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Claims  |
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What is claimed is:
1. A pharmaceutical composition useful for the treatment of and prophylaxis
against coccidiosis in humans and animals which comprises a
therapeutically effective amount of a compound of the formula:
##SPC14##
or a pharmaceutically acceptable nontoxic salt thereof wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7 r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, straight or branched chain lower alkyl, halo lower
alkyl, lower alkoxy, halo lower alkoxy, lower alkylthio, halo lower
alkylthio, halogen, nitro, cyano, amino, lower alkanoylamino, lower
alkoxycarbonylamino, carboxy, lower alkoxycarbonyl, carbamoyl, lower
alkanoyl, halo lower alkanoyl, lower alkylsulphinyl, lower alkylsulphonyl,
halo lower alkylsulphonyl, and sulphamoyl;
R.sub.10 is hydrogen, straight or branched chain lower alkyl, cycloalkyl of
3 to 7 carbon atoms, halo lower alkyl, lower alkoxy, lower alkoxy lower
alkyl, halo lower alkoxy lower alkyl, lower alkylthio lower alkyl, halo
lower alkylthio lower alkyl, lower alkenyl, lower alkynyl, lower
alkoxycarbonyl, (lower alkylthio)carbonyl, (lower alkylthio)thiocarbonyl,
lower alkanoylamino, succinimido, phthalimido, amino, dilower alkylamino,
benzyl, phenyl, or benzyl or phenyl substituted by halogen;
R.sub.11 is hydrogen or lower alkyl;
X is sulphur, sulphinyl or sulphonyl; and
Y is oxygen or sulphur; in combination with a pharmaceutically acceptable
nontoxic inert diluent or carrier.
2. A composition according to claim 1 wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon
atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms,
trifluoromethyl, chlorine, bromine, nitro, cyano, amino, alkamoylamino of
1 to 4 carbon atoms, alkoxycarbonylamino of 1 to 4 carbon atoms in the
alkoxy moiety, carboxy, alkoxycarbonyl of 1 to 4 carbon atoms in the
alkoxy moiety, haloalkoxy of 1 to 4 carbon atoms in the alkoxy moiety,
haloalkylthio of 1 to 4 carbon atoms in the alkyl moiety, carbamoyl,
alkanoyl of 1 to 5 carbon atoms, haloalkanoyl of 1 to 4 carbon atoms,
alkylsulphonyl of 1 to 4 carbon atoms, and haloalkylsulphonyl of 1 to 4
carbon atoms;
R.sub.10 is hydrogen, straight chain alkyl of 1 to 12 carbon atoms,
branched chain alkyl of 3 to 5 carbon atoms, .omega.-chloroalkyl of 1 to 6
carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 6 carbon
atoms, haloalkoxyalkyl of 2 to 6 carbon atoms, alkenyl of 2 to 4 carbon
atoms, alkynyl of 2 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon
atoms, (alkylthio)carbonyl of 1 to 4 carbon atoms, dialkylamino wherein
the alkyl groups are the same and each alkyl group is of 1 to 4 carbon
atoms, alkanoylamino of 1 to 5 carbon atoms, dilower alkanoylamino,
polymethyleneimino, polymethyleneimino interrupted by oxygen, phenyl or
halophenyl.
3. A composition according to claim 1 wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2
carbon atoms, alkylthio of 1 or 2 carbon atoms, trifluoromethyl, chlorine,
bromine, nitro, cyano, amino, alkanoylamino of 1 or 2 carbon atoms,
alkoxycarbonylamino of 1 or 2 carbon atoms, carboxy, alkoxycarbonyl of 1
or 2 carbon atoms, trifluoromethoxy, trifluoromethylthio, carbonyl,
alkanoyl of 1 or 2 carbon atoms, trifluoroacetyl, alkylsulphonyl of 1 or 2
carbon atoms, and trifluoromethylsulphonyl; and
R.sub.10 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 or 2 carbon
atoms, alkoxyalkyl of 2 to 4 carbon atoms, trifluoromethoxymethyl, alkynyl
of 2 or 3 carbon atoms, alkoxycarbonyl of 1 or 2 carbon atoms,
(alkylthio)carbonyl of 1 or 2 carbon atoms, dimethylamino, diethylamino,
phthalimido, succinimido, phenyl, chlorophenyl, or bromophenyl.
4. A composition according to claim 1 wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2
carbon atoms, chlorine, bromine, nitro, cyano, trifluoromethyl,
alkoxycarbonylamino of 1 or 2 carbon atoms, alkanoylamino of 1 to 2 carbon
atoms, alkylsulphonyl of 1 or 2 carbon atoms and trifluoromethylsulphonyl;
R.sub.10 is alkyl of 1 to 4 carbon atoms, amino or phthalimido; and
R.sub.11 is hydrogen.
5. A composition according to claim 4 wherein
Y is oxygen.
6. A composition according to claim 1 wherein
R.sub.1, r.sub.4, r.sub.9 and R.sub.11 are each hydrogen;
R.sub.2 is hydrogen, alkyl of 1 or 2 carbon atoms, chlorine or bromine;
R.sub.3 is hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2 carbon
atoms, chlorine or bromine;
R.sub.5 is alkyl of 1 or 2 carbon atoms, chlorine, bromine, nitro, cyano,
trifluoromethyl, alkoxy, carbonylamino of 1 or 2 carbon atoms,
alkanoylamino of 1 or 2 carbon atoms, alkylsulphonyl of 1 or 2 carbon
atoms, or trifluoromethylsulphonyl;
R.sub.6 is hydrogen, alkyl of 1 or 2 carbon atoms, chlorine, or bromine;
R.sub.7 is hydrogen or alkyl of 1 or 2 carbon atoms;
R.sub.8 is hydrogen, alkyl of 1 or 2 carbon atoms, chlorine, or bromine;
R.sub.10 is alkyl of 1 to 4 carbon atoms, amino, or phthalimido; and
Y is oxygen.
7. A composition according to claim 1 wherein
R.sub.1 is hydrogen;
R.sub.2 is hydrogen, methyl, or chlorine;
R.sub.3 is hydrogen, methyl, methoxy, or chlorine;
R.sub.4 is hydrogen;
R.sub.5 is methyl, chlorine, nitro, cyano, trifluoromethyl,
ethoxycarbonylamino, acetamido, methylsulphonyl, or
trifluoromethylsulphonyl;
R.sub.6 is hydrogen, methyl, or chlorine;
R.sub.7 is hydrogen, or methyl;
R.sub.8 is hydrogen, methyl, or chlorine;
R.sub.9 is hydrogen;
R.sub.10 is methyl, ethyl, propyl, butyl, amino, or phthalimido;
R.sub.11 is hydrogen; and
Y is oxygen.
8. A composition according to claim 1 wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 or 2
carbon atoms, chlorine, bromine, nitro, cyano, trifluoromethyl,
trifluoromethoxy, alkanoylamino of 1 or 2 carbon atoms,
alkoxycarbonylamino of 1 or 2 carbon atoms, alkanoyl of 1 or 2 carbon
atoms, or alkylsulphonyl of 1 or 2 carbon atoms;
R.sub.10 is hydrogen, straight or branched chain alkyl of 1 to 4 carbon
atoms, alkenyl of 2 or 3 carbon atoms, alkoxyalkyl of 2 to 5 carbon atoms,
alkoxy of 1 or 2 carbon atoms, or phthalimido; and
R.sub.11 is hydrogen, or alkyl of 1 to 3 carbon atoms.
9. A composition according to claim 1 wherein
R.sub.1 is hydrogen, or alkyl of 1 or 2 carbon atoms;
R.sub.2 is hydrogen, alkyl of 1 or 2 carbon atoms, chlorine, or bromine;
R.sub.3 is hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2 carbon
atoms, chlorine, or bromine;
R.sub.4 is hydrogen, alkoxy of 1 or 2 carbon atoms, or cyano;
R.sub.5 is hydrogen, straight or branched chain alkyl of 1 to 4 carbon
atoms, chlorine, bromine, nitro, cyano, trifluoromethyl, trifluoromethoxy,
alkanoylamino of 1 or 2 carbon atoms, alkoxycarbonyl of 1 or 2 carbon
atoms, alkanoyl of 1 to 2 carbon atoms, or alkylsulphonyl of 1 or 2 carbon
atoms;
R.sub.6 is hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2 carbon
atoms, chlorine, bromine, or trifluoromethyl;
R.sub.7 is hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2 carbon
atoms, chlorine, or bromine;
R.sub.8 is hydrogen, alkyl of 1 to or 2 carbon atoms, chlorine, or bromine;
R.sub.9 is hydrogen;
R.sub.10 is hydrogen, straight or branched chain alkyl of 1 to 4 carbon
atoms, alkenyl of 2 or 3 carbon atoms, alkoxyalkyl of 2 to 5 carbon atoms,
alkoxy of 1 or 2 carbon atoms, or phthalimido; and
R.sub.11 is hydrogen, or alkyl of 1 to 3 carbon atoms.
10. A composition according to claim 1 wherein
R.sub.1 is hydrogen, or methyl;
R.sub.2 is hydrogen, methyl, or chlorine;
R.sub.3 is hydrogen, methyl, ethyl, methoxy, or chlorine;
R.sub.4 is hydrogen, ethoxy, or cyano;
R.sub.5 is hydrogen, methyl, tert.-butyl, chlorine, bromine, nitro, cyano,
trifluoromethyl, trifluoromethoxy, acetamido, ethoxycarbonylamino, acetyl,
or methylsulphonyl;
R.sub.6 is hydrogen, methyl, methoxy, chlorine, or trifluoromethyl;
R.sub.7 is hydrogen, methyl, methoxy, or chlorine;
R.sub.8 is hydrogen, methyl, or chlorine;
R.sub.9 is hydrogen;
R.sub.10 is hydrogen, methyl, ethyl, n-propyl, i-propyl, tert.-butyl,
allyl, methoxyethyl, methoxypropyl, ethoxypropyl, methoxy, ethoxy, or
phthalimido; and
R.sub.11 is hydrogen, or propyl.
11. The composition according to claim 1 wherein the compound is
1-[4-(4'-ethoxycarbonylamino-phenylthio)-phenyl]-3-methyl-1,3,5-triazine-2
,4,6(1H,3H,5H)-trione.
12. The composition according to claim 1 wherein the compound is
1-[4-(4'-nitrophenylthio)-phenyl]-3-methyl-1,3,5-triazine-2,4,6(1H,3H,5H)-
trione.
13. The composition according to claim 1 wherein the compound is
1-[4-(4'-nitrophenylthio)-phenyl]-3-ethyl-1,3,5,-triazine-2,4,6(1H,3H,5H)-
trione.
14. The composition according to claim 1 wherein the compound is
1-[4-(4'-nitrophenylthio)-phenyl]-3-propyl-1,3,5-triazine-2,4,6(1H,3H,5H)-
trione.
15. The composition according to claim 1 wherein the compound is
1-[4-(4'-cyanophenylthio)-phenyl]-3-methyl-1,3,5-triazine-2,4,6(1H,3H,5H)-
trione.
16. The composition according to claim 1 wherein the compound is
1-[4-(4'-chlorophenylsulphonyl)-phenyl]-3-methyl-1,3,5-triazine-2,4,6(1H,3
H,5H)-trione.
17. A composition according to claim 1 in oral administration form.
18. A composition according to claim 1 in parenteral administration form.
19. A composition according to claim 1 in topical application form.
20. An animal feedstuff which comprises 25 to 5,000 ppm of a compound of
the formula:
##SPC15##
or a pharmaceutically acceptable nontoxic salt thereof
wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, straight or branched chain lower alkyl, halo lower
alkyl, lower alkoxy, halo lower alkoxy, lower alkylthio, halo lower
alkylthio, halogen, nitro, cyano, amino, lower alkanoylamino, lower
alkoxycarbonylamino, carboxy, lower alkoxycarbonyl, carbamoyl, lower
alkanoyl, halo lower alkanoyl, lower alkylsulphinyl, lower alkylsulphonyl,
halo lower alkylsulphonyl, and sulphamoyl;
R.sub.10 is hydrogen, straight or branched chain lower alkyl, cycloalkyl of
3 to 7 carbon atoms, halo lower alkyl, lower alkoxy, lower alkoxy lower
alkyl, halo lower alkoxy lower alkyl, lower alkylthio lower alkyl, halo
lower alkylthio lower alkyl, lower alkenyl, lower alkynyl, lower
alkoxycarbonyl, (lower alkylthio)carbonyl, (lower alkylthio)thiocarbonyl,
lower alkanoylamino, succinimido, phthalimido, amino, dilower alkylamino,
benzyl, phenyl, or benzyl or phenyl substituted by halogen;
R.sub.11 is hydrogen or lower alkyl;
X is sulphur, sulphinyl or sulphonyl; and
Y is oxygen or sulphur;
in combination with an edible nutritious material.
21. A feedstuff according to claim 20 wherein the compound is present in an
amount of 50 to 250 ppm.
22. Coccidiocidal drinking water for animals which comprises 25 to 5,000
ppm of a compound of the formula:
##SPC16##
or a pharmaceutically acceptable nontoxic salt thereof
wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, straight or branched chain lower alkyl, halo lower
alkyl, lower alkoxy, halo lower alkoxy, lower alkylthio, halo lower
alkylthio, halogen, nitro, cyano, amino, lower alkanoylamino, lower
alkoxycarbonylamino, carboxy, lower alkoxycarbonyl, carbamoyl, lower
alkanoyl, halo lower alkanoyl, lower alkylsulphinyl, lower alkylsulphonyl,
halo lower alkylsulphonyl, and sulphamoyl;
R.sub.10 is hydrogen, straight or branched chain lower alkyl, cycloalkyl of
3 to 7 carbon atoms, halo lower alkyl, lower alkoxy, lower alkoxy lower
alkyl, halo lower alkoxy lower alkyl, lower alkylthio lower alkyl, halo
lower alkylthio lower alkyl, lower alkenyl, lower alkynyl, lower
alkoxycarbonyl, (lower alkylthio)carbonyl, (lower alkylthio)thiocarbonyl,
lower alkanoylamino, succinimido, phthalimido, amino, dilower alkylamino,
benzyl, phenyl, or benzyl or phenyl substituted by halogen;
R.sub.11 is hydrogen or lower alkyl;
X is sulphur, sulphinyl or sulphonyl; and
Y is oxygen or sulphur;
dissolved in water suitable for drinking by animals.
23. An animal concentrate or premix which comprises 1 to 30% by weight of a
compound of the formula:
##SPC17##
or a pharmaceutically acceptable nontoxic salt thereof
wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, straight or branched chain lower alkyl, halo lower
alkyl, lower alkoxy, halo lower alkoxy, lower alkylthio, halo lower
alkylthio, halogen, nitro, cyano, amino, lower alkanoylamino, lower
alkoxycarbonylamino, carboxy, lower alkoxycarbonyl, carbamoyl, lower
alkanoyl, halo lower alkanoyl, lower alkylsulphinyl, lower alkylsulphonyl,
halo lower alkylsulphonyl, and sulphamoyl;
R.sub.10 is hydrogen, straight or branched chain lower alkyl, cycloalkyl of
3 to 7 carbon atoms, halo lower alkyl, lower alkoxy, lower alkoxy lower
alkyl, halo lower alkoxy lower alkyl, lower alkylthio lower alkyl, halo
lower alkylthio lower alkyl, lower alkenyl, lower alkynyl, lower
alkoxycarbonyl, (lower alkylthio)carbonyl, (lower alkylthio)thiocarbonyl,
lower alkanoylamino, succinimido, phthalimido, amino, dilower alkylamino,
benzyl, phenyl, or benzyl or phenyl substituted by halogen;
R.sub.11 is hydrogen or lower alkyl;
X is sulphur, sulphinyl or sulphonyl; and
Y is oxygen or sulphur;
in combination with an edible organic or inorganic carrier.
24. A concentrate or premix according to claim 23 wherein the compound is
present in the amount of 10 to 20% by weight.
25. A method of treating coccidiosis or effecting prophylaxis against
coccidiosis in humans and animals which comprises administering to such
human or animal an effective amount of a compound of the formula:
##SPC18##
or a pharmaceutically acceptable nontoxic salt thereof
wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, straight or branched chain lower alkyl, halo lower
alkyl, lower alkoxy, halo lower alkoxy, lower alkylthio, halo lower
alkylthio, halogen, nitro, cyano, amino, lower alkanoylamino, lower
alkoxycarbonylamino, carboxy, lower alkoxycarbonyl, carbamoyl, lower
alkanoyl, halo lower alkanoyl, lower alkylsulphinyl, lower alkylsulphonyl,
halo lower alkylsulphonyl, and sulphamoyl;
R.sub.10 is hydrogen, straight or branched chain lower alkyl, cycloalkyl of
3 to 7 carbon atoms, halo lower alkyl, lower alkoxy, lower alkoxy lower
alkyl, halo lower alkoxy lower alkyl, lower alkylthio lower alkyl, halo
lower alkylthio lower alkyl, lower alkenyl, lower alkynyl, lower
alkoxycarbonyl, (lower alkylthio)carbonyl, (lower alkylthio)thiocarbonyl,
lower alkanoylamino, succinimido, phthalimido, amino, dilower alkylamino,
benzyl, phenyl, or benzyl or phenyl substituted by halogen;
R.sub.11 is hydrogen or lower alkyl;
X is sulphur, sulphinyl or sulphonyl; and
Y is oxygen or sulphur.
26. A method according to claim 25 wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon
atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms,
trifluoromethyl, chlorine, bromine, nitro, cyano, amino, alkanoylamino of
1 to 4 carbon atoms, alkoxycarbonylamino of 1 to 4 carbon atoms in the
alkoxy moiety, carboxy, alkoxycarbonyl of 1 to 4 carbon atoms in the
alkoxy moiety, haloalkoxy of 1 to 4 carbon atoms in the alkoxy moiety,
haloalkylthio of 1 to 4 carbon atoms in the alkyl moiety, carbamoyl,
alkanoyl of 1 to 5 carbon atoms, halo alkanoyl of 1 to 4 carbon atoms,
alkylsulphonyl of 1 to 4 carbon atoms and haloalkylsulphonyl of 1 to 4
carbon atoms;
R.sub.10 is hydrogen, straight chain alkyl of 1 to 12 carbon atoms,
branched chain alkyl of 3 to 5 carbon atoms, -chloroalkyl of 1 to 6 carbon
atoms, alkoxy of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 6 carbon atoms,
haloalkoxyalkyl of 2 to 6 carbon atoms, alkenyl of 2 to 4 carbon atoms,
alkynyl of 2 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms,
(alkylthio)carbonyl of 1 to 4 carbon atoms, dialkylamino wherein the alkyl
groups are the same and each alkyl group is of 1 to 4 carbon atoms,
alkanoylamino of 1 to 5 carbon atoms, succinimido, phthalimido, phenyl or
halophenyl.
27. A method according to claim 25 wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2
carbon atoms, alkylthio of 1 or 2 carbon atoms, trifluoromethyl, chlorine,
bromine, nitro, cyano, amino, alkanoylamino of 1 or 2 carbon atoms,
alkoxycarbonylamino of 1 or 2 carbon atoms, carboxy, alkoxycarbonyl of 1
or 2 carbon atoms, trifluoromethoxy, trifluoromethylthio, carbonyl,
alkanoyl of 1 or 2 carbon atoms, trifluoroacetyl, alkylsulphonyl of 1 or 2
carbon atoms, and trifluoromethylsulphonyl; and
R.sub.10 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 or 2 carbon
atoms, alkoxyalkyl of 2 to 4 carbon atoms, trifluoromethoxymethyl, alkynyl
of 2 or 3 carbon atoms, alkoxycarbonyl of 1 or 2 carbon atoms,
(alkylthio)carbonyl of 1 or 2 carbon atoms, dimethylamino, diethylamino,
phthalimido, succinimido, phenyl, chlorophenyl, or bromophenyl.
28. A method according to claim 25 wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2
carbon atoms, chlorine, bromine, nitro, cyano, trifluoromethyl,
alkoxycarbonylamino of 1 or 2 carbon atoms, alkanoylamino of 1 or 2 carbon
atoms, alkylsulphonyl of 1 or 2 carbon atoms and trifluoromethylsulphonyl;
R.sub.10 is alkyl of 1 to 4 carbon atoms, amino or phthalimido; and
R.sub.11 is hydrogen.
29. A method according to claim 28 wherein Y is oxygen.
30. A method according to claim 25 wherein
R.sub.1, r.sub.4, r.sub.9 and R.sub.11 are each hydrogen;
R.sub.2 is hydrogen, alkyl of 1 or 2 carbon atoms, chlorine or bromine;
R.sub.3 is hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2 carbon
atoms, chlorine or bromine;
R.sub.5 is alkyl of 1 or 2 carbon atoms, chlorine, bromine, nitro, cyano,
trifluoromethyl, alkoxy, carbonylamino of 1 or 2 carbon atoms,
alkanoylamino of 1 or 2 carbon atoms, alkylsulphonyl of 1 or 2 carbon
atoms, or trifluoromethylsulphonyl;
R.sub.6 is hydrogen, alkyl of 1 or 2 carbon atoms, chlorine, or bromine;
R.sub.7 is hydrogen or alkyl of 1 or 2 carbon atoms;
R.sub.8 is hydrogen, alkyl of 1 or 2 carbon atoms, chlorine, or bromine;
R.sub.10 is alkyl of 1 to 4 carbon atoms, amino, or phthalimido; and
Y is oxygen.
31. A method according to claim 25 wherein
R.sub.1 is hydrogen;
R.sub.2 is hydrogen, methyl, or chlorine;
R.sub.3 is hydrogen, methyl, methoxy, or chlorine;
R.sub.4 is hydrogen;
R.sub.5 is methyl, chlorine, nitro, cyano, trifluoromethyl,
ethoxycarbonylamino, acetamido, methylsulphonyl, or
trifluoromethylsulphonyl;
R.sub.6 is hydrogen, methyl, or chlorine;
R.sub.7 is hydrogen, or methyl;
R.sub.8 is hydrogen, methyl, or chlorine;
R.sub.9 is hydrogen;
R.sub.10 is methyl, ethyl, propyl, butyl, amino, or phthalimido;
R.sub.11 is hydrogen; and
Y is oxygen.
32. A method according to claim 25 wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 or 2
carbon atoms, chlorine, bromine, nitro, cyano, trifluoromethyl,
trifluoromethoxy, acylamino of 1 or 2 carbon atoms, alkoxycarbonylamino of
1 or 2 carbon atoms, alkanoyl of 1 or 2 carbon atoms, or alkylsulphonyl of
1 or 2 carbon atoms;
R.sub.10 is hydrogen, straight or branched chain alkyl of 1 to 4 carbon
atoms, alkenyl of 2 or 3 carbon atoms, alkoxyalkyl of 2 to 5 carbon atoms,
alkoxy of 1 or 2 carbon atoms, or phthalimido; and
R.sub.11 is hydrogen, or alkyl of 1 to 3 carbon atoms.
33. A method according to claim 25 wherein
R.sub.1 is hydrogen, or alkyl of 1 or 2 carbon atoms;
R.sub.2 is hydrogen, alkyl of 1 or 2 carbon atoms, chlorine, or bromine;
R.sub.3 is hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2 carbon
atoms, chlorine, or bromine;
R.sub.4 is hydrogen, alkoxy of 1 or 2 carbon atoms, or cyano;
R.sub.5 is hydrogen, straight or branched chain alkyl of 1 to 4 carbon
atoms, chlorine, bromine, nitro, cyano, trifluoromethyl, trifluoromethoxy,
acylamino of 1 or 2 carbon atoms, alkoxycarbonyl of 1 or 2 carbon atoms,
alkanoyl of 1 or 2 carbon atoms, or alkylsulphonyl of 1 or 2 carbon atoms;
R.sub.6 is hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2 carbon
atoms, chlorine, bromine, or trifluoromethyl;
R.sub.7 is hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2 carbon
atoms, chlorine, or bromine;
R.sub.8 is hydrogen, alkyl of 1 or 2 carbon atoms, chlorine, or bromine;
R.sub.9 is hydrogen;
R.sub.10 is hydrogen, straight or branched chain alkyl of 1 to 4 carbon
atoms, alkenyl of 2 or 3 carbon atoms, alkoxyalkyl of 2 to 5 carbon atoms,
alkoxy of 1 or 2 carbon atoms, or phthalimido; and
R.sub.11 is hydrogen, or alkyl of 1 to 3 carbon atoms.
34. A method according to claim 25 wherein
R.sub.1 is hydrogen, or methyl;
R.sub.2 is hydrogen, methyl, or chlorine;
R.sub.3 is hydrogen, methyl, ethyl, methoxy, or chlorine;
R.sub.4 is hydrogen, ethoxy, or cyano;
R.sub.5 is hydrogen, methyl, tert.-butyl, chlorine, bromine, nitro, cyano,
trifluoromethyl, trifluoromethoxy, acetamido, ethoxycarbonylamino, acetyl,
or methylsulphonyl;
R.sub.6 is hydrogen, methyl, methoxy, chlorine, or trifluoromethyl;
R.sub.7 is hydrogen, methyl, methoxy, or chlorine;
R.sub.8 is hydrogen, methyl, or chlorine;
R.sub.9 is hydrogen;
R.sub.10 is hydrogen, methyl, ethyl, n-propyl, i-propyl, tert.-butyl,
allyl, methoxyethyl, methoxypropyl, ethoxypropyl, methoxy, ethoxy, or
phthalimido; and
R.sub.11 is hydrogen, or propyl.
35. The method according to claim 25 wherein the compound is
1-[4-(4'-ethoxycarbonylamino-phenylthio)-phenyl]-3-methyl-1,3,5-triazine-2
,4,6(1H,3H,5H)-trione.
36. The method according to claim 25 wherein the compound is
1-[4-(4'-nitro-phenylthio)-phenyl]-3-methyl-1,3,5-triazine-2,4,6(1H,3H,5H)
-trione.
37. The method according to claim 25 wherein the compound is
1-[4-(4'-nitro-phenylthio)-phenyl]-3-ethyl-1,3,5-triazine-2,4,6-(1H,3H,5H)
-trione.
38. The method according to claim 25 wherein the compound is
1-[4-(4'-nitro-phenylthio)-phenyl]-3-propyl-1,3,5-triazine-2,4,6(1H,3H,5H)
-trione.
39. The method according to claim 25 wherein the compound is
1-[4-(4'-cyano-phenylthio)-phenyl]-3-methyl-1,3,5-triazine-2,4,6-(1H,3H,5H
)-trione.
40. The method according to claim 25 wherein the compound is
1-([4-(4'-chloro-phenylsulphonyl)-phenyl]-3-methyl-1,3,5-triazine-2,4,6-(1
H,3H,5H)-trione.
41. A method according to claim 25 wherein the administration is oral.
42. A method according to claim 25 wherein the administration is
parenteral.
43. A method according to claim 25 wherein the administration is by topical
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Claims |
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Description |
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The present invention relates to 1-phenyl-substituted 1,3,5-triazines,
processes for their production, pharmaceutical compositions wherein said
triazines are the active ingredient, and methods of treating coccidiosis
in humans and animals which comprises utilizing said compound as the
active agent.
It is known in the art that 2-(4-phenylthio-phenyl)-,
2-(4-phenylsulphinyl-phenyl)- and
2-(4-phenylsulphonyl-phenyl)-1,2,4-triazine-3,5(2H,4H)-diones possess a
coccidiostatic action See e.g., Belgian Patent Nos. 740,403 and 773,583
dealing with 2-phenyl-as-triazine-3,5-(2H,4H)-diones and the use of these
compounds for combatting coccidiosis.
Those compounds, however, are known only for their activity against poultry
coccidiosis and they exhibit only coccidiostatic activity.
More particularly, the present invention is concerned with
1-phenyl-substituted 1,3,5-triazines of the formula:
##SPC2##
Or pharmaceutically acceptable nontoxic salts thereof
Wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, straight or branched chain alkyl, haloalkyl,
alkoxy, haloalkoxy, alkylthio, haloalkylthio, halogen, nitro, cyano,
amino, acylamino, alkoxycarbonylamino, carboxy, alkoxycarbonyl, carbamoyl,
acyl, haloacyl, alkylsulphinyl, alkylsulphonyl, haloalkylsulphonyl and
sulphamoyl;
R.sub.10 is hydrogen, straight or branched chain alkyl, cycloalkyl,
haloalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, alkylthioalkyl,
haloalkylthioalkyl, alkenyl, alkinyl, alkoxycarbonyl, (alkylthio)carbonyl,
(alkylthio)thiocarbonyl, acylamino, diacylamino, amino, dialkylamino,
polymethyleneimino, polymethyleneimino interrupted by a heteroatom in the
chain, or unsubstituted or substituted benzyl or aryl;
R.sub.11 is hydrogen, or alkyl;
X is sulphur, sulphinyl, or sulphonyl; and
Y is oxygen or sulphur.
These compounds are active against protozoa and have particular activity
against coccidiosis both in humans, mammals generally, and poultry in
particular.
The compounds of the present invention may be produced by (a) reacting a
compound of the formula:
##SPC3##
wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r7, r.sub.8, r.sub.9,
x and Y are as above defined; and
R'.sub.10 is hydrogen, straight or branched chain lower alkyl, cycloalkyl
of alkyl, to 7 carbon atoms, halo lower alkyl lower alkoxy, lower alkoxy
lower alkyl, halo lower alkoxy lower alkyl, lower alkylthio lower alkyl,
halo lower alkylthio lower alkyl, lower alkenyl, lower alkinyl, lower
alkoxycarbonyl, (lower alkylthio)carbonyl, (lower alkylthio)thiocarbonyl,
lower acylamino, dilower acylamino, dilower alkylamino,
polymethyleneimino, polymethyleneimino interrupted by a heteroatom,
benzyl, monoaryl, or benzyl or monoaryl substituted by halogen,
with a carbonylisocyanate of the formula:
##EQU1##
wherein R.sub.12 is halogen, lower alkoxy, or monoaryloxy, to produce a
1,3,5-triazine of the formula:
##SPC4##
wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8,
r.sub.9, r'.sub.10, x and Y are as above defined,
and if desired reacting said 1,3,5-triazine with an alkylating agent of the
formula:
(A).sub.n Z (V)
wherein
A is alkyl;
n is 1, 2 or 3; and
Z is a moiety which easily forms an anion and which together with the acid
hydrogen of the imino group of the 1,3,5-triazine forms the moiety
(H).sub.n Z wherein n and Z are as above defined;
(b) converting a compound of the formula:
##SPC5##
wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8,
r.sub.9, r.sub.10 and R.sub.11 are as above defined:
X is sulphur; and
Y is oxygen,
by reaction with the appropriate amount of an oxidizing agent into a
compound of the formula:
##SPC6##
wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8,
r.sub.9, r.sub.10 and R.sub.11 are as above defined; and
B is SO or SO.sub.2 ; or
(c) converting a compound of the formula:
##SPC7##
wherein
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8,
r.sub.9, r.sub.11, x and Y are as above defined; and
R".sub.10 is acylamino or dilower acylamino.
According to process (c) above, the acyl moiety is split off and compounds
of formula I wherein R.sub.10 is amino are thus produced.
The method by which compounds of formula I, which are used as starting
materials according to process (c) above, can specifically be converted
into the corresponding amino compounds merely comprises the application of
techniques per se known from the literature and thus any suitable
conversion method may be utilized.
The compounds of the present invention and their pharmaceutically
acceptable nontoxic salts can be interconverted in any suitable manner
according to techniques which are per se known.
The compounds of the present invention are particularly useful because they
exhibit a far better activity against poultry coccidium E. tenella than do
commercially available substances which are known such as
3,5-dinitrotoluylamide,
1-[(4-amino-2-propyl-5-pyrimidinyl)-methyl]-2-picolinium chloride
hydrochloride, 3,5-dichloro-2,6-dimethylpyridone-4 and the complex
obtained from 4,4'-di-(nitrophenyl)urea and
4,6-dimethyl-2-hydroxy-pyrimidine.
In addition, the compounds of the present invention are active as indicated
above both against poultry coccidiosis and against mammalian coccidiosis,
and thus the compounds of the present invention exhibit a broad spectrum
of activity which is not shown by commercially available compounds.
If N-[4-(4'-nitro-phenylthio)-phenyl]-N'-methylurea and
chlorocarbonylisocyanate are used as starting substances and methyl iodide
is used as the alkylating agent, the course of the reaction can be
represented by the following equation:
##SPC8##
According to one embodiment of the present invention:
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon
atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms,
trifluoromethyl, chlorine, bromine, nitro, cyano, amino, acylamino of 1 to
4 carbon atoms, alkoxycarbonylamino of 1 to 4 carbon atoms in the alkoxy
moiety, carboxy, alkoxycarbonyl of 1 to 4 carbon atoms in the alkoxy
moiety, haloalkoxy of 1 to 4 carbon atoms in the alkoxy moiety,
haloalkylthio of 1 to 4 carbon atoms in the alkyl moiety, carbamoyl, acyl
of 1 to 5 carbon atoms, haloacyl of 1 to 4 carbon atoms, alkylsulphonyl of
1 to 4 carbon atoms, and haloalkylsulphonyl of 1 to 4 carbon atoms;
R.sub.10 is hydrogen, straight chain alkyl of 1 to 12 carbon atoms,
branched chain alkyl of 3 to 5 carbon atoms, .omega.-chloroalkyl of 1 to 6
carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 6 carbon
atoms, haloalkoxyalkyl of 2 to 6 carbon atoms, alkenyl of 2 to 4 carbon
atoms, alkynyl of 2 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon
atoms, (alkylthio)carbonyl of 1 to 4 carbon atoms, dialkylamino wherein
the alkyl groups are the same and each alkyl group is of 1 to 4 carbon
atoms, acylamino of 1 to 5 carbon atoms, dilower acylamino,
polymethyleneimino, polymethyleneimino interrupted by oxygen, phenyl or
halophenyl.
According to another embodiment of the present invention:
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2
carbon atoms, alkylthio of 1 or 2 carbon atoms, trifluoromethyl, chlorine,
bromine, nitro, cyano, amino, acylamino of 1 or 2 carbon atoms,
alkoxycarbonylamino of 1 or 2 carbon atoms, carboxy, alkoxycarbonyl of 1
or 2 carbon atoms, trifluoromethoxy, trifluoromethylthio, carbamoyl, acyl
of 1 or 2 carbon atoms, trifluoroacetyl, alkylsulphonyl of 1 or 2 carbon
atoms, and trifluoromethylsulphonyl; and
R.sub.10 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 or 2 carbon
atoms, alkoxyalkyl of 2 to 4 carbon atoms, trifluoromethoxymethyl, alkinyl
of 2 or 3 carbon atoms, alkoxycarbonyl of 1 to 2 carbon atoms,
(alkylthio)carbonyl of 1 or 2 carbon atoms, dimethylamino, diethylamino,
phthalimido, succinimido, phenyl, chlorophenyl, or bromophenyl.
According to another embodiment of the present invention:
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2
carbon atoms, chlorine, bromine, nitro, cyano, trifluoromethyl,
alkoxycarbonylamino of 1 or 2 carbon atoms, acylamino of 1 or 2 carbon
atoms, alkylsulphonyl of 1 or 2 carbon atoms and trifluoromethylsulphonyl;
R.sub.10 is alkyl of 1 to 4 carbon atoms, amino or phthalimido; and
R.sub.11 is hydrogen.
According to another embodiment of the present invention:
Y is oxygen.
According to another embodiment of the present invention:
R.sub.1, r.sub.4, r.sub.9 and R.sub.11 are each hydrogen;
R.sub.2 is hydrogen, alkyl of 1 or 2 carbon atoms, chlorine or bromine;
R.sub.3 is hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2 carbon
atoms, chlorine or bromine;
R.sub.5 is alkyl of 1 or 2 carbon atoms, chlorine, bromine, nitro, cyano,
trifluoromethyl, alkoxy, carbonylamino of 1 or 2 carbon atoms, acylamino
of 1 or 2 carbon atoms, alkylsulphonyl of 1 or 2 carbon atoms, or
trifluoromethylsulphonyl;
R.sub.6 is hydrogen, alkyl of 1 or 2 carbon atoms, chlorine, or bromine;
R.sub.7 is hydrogen or alkyl of 1 or 2 carbon atoms;
R.sub.8 is hydrogen, alkyl of 1 or 2 carbon atoms, chlorine, or bromine;
R.sub.10 is alkyl of 1 to 4 carbon atoms, amino, or phthalimido; and
Y is oxygen.
According to another embodiment of the present invention:
R.sub.1 is hydrogen;
R.sub.2 is hydrogen, methyl, or chlorine;
R.sub.3 is hydrogen, methyl, methoxy, or chlorine;
R.sub.4 is hydrogen;
R.sub.5 is methyl, chlorine, nitro, cyano, trifluoromethyl,
ethoxycarbonylamino, acetamido, methylsulphonyl, or
trifluoromethylsulphonyl;
R.sub.6 is hydrogen, methyl, or chlorine;
R.sub.7 is hydrogen, or methyl;
R.sub.8 is hydrogen, methyl, or chlorine;
R.sub.9 is hydrogen;
R.sub.10 is methyl, ethyl, propyl, butyl, amino, or phthalimido;
R.sub.11 is hydrogen; and
Y is oxygen.
According to another embodiment of the present invention:
R.sub.1, r.sub.2, r.sub.3, r.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and
R.sub.9 are the same or different and each is selected from the group
consisting of hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 or 2
carbon atoms, chlorine, bromine, nitro, cyano, trifluoromethyl,
trifluoromethoxy, acylamino of 1 or 2 carbon atoms, alkoxycarbonylamino of
1 or 2 carbon atoms, acyl of 1 or 2 carbon atoms, or alkylsulphonyl of 1
or 2 carbon atoms;
R.sub.10 is hydrogen, straight or branched chain alkyl of 1 to 4 carbon
atoms, alkenyl of 2 or 3 carbon atoms, alkoxyalkyl of 2 to 5 carbon atoms,
alkoxy of 1 or 2 carbon atoms, or phthalimido; and
R.sub.11 is hydrogen, or alkyl of 1 to 3 carbon atoms.
According to another embodiment of the present invention:
R.sub.1 is hydrogen, or alkyl of 1 or 2 carbon atoms;
R.sub.2 is hydrogen, alkyl of 1 or 2 carbon atoms, chlorine, or bromine;
R.sub.3 is hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2 carbon
atoms, chlorine, or bromine;
R.sub.4 is hydrogen, alkoxy of 1 or 2 carbon atoms, or cyano;
R.sub.5 is hydrogen, straight or branched chain alkyl of 1 to 4 carbon
atoms, chlorine, bromine, nitro, cyano, trifluoromethyl, trifluoromethoxy,
acylamino of 1 or 2 carbon atoms, alkoxycarbonyl of 1 or 2 carbon atoms,
acyl of 1 or 2 carbon atoms, or alkylsulphonyl of 1 or 2 carbon atoms;
R.sub.6 is hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2 carbon
atoms, chlorine, bromine, or trifluoromethyl;
R.sub.7 is hydrogen, alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2 carbon
atoms, chlorine, or bromine;
R.sub.8 is hydrogen, alkyl of 1 or 2 carbon atoms, chlorine, or bromine;
R.sub.9 is hydrogen;
R.sub.10 is hydrogen, straight or branched chain alkyl of 1 to 4 carbon
atoms, alkenyl of 2 or 3 carbon atoms, alkoxyalkyl of 2 to 5 carbon atoms,
alkoxy of 1 to 2 carbon atoms, or phthalimido; and
R.sub.11 is hydrogen, or alkyl of 1 to 3 carbon atoms.
According to another embodiment of the present invention:
R.sub.1 is hydrogen, or methyl;
R.sub.2 is hydrogen, methyl, or chlorine;
R.sub.3 is hydrogen, methyl, ethyl, methoxy, or chlorine;
R.sub.4 is hydrogen, ethoxy, or cyano;
R.sub.5 is hydrogen, methyl, tert.-butyl, chlorine, bromine, nitro, cyano,
trifluoromethyl, trifluoromethoxy, acetamido, ethoxycarbonylamino, acetyl,
or methylsulphonyl;
R.sub.6 is hydrogen, methyl, methoxy, chlorine, or trifluoromethyl;
R.sub.7 is hydrogen, methyl, methoxy, or chlorine;
R.sub.8 is hydrogen, methyl, or chlorine;
R.sub.9 is hydrogen;
R.sub.10 is hydrogen, methyl, ethyl, n-propyl, i-propyl, tert-butyl, allyl,
methoxyethyl, methoxypropyl, ethoxypropyl, methoxy, ethoxy, or
phthalimino; and
R.sub.11 is hydrogen, or propyl.
R.sub.12 is preferably chlorine, methoxy or phenoxy;
Z is preferably halogen, especially chlorine, bromine or iodine, or
SO.sub.4 ; and
A is preferably alkyl of 1 to 4 carbon atoms.
According to the process above set forth,
R'.sub.10 is preferably hydrogen, straight chain alkyl of 1 to 12 carbon
atoms, branched chain alkyl of 3 to 5 carbon atoms, .omega.-chloroalkyl of
1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 6
carbon atoms, haloalkoxyalkyl of 2 to 6 carbon atoms, alkenyl of 2 to 4
carbon atoms, alkinyl of 2 to 4 carbon atoms, alkoxycarbonyl of 1 to 4
carbon atoms, (alkylthio)carbonyl of 1 to 4 carbon atoms, dialkylamino
wherein the alkyl groups are the same and each alkyl group is of 1 to 4
carbon atoms, acylamino of 1 to 5 carbon atoms, dilower acylamino,
polymethyleneimino, polymethyleneimino interrupted by oxygen, phenyl, or
halophenyl.
According to another embodiment of the above described process,
R'.sub.10 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 or 2
carbon atoms, alkoxyalkyl of 2 to 4 carbon atoms, trifluoromethoxymethyl,
alkenyl of 2 or 3 carbon atoms, alkoxycarbonyl of 1 or 2 carbon atoms,
(alkylthio)carbonyl of 1 or 2 carbon atoms, dimethylamino, diethylamino,
phthalimido, succinimido, phenyl, chlorophenyl or bromophenyl.
According to another embodiment of the above described process,
R'.sub.10 is alkyl of 1 to 4 carbon atoms, or phthalimido.
According to another embodiment of the above described process,
R'.sub.10 is methyl, ethyl, propyl, butyl, or phthalimido.
According to another embodiment of the above described process,
R'.sub.10 is hydrogen, straight or branched chain alkyl of 1 to 4 carbon
atoms, alkenyl of 2 to 3 carbon atoms, alkoxyalkyl of 2 to 5 carbon atoms,
alkoxy of 1 or 2 carbon atoms, or phthalimido.
According to another embodiment of the above described process,
R'.sub.10 is hydrogen, methyl, ethyl, n-propyl, i-propyl, tert.-butyl,
allyl, methoxyethyl, methoxypropyl, ethoxypropyl, methoxy, ethoxy, or
phthalimido.
According to another embodiment of the above described process, when
R".sub.10 is acylamino, it is preferably lower acylamino, especially
acylamino of 1 to 4 carbon atoms and particularly of 1 to 2 carbon atoms.
The substituted ureas or thioureas of the formula II above which are used
as starting materials for producing the compounds of the present invention
are not per se known but can be prepared according to techniques which are
themselves per se known by either:
a. reacting substituted 4-aminodiphenyl-thioethers, -sulphoxides or
-sulphones with the appropriate substituted isocyanates or isothiocyanates
in inert organic solvents, if necessary in the presence of tertiary bases
such as triethylamine, pyridine or several others, at temperatures between
0.degree.C and 100.degree.C; or, reversing the sequence, by
b. reacting substituted amines with the appropriately substituted
4-isocyanato- or 4-isothiocyanato-diphenylthioethers, -sulphoxides or
-sulphones under the same conditions.
If the amount of solvent is suitably chosen, the reaction products as a
rule crystallize out on cooling the solution. Details of the preparation
of ureas by interaction of amines and isocyanates are to be found in
"Methoden der Org. Chemie" (Methods of Organic Chemistry) (Houben-Weyl),
4th edition, volume VIII, pages 157-158.
Representative compounds of formula II above which may be used according to
the process of the present invention include:
N-[4-(2',4',6'-trimethyl-phenylthio)-phenyl]-N'-methyl-urea,
N-[4-(2',4'-dichloro-phenylthio)-3,5-dimethyl-phenyl]-N' -methyl-urea,
N-[3,5-dichloro-4-(2'-chloro-4'-trifluoromethyl-phenylthio)-phenyl]-N'-ethy
l-urea,
N-[3,5-dichloro-4-(4'-methylsulphonyl-phenylthio)-phenyl]-N'-methyl-urea,
N-[4-(4'-trifluoromethylsulphonyl-phenylthio)-phenyl]-N' -ethyl-urea,
N-[3,5-dichloro-4(4'-trifluoromethylsulphonyl-phenylthio)-phenyl]-N'-methyl
-urea,
N-[4-(4'-chloro-phenylsulphinyl)-phenyl]-N'-methyl-urea,
N-[4-(4'-chloro-phenylsulphinyl)-phenyl]-N'-ethyl-urea,
N-[4-(4'-chloro-phenylsulphinyl)-phenyl]-N'-propyl-urea,
N-[4-(5'-chloro-2'-methoxy-phenylsulphinyl)-3,5-dimethylphenyl]-N'-ethyl-ur
ea,
N-[3,5-dichloro-4-(5'-chloro-2'-methyl-phenylsulphinyl)-phenyl]-N'-methyl-u
rea,
N-[3,5-dichloro-4-(2'-methoxy-5'-methyl-phenylsulphinyl)-phenyl]-N'-methyl-
urea,
N-[3-chloro-4-(4'-chloro-phenylsulphinyl)-5-methyl-phenyl]-N'-ethyl-urea,
N-[4-(2'-chloro-6'-methyl-4'-nitro-phenylsulphinyl)-phenyl] -N'-ethyl-urea,
N-[4-(4'-methyl-phenylsulphinyl)-phenyl]-N'-ethyl-urea,
N-[4-(4'-nitro-phenylsulphinyl)-phenyl]-N'-propyl-urea,
N-[3,5-dichloro-4-(5'-chloro-2'-methoxy-phenylsulphonyl)-phenyl]-N'-methyl-
urea,
N-[4-(5'-chloro-2'-methoxy-phenylsulphonyl)-3,5-dimethylphenyl]-N'-ethyl-ur
ea,
N-[3,5-dichloro-4-(5'-chloro-2'-methyl-phenylsulphonyl)-phenyl]-N'-methyl-u
rea,
N-[3,5-dichloro-4-(2'-methoxy-5'-methyl-phenylsulphonyl)-phenyl]-N'-methyl-
urea,
N-[4-(2'-chloro-6'-methyl-4'-nitro-phenylsulphonyl)-phenyl]-N'-ethyl-urea,
N-[3-chloro-4-(4'-chloro-phenylsulphonyl)-5-methyl-phenyl]-N'-ethyl-urea,
N-[4-(4'-nitro-phenylsulphinyl)-phenyl]-N' -phthalimido-urea,
N-[4-(4'-nitro-phenylsulphonyl)-phenyl]-N'-phthalimido-urea,
N-[3,5-dichloro-4-(4'-trifluoromethyl-phenylsulphonyl)-phenyl]-N'-methyl-ur
ea,
N-[4-(4'-trifluoromethylsulphonyl-phenylsulphonyl)-phenyl]-N'-ethyl-urea,
N-[3,5-dichloro-4-(4'-trifluoromethylsulphonyl-phenylsulphonyl)-phenyl]-N'
-methyl-urea and
N-[4-(4'-acetamido-phenylthio)-phenyl]-N'-ethyl-urea.
As diluents in process (a) and in process (b) according to the invention it
is possible to use any organic solvents which are inert towards this
reaction. These include, in addition to pyridine, preferably aromatic
hydrocarbons such as benzene, toluene or xylene, halogenated aromatic
hydrocarbons such as chlorobenzene and dichlorobenzene, and ethers such as
tetrahydrofurane and dioxane.
The hydrochloric acid produced in the reaction (a) (if R.sub.12 = Cl) is
evolved as a gas or can be bound by organic or inorganic acid acceptors.
Preferred acid acceptors include tertiary organic bases such as
triethylamine, pyridine, and inorganic bases such as alkali metal
carbonates or alkaline earth metal carbonates.
For both the above mentioned reaction steps, the reaction temperatures can
be varied within a substantial range. In general, the reaction is carried
out at between about 0.degree.C and about 150.degree.C, preferably between
20.degree.C and 100.degree.C.
According to the above reactions, the pressure is generally atmospheric but
elevated pressure may also be used. Atmospheric pressure is generally used
however.
In carrying out the process according to the invention, the substances
participating in the reaction are employed in molar amounts.
The following can optionally be employed as oxidizing agents in process
(b): H.sub.2 O.sub.2 /glacial acetic acid, H.sub.2 O.sub.2 /acetic
anhydride, per-acids (for example, m-chloroperbenzoic acid), chromic acid
and potassium permanganate.
The following compounds are representative of those of the present
invent | | |
