[(1-[4-isopropylphenyl])(1-hydroxy)methyl]-piperidine,
2-[(1-[4-methoxyphenyl])(1-hydroxy)methyl]piperidine,
2-[(1-[benzyloxymethyl])(1-hydroxy)methyl] piperidine,
2-[(1-thienyl)(1-hydroxy)methyl]piperidine,
6,6-dimethyl-2-[(1-[4-chlorph- enyl])(1-hydroxy)methyl]piperidine,
N-acetyl-2-[(1-hydroxy)(1-undecyl)]pip- eridine or
N-ethoxycarbonyl-2-[(1-hydroxy)(1-undecyl)]piperidine.
9. Process according to one of claims 1 to 8, whereby the compound
of formula (I) is applied in the form of a pour-on or spot-on
formulation.
10. Process for deterring vermin from places or materials where
they are not wanted, whereby an effective amount of a compound of
formula (I) according to one of claims 1 to 8 is applied to the
place or to the material, at which one would like to deter the
insect.
11. Composition for deterring vermin, whereby it contains a
compound of formula (I) according to one of claims 1 to 8 and a
spreading additive.
12. Process for the preparation of a composition for deterring
vermin, whereby a compound of formula (I) according to one of
claims 1 to 8 is mixed with a spreading additive.
13. A compound of formula (I) selected from the group consisting of
2-[n-(1-hydroxyhexyl)]piperidine,
2-[n-(1-hydroxyheptyl)]piperidine, 2-[n-(1-hydroxyoctyl)]
-piperidine, N-acetyl-2-[(1-hydroxy)(1-undecyl)]pi- peridine and
N-ethoxycarbonyl-2-[(1-hydroxy)(1-undecyl)]piperidine.
Description
[0001] The present invention relates essentially to a
non-therapeutical process for deterring vermin, which is based on
the usage of the largely known compounds of formula (I) shown
below. Furthermore, it relates to corresponding vermin-deterring
compositions which contain these substances as the active
ingredient, to compounds of formula (I) for the preparation of
vermin-deterring compositions, and to the use of compounds of
formula (I) in the defence against vermin.
[0002] It has surprisingly been found that the compounds of formula
(I) below 2
[0003] or their acid addition salts, wherein
[0004] R is hydrogen, C.sub.1-C.sub.20-alkyl or --C(O)--R.sub.8,
whereby R.sub.8 is C.sub.1-C.sub.20-alkyl, C.sub.1-C.sub.20-alkoxy,
unsubstituted phenyl or phenyl which is substituted once or many
times by C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalk- oxy, halogen, cyano, hydroxyl, alkoxy,
amino or nitro;
[0005] R.sub.1 is hydrogen, C.sub.1-C.sub.20-alkyl,
--C(O)--R.sub.3, --C(S)--R.sub.4, C(O)--O--R.sub.5,
--C(O)--NH--R.sub.6 or --C(S)--NH--R.sub.7; whereby R.sub.3,
R.sub.4, R.sub.5, R.sub.6 and R.sub.7, independently of one
another, signify C.sub.1-C.sub.10-alkyl, acetoxy,
C.sub.1-C.sub.10-haloalkyl, C.sub.1-C.sub.10-alkoxy or
C.sub.1-C.sub.10-haloalkoxy, or independently of one another,
denote unsubstituted phenyl or phenyl which is substituted once or
many times by C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalk- oxy, halogen, cyano, hydroxyl,
C.sub.1-C.sub.3-alkoxy, amino, CHO or nitro;
[0006] R.sub.2 and R.sub.3, independently of one another, are
hydrogen, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalk- oxy, halogen, cyano, hydroxyl, amino, aryl
or nitro;
[0007] R.sub.4 denotes hydrogen, unsubstituted
C.sub.1-C.sub.20-alkyl or C.sub.1-C.sub.20-alkyl which is
substituted once or many times by halogen, cyano, hydroxyl, alkoxy,
nitro, phenyl, biphenyl, benzyloxy or phenoxyphenyl, whereby each
phenyl, biphenyl, benzyloxy or phenoxyphenyl in turn is
unsubstituted or substituted once or many times by
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalk- oxy, C.sub.1-C.sub.3-alkoxy, halogen,
cyano, hydroxyl, amino or nitro; or it denotes
C.sub.3-C.sub.8-cycloalkyl, phenyl, biphenyl, phenoxyphenyl or
heterocyclyl, whereby each of these cyclic radicals is
unsubstituted or substituted once or many times by
C.sub.1-C.sub.3-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy,
C.sub.1-C.sub.3-alkoxy, halogen, cyano, hydroxyl, amino,
(C.sub.1-C.sub.3-alkyl).sub.2N, acetyl or nitro; or it denotes
C.sub.1-C.sub.6-alkylene-aryl , whereby the aryl radical is
unsubstituted or substituted once or many times by
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, halogen, cyano, hydroxyl or nitro; or
it denotes C.sub.1-C.sub.20-alkyl which, depending on the number of
carbon atoms, is interrupted by oxygen at one or several positions;
and
[0008] R.sub.b signifies hydrogen, C.sub.1-C.sub.20-alkyl,
heterocyclyl or aryl, whereby each of the cyclic radicals is
unsubstituted or substituted once or many times by
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, C.sub.2-C.sub.6-alkenyl, halogen,
cyano, hydroxyl, C.sub.1-C.sub.3-alkoxy, amino,
(C.sub.1-C.sub.3-alkyl).sub.2N, or nitro;
[0009] are eminently suitable for deterring vermin. Through the
usage according to the invention of the above compounds, the most
varied vermin of humans, animals, objects or certain places can be
deterred, whereby numerous compounds within the scope of formula
(I) are notable for their particularly long duration of
efficacy.
[0010] Compounds of formula (I) having at least one basic centre
may form e.g. acid addition salts. These are formed for example
with strong inorganic acids, such as mineral acids, e.g. perchloric
acid, sulphuric acid, nitric acid, nitrous acid, a phosphoric acid
or a hydrohalic acid, with strong organic carboxylic acids,
typically C.sub.1-C.sub.4alkanecarb- oxylic acids substituted where
appropriate for example by halogen, e.g. acetic acid, such as
dicarboxylic acids that are unsaturated where appropriate, e.g.
oxalic, malonic, succinic, maleic, fumaric or phthalic acid,
typically hydroxycarboxylic acids, e.g. ascorbic, lactic, malic,
tartaric or citric acid, or benzoic acid, or with organic sulphonic
acids, typically C.sub.1-C.sub.4alkanesulphonic or arylsulphonic
acids substituted where appropriate for example by halogen, e.g.
methanesulphonic or p-toluenesulphonic acid. Of the salts,
particular preference is given to those formed with strong acids,
especially with mineral acids, in particular with the hydrohalic
acids HCI and HBr.
[0011] All multiple substitutions are to be interpreted such that
identical or different substituents may occur simultaneously.
[0012] The alkyl groups present in the definitions of the
substituents may be straight-chained or branched, depending on the
number of carbon atoms, and they may be for example methyl, ethyl,
propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,
dodecyl, tetradecyl, hexadecyl, octadecyl or eicosyl, as well as
the branched isomers thereof, for example isopropyl, isobutyl,
sec.-butyl, tert.-butyl, isopentyl, neopentyl or isohexyl. Alkoxy,
haloalkyl and haloalkoxy radicals are derived from the said alkyl
groups.
[0013] Halo denotes halogen and normally signifies fluorine,
chlorine, bromine or iodine, preferably fluorine or chlorine,
especially chlorine, whereby the corresponding substituent may
contain one or more identical or different halogen atoms.
[0014] Halogen-substituted carbon-containing groups, such as
haloalkyl or haloalkoxy, may be partially halogenated or
perhalogenated, whereby in the case of multiple halogenation, the
halogen substituents may be identical or different. Examples of
haloalkyl--as a group per se and as structural element of other
groups and compounds such as haloalkoxy--are methyl which is mono-
to trisubstituted by fluorine, chlorine and/or bromine, such as
CHF.sub.2 or CF.sub.3; ethyl which is mono- to pentasubstituted by
fluorine, chlorine and/or bromine, such as CH.sub.2CF.sub.3,
CF.sub.2CF.sub.3, CF.sub.2CCl.sub.3, CF.sub.2CHCl.sub.2,
CF.sub.2CHF.sub.2, CF.sub.2CFCl.sub.2, CF.sub.2CHBr.sub.2,
CF.sub.2CHClF, CF.sub.2CHBrF or CClFCHClF; propyl or isopropyl,
mono- to heptasubstituted by fluorine, chlorine and/or bromine,
such as CH.sub.2CHBrCH.sub.2Br, CF.sub.2CHFCF.sub.3,
CH.sub.2CF.sub.2CF.sub.3 or CH(CF.sub.3).sub.2; and butyl or one of
its isomers, mono- to nonasubstituted by fluorine, chlorine and/or
bromine, such as CF(CF.sub.3)CHFCF.sub.3 or
CH.sub.2(CF.sub.2).sub.2CF.sub.3.
[0015] Alkenyl--as a group per se and as structural element of
other groups and compounds such as alkeneoxy, halogenalkenyl or
halogenalkeneoxy--is, in each case with due consideration of the
specific number of carbon atoms in the group or compound in
question, either straight-chained, for example vinyl,
1-methylvinyl, allyl, 1-butenyl or 2-hexenyl, or branched, for
example isopropenyl.
[0016] Appropriate cycloalkyl substituents contain 3 to 8 carbon
atoms and are, for example, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl or cyclooctyl. Corresponding cycloalkenyl
substituents may be mono- or also repeatedly unsaturated, for
example cyclopentadienyl or cyclooctatetraenyl. Cyclopentyl and
cyclohexyl are preferred.
[0017] In the context of the present invention, aryl is understood
to be phenyl or naphthyl, especially phenyl. These aryl groups are
either unsubstituted or are substituted once or many times by
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.3-haloalkoxy, halogen, cyano,
hydroxyl, amino or nitro, whereby each multiple substitution is not
limited to identical substituents; instead, mixed substituents may
appear.
[0018] In the context of the present invention, heterocyclyl is
understood to mean aliphatic or aromatic and additionally also
benzo-condensed cyclic radicals, which contain at least one oxygen,
sulphur or nitrogen atom. Five- and six-membered heterocycles are
preferred. Heterocyclyl typically includes substituents such as
dioxolanyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl,
pyrryl, furyl, thienyl, imidazolyi, tetrahydrofuryl,
tetrahydropyrryl, tetrahydropyranyl, dihydrofuryl, dihydropyranyl,
benzofuryl, benzothienyl, isoxazolyl, oxazolyl, thiazolyl,
oxazolinyl, oxazolidinyl, indolyl, imidazolinyl, imidazolidinyl and
dioxanyl. Preference is given especially to those which are
unsubstituted or have one or two halogen atoms, halogen in this
case denoting fluorine, chlorine or bromine, but especially
chlorine. Of these heterocyclyl radicals, pyrrolidinyl,
piperidinyl, pyridyl, pyrryl, furyl, thienyl, tetrahydrofuryl,
benzofuryl and benzothienyl are especially notable.
[0019] A preferred sub-group in the context of formula (I) is
formed by compounds wherein
[0020] R is hydrogen or C.sub.1-C.sub.6alkyl;
[0021] R.sub.1 is hydrogen, C.sub.1-C.sub.6-alkyl, --C(O)--R.sub.3
or --C(S)--R.sub.4; whereby R.sub.3 and R.sub.4 independently of
one another, are C.sub.1-C.sub.3-alkyl, acetoxy,
C.sub.1-C.sub.3-haloalkyl, or independently of one another, are
unsubstituted phenyl or phenyl which is substituted once or many
times by C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl or
halogen;
[0022] R.sub.2 and R.sub.3 independently of one another, are
hydrogen or C.sub.1-C.sub.3-alkyl;
[0023] R.sub.a is hydrogen, C.sub.5-C.sub.20-alkyl,
C.sub.3-C.sub.8-cycloalkyl or phenyl, whereby each of the cyclic
radicals is unsubstituted or is substituted once or many times by
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-alkoxy, halogen, amino,
(C.sub.1-C.sub.3-alkyl).sub.2N, or acetyl; and
[0024] R.sub.b is hydrogen, unsubstituted phenyl or phenyl which is
substituted once or many times by C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-alkoxy, halogen, amino
or (C.sub.1-C.sub.3-alkyl).sub.2N; including the acid addition
salts thereof.
[0025] In the context of formula (I), the compounds which are
especially preferred are those wherein R is hydrogen and the
remaining substituents are defined as under formula (I), as well as
the acid addition salts thereof. A further sub-group, which is
preferred because of its marked activity, is formed by compounds of
formula I, wherein R.sub.1 is --C(O)--R.sub.3, whereby R.sub.3
represents unsubstituted phenyl or phenyl which is substituted once
or many times by C.sub.1-C.sub.3-alkyl, especially by methyl, ethyl
or isopropyl, and the remaining substituents are defined as under
formula (I), as well as the acid addition salts thereof. Also of
interest are the compounds of formula (I), wherein R.sub.2 and
R.sub.3 independently of one another, are the compounds of formula
(I), wherein R.sub.2 and R.sub.3 independently of one another, are
hydrogen or methyl, and the remaining substituents are defined as
under formula (I), as well as the acid addition salts thereof. Of
the above-mentioned compounds of formula (I), particular preference
is given to those in which R.sub.a is C.sub.5-C.sub.20-alkyl,
benzoyloxymethyl, 2,3-dihydrobenzo(b)furryl-2, unsubstituted phenyl
or phenyl which is substituted once or many times by
C.sub.1-C.sub.3-alkyl, methoxy or chlorine; including the acid
addition salts thereof, and in particular representatives in which
R.sub.a is a straight-chained C.sub.7-C.sub.20-alkyl; including the
acid addition salts thereof. The free active ingredients are
clearly preferred over the acid addition salts. Each representative
of the group of individual substances listed below is especially
preferred owing to its marked activity, those marked with the
asterix being new and representing a constituent of the present
invention: 2-[n-(1-hydroxyhexyl)]piperidine*,
2-[n-(1-hydroxyheptyl)]pipe- ridine*,
2-[n-(1-hydroxyoctyl)]piperidine*, 2-[n-(1-hydroxynonyl)]piperidi-
ne, 2-[n-(1-hydroxydecyl)]piperidine,
2-[n-(1-hydroxyundecyl)]piperidine,
2-[n-(1-hydroxydodecyl)]piperidine, 2-[
n-(1-hydroxytridecyl)]piperidine,
2-[n-(1-hydroxytetradecyl)]piperidine, 2-[n-(1-hydroxypentade-cyl)]
piperidine, 2-[n-(1-hydroxyhexadecyl)]piperidine,
2-[n-(1-hydroxyheptadec- yl)]piperidine,
2-[n-(1-hydroxyoctadecyl)]piperidine,
2-[n-(1-hydroxynonadecyl)]piperidine,
2-[n-(1-hydroxyeicosyl)]-piperidine- ,
2-[n-(1-hydroxyeneicosyl)]piperidine,
2-[(1-cyclopentyl)(1-hydroxy)methy- l]piperidine,
2-[(1-phenyl)(1-hydroxy)methyl]-4-tert.butyl-piperidine,
2-[(-phenyl)(1-hydroxy)methyl]pipeidine,
N-methyl-2-[(1-phenyl)(1-hydroxy- )methyl]piperidine,
2-[(1-diphenyl)(1-hydroxy)methyl]piperidine,
2-[(1-phenyl)(1-[2,3-dihydrobenzo(b)furryl](1-hydroxy)methyl]piperidine,
N-methyl-2-[(1-[4- methylphenyl] )-(1-hydroxy)methyl]piperidine,
2-[(1-[4-methylphenyl])(1-hydroxy)methyl]piperidine,
2-[(1-[4-isopropyl-phenyl])(1-hydroxy)methyl]piperidine,
N-methyl-2-[(1-[4-isopropylphenyl])(1-hydroxy)methyl] -piperidine,
2-[(1-[4-methoxyphenyl])(1-hydroxy)methyl]piperidine,
2-[(1-[benzyloxymethyl])(1-hydroxy)methyl]piperidine,
2-[(1-thienyl)(1-hydroxy)methyl]piperidine,
6,6-dimethyl-2-[(1-[4-chlorph- enyl])(1-hydroxy)methyl]piperidine,
N-acetyl-2-[(1-hydroxy)(1-undecyl)]pip- eridine* or
N-ethoxycarbonyl-2-[(1-hydroxy)(1-undecyl)]piperidine*.
[0026] Chemical Abstracts, Vol. 107, No. 23, Dec. 7, 1987,
Columbus, Ohio, US; abstract no. 215128 discloses amongst other
compounds deoxynojirimicin as a deterrent exhibiting slight
activity against certain plant damaging insects. GB-A-2,071,653
discloses compounds that are structurally related to the compounds
of the formula I of the present invention. They can be used in
marine and fresh-water environments particularly to reduce algal,
barnacle or fungal growth. EP-A-0,281,908 and EP-A-0,289,842
disclose the use of certain .alpha.,.omega.-aminoalcoh- ol
derivatives, e.g. some piperidines as insect and tick
repellents.
[0027] In the context of the present invention, vermin are
understood to be in particular insects, mites and ticks. These
include insects of the order: Lepidoptera, Coleoptera, Homoptera,
Heteroptera, Diptera, Thysanoptera, Orthoptera, Anoplura,
Siphonaptera, Mallophaga, Thysanura, Isoptera, Psocoptera and
Hymenoptera. However, the vermin which may be mentioned in
particular are those which trouble humans or animals and carry
pathogens, for example flies such as Musca domestics, Musca
vetustissima, Musca autumnalis, Fannia canicularis, Sarcophaga
camaria, Lucilia cuprina, Hypoderma bovis, Hypoderma lineatum,
Chrysomyla chloropyga, Dermatobia hominis, Cochliomyia hominivorax,
Gasterophilus intestinalis, Oestrus ovis, Stomoxys calcitrans,
Haematobia irritans and midges (Nematocera), such as Culicidae,
Simullidae, Psychodidae, but also blood-sucking vermin, for example
fleas, such as Ctenocephalides felis and Ctenocephalides canis (cat
and dog fleas), Xenopsylla cheopis, Pulex irritans, Dermatophilus
penetrans, lice, such as Damalina ovis, Pediculus humanis, biting
flies and horse-flies (Tabanidae), Haematopota spp. such as
Haematopota pluvialis, Tabanidea spp. such as Tabanus
nigrovittatus, Chrysopsinae spp. such as Chrysops caecutiens,
tsetse flies, such as species of Glossinia, biting insects,
particularly cockroaches, such as Blatella germanica, Blatta
orientalis, Periplaneta americana, mites, such as Dermanyssus
gallinae, Sarcoptes scabiei, Psoroptes ovis and Psorergates spp.
and last but not least ticks. The latter belong to the order
Acatina. Known representatives of ticks are, for example,
Boophilus, Amblyomma, Anocentor, Dermacentor, Haemaphysalis,
Hyalomma, Ixodes, Rhipicentor, Margaropus, Rhipicephalus, Argas,
Otobius and Omithodoros and the like, which preferably infest
warm-blooded animals including farm animals, such as cattle, pigs,
sheep and goats, poultry such as chickens, turkeys and geese,
fur-bearing animals such as mink, foxes, chinchillas, rabbits and
the like, as well as domestic animals such as cats and dogs, but
also humans.
[0028] Ticks may be divided into hard and soft ticks, and are
characterised by infesting one, two or three host animals. They
attach themselves to a passing host animal and suck the blood or
body fluids. Fully engorged female ticks drop from the host animal
and lay large amounts of eggs (2000 to 3000) in a suitable crack in
the floor or in any other protected site where the larvae hatch.
These in turn seek a host animal, in order to suck blood from it.
Larvae of ticks which only infest one host animal moult twice and
thus become nymphs and finally adult ticks without leaving the host
they have selected. Larvae of ticks which infest two or three host
animals leave the animal after feeding on the blood, moult in the
local environment and seek a second or third host as nymphs or as
adult ticks, in order to suck its blood. Ticks are responsible
world-wide for the transmission and spread of many human and animal
diseases. Because of their economic influence, the most important
ticks are Boophilus, Rhipicephalus, Ixodes, Hyalomma, Amblyomma and
Dermacentor. They are carriers of bacterial, viral, rickettsial and
protozoal diseases and cause tick-paralysis and tick-toxicosis.
Even a single tick can cause paralysis whereby its saliva
penetrates into the host animal during ingestion. Diseases caused
by ticks are usually transmitted by ticks, which infest several
host animals. Such diseases, for example babesiosis, anaplasmosis,
theileriasis and heart water disease, are responsible for the death
or impairment of a large number of domestic and farm animals in the
entire world. In many countries of temperate climate, Ixodide ticks
transmit the agent of the chronically harmful Lyme's disease from
wild animals to humans. Apart from the transmission of disease, the
ticks are responsible for great economic losses in livestock
production. Losses are not confined to the death of the host
animals, but also include damage to the pelts, loss of growth, a
reduction in milk production and reduced value of the meat.
Although the harmful effects of a tick infestation on animals have
been known for years, and enormous progress has been made using
tick-control programmes, until now no completely satisfactory
methods of controlling or eliminating these parasites have been
found, and in addition, ticks have often developed resistance to
chemical active ingredients.
[0029] The infestation of fleas on domestic animals and pets
likewise still represents for the owner a problem which has not
been satisfactorily resolved or can only be resolved at
considerable expense. As with ticks, fleas are not only
troublesome, but are carriers of disease, and transmit various
fungal diseases from host animal to host animal and to the animal
keeper, particularly in moist, warm climatic areas, for example in
the Mediterranean, in the southern part of USA, etc. Those at risk
in particular are people with a weakened immune system or children
whose immune system has not yet fully developed. Owing to their
complex life cycle, none of the known methods for the control of
fleas is completely satisfactory, especially as most known methods
are basically directed towards the control of adult fleas in the
pelt, and leave completely untouched the different juvenile stages
of the fleas, which exist not only in the pelt of the animal, but
also on the floor, in carpets, in the bedding of the animal, on
chairs, in the garden and all other places with which the infested
animal comes into contact. Flea treatment is usually expensive and
has to be continued over long periods of time. Success usually
depends on treating not only the infested animal, e.g. the dog or
cat, but at the same time all the locations which the infested
animal frequents.
[0030] Such a complicated procedure is unnecessary with the present
compounds of formula (I), since a particular advantage of the
compounds of formula (I) under discussion is that they are
extremely effective and at the same time of very low toxicity both
for the target parasites and for the warm-blooded animals. This is
because their activity is based not on the death of the target
parasite, but on the parrying defence thereof, before it attacks,
sting, bites or in any other way harms the host organism. The
presence of the compounds of formula (I) being discussed here
appears to disturb the parasites in such a way that they suddenly
leave the treated environment without biting or stinging, or even
do not infest a treated host animal at all. What is striking is
that the effect sets in when the parasite comes into contact with
the active ingredient for a short time. After contact for a short
time, the parasite avoids any further contact with the active
ingredient. An additional advantage lies in the long-term action,
e.g. compared with DEET (N,N-diethyl-m-toluamide- ), which although
very effective, volatilizes rather rapidly and therefore has to be
reapplied already after ca. 2 hours, and is thus not appropriate
for the long-term treatment of animals. Usage of the present active
ingredients is also pleasant because they are almost odourless.
[0031] Although the present active ingredients can of course be
mixed with other substances having the same sphere of activity or
with parasiticides or with other activity-improving substances to
achieve further improved or longer-lasting action, and then
applied, in contrast to many compounds of the prior art, this is
totally unnecessary, as they already combine all the advantageous
properties.
[0032] If the parasite is not only to be kept at bay, but also
killed, of course this can be achieved by adding appropriate
insecticides and/or acaricides. In practice, however, this is
unnecessary in most cases.
[0033] The present active ingredients are preferably used in
diluted form. Normally, they are brought to the final application
form by using appropriate formulation excipients, and they then
contain between 0.1 and 95% by weight, preferably 0.5 to 90% by
weight of the active ingredient.
[0034] Since the active ingredients are in many instances applied
to warm-blooded animals and of course come into contact with the
skin, suitable formulation excipients are the excipients and
administration forms that are known in cosmetics. They may be
administered in the form of solutions, emulsions, ointments,
creams, pastes, powders, sprays, etc.
[0035] For administration to farm animals or pets, such as cows,
horses, asses, camels, dogs, cats, poultry, sheep, goats, etc., the
so-called `pour-on` or `spot-on` formulations are especially
suitable; these liquid or semi-liquid formulations have the
advantage that they only have to be applied to a small area of the
pelt or plumage, and, thanks to the proportion of spreading oils or
other spreading additives, they disperse by themselves over the
whole pelt or plumage, without having to do anything else, and
become active over the whole area.
[0036] Of course, inanimate materials, for example clothing or dog
and cat baskets, stables, carpets, curtains, living quarters,
conservatories, etc. may be treated with said formulations and thus
protected from parasite infestation.
[0037] To control cockroaches, their locus, usually cracks in the
walls, furniture, etc., can be sprayed or powdered. Since
cockroaches are extremely vigorous and it is almost impossible to
drive them away completely, it is recommended that when using the
present active ingredients, insecticides having activity against
cockroaches are used additionally.
[0038] For application on humans, a pleasant-smelling essence, e.g.
a perfume, can be added to make application more attractive.
[0039] The following examples of preparation and usage of the
active ingredients according to the invention serve to illustrate
the invention without restricting it. In particular, preferred
formulations are made up as follows:
FORMULATION EXAMPLE 1
[0040] A vermin-deterring composition in the form of a lotion for
application to the skin is prepared by mixing 30 parts of one of
the active ingredients according to the invention from Table 1, 1.5
parts of perfume and 68.5 parts of isopropanol, whereby the latter
may be replaced by ethanol.
FORMULATION EXAMPLE 2
[0041] A vermin-deterring composition in the form of an aerosol for
spraying onto the pelt of a pet is prepared by formulating 50%
active ingredient solution, consisting of 30 parts of one of the
active ingredients according to the invention from Table 1, 1.5
parts of perfume and 68.5 parts of isopropanol, with 50% Frigen
11/12 (a halogenated hydrocarbon) as propellant gas in an aerosol
can.
FORMULATION EXAMPLE 3
[0042] A vermin-deterring composition in the form of an aerosol for
spraying onto the skin is prepared by formulating 40% active
ingredient solution, consisting of 20 parts of one of the active
ingredients according to the invention, 1 part of perfume, 79 parts
of isopropanol, with 60% propane/butane (in a ratio of 15:85) as
propellant gas in an aerosol can.
[0043] By way of example, the following Tables reproduce a few of
the compounds included under formula (I) which can be used
according to the invention, but do not claim to be a total list.
The substances shown in italics are new and are part of the present
invention. The remaining substances, including their preparation
processes, are known from literature. The subsequent preparation
example merely serves to exemplify and relates to one particularly
preferred substance. Most of these known substances are used in
human medicine for various illnesses, for example as
bronchodilators, anti-allergic agents, analgesics, diuretics,
antidepressants, dopamine-antagonists, etc. Some are attributed
with having herbicidal or fungicidal activity. The new
representatives within the scope of formula (I), shown in italics
in Table 1 below, may be prepared analogously to the known
substances. In column "R", the representatives having an acid in
round parenthesis are the corresponding acid addition salts.
Preparation Example:Preparation of 2-(n-decylhydroxy)piperidine in
accordance with the following reaction scheme:
[0044] 3
[0045] A mixture of bromomagnesium decane (0.31 mols) in 350 ml of
dry diethyl ether is mixed dropwise at 25.degree. C. with a
solution of 2-cyanopyridine (0.3 mols) in 250 ml of dry ethyl
ether. The reaction mixture is heated for 2 hours under reflux,
then cooled to 10.degree. C. and mixed with aqueous sulphuric acid
(70 ml water/200 ml 5N H.sub.2SO.sub.4). The reaction product is
extracted with diethyl ether. The ether phase is washed repeatedly
with saturated sodium chloride solution, dried over magnesium
sulphate, filtered and concentrated in a vacuum. 72.5 g of compound
B (97.7% yield) are obtained as an oil, which is used for the next
stage without further purification. In this stage, a mixture of 4.6
g of compound B and 0.25 g of PTO.sub.2 in 45 ml of acetic acid is
mixed with elementary hydrogen for hydrogenation at room
temperature. After 17 hours, all solid constituents are filtered
and the liquid phase is mixed with 2-normal caustic soda solution.
Extraction with dichloroethane follows next. The organic phase is
washed repeatedly with saturated sodium chloride solution, dried
over magnesium sulphate, filtered and concentrated in a vacuum. The
residue is mixed with methanol, whereby the title compound
precipitates as an amorphous powder. After filtration and drying in
a vacuum, 2.8 g (62% yield) of the title substance are obtained
with a m.p. of 61-63.degree. C.
[0046] In the following Table, Ac is acetyl, AcO is acetyloxy, Me
is methyl, MeO is methoxy, Et is ethyl, EtO is ethoxy, P is propyl,
PO is propoxy, nP is n-propyl, iP is iso-propyl, B is butyl, nB is
n-butyl, iB is iso-butyl, sB is sec.-butyl, tB is tert.-butyl, Ph
is phenyl; Bz is benzyl, cPro is cyclopropyl, cBu is cyclobutyl,
cPen is cyclopentyl, cHex is cyclohexyl, cHep is cycloheptyl, cOc
is cyclooctyl, and me is methylene.
1TABLE 1 Compounds of formula (I) No. R.sub.1 R.sub.2 R.sub.3
R.sub.a R.sub.b R 1.01 H H H Me H H 1.02 H H H Me 2-Me-indolyl H
1.03 H 3-Me H Me H H 1.04 H 5-Me H Me H H 1.05 H H H Me 1-Me-indol-
H 2-yl 1.06 H 6-Me H Me H H 1.07 H H H Et H H 1.08 6-Me H H Et H H
1.09 5-Me H H Et H H 1.10 H H H nP H H 1.11 H H H iP H H 1.12 6-Me
H H iP H H 1.13 5-Et H H iP H H 1.14 H H H nB H H 1.15 H H H iB H H
1.16 H H H 4-Et-cHex H H 1.17 H H H 4-Et-cHex H H (HCl) 1.18 H H H
1-Me-3-iP- Ph H cPen 1.19 H H H 4-Me-cPen Ph H 1.20 H H H 4-Me-cPen
Ph H (HCl) 1.21 H H H cPen H 1.22 H H H -(me).sub.4-Me H H 1.23 H H
H -(me).sub.5-Me H H 1.24 H H H -(me).sub.6-Me H H 1.25 H H H
-(me).sub.7-Me H H 1.26 H H H -(me).sub.8-Me H H 1.27 H H H
-(me).sub.9-Me H H 1.28 H H H -(me).sub.10-Me H H 1.29 H H H
-(me).sub.11-Me H H 1.30 H 2-(me).sub.4- -(me).sub.11Me H H 1.31 H
H H -(me).sub.12-Me H H 1.32 H H H -(me).sub.13-Me H H 1.33 H H H
-(me).sub.14-Me H H 1.34 H H H -(me).sub.15-Me H H 1.35 H H H
-(me).sub.16-Me H H 1.36 H H H -(me).sub.17-Me H H 1.37 H H H
-(me).sub.18-Me H H 1.38 H H H -(me).sub.19-Me H H 1.39 H H H
-(me).sub.20-Me H H 1.40 H H H Ph H H 1.41 H 4-Me H Ph H H 1.42 H
6-Me H Ph H H 1.43 H 3-Me H Ph H H 1.44 H H H Ph H H (HCl) 1.45 Me
H H Ph H H (HCl) 1.46 H 4-tB H Ph H H 1.47 H 4-Et H Ph H H 1.48 H
4-Et H Ph H H (HCl) 1.49 2,4,6-tri-iP- H H Ph H H Ph-CO- 1.50 H H H
Ph Ph H 1.51 H H H Ph Ph H (HCl) 1.52 H 4-Me H Ph Ph H 1.53 H 4-Me
H Ph Ph H (HCl) 1.54 H 6-Me H Ph Ph H 1.55 H 6-Me H Ph Ph H (HCl)
1.56 3,5-diMePh- H H Ph H H CO- 1.57 H H H Ph 2-piperidinyl H (HCl)
1.58 3,5-diMePh- H H Ph 2-piperidinyl H CO- 1.59 H H H Ph
2,3-dihydro- H (HCl) benzo(b)- furryl 1.60 H H H Ph thienyl H (HCl)
1.49 H 4-diphenyl- H Ph Ph H (HCl) hydroxymeth yl- 1.61
2,4,6-tri-iP- H H Ph Ph H Ph-CO- 1.62 2,4,6-tri-iP- tB H Ph Ph H
Ph-CO- 1.63 H H H 2-Me-Ph Ph H 1.64 H H H 2-Me-Ph Ph H (HCl) 1.65 H
H H 3-Me-Ph Ph H 1.66 H H H 3-Me-Ph Ph H (HCl) 1.67 H H H 4-Me-Ph
Ph H 1.68 H H H 4-Et-Ph Ph H 1.69 H H H 4-Et-Ph Ph H (HCl) 1.70 H H
H 4-EtO-Ph Ph H 1.71 H H H 4-EtO-Ph Ph H (HCl) 1.72 H H H
2,4,6-tri-Me- Ph H Ph 1.73 H H H 2,4,6-tri-Me- Ph H Ph 1.74 H H H
2,5-di-MeO- Ph H Ph 1.75 H H H 2,5-di-MeO- Ph H (HCl) Ph 1.76 H H H
3,4,5-tri- Ph H (HCl) MeO-Ph 1.77 H H H 2-OH-Ph H H (HCl) 1.78 H H
H 2-Me-Ph H H 1.79 H H H 2-Me-Ph H H (HCl) 1.80 H H H 3-OH-Ph H H
(HCl) 1.81 H H H 3-F-Ph H H 1.82 H H H 3-Cl-Ph H H 1.83 H 6-Me 6-Me
3-Cl-Ph H H (HCl) 1.84 H 6-Me 6-Me 3-Cl-Ph H H (HCl) 1.85 H H H
3-MeO-Ph H H 1.86 H H H 4-OH-Ph H H (HCl) 1.87 Me H H 4-Me-Ph H H
(HCl) 1.88 H H H 4-Me-Ph H H 1.89 H H H 4-Me-Ph H H (HCl) 1.90 H H
H 4-MeO-Ph H H 1.91 H H H 4-MeO-Ph H H (HCl) 1.92 H H H 4-EtO-Ph H
H 1.93 H H H 4-EtO-Ph H H (HCl) 1.94 H H H 4-Me.sub.2N-Ph H H 1.95
H H H 4-iP-Ph H H (HCl) 1.96 Me H H 4-iP-Ph H H (HCl) 1.97 H H H
4-MeO-Ph H H (HCl) 1.98 H H H 4-F-Ph H H 1.99 H H H 4-Cl-Ph H H
1.100 H H H 4-Cl-Ph 2-piperidinyl H (HCl) 1.101 H 6-Me 6-Me 4-Cl-Ph
H H (HCl) 1.102 H H H 4-CF.sub.3-Ph H H 1.103 H H H 4-F-Ph
2-piperidinyl H 1.104 H H H 6-Me-Ph H H 1.105 H H H 6-MeO-Ph H H
1.106 6-Me H H 6-MeO-Ph H H 1.107 6-Me H H 3,4-di-OH- H H (HCl) PH
1.108 5-Me H H 3,4-di-OH- H H (HCl) PH 1.109 2,4,6-tri-iP- H H Ph H
H Ph-CO- 1.110 4-Me H H 3,4-di-OH- H H (HBr) PH 1.111 H H H
3,4-di-Me-Ph H H H H H 3,4-di-Me-Ph H H (HCl) 1.112 H H H
3,4-di-MeO- H H Ph 1.113 H H H 3,4-di-MeO- H H (HCl) Ph 1.114 H
6-Me 6-Me 3,4-di-Cl-Ph H H 1.115 H 6-Me 6-Me 3,4-di-Cl-Ph H H (HCl)
1.116 H H H 2,5-di-MeO- H H Ph 1.117 H H H 3,4-di-OH-5- H H Me-Ph
1.118 H H H 3-MeO-4- H H OH-Ph 1.119 6-Me H H 3,4-di OH-Ph H H
(HBr) 1.120 H H 3-NH.sub.2-4-OH- H H (HBr) Ph 1.121 H H H
3-Cl-4-NH.sub.2- H H Ph 1.122 H H H 3-Cl-4-Ac-Ph H H (HCl) 1.123 H
H H 3-MeO-4- H H (HCl) OH-Ph 1.124 H H H 2-Me-3,4-di- H H (HCl)
OH-Ph 1.125 H H H 2-Me-3,4-di- H H (HBr) OH-Ph 1.126 H H H 2-Me-Ph
2-Me-Ph H 1.127 H H H 2-Me-Ph 2-Me-Ph H (HCl) 1.128 H H H 4-Me-Ph
4-Me-Ph H 1.129 H H H 4-Me-Ph 4-Me-Ph H (HCl) 1.130 H 4-Me H
4-Me-Ph 4-Me-Ph H 1.131 H H H 4-MeO-Ph 4-MeO-Ph H 1.131 H H H
4-MeO-Ph 4-MeO-Ph H (HCl) 1.133 H H H 4-Me.sub.2N-Ph 4-Me.sub.2N-Ph
H 1.134 H H H 4-Me.sub.2N-Ph 4-Me.sub.2N-Ph H (HCl) 1.135 H H H
4-EtO-Ph 4-EtO-Ph H 1.136 H H H 4-EtO-Ph 4-EtO-Ph H (HCl) 1.137 H H
H CH.sub.2OBz H H 1.138 H H H thienyl thienyl H 1.139 H 6-Me 6-Me
4-Cl-Ph H H 1.140 Me-CO H H -(me).sub.9-Me H H 1.141 Et-O-CO H H
-(me).sub.9-Me H H 1.142 MeHN-CS H H -(me).sub.9-Me H H 1.143
EtHN-CO H H -(me).sub.9-Me H H
Biological Examples
[0047] Arena test method for testing vermin-deterring
substances
[0048] This method is carried out in titre plates having 6 wells
with a cross-section of 5 cm each, using a computer-supported video
system. Each well of the titre plate is lined with a circular
filter paper or another suitable carrier material. The substance of
formula I to be tested is dissolved in methanol, acetonitrile or
another suitable solvent, with ultrasound treatment and heating
being employed for poorly-soluble substances. In an amount of 1 to
100 .mu.g/cm.sup.2, the dissolved test substance is placed in the
centre of the filter paper on a quadrant or circular area of ca.
2.4 cm.sup.2 radius. 4 of the 6 wells are filled with different
test substances or with the same test substance in different
dilutions (e.g. 1, 3.2, 5, 10 and 20 .mu.g/cm.sup.2). The 5th well
is treated with DEET (N,N-diethyl-m-toluamide) as standard
substance. The 6th well is filled with the pure solvent and serves
as a control. 60 to 100 larvae or 25 to 50 nymphs or 10 to 25
adults of the parasite to be tested, e.g. ticks, are added to each
filter paper, and the system is covered with a pane of glass and
positioned under a video camera.
[0049] At intervals of 5 seconds, the video camera takes individual
pictures of all 6 wells. For a qualitative evaluation, these images
are observed in a time-lapse as a continuous film, optically
following the movements of the parasites on the filter paper and
comparing them with the movements in the control well no. 6 or with
the standard in the 5th well. A qualitative observation is thus
made as to whether the test parasites move evenly over the whole
surface of the filter paper and ignore the test substance, or
whether and over what period they avoid the treated zone, and what
influence the dilution of the test substance has on the behaviour
of the test parasites. In this way, neutral and deterring
substances are determined. At the same time, the duration of
activity of the test substance is determined and compared with that
of the standard. By plotting all the images for each individual
well over one another, different areas of density are obtained.
This represents the frequency at which the parasites visit certain
places. This frequency is evaluated statistically and thus
quantitatively by the Willcoxon method in a comparison with the
control and with the standard. Compounds of Table 1, for example
nos. 1.22 to 1.41, 1.44, 1.45, 1.59, 1.87, 1.89, 1.95, 1.96, 1.97,
1.101, 1.137, 1.138 and 1.139, display excellent activity.
[0050] Arena test in vitro against Amblyomma hebraeum or variepatum
(nymphs)
[0051] The test is carried out as described above, with ca. 25 to
50 nymphs being added per well. 10 mg of dissolved test substance
is applied to an area of 2.4 cm.sup.2 radius. An evaluation of the
video images shows that the compounds of formula I display marked
deterrent action against Amblyomma nymphs, which lasts considerably
longer than that of DEET. Particularly marked long-term activity is
shown for example by compounds nos. 1.26 to 1.36, 1.40, 1.45, 1.47,
1.95, 1.96, 1.97, 1.137, and 1.139, even up to a dilution of 3.2
.mu.g/cm.sup.2.
[0052] Arena test in vitro against Boophilus microolus Biarra
(larvae)
[0053] The test is carried out as described above, with ca. 60 to
100 larvae being added per well. 10 mg of dissolved test substance
is applied to an area of 2.4 cm.sup.2 radius. An evaluation of the
video images shows that the compounds of formula I display marked
deterring action against Bophilus larvae, which lasts considerably
longer than that of DEET. Particularly marked long-term activity is
shown for example by compounds nos.1.26 to 1.36, 1.40, 1.45, 1.47,
1.95, 1.96, 1.97, 1.137, 1.139, 1.140, 1.141, 1.142 and 1.143 even
up to a dilution of 10 .mu.g/cm.sup.2.
[0054] Arena test in vitro against Rhipicephalus sanguineus
(nymphs)
[0055] A test is carried out analogously to example B using ca. 40
to 50 nymphs. An evaluation of the video images shows that the
compounds according to the invention display good deterring action.
In particular, the compounds are notable for their almost complete
deterring action, which lasts considerably longer than that of
DEET. Particularly marked long-term activity is shown for example
by compounds nos. 1.27, 1.29, 1.32, 1.34, 1.36, 1.40, 1.45, 1.59,
1.96, 1.137, and 1.139, even up to a dilution of 10
.mu.g/cm.sup.2.
[0056] In analogous test set-ups, the same test substances are
tested for their attractant activity to various species of fly,
such as Musca domestics. It is shown that the substances mentioned
above display strong deterring action even with these tested
models.
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