CA2071566A1 - 6(7)-amino-substituted quinoline-5,8-quinones for combating endoparasites, new 6(7)-amino-substituted quinoline-5,8-quinones and processes for their preparation - Google Patents

Abstract

Use of 6(7)-amino-substituted quinoline-5,8-quinones for combating endoparasites, new 6(7)-amino-substituted quinoline-5,8-quinones and processes for their preparation A b s t r a c t The present invention relates to the use of 6(7)-amino-substituted quinoline-5,8-quinones of the general formula (I) (I) in which R1 represents substituted C1-C6-alkyl or optionally substituted cycloalkylalkyl, cycloalkyl, aralkyl or aryl, substituents which may be mentioned being halogen, nitro, alkyl, alkylamino, aminoacyl, aryl, aryloxy, arylthio, aralkyl, halogenoalkyl, alkoxy, halogenoalkoxy, alkylthio, halogenoalkylthio, alkylsulphinyl, halogenoalkylsulphinyl, alkyl-sulphonyl or halogenoalkylsulphonyl, R2 represents hydrogen or alkyl, or R1 and R2, together with the adjacent N atom, represent a carbocyclic Le A 28 421 5-, 6- or 7-membered ring, which can optionally also be interrupted by O, N or S and is optionally substituted by C1-4-alkyl, R3 represents halogen or -S-R4 and R4 represents alkyl, for combating endoparasites in medicine and veterinary medicine, and to new 6(7)-amino-substituted quinoline-5,8-quinones and their preparation.

Le A 28 421

Description

2~7~66 The present invention relates to the use of 6(7)-amino-substituted quinoline-5,8-quinones for combating endo-parasites, new 6(7)-amino-substituted quinoline-5,8-quinones and processes for their preparation.

6(7)-Amino-substituted quinoline-5,8-quinones are already known. ~owever, nothinq is known of their use against endoparasites (compare DE-OS (German Published Specifica-tion) 2,136,037; JP 58 067,672; and NL 6,505,524).

The present invention relates to:

1.the use of 6(7)-amino-substituted quinoline-5,8-quinones of the general formula (I) Rl ~ 3\ R2 in which R1 represents substituted Cl-C6-alkyl or optionally substituted cycloalkylalkyl, cycloalkyl, aralkyl or aryl, substituents which may be mentioned being halogen, nitro, alkyl, alkyl-amino, aminoacyl, aryl, aryloxy, arylthio, Le A 28 421 - i -.. _ . _ ,, , ._, _ _,,, _ _ .. ~ _ . ......

~7~6 aralkyl, halogenoalkyl, alkoxy, halogenoalkoxy, alkylthio, halogenoalkylthio, alkylsulphinyl, halogenoalkylsulphinyl, alkylsulphonyl or halogenoalkylsulphonyl, R2 represents hydrogen or alkyl, or R1 and R2, - together with the adjacent N atom, represent a carbocyclic 5-, 6- or 7-membered ring, which can optionally also be interrupted by 0, N or S and is optionally substituted by C,~-alkyl, R3 represents halogen or -S-R4 and R4 represents alkyl, for combating endoparasites in medicine and veterin-ary medlcine.

The compounds of the formula (I) are known in some cases and can be prepared by processes analogous to known processes.

2. New 6(7~-amino-substituted quinoline-5,8-quinones of the general formula (Ia) O ~R

~ H \ R~ (Ia~

Le A 28 421 - 2 -in which R1 represents cycloalkylalkyl or aralkyl, which are optionally substituted by halogen, nitro, alkyl, alkylamino, am:inoacyl, aryl, aryloxy, S arylthio, aralkyl, halogenoalkyl, alkoxy, halogenoalkoxy, alkylthio, halogenoalkylthio, alkylsulphinyl, halogenoalkylsulphinyl, alkyl-sulphonyl or halogenoalkylsulphony]., R2 represents hydrogen and ~al represents halogen, preferably chlorine or bromine, in particular chlorine.

3. Process for the preparation of the new 6(7)-amino-substituted quinoline-S,B-quinones of the formula (Ia) ~ \ R2 (I~) in which R1, R2 and Hal have the meaning given under Item 2, characterised in that Le A 2B 42l - 3 -.

~Q7 ~

a) compounds of the formula (II~
o N ~ H~ (II) in which Hal has the abovementioned meaning, are reacted with amino compounds of the ~ormula (III) Rl H N/ (III) in which Rl and R2 have the abovementioned meaning, if appropriate in the presence of metal salts and if appropriate in the presence of adiluent, or in that b) compounds of the formula (IV) Le ~ ?8 421 - 4 ~

2~71~6~
o N ~ H~
in which Hal has the abovementioned meaning, are reacted with amino compounds of the formula (III) R1 -:
/ ~III) H N
in which R~ and R2 have the abovementioned meaning, if appropriate in the presence of a diluent.

4. New6(7)-amino-su~stitutedquinoline-5,8-quinones of the formula ~Ib C ~ (Ib~

Le A 28 421 ~ S -~ t . _ ~ _ _ , _ _ _ _ _ _ _ _ _ _ _ . ~ _ _, _ _ 2~7~56~

in which R1 represents substituted C1-C6-alkyl or optionally substituted ~ycloalkylalkyl, cycloalkyl, aralkyl or aryl, substituents which may be mentioned being halogen, nitro, alkyl, alkyl-amino, aminoaryl, aryl, aryloxy, arylthio, aralkyl, halogencalkyl, alkoxy, halogenoalkoxy, alkylthio, halogenoalkylthio, alkylsulphinyl, halogenoalkylsulphinyl, alkylsulphonyl or halogenoalkylsulphonyl, R2 represents hydrogen or alkyl, or R1 and R2, together with the adjacent N atom, represent a carbocyclic 5-, 6- or 7-membered ring, which can optionally also be interrupted by O, N or S and is optionally substituted by C14-alkyl and R4 represents alkyl~

5. Process for the preparation of the new 6(7)-amino-substituted quinoline-5,8-quinones of the formula (Ib) o ~Rl ~-R~ R2 (Ib) Le A 28_421 - 6 -2~7156~

in which R1, R2 and R4 have the meaning given under Item 4, characterised in that a) the 6(7)-amino-substituted quinoline-5,8-quinones, obtainable, for example, according to process 3, of the formula (Ia) N
o in which Rl, R2 and ~al have the meaning given under Item 2 and 4, are reacted in a first reaction step with alkali metal sulphides of the formula (V) M2S ~ V ~

in which M represents a monovalent alkali metal cation, preferably potassium or sodium, in Le A 28 421 - 7 -2Q7~66 particular sodium, and in a second reaction step the resulting alkali metal salt of the formula (VI) o ~Rl - ~ R2 (VI) in which Rl and R2 have the abovementioned meani~g and M represents one metal cation equivalent bonded in salt form, is then reacted with alkylating agents of the formula (VII) R~-E (VII) in which R4 has the abovementioned meaning and E represents an electron-withdrawing leaving group, if appropriate in the presence of a diluent, or in that Le A 28 421 - 8 -- :

2~7 1~6~
b) compounds of the formula (Ia) O Rl N / (Ia) N

O
in which R1, R2 and Hal have the meaning given under Item 2 and 4, are reacted with thiols or alkali metal salts thereof, of the formula (VIII) R4-S Mt (VIII) in which M represents hydrogen, or represents one metal cation equivalent bonded in salt form and R4 has the abovementioned meaning, in the presence of a diluent and if appropriate in the presence of a reaction auxiliary.

The compounds of the formula (I) are outstandingly suitable for combating endoparasites, in particular in Le A 28 421 - 9 ~

2 ~ 6 the field of veterinary medicine.

Formula (I) provides a general definition of the 6(7)-amino-substitutad quinoline-5,8-quinone derivati~es according to the invention.

Preferred compounds of the formula (I) axe those in which Rl represents substituted Cl-C~-alkyl, or represents optionally substituted C3-C6-cycloalkyl-Cl-C2-alkyl, C3-C6-cycloalkyl, phenyl-Cl-Cz-alkyl, naphthyl-Cl-C2-alkyl or phenyl, substituents which may be mentioned being one or more identical or different radicals from the group comprising Cl-C4-alkyl, in particular methyl or ethyl, Cl-C4-alkoxy, in particular methoxy, ethoxy, methylenedioxy or ethylenedioxy, which are optionally substituted by fluorine or chlorine, Cl-C4-halogenoalkoxy, in particular trifluoromethoxy or fluorochloroethoxy, Cl-C4-alkylthio, in particular methylthio, Cl-C4-halogenoalkylthio, in particular trifluoromethylthioorfluorochloromethylthio, C1-C4-alkylsulphonyl, in particular methylsulphonyl, Cl-C4-halogenoalkylsulphonyl, in particular trifluoro-methylsulphonyl, Cl-C~-halogenoalkyl, in particular trifluoromethyl, halogen, in particular fluorine or chlorine, NOz, CN, amino, Cl-C4-alkyl- or -dialkyl-amino, Cl-C4-halogenoalkylamino, acylamino, in particular acetylamino, and phenyl, phenylthio and phenoxy, which are optionally substituted by one of the abovementioned radicals, Le A 28 421 - 10 -2~71~
R2 represents hydrogen or C1-C6-alkyl, or R1 and R2, together with the adjacent N atom, represent a carbocyclic 5-, 6- or 7-membered ring, which can optionally also be interrupted by 0, N or S and is optionally substituted by C1-C4-alkyl, and R3 represents halogen, preferably chlorine or bromine, in particular chlorine, or Cl-C4-alkylthio.

Particularly preferred compounds of the formula (I) O ~RI
~ R~ ~2 (I) are those in which R1 has the abovementioned preferred meaning, R2 represents hydrogen and R3 represents halogen, such as chlorine, or C1-C4-alkylthio.

Especially preferred compounds of the formula (I) are those in which R1 represents substituted Cl-C6-alkyl, or represents optionally substituted 1-cyclohexyl-ethyl, cyclo-_e A 28 421 - 11 -2~7~ ~6 propyl, cyclopentyl, cyclohexyl, benzyl, l-phenyl-ethyl, l-naphthyl-ethyl or phenyl, substituents which may be mentioned beincl hydrogen, halog0n, in particular chlorine or fluorine, Cl-C4-alkyl, in particular methyl or ethyl, C~-C4-halogenoalkyl, in particular trifluoromethyl, C1-C4-alkylthio, in particular methylthio, Cl-C4-halogenoalkylthio, in particular trifluoromethylthio, Cl-C4-alkoxy, in particular methoxy, C1-C4-halogenoalkoxy, in parti-cular trifluoromethoxy, phenyl and NO2, R2 represents hydrogen and R3 represents chlorine or Cl-C4-alkylthio, in particular methylthio, ethylthio or propylthio.

The following compounds of the formula (I) in which the radicals R1, R2 and R3 have the following meaning may be mentioned specifically:
(+)-6(7)-methylthio-7(6)-tl-14-methoxy-phenyl)-ethyl-amino]-quinoline-5,8 quinone, (+)-6(7)-methylthio-7(6)-[1-(4-methyl-phenyl)-ethyl-amino]-quinoline-5,8-quinone, (+)-6(7)-methylthio-7(6)-[1-(4-chloro-phenyl)-ethyl-amino]-quinoline-5,8-quinone, (+)-6(7)-propylthio-7(6)-[1-(2,4-dichloro phenyl)-ethyl-amino]-quinoline-5,8-quinone, (+)-6(7)-propylthio-7(6)-[1-(3,4-dichloxo-phenyl)-ethyl-amino]-quinoline-5,8-quinone, (+)-6(7)-propylthio-7(6)-[1-(4-fluoro-phenyl)-ethyl-Le A 28 421 - 12 -2~7~
amino]-quinoline-5,8-quinone, R-(+)-7-propylthio-6-(1-phenyl-e~hylamino) q~inoline-5,8-quinone, S-(-)-7-propylthio-6-(1-phenyl-ethylamino)-quinoline-5,8-S quinone, R-(~)-7-methylthio-6-(1-cyclohexy:L-2thylamino)-quinoline-5,8-quinone, S-(-)-7-methylthio-6-(1-cyclohexyl-ethylamino)-quinoline-5,8-quinone, 7-methylthio-6-cyclopropylamino-quinoline-5,8-quinone, 7-propylthio-6-cyclopentylamino-quinoline-5,8-quinone, 7-ethylthio-6-(4 trifluoromethoxy-phenylamino)-quiRoline-5,8-quinone, 7-ethylthio-6-(4-trifluoromethylthio-phenylamino)-quino~
line-5,8-quinone, 7-methylthio-6-(4-chloro-3-trifluoromethyl-phenylamino)-quinoline-5,8-quinone, 7-propylthio-6-(4-chloro-3-trifluoromethyl-phenylamino)-quinoline-5,8-quinone, 7-methylthio-6-(2-trifluoromethylthio-phenylamino)-quinoline-5,8-quinone, 7-ethylthio-6-(3-trifluoromethylthio-phenylamino)-quino-line-5,8-quinone, 7-propylthio-6-(2,6-dichloro-4-trifluoromethylthio-phenyl-amino)-quinoline-5,8-quinone, 7-methylthio-6-(2-chloro-4-trifluoromethylthio-phenyl-amino)-quinoline-5,8-quinone, 7-methylthio-6-(3-chloro-4-trifluoromethylthio-phenyl-amino)-quinoline-5,8-quinone, 7-methylthio-6-thiomorpholino-quinoline-5,8-quinone, Le A 28 421 - 13 -- 2~7~6~

7-methylthio-6-[1-(3-trifluoromethyl-4-chloro-phenyl)-piperaziny1 ]-quinoline-5,8-quinone, and 7-propylthio-6-morpholino-quinoline-5,8-quinone.

The compounds of the formula (I~ are known in some cases, and they can be prepared by processes a) to b) mentioned above under Item 3 and 5 (compare, for example, DE-OS (German Published Specification) 2,136,037;
JP 58,067,672; C.-W. Schellhammer et al., Liebigs Ann.
Chem. 624 ~1959), pages 108-119; O.S. Klimovich et al., Zh. Prikl. Khim. 49 (1976), pages 1823-1826; and CA 86 (1976) 29,288).

If 6,7-dichloro~uinoline-5,8-quinone is employed as the compound of the formula (II) and (+)-1-(3,4-dichloro-phenyl)-ethylamine is employed as the compound of the formula (III) in process 3a for the preparation of the new 6(7)-amino-substituted quinoline-5,8-quinones and regio-isomers thereof, the process can be represented by the following reaction equation:

+ El2~3,~_~CI

~N~Cl + ~CI CH3 Cl N ~ CH3 O H ~ Cl o Le A 28 421 - 14 -- 2~7~6 Formula (II) provides a general definition of the 6,7-dihalo-quinoline-5,B-quinones required as starting substances for carrying out process 3a according to the invention. In this formula, Hal preferably represents those halogens which have already been mentioned as preferred for these substituents in connection with the dèscription of the substances of the formula (Ia) accord-ing to the invention.

The compounds of the formula (II) used as starting materials are known (compare, for example, T. Urbanski et al., Roczniki Chem. tAnn. Soc. chim. Polonorum] 27 tl953), pages 390-394; CA 49 (1955) 1041; R. Long et al., J. Chem. Soc. [London] (1953), page 3919; and Brit. 856,505), and can be obtained by the processes described in these references.

The amino compounds of the formula (III) also to be used as starting substances for carrying out process 3a according to the invention are defined generally. In this formula (III), R1 and R2 have the meanings which have already been mentioned as preferred for these substi-tuents in connection with the description of the substan-ces of the formula (Ia) according to the invention. The amino compounds of the formula (III) are commercially obtainable in many cases or can be prepared in a manner which is known per se by the "Leuckart-Wallach reaction"
(compare, for example, Houben-Weyl, Methoden der Organis-chen Chemie (Methods of Organic Chemistry), Volume XItl, 4th edition 1957, G. Thieme Verlag, Stuttgart, page 648;

Le A 28 421 - 15 -_ ~ __, . . . . . _ .. . _ . . _ 2071~66 M.~. Moore in ~The Leuckart Reaction" in: Organic Reac-tions, Volume 5, 2nd edition 1952, New York, John Wiley & Sons, Inc. London: Chapman & Hall, Ltd. ~editor R. Adams), page 301).

The reaction of the compounds of the formula (II) and (III) is preferably carried out using diluents. Possible diluents for carrying out process 3a according to the invention are all the inert organic solvents.

Examples which may be mentioned are: halogenohydro-carbons, in particular chlorohydrocarbons, such as tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichloroethylene, pentachloroethane, difluorobenzene, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, chlorotoluene and tri-chlorobenzene; alcohols, such as methanol, ethanol, isopropanol and butanol, ethers, such as ethyl propyl ether, methyl tert.-butyl ether, n-butyl ethyl ether, di-n-butyl ether, di-isobutyl etherr diisoamyl ether, diisopropyl ether, anisole, phenetole, cyclohexyl methyl ether, diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane and dichlorodiethyl ether;
nitrohydrocarbons, such as nitromethane, nitroethane, nitrobenzene, chloronitrobenzene and o-nitrotoluene;
nitriles, such as acetonitrile, butyronitrile, isobutyro-nitrile, ben~onitrile and m-chlorobenzonitrile;
aliphatic, cycloaliphatic or aromatic hydrocarbons, such as heptane, hexane, nonane, cymene, benzine fractions Le A 2~3 421 - 16 -2~7~5~
-within a boiling-point ran~e of 70C to 190C, cyclo-hexane, methylcyclohexane, petroleum ether, ligroin, octane, benzene, toluene and xylene; esters, such as ethyl acetate and isobutyl acetate; amides, for example formamide, N-methylformamide, N,N-dimethylformamide and N-methylpyrrolidone; and ketones, such as acetone and methyl ethyl ketone. Mixtures of the solvents and dilu-ents mentioned are also possible.

Aliphatic alcohols are preferred.

Process 3a is carried out by bringing together and heating compounds of the formula (II) and an excess of the compounds of the formula (III) in one of the diluents mentioned. The reaction time i5 about 2 to 10 hours. The reaction is carried out at temperatures between +20C and +200C, preferably between +50C and +150C, particularly preferably at the boiling point of the diluent. The reaction is preferably carried out under ~he pressure which is established when the reactants are heated to the required reaction temperature under the reaction condi-tions.

For carrying out the process according to the invention, in general 1.0 to 4.0 mol, preferably 2.S to 3.5 mol, of amino compound of the formula (III3 are employed per mol of 6,7-dihalo-quinoline-5,8-quinone of the formula (II).

When the reaction has ended, the reaction mixture is cooled to 0C and the solid which has precipitated out is Le A 28 421 - 17 -~ Q 7 ~

filtered off, washed and dried. The regio-ismer mixture obtained can be purified in the customary manner by recrystallisation or separated into the particular position isomer products by chromatography (compare also the preparation examples).

Alternatively, this amination reaction can also be carried out regio-selectively in the 6-position on an activated metal complex formed in situ in the presence of suitable salts of metals of sub-group I, III and VIII of the periodic table of the elements (compare, for example, Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Volume VII/3a, 4th edition 1988, G.
Thieme Verlag, Stuttgart, page 580; Katsuhira Yoshida et al., Bull. Chem. Soc. Jpn. 61 (1988), pages 4335-4340;
and JP 58,067,672). Chlorides of nickel and cerium are particularly preferred here.

If 7-chloro-6-methoxy-quinoline-5,8 quinone is employed as the compound of the formula (IV) and (_)-1-(4-fluoro-phenyl)-ethylamine is employed as the compound of the formula ~III) in process 3b, the process can be described by the following reaction equation:
O

OCH3 H~N ~ -CH30H

~ N ~ F

Le A 28 421 - 18 -.

2~7~6 In this ca~e, the compounds of the formula (Ia) are formed regio-spe~ifically.

The compounds of the formula (IV) in which the radical Hal has the preferred and particularly preferred meaning S mentioned in the case of the compounds of the formula (Ia) are preferably employed in process 3b.

The compounds of the formula (IV) required as starting substances for carrying out process 3b according to the invention are known ~compare Hsien-Saw Kuo et al., Tai-wan Yao Hsueh Tsa Chih 33 (1981), pages 104-110; CA 97 (1982), 23,604; and T.R. Liao et al.~ J. ~eterocyclic Chem. 13 (1976), pages 1063-1065).

The amines (III) also to be used as starting substances for carrying out process 3b according to the invention are defined generally. The amines of the formula (III) are generally known compounds of organic chemistry.

Process 3b is carried out by bringing together and heating compounds of the formula (IV) and an excess of the compounds of the formula (III) in one of the diluents mentioned. The reaction time is 10 to 40 hours. The reaction is carried out at temperatures between +20C and +200C, preferably between +50C and +150C, particularly preferably at the boiling point of the diluent. The reaction is carried out under normal pressure.

For carrying out the process according to the invention, Le A 28 421 - 19 -2~7~66 in general 1.0 to 4.0 mol, preferably 1.5 to 2.5 mGl, of amino compound of the formula (III) are employed per mol of 7-chloro-6-methoxy-quinoline-5,8-quinone of the formula (IV).

When the reaction has ended, the mixture is cooled and concentrated in vacuo and the solid which has precipita-ted out is filtered off, washed and dried (compare also . the preparation examples).

If 6-[3,5-bis-(trifluoromethyl)phenylamino]-7-chloro-quinoline-5,8-quinone is employed as ~he compound of the formula (Ia), disodium sulphide nonahydrate is employed as the compound of the formula (V) and dimethyl sulphate is employed as the compound of the formula (VII) in process 5a, the process can be described by the following reaction equation.

N ~ + Na2S-9H2O NaCI

~ ~ ~C~ CH O /

Le A 28 421 - 20 - -~

o ~ ,~

N ~\ ~

The compounds of the formula (Ia) in which the radicals R1, RZ and Hal have the preferred and particularly pre-ferred meanings mentioned in the case of the compounds of the formula (Ia) are preferably employed in process 5a.

The alkali metal sulphides of the formula (V) alsQ to be used as starting substances in carrving out process 5a accordiny to the invention are generally known compounds of inorganic chemistry.

The alkylating agents of the formula tVII) also to be used as starting substances for carrying out process 5a according to the invention are generally known compounds of organic chemistry. In this formula (VII), R4 has the meaning which has already been mentioned as preferred for these substituents in connection with the description of the substances of the formula (I) according to the invention, and E has the meaning of an electron-withdraw-ing leaving group.

Suitable leaving groups ~ are, for example, halogen, such as chlorine, bromine or iodine, or a radical of the formula O-SO2-C6H5, O-SO2-C6~4-CH3 or o-So2-oR4, wherein R4 has the abovementioned meaning.

Le A 28 421 - 21 -~o7~6 The use of C1-Cb-dialkyl sulphates, in particular dimethyl sulphate or diethyl sulphate, is preferred.

Process 5a is carried out by bringing together compounds of the formula (Ia) and equimolar amounts of the com-pounds of the formula (V) at room temperature in one ofthe diluents mentioned. The formation of the alkali metal salts of the formula (VI) formed in situ takes about 1 to 30 minutesO

In a second reaction step, these salts are alkylated with compounds of the formula (VII) during a reaction time of about 10 to 60 minutes and a reaction temperature of between +20 and +200C, preferably between ~50 and +150C, particularly preferably at the boiling point of the diluent. The reaction is carried out under normal pressure. The reaction products are worked up and iso-lated by generally customary methods (compare also the preparation examples).

If a mixture of the regio-isomeric 6-chloro-7-(4-tri-fluoromethyl-phenylamino)- and 7-chloro-6-~4-trifluoro-methyl-phenylamino)-quinoline-5,8-quinones is used as the compound of the formula (Ia) and sodium 1-propanethiolate is employed as the compound of the formula (VIII) in procesR Sb, the process can be described by the following reaction equation:

Le A 28 421 - 22 ~

2~7i ~6~

O H ~ +N~ CH2-cH2-cH3 N

o H O
N ~ CF3 ~ S-CHrCH2-CH3 N S-CH2-CH2-CH3 o ' ~ CF3 Process 5b is carried out by bringing together and if appropriate heating compounds of the formula (Ia)-and an excess of the compounds of the formula (VIII) in one of the diluents mentioned.

The reaction time is 10 to 40 hours. The reaction is carried out at temperatures between 0C and +200C, preferably between +20C and +150C, particularly prefer-ably at room temperature. It is carried out under normal pressure.

For carrying out the process according to the invention, in general 1.0 to 3.0 mol, preferably 1.0 to 1.5 mol, of alkali metal salts of the thiols of the formula (VIII) are employed per mol of mixture of regio-isomeric 6-chloro-7-(4-trifluoromethyl-phenylamino)- and 7-chloro-6-(4-trifluoromethyl-phenylamino)-quinoline-5,8-quinones of the formula (Ia).

Alternatively, this reaction can also be carried out with Le A 28 421 - 23 _ . ._ ~,.,. . .. _ _ . .. . . .. ,,~.,.. _ _ _ _ . . _ 2~7~66 thiols of the general formula (VIII) in which M repres-ents hydrogen, in the presence of a basic reaction auxiliary. Reaction auxiliaries which can be employed as bases are all the suitable acid-binding agents, such as amines, in particular tertiary amines, and alkali metal and alkaline earth metal compounds. Examples of these which may be mentioned are the hydroxides, oxides and carbonates of lithium, sodium, potassium, magnesium, calcium and barium, and furthermore other basic com-pounds, such as trimethylamine, tribenzylamine, triiso-propylamine, tributylamine, tribenzylamine, tricyclo-hexylamine, triamylamine, trihexylamine, N,N-dimethylani-line, N,N-dimethyltoluidine, N,N-dimethyl-p-aminopyri-dine, N-methyl-pyrrolidine, N-methyl-piperidine, N-methyl-imidazole, N-methyl-pyrrole, N-methyl-morpholine, N-methyl-hexamethyleneimine, pyridine, quinoline, ~-picoline, ~-picoline, isoquinoline, pyrimidine, acridine, N,~,N',N'-tetra-methylenediamine, N,N,N',N'-tetraethyl-enediamine, quinoxaline, N-propyl-diisopropylamine, N,N'-dimethylcyclohexylamine, 2,6-lutidine, 2,4-luditine, triethylenediamine, diazabicyclooctane (DABCO), diazabi-cyclononene (DsN) or diazabicycloundecene (DBU).

Alkali metal compounds, such as, for example, sodium hydroxide, potassium hydroxide or corresponding carbonates, are preferably used.

When the reaction has ended, the reaction mixture is concentrated in vacuo (to about 50~), aqueous acid is added to the residue and the compounds of the formula Le A 28 421 - 24 -. , . _ .. . . . ~ _ . . . , . . ~ . _ _ _ 2~71 ~6 (Ib) are isolated in a manner which is known per se by extracting them with a suitablle solvent, for example chloroform or methylene chloride. The compounds of the formula (Ia) can then be purified or separated into the particular position isomer products in the customary manner, for example by chromatography.

The active compounds are suitable for combating patho-genic endoparasites which occur on humans and in animal keeping and animal husbandry on stock, breeding, zoo, laboratory and experimental animals and pets, and have a favourable toxicity to warm-blooded animals. They are active here against all or individual stages of develop-ment of the pests and against resistant and normally sensitive species. Disease, fatalities and reductions in output (for exanple in the production of meat, milk, wool, skins, eggs, honey and the like) are to be reduced by combating the pathogenic endoparasites, so that more economic and easier keeping of the animals is possible by usir~g the active compounds. The pathogenic endoparasites include cestodes, trematodes, nematodes and Acantoce-phalae, in particular:

From the order of the Pseudophyllidea, for example:
Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diplogonoporus spp..

From the order of the Cyclophyllidea, for example:
Mesocestides sppO, Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Le A 28 421 - 25 -2~7 ~ ~$
.

A~itellina spp~, Stilea~ia spp., Cittotaenia spp., Andyra spp., ~ertiella spp., Taenia spp., Echinococcus 9pp., ~ydatigera spp., Davainea spp., Rilillietina spp., Hymeno-lepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxie;Lla spp., Diplopylidium spp..

From the subclass of the Monogenea, for example: Gyro-dactylus spp., Dactylogyrus spp., Polystome spp..

From the subclass of the Digenea, for example: Diplos-tomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobil-harzia spp., Gigantobilharzia spp., Leucochloridium spp., ~rachylaima spp., Echinostoma spp., Echinoparyphium spp., ~chinochasmus spp., Hypoderaeum spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhlocoelum spp., Paramphistomum spp., Calicophoron spp., Cotylophoron spp., Gigantocotyle spp., Fischoede-rius spp. Gastrothylacus spp., Notocotylus spp., Cata-tropis spp., Plagiorchis spp., Prosthogonimus spp., Dicrocoelium spp., Eurytrema spp., Troglotrema spp., Paragoniums spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp~, Clonorchis spp., Metorchis spp., Heterophyes spp., Metagonimus spp..

From the order of the Enoplida, for example: Trichuris spp., Capillaria spp., Trichomosoides spp., Trichinella spp..

Le A 2a 421 - 26 -2Q713~
.

From the order of the Rhabditia, for example: Micronema spp., Strongyloides spp..

From the order of the Strongylida, for example: Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Tricho-nema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostomum spp., Cyclicocercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elapho-strongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aeluro-lS strongylus spp., Filaroides spp., Parafilaroides spp.,Trichostrongylus spp., Haemonchus spp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirus spp., ~yostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp..

From the order of the Oxyurida, for example: Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp..

From the order of the Spirurida, for example: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracun-culus spp..

~e A 28 421 - 27 -.. _ . . .. .. . . _ _ . .. _ _ .. . . . ~ .. . _ .. _ _ . _ , , _ , , _, , _ 2~L3~6 From the order of the Filariida, for example:
Stephanofilaria 6pp., Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp..

From the order of the Gigantorhynchida, for example:
Filicollis spp., Monoliformis spp., Macracanthorhynchus spp., Prosthenorchis spp..

The stock and breeding animals include mammals, such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer and fur-bearing animals, such as, for example, mink, chinchillas and racoons, birds, such as, for example, chickens, geese, turkeys and ducks, fresh- and salt-water fishes, such as, for example, trout and carp, eels, reptiles and insects, such as, for example, honey bees and silkworms.

Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.

Pets include dogs and cats.

Application can be either prophylactically or therapeuti-cally.

The active compounds are used, directly or in the form of suitable formulations, enterally, parenterally, dermally, nasally, by treatment of the environment or with the aid Le A 28 421 - 28 -2~7~
.

of shaped articles containing the active compound, such as, for example, strips, sheets, bands, collars, ear-marks, limb bands and marking deYices.

Enteral use of the active compounds is effected, for example, orally in the form of powders, tablets, cap-sules, pastes, drinks, granules, orally administered solutions, suspensions and emulsions, boli, medicated feed or drinking wa'er~ Dermal use is effected, for example, in the form of dips, sprays or pour-on and spot-on formulations. Parenteral use is effected, for example,in the form of inject.ion (intramuscular, subcut~neous, intravenous or intraperitoneal) or by implants.

Suitable formulations are:
solutions, such as injection solutions, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, pour-on and spot-on formulations and gels;

emulsions and suspensions for oral or dermal use and for injection; semi-solid formulations;

formulations in which the active compound is processed in an ointment base or in an oil-in-water or water-in-oil emulsion base;

solid formulations, such as powders, premixes or concen-trates, granules, pellets, tablets, boli or capsules;
aerosols and inhalates, and shap~d articles containing Le A 28 421 - 29 -2~7~6~

active compound.

Injection solutions are administered intravenously, intramuscularly and subcutaneously.

Injection solutions are prepared by dissolving the active S compound in a suitable solvent and adding any additives, such as solu~ilising ager.ts, acids, bases, buffer salts, antioxidants and preservatives. The solutions are subjected to sterile filtration and bottled.

Solvents which may be mentioned are: physiologically tolerated solvents, such as water, alcohols, such as ethanol, butanol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycols and N-methyl-pyrrolidone, and mixtures thereof.

If appropriate, the active compounds can also be dis-solved in physiologically tolerated vegetable or syn-thetic oils which are suitable for injection.

Solubilising agents which may be mentioned are: solvents which promote solution of the active compound in the main solvent or prevent its precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil and polyoxyethylated sorbitan esters.

Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid esters and n-butanol.

Le A 28 421 - 30 -207~

Oral solutions are used directly. Concentrates are used orally after prior dilution to the use concentration.
Oral solutions and concentrates are prepared as described above for the injection solutions, in which case sterile working can be omittedO

Solutions for use on the skin are dripped on, brushed on, massaged in, sprinkled on or sprayed on. These solutions are prepared as described above for the injection solu-tions.

It may be advantageous to add thickeners during the preparation. Thickeners are: inorganic thickeners, such as bentonites, colloidal silicic acid and aluminium monostearate, and organic thickeners, such as cellulose derivatives, polyvinyl alcohols and copolymers thereof, acrylates and methacrylates.

Gels are applied to or brushed on the skin or introduced into body cavities. Gels are prepared by adding thick-eners io solutions, which have been prepared as described above for injection solutions, in an amount such that a clear mass having an ointment-like consistency is formed.
The thickeners mentioned above are employed as the thickeners.
.

Pour-on formulations are poured or sprayed onto limited areas of the skin, the active compound penetrating the skin and having a systemic action.

Le A 28 421 - 31 -2~711 ~6~
Pour-on formulations are prepared by dissolving, ~uspend-ing or emulsifying the active compound in suitable solvents or solvent mixtures tolerated by the skin. Other auxiliaries, such as dyestuffs, absorption-promoting substances, antioxidants, light stabilisers and adhes-ives, are added if appropriate.
. .
Solvents which may be mentioned are: water, alkanols, glycols, polyethylene glycols, polypropylene glycols and glycerol, aromatic alcohols, such as benzyl alcohol, phenylethanol and phenoxyethanol, esters, such as ethyl acetate, butyl acetate and benzyl benzoate, ethers, such as alkylene glycol alkyl ethers, such as dipropylene glycol monomethyl ether and diethylene glycol monobutyl ether, ketones, such as acetone and methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, dimethylformamide, dimethylacet~mide, N-methylpyrrolidone and 2,2-dimethyl-4-oxy-methylene-1,3-dioxolane.

Dyestuffs are all the dyestuffs which are permitted for use on animals and can be dissolved or suspended.

Absorption-promoting substances are, for example, dimethylsulphoxide, spreading oils, such as isopropyl myristate and dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides and fatty alco-hols.

Antioxidants are sulphites or metabisulphites, such as Le A 28 421 - 32 -2 ~ 7 ~

potassium metabisulphite, ascorbic acid, ~utylhydroxy-toluene, butylhydroxyanisole and tocopherol.
Light stabilisers are, for example, novantisol acid.

Adhesives are, for example, cellulose derivatives, starch S derivatives, polyacrylates and naturally occurring polymers, such as alginates and qelatine.

Emulsions can be used orally, dermally or as injections.

Emulsions are either of the water-in-oil type or of the oil-in-water type.

They are prepared by dissolving the active compound either in the hydrophobic or in the hydrophilic phase and homogenising this ~ith the solvent of the other phase with the aid of suitable emulsifiers and if appropriate other auxiliaries, such as dyestuffs, absorption-promot-ing substances, preservatives, antioxidants, lightstabilisers and viscosity-increasing substances.

Hydrophobic phases (oils) which may be mentioned are:
paraffin oils, silicone oils, naturally occurring veget-able oils such as sesame oil, almond oil and castor oil, synthetic triglycerides, such as caprylic/capric acid biglyceride, a triglyceride mixture with plant fatty acids of chain length C8l2 or other specifically selected naturally occurring fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids, which may also contain hydroxyl groups, and mono- and Le A 2~ 421 - 33 -2Q7~66 diglycerides of the C8/C10-fatty acids.

Fatty acid esters, such as ethyl stearate, di-n-'outyryl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of chain length C16-C1~, isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of chain length C12-C10, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, e~hyl lactate, waxy fatty acid esters, such as synthetic duck uropygial gland fat, dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter and the like.

Fatty alcohols, such as isotridecyl alcohol, 2-octyl-dodecanol, cetyl stearyl alcohol and oleyl alcohol.

Fatty acids, such as, for example, oleic acid and its mixtures.

Hydrophilic phases which may be mentioned are:
water, alcohols, such as, for example, propylene glycol, glycerol and sorbitol, and their mixtures.

Emulsifiers which may be mentioned are: non-ionic surfac-tants, for example polyoxyethylated castor oil, polyoxy-ethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate and alkyl-phenol polyglycol ethers;

Le A 28 421 - 34 -_ . . .. . _ _ .. . . . . .. . _ _ . . ~

2~71~66 ampholytic surfactants, such as di-Na N-lauryl-~-iminodi-propionate or lecithin;
anionic surfactants, such as Na lauryl-sulphate, fatty alcohol ether-sulphates and mono/dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt; and cationic surfactants, such as cetyltrimethylammonium chloride.

Other auxiliaries which may be mentioned are: substances which increase the viscosity and stabilise the emulsion, such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, algin-ates, gelatine, gum arabic, polyvinylpyrrolidone, poly-~inyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes, colloidal lS silicic acid or mixtures of the substances mentioned.

Suspensions can be used orally, dermally or as an injec-tion. They are prepared by suspending the active compound in a carrier liquid, if appropriate with addition of other auxiliaries, such as wetting agents, dyestuffs, absorption-promotingsubstances, preservatives, antioxid-ants and light stabilisers.

Carrier liquids which may be mentioned are all the homogeneous solvents and solvent mixtures.

Wetting agents (dispersing agents) which may be mentioned are the surfactants mentioned above.

Le A 28 421 - 35 -2~71~66 Other auxiliaries which may be mentioned are those mentioned above.

Semi-solid formulations can be administered orally or dermally. They differ fro~ the suspensions and emulsions described above only by their higher viscosity.

To prepare solid formulations, the active compound is mixed with suitable carrier substances, if appropriate with the addition of auxiliaries, and brought into the desired form.

Carrier substances which may be mentioned are all the physiologically tolerated solid inert substances. In-organic and organic substances are used as these. In-organic substances are, for example, sodium chloride, carbonates, such as calcium carbonate, bicarbonates, aluminium oxides, silicic acids, aluminas, precipitated or colloidal silicon dioxide and phosphates.

Organic substances are, for example, sugars, cellulose, food- and feedstuffs, such as milk powder, anLmal meals, cereal meals and crushed cereal, and starches.

Auxiliaries are the preservatives, antioxidants and dyestuffs which have already been mentioned above.

Other suitable auxiliaries are lubricants and anti-friction agents, such as, for example, magnesium Le A 28 _21 - 36 -.,, _ .. _ , . .
_ _ , . , . _ _ ,_, . . .. , . . . . . _. _ _ _ _ . . .. . ._ .. ...

23189-7353 2 ~ 7 1 ~ 6 ~

stearate, stearic acid, talc and bentonites, disintegra-tion-promoting substances, such as starch or cro~linked polyvinylpyrrolidone, binders, such as, for example, starch, gelatine or linear polyvinylpyrrol~done, and dry binders, such as mlcrocrystalline cellulose.

The active compounds can also be present in the formula-tions as a mixture with synergists or with other active compounds which act against pathogenic endoparasites.
Such active compounds are, for example, L-2,3,5,6-tetra-hydro-6-phenylimidazothia~ole, benzimidazole carbamate, pra~iquantel, pyrantel and febantel.

Ready-to-uqe formulations contain the active compound in concentrations of 10 ppm - 20 per cent by weight, prefer-ably 0.1 to 10 per cent by weight.

Formulations which are diluted before use contain the active compound in concentrations of 0.5 to 90 per cent by weight, preferably 5 to 50 per cent by weight.

In general, it has proved advantageous to administer amounts of about 1 to about 100 mg of active compound per kg of body weight per day to achieve effective results.

The invention also extends to commercial packages contain-ing a 6(7)-amino-substitute quinoline-5,8-quinone of formula (I),together with instructions for its use in combating endoparasites.

. .~ ~. .

Le A 28 421 - 37 -Exam~le A

In-vivo nematode test Trichostrongylus colubriformis / ~heep Sheep experimentally infected with Trichostrongylus colubriformis were treated after the end of the pre-patency period of the parasite. The active compounds were administered orally as pure active compound in gelatine capsules.

The degree of effectiveness is determined by quanti-tatively counting the worm eggs excreted with the faeces, before and after treatment~

Complete cessation of the excretion of eggs after the treatment means that the worms have been expelled or are so severely damaged that they can no longer produce any eggs (effective dose)O

The active compounds tested and effective doses can be seen from the following table.

Active compound Effective dose in Example No. mg/kg ~e A 28 421 - 38 -_ _ .

2071~66 Example B

In-vivo nematode test Haemonchus contortus / sheep Sheep experimentally infected with Raemonchus contortus were treated after the end of the pre-patency period of the parasite. The active compounds were administered orally as pure active compound in gelatine capsules.

The degree of effectiveness is determined by quanti-tatively counting the worm eggs excreted with the faeces, before and after treatment.

Complete cessation of the excretion of eggs after the treatment means that the worms have been expelled or are so severely damaged that they can no longer produce any eggs (effective dose).

The active compounds tested and effective doses can be seen from the following table.

Active compoundEffective dose in Example No. mg/kg Le A 28 421 - 39 -._ _ ",, _ .. ..

2~7~6 Preparation Examples Example_l H~ ~ H CF3 5.O g (21.9 ~mol) of 6,7-dichloro-quinoline-5,8-quinone are înitially introduced into 35 ml of absolute ethanol, and 10.6 g (65.7 mmol) of 4-trifluoromethyl-aniline are added. The mixture is then stirred at the reflux tempera-ture until conversion is complete (2.5 hours) and is ~ubsequently cooled to O~C. The solid which has precipi-tated out is filtered off with suction and dried. 7.7 gof a crude product of a regio isomer mixture are obtained and are chromatographed over a silica-gel column (silica gel 60 - Merck, particle size: 0.040-0.063 mm) with the mobile solvent toluene: ethanol (15:1).

6-Chloro-7-(4-trifluoromethyl-phenYlamino)-~uinoline-5,8-auinone Melting point: 238-239C 1.5 g (19.5% of theory) 1H-NMR (CDCl3, 6): 7.16; 7.63 (2d, 4H, aromatic;
J = 8.4 Hz); 7.73 (dd, lH, HB; JHB,HA: 4.8 HZ; JHB,H~:

7.9 Hz3; 7.85 (s, lH, NH); 8.53 (dd, lH, ~; JH~, Le A 28 421 - 40 -2~71~6 HB: 7.9 Hz; JH~,H^: 1.7 Hz); 9.01 (dd, lH, HA; JH~,~:
1.7 Hz; JHA,H8: 4.8 Hz) ppm.

Example 2 qulnone Melting point: 188-190C 2.3 g (29.9~ of theory) lH-NMR (DMSO-d&; ~): 7.28; 7.65 (2d, 4H, aromatic;
J = 8.4 Hz~; 7.83 (dd, lH, H~; JH~,HA: 4.8 Hz; JHB,HC:
7.9 Hz); 8.39 (dd, lH, ~; JH~,H~: 7.9 Hz; JHF,H^: 1.7 Hz);
9.00 (dd, lH, H~; JHA,HC: 1.7 Hz; JHA,HB: 4.8 Hz); 9.57 (s, lH, NH) ppm Example 3 7-Chloro-6-(2~3-dimethyl-phenylamino!-quinoline-s~8 quinone Hs ~ H
HA N Cl O
5.0 g (0.022 mol) of 7-chloro-6-methoxy-quinoline-5,8-quinone are initially introduced into 100 ml of hot ethanol, and 5.3 g (0.044 mol) of 2,3-dimethyl-aniline are added dropwise. The mixture is then stirred at the reflux temperature until the conversion is complete Le A 28 421 - 41 -... _ . . . _ , _ _ , . ~ . . " ;, _ _ . _ _ _ _ , . . ..

2 ~ 7 ~
(16 hours) and the entire mixture is concentrated in vacuo. The residue is rinsed with a little cold ethanol and recrystallised from ethanol. 3.9 g (S6.7~ of theory) of 7-chloro-6-(2,3-dimethyl~phenylamuno)-quinoline-5,8-quinone are obtained.
Melting point: 202-203C

H-NMR (DMSO-d6, ~): 2.20; 2.33 (2s, 3H, CH3); 6.98-7.10 (m, 3H, aromatic); 7.78 (dd, lH, H3; JH3,H~: 4.8 Hæ;
JH ,H : 7.9 ~z); 8.38 (dd, lH, ~c; JHc ~3 7 9 Hz; J~C HA:
1.7 Hz); 8.97 (dd, lH, HA; JHA,HC: 1.7 Hz; JHA HB: 4 8 H ) 9.13 (s, lH, NH) ppm The compounds of the formula (Ia, Hal = Cl) listed in the following Table 1 can be prepared analogously.

Le A 28 421 - 42 -2071~66 Table 1 Examples of the compounds of the formula (Ia) ~ Cl (Ia) Example Position ~Position-) Physi No.of Cl NRl data RZ ._ G~
4 6 (7~
m . p : 192C
7 (6-) NH~

6 (7-) NH~ C~I3 m .p . :183C
7 (6-) NH~ CH3 .

6 7 (6-) NH~ m.p.: 19~195C

7 7 (~ ) NH~ m .p .: 197-199C

~3 /

8 7 (6-) NH~ m.p.: 188-189C
Cl 9 7 (6-) NH~ m.p.: 111-114C

Le A ~8 421 - 43 -,~ ~

2Q71~
Table 1 (Continuation) Example Position ( Position- ) P~5i~
No. of Cl Rl data N
____ _ R
r-~
6 (7-)~nH~
C1 m . p .: 188C
7 (~ ) ~nH~

I 1 7 (6-) ~nH~ Cl m. p .: 217-218C

12 6 (7^) ~nH~ Cl m . p .: 20BC
7 (6-) ~nH~ Cl 13 7 (6-)~nH~ Cl m.p .: 213-216C

Cl 14 7 (6-) ~nH~ Cl m. p .: 246-248C

7 (6-) ~nH~ m.p.: >250C

/=\ o 16 7 (6-~ ~nH~Cl m.p.: æ3-224 C

17 (6-) Nn~ F3 m . p .: 20QC
7 (6-) ~n~ C~F3 Le A 28 421 - 44 --2Q71~66 Table 1 (Con~inuation) _ _ _ _ Example Position ~Position-) Phys;~l No. of Cl Rl data S N R _ 18 7 (6-) NnH~ m.p.: 208-209C
C~F3 19 7 (6-) NH~ F m.p: 22CL221C
C~H3O
7 (6-)NHb m-p:l75-178C

21 6 (7_) NnH~OCH3 m . p .: 203C
7 (6-) ~nH~ OCH3 22 7 (6-) NnH~OCF3 m.p.:188-190C

23 7 (6-) NnH~ SCF3 m.p.: 192-193C

24 7 (6-) NnH~No2 m.p.: >250C

6 (i~7-) NH

~ m.p :133C
7 (i)~6-) NH~ J

Le A 28 421 - 45 -~ .

2~7~

Table 1 (Continuation) Example Position (Position-) Phy5;~
~o. of Cl ~ Rl data N

_ . _ ~6 6 (+)~7-)NH~

7 (iH6-) N~ p.:159C

27 6 (+) (7-) NH~

CH3 ~p.:110C

7 (:t)(~) NH

28 6 (+)-(7~

~ nLp.:118C
7 (+) (~ Q J

29 6 (+~ (7 ~ NH ~ CH3 7 ( )( ) Cll/ -CH3 ¦IILp:l3soc Le A 28 4~1 - 46 -2~71~6~
Table 1 (Continuation) .
Example Position (Position-) Physi No. of Cl N = R1 data R
6 (+)-(7-) NH ~ C2Hs CH3 ~p:98C
7 (+)-(6-) NH ~ C2H5 Cl 31 6 (~{7-) NH

Cl , ~ ~p.:165C
7 (i)~6-) N~

32 6 (+~7-)NH

Cl~nLp.:118C
7 (+)-(6-)NH ~

33 6 (i)~7-) N~ ~ Cl ~p.:172C
NH ~ Cl Le A 28 421 - 47 -2~7~66 Table 1 ~Continuation) Example Position(Position-) Physical No.of Cl N = R1 data _ __ R

34 6 (~)-(7-) NH ~ Cl Cl l IlLp:128C
7 (-+)~) NH ~ Cl J

3~; 6 (+)-~7-) --~ Cl CH3 Cl m.p.: 152C
7 (+)-(6-) NH~CI
CH3 Cl F

36 6 (+) (7 ~ NH ~b - - -F ¦ 1~Lp :155C
7 (i:)-(6-) NH~b J

37 6 (i)~7-) ~ F
CH3 ~P 1380C
~ F J
7 (+)~) ~
~H3 Le A 28 421 - 48 -2~71~6~

Table 1 ( Continuation ) Example Po~:ition( Po~3ition- ) Plysi~
No. of Cl _Rl data N----_ --RZ

38 6 (~ 7~) ~

F\ m~p :l25C
7(+)(O NH~

(~) NH {~ m.p. :12~125C

453 7 (6-) NH--(CH2)2~ m.p. :129-130C
41 7 (6-) NH-(CH2)2-CF3 Fp.: 160-162C

42 7 (6-) NH-CH(CH3)2 Fp.: 109-110C
43 7 (6-) NH-CH(CH3)-CF3 Fp.: 180-181C
44 7 (6-) NH-CH(CH3)-C2H5 Fp.: 77-78C
7 (6-) NH-CH2-CH(CH3)2 Fp.: 102-103C
46 7 (6-) NH-C(CH3)3 Fp.: 130-131C

Le A 28 421 - 49 ~

_. , _ , . _ . _ _ ,, , - , _ .. . ~ _ _, _ _ .. .. . . _ _ 2~7~ 76~
Example 47 6- r 3~5-Bisttrifluoromethyllphenylamino~-7-methylthio-quinoline-5,8-quinone ~ CF3 H ~ N ~

~A N SCH3 CF3 o 4.6 g (10.9 mmol) of 6-[3,5-bis~trifluoromethyl)phenyl-amino]-7-chloro-quinoline-5,8-quinone are initially introduced into 40 ml of ~thanol, and 2.6 g (10.9 mmol~
of disodium sulphide nonahydrate (dissolved in 40 ml of water) are added at room temperature. During this opera-tion, the previously red solution becomes blue-blac~ in colour. The mixture is subsequently stirred at room temperature for 5 minutes, 1.0 g 110.9 mmol) of dimethyl sulphate is added dropwise and the mixture is heated under reflux for a further 15 minutes. After the mixture has been stirred at room temperature for one hour, the entire mixture is concentrated in vacuo, the residue is stirred with water and the solid is separated off and recrystallised from ethanol. 1.0 g (21.2% of theory) of 6-r3,5-bis(trifluoromethyl)phenylamino]-7-methylthio-quinoline-5,8-quinone is obtained.
Melting point: 135-137C.

~-NMR (CDCl3, ~: 2.28 (s, 3H, -SCH3); 7.39 (s, 2H, Le A 28 421 - 50 -2~ 6 .

aromatic); 7.S3 (s, l~, aromatic); 7.66 (dd, 1~, H8;
JE~A,JH~: 4.8 I~Z; J~,HC: 7.9 ~z); 7.85 (s, lH, NE~); 8.43 (dd, 1~, ~c; JH~, H~: 7.9 ~z; J~,H~: 1.7 Hz); 9.03 (dd, lH, ~; J~A,~: 1 7 ~z; J~A ~B: 4 8 Example 48 ~ rC~3 10 g (28.3 mmol) of a mixture of 6-chloro-7-(4-trifluoro-methyl-phenylamino)- and 7-chloro-6-(4-trifluoromethyl-phenylamino)-quinoline-5,8-quinone are initially intro-duced into 100 ml of absolute tetrahydrofuran, and 3.4 g (34.6 mmol) of sodium l-propanethiolate are added in portions. The mixture is stirred at room temperature until conversion is complete (15 to 20 hours). The entire reaction mixture is then concentrated in vacuo, the syrupy residue is taken up in 200 ml of chloroform, the chloroform mixture is extracted by shaking with 200 ml of 0.5 N hydrochloric acid and the extract is washed with water. The organic phase is dried o~er sodium sulphate and the solvent is then distilled off. The crude product of the regio-isomer mixture which remains can be chroma-tographed over a silica-gel column (silica gel 60 Merck, particle size: 0.040-0.063 mm) using the mobile solvent toluene:ethanol (10:1)~

Le A 2~ 421 - 51 -~ ~ 7 ~
-6~ propylthio)~7-(4-trifluoromethyl-phenylamino) quinoline-5,8-quinone Melting point: 175-176C 1.8 g (16.2% of theory) H, NM~ ( DMSO-d6, ~ ): 0.73 ( t, 3H, -CH3; J = 7.3 Hz ); 1.31 (m, 2H, -CH2-; J = 7.3 Hz~; 2.56 (t, 2H, -SCH2-; J
7.3 Hz); 7.20; 7.62 (d, 4H; aromatic J = 8.4 Hz); 7.82 (dd, lH, HB; JH~,HA: 4.8 Hz; JHB, H~: 7.9 Hz); 8.36 (dd, lH, HC; JHC, H~: 7.9 Hz; JHC, HA: 1.7 Hz); 8.96 (dd, lH, HA; JHA,HC: 1.7 Hz; JHA,H~: 4.8 Hz); 9.49 (s, lH, NH) ppm.

~xample 49 7 - ( 1-Propylthio)-7-(4-trifluorome~h~l-phenylamino)-quinoline-5,8-quinone Melting point: 85-86C 1.65 g (14.796 o f theory) lH--NMR (DMSO-d6, ~): 0.74 (t, 3H, --CH3; J = 7.3 Hz); 1.32 (m, 2H, -CH2-; J = 7.3 Hz); 2.57 (t, 2H, -SCH2-; J =
7.3 Hz); 7.19; 7.61 (2d, 4H; aromatic J = 8.4 Hz); 7.79 (dd, lH, H~; JHa,HA: 4.8 Hz; JH3,HC: 7.9 Hz); 8.38 (dd, lH, HC; JHC,H~: 7.9 Hz; JHC,HA: 1.7 Hz); 8.98 (dd, lH, HA;JHA, HC: 1.7 Hz; JHA,H~: 4.8 Hz); 9.39 (s, lH, NH) ppm.

The compounds of the formula (Ib) listed in the following Table 2 can be prepared analogously.

L~ A 28 421 - 52 -~7~66 Table 2 Examples of the compounds of the formula (Ib) e~ N'R (Ib~

_ Example (Position-) (Position-) P~ysical No. S-R4 N--n2 data (~)S-CH3 (7-)NH~
c~ J m P 1180C

(7-)S-CH3 (6-) 51 (~) S-C3H7 (7~) NH--b m p.: 94-95C

52 (7-) S-C3H~ (6-) NH~ m.p.: oil 53 (~) S-CH3 (7-)NH~ Cl m. p .: 208-210C

54 (7-) S-CH3 (6-)NH~ C1 m . p .: 122-124C

(6-) S-C3H7 (7-) N~I~ Cl m . p .: 202-203C

Le A 28 42l - ~3 -~Q7~66 Table 2 (Continuation~

Example (Position-) (Position-) Pl~
No . S-R4 N--R1 data ~2 ._ 56 (7-) S~3H7 (6-) NH~CI m.p. :117-119C

57 (7-) S CH3 (5-) NH~CI m . p -: 86-87C

58 (7-)S-C3H1 (6-)NH~CI m.p. :83-84C

59 (7-)S{~H3 (6-) NH~ m.p. :18~185C

Cl (7-) S~c2Hs (6-) NH~ m.p.: 132-133C

Cl 61 (~) 5-C~H3 (7-) NH~ m.p. 202-203C

Cl 62 (7-)S~3H7 (6-)NH~CI m.p. :113-114C

Le A 28 421 - 54 -- 2~156~

Table 2 ( Continuation ) Example (Position-) (Position-) Physi~al No. S-R4 R1 data N--~ R2 Cl -63 (6-) S-CH3 (7-) NH~
Cl ~ m.p. :152C
(7-) S-CH3 (6-) NH~ J

(6-)S-CH3 (7-)NH~ F m.p.: 158-160C

(7-) S-CH3 (6-)NH~ F m.p. :102-103C

(7-) S-C3H7 (6-)NH~ F m . p .: 95- 96C

(6-)S-CH3 (7-)NH~CF3 m.p.: 141-143C

(7-) S-CH3 (6-)NH~ CF3 m . p .: i 80-181C

69 (~) S-CH3 (7-)NH~CF3 m.p .: 190-192C

(7-) S-CH3 (6-) NH~ m.p .: 165-167C

Le A 28 421 - 55 -2~71566 Table 2 ( Continuation ~

Exa}nple (Position-) (Po~ition-) Ply~i~al No~ S-R4 iRl data N

71 (6-)S-C3H7 (7-) NH~ m.p.: 126-128C

72 (7-) S-C3H7 (6-) NH~CF3 m . p .: 87- 88C

73 (~) S~H3 (7-) NH~ O~F3 m.p.: 15~155C

74 (7-)S-CH3 (6-) NH~oCF3 m.p.: 112-113C

(6-)S-C3H~ (7) NH~oCF3 m.p.: 154-155C

76 (7-)S-C3H7 (6-) NH~OCF3 m.p.: 108-109C

77 (~) S-CH3 (7-) NH~ SCF3 m . p . :143C
(7-) S-CH3 (6-) NH~ SCF3 J

Le A 28 421 - 56 -2~7~6 Table 2 (Continuation3 . . _ _ Example (Po~ition-) (Position-) Physi No. S-R4 -Rl data N
~2 _ 78 (6-)S-C3H7 (7~) NH ~ SCF3 ~ m.p.:103C
(7-)S-C3H7 (6-) NH ~ SCF3 J

79 (7-)S-CH3 (6-) ~ ~ m.p.: 11~115C

(7-)S-C3H7 (6-~ ~ ~ m.p : 92C

81 (7-)S-~H3 (6-) ~ ~ ~.p.: oil 82 (6-)S-cH3 (7~) ~ ~ m.p.:105-106C

83 (~)S~C3H7 (7) ~ ~ m.p.:l45-146C

Le A 28 421 - 57 -- 2~7~6 .
Table 2 (Continuation) Example (Position-) (Position-) Physi~
No. S-R4 ____-Rl data N
_ - -R

84 (6^)S-CH3 (7-) N~ 2 ~
~ m.P-:114C
(7-)S-CH3 (6-) NH-CH2 ~

(6-)S-C3H7 (7-) NH-CH2 ~ m.p.:125-127C

86 (7-)S-CH3 ~6-)NH-(cH2)2 ~ m.p.: 91-93C

87 (6-)S-C3H7 (+)-(7-)NH ~ CH3 m.p.: oil (7-)S-C3H7 (+)-(6-) NH ~ CH3 88 (6-)S-C3H7 (+)-(7-)NH ~

CH3 m.p.: oil (7-)S-C3H7 ~-(6-) NH

Le A 28 421 - 58 -2o7l5~6 Table 2 (Continuation) Example (Position-3 (Position-) Physi~l No. S-R~ N = R1 data 89 (7-) S-CH3 (6-) NH-(CH2)2-CF3 mOp~ 142-144C

(7-) S-CH3 (6-) NH-CH(C~I3)2 m.p.: 103-104C
91 (7-) S-CH3 (6-)NH-CH(CH3)-CF3 m.p. 102-103C

92 (7-) S-CH3 (6-) NH-CH(CH3)-C2H5 m.p. ol 93 (7-) S-CH3 (6-) NH-cH2-cH(cH3)2 m.p. 81-83C
94 (7-) S-CH3 (6-) NH-C(CH3)3 ` m.p. 66-68C

Le A 28 421 - 59 -~715~

Examples of the preparation of the starting substances Example ~IV-l~

7-Chloro-6-methoxy-quinoline-5,8-quinone HC O
H~ ~OCH3 2.0 g (0.029 mol) of potassium methanolate are added in portions to a suspension, cooled to 0 to -5C, of 6.6 g (0.029 mol) of 6,7-dichloro-quinoline-5,8-quinone in 200 ml of methanol. During this operation, a slight evolution of heat occurs. The mixture is then subsequently stirred at room temperature for a further 2 hours and the entire mixture is concentrated in vacuo. The residue which remains is washed with water and recrystallised from a little methanol. 4.5 g (69.4% of theory) of 7-chloro-6-methoxy-quinoline-5,8-quinone are obtained.
Melting point: 175-177C

lH-NMR (DMSO-d6, ~): 4.24 (s, 3H, -OCH3); 7.85 (dd, lH, HB; JE~B,E[A: 4.8 Hz; JH~,HC: 7.9 HZ); 8.38 (dd, lH, HC;
JHC,HB: 7.9 Hz, JE~C,HA: 1.7 HZ); 9.00 (dd, lH, ~IA; JHA,HC:
1.7 HZ; JHA,HB 4.8 Hz) ppm.

Le A 28 421 - 60 -, . .

Claims (12)

1. Use of 6(7)-amino-substituted quinoline-5,8-quinones of the general formula (I) (I) in which R1 represents substituted C1-C6-alkyl or optionally substituted cycloalkylalkyl, cycloalkyl, aralkyl or aryl, substituents which may be mentioned being halogen, nitro, alkyl, alkylamino, aminoacyl, aryl, aryloxy, arylthio, aralkyl, halo-genoalkyl, alkoxy, halogenoalkoxy, alkylthio, halogenoalkylthio, alkylsulphinyl, halogenoalkylsulphinyl, alkylsulphonyl or halogenoalkylsulphonyl, R2 represents hydrogen or alkyl, or R1 and R2, together with the adjacent N atom, represent a carbocyclic 5-, 6- or 7-membered ring, which can optionally also be interrupted by O, N
or S and is optionally substituted by C1-4-alkyl, R3 represents halogen or -S-R4 and R4 represents alkyl, for combating endoparasites in medicine and veterinary medicine.

2. Use according to claim 1, in which in the 6(7)-amino-substituted quinoline-5,8-quinone of formula (I) R1 represents substituted C1-C6-alkyl, or represents optionally substituted C3-C6-cycloalkyl-C1-C2-alkyl, C3-C6-cyclo-alkyl, phenyl-C1-C2-alkyl, naphthyl-C1-C2-alkyl or phenyl, substituents being one or more identical or different radicals from the group comprising C1-C4-alkyl, C1-C4-alkoxy, which are optionally substituted by fluorine or chlorine, Cl-C4-halogeno-alkoxy, C1-C4-alkylthio, C1-C4-halogenoalkylthio, C1-C4-alkyl-sulphonyl, C1-C4-halogenoalkylsulphonyl, C1-C4-halogenoalkyl, halogen, NO2, CN, amino, C1-C4-alkyl- or -dialkylamino, C1-C4-halogenoalkylamino, acylamino, and phenyl, phenylthio and phenoxy, which are optionally substituted by one of the above-mentioned radicals, R2 represents hydrogen or C1-C6-alkyl, or R1 and R2, together with the adjacent N atom, represent a carbocyclic 5-, 6- or 7-membered ring, which can optionally also be interrupted by O, N or S and is optionally substituted by C1-C4-alkyl, and R3 represents halogen, or C1-C4-alkylthio.

3. Use according to claim 2, in which in the 6(7)-amino-substituted quinoline-5,8-quinone of formula (I) R1 represents substituted C1-C6-alkyl, or represents optionally substituted C3-C6-cycloalkyl-C1-C2-alkyl, C3-C6-cycloalkyl, phenyl-C1-C2-alkyl, naphthyl-C1-C2-alkyl or phenyl, substituents being one or more identical or different radicals from the group comprising methyl or ethyl, methoxy, ethoxy, methylenedioxy or ethylenedioxy, which are optionally substituted by fluorine or chlorine, trifluoromethoxy, or fluorochloroethoxy, methylthio, trifluoromethylthio or fluorochloromethylthio, methyl-sulphonyl, trifluoromethylsulphonyl, trifluoromethyl, fluorine or chlorine, NO2, CN, amino, C1-C4-alkyl- or -dialkylamino, C1-C4-halogenoalkylamino, acetylamino, and phenyl, phenylthio and phenoxy, which are optionally substituted by one of the above-mentioned radicals.

4. Use according to claim 1, in which in the 6(7)-amino-substituted quinoline-5,8-quinone of formula (I) R1 represents substituted C1-C6-alkyl, or represents optionally substituted 1-cyclohexyl-ethyl, cyclopropyl, cyclo-pentyl, cyclohexyl, benzyl, 1-phenyl-ethyl, 1-naphthyl-ethyl or phenyl, substituents which may be mentioned being halogen, C1-C4-alkyl, C1-C4-halogenoalkyl, C1-C4-alkylthio, C1-C4-halogeno alkylthio, C1-C4-alkoxy, C1-C4-halogenoalkoxy, phenyl and NO2, R2 represents hydrogen and R3 represents chlorine or C1-C4-alkylthio.

5. Use according to claim 1, in which in the 6(7)-amino-substituted quinoline-5,8-quinone of formula (I) R1 represents substituted C1-C6-alkyl, or represents optionally substituted 1-cyclohexyl-ethyl, cyclopropyl, cyclo-pentyl, cyclohexyl, benzyl, 1-phenyl-ethyl, 1-naphthyl-ethyl or phenyl, substituents being chlorine or fluorine, methyl or ethyl, trifluoromethyl, methylthio, trifluoromethylthio, methoxy, trifluoromethoxy, phenyl and NO2, R2 represents hydrogen and R3 represents chlorine or methylthio, ethylthio or propylthio.

6. 6(7)-Amino-substituted quinoline-5,8-quinones of the general formula (I) (I) in which R3 represents halogen or alkylthio, when R3 represents halogen R1 represents cycloalkylalkyl or aralkyl, which are optionally substituted by halogen, nitro, alkyl, alkylamino, aminoacyl, aryl, aryloxy, arylthio, aralkyl, halogenoalkyl, alkoxy, halogenoalkoxy, alkylthio, halogenoalkylthio, alkyl-sulphinyl, halogenoalkylsulphinyl, alkylsulphonyl or halogeno-alkylsulphonyl and R2 represents hydrogen; and when R3 represents alkylthio R1 represents substituted C1-C6-alkyl or optionally substituted cycloalkylalkyl, cyclo-alkyl, aralkyl or aryl, substituents which may be mentioned being halogen, nitro, alkyl, alkylamino, aminoaryl, aryl, aryloxy, arylthio, aralkyl, halogenoalkyl, alkoxy, halogeno-alkoxy, alkylthio, halogenoalkylthio, alkylsulphinyl, halogeno-alkylsulphinyl, alkylsulphonyl or halogenoalkylsulphonyl and R2 represents hydrogen or alkyl, or R1 and R2 together with the adjacent N atom, represent a heterocyclic 5-, 6- or 7-membered ring which can optionally also be interrupted by O, N or S and is optionally substituted by C1-4-alkyl.

7. 6(7)-Amino-substituted quinoline-5,8-quinones of the general formula (Ia) (Ia) in which R1 represents cycloalkylalkyl or aralkyl, which are optionally substituted by halogen, nitro, alkyl, alkylamino, aminoacyl, aryl, aryloxy, arylthio, aralkyl, halogenoalkyl, alkoxy, halogenoalkoxy, alkylthio, halogenoalkylthio, alkyl-sulphinyl, halogenoalkylsulphinyl, alkylsulphonyl or halogeno-alkylsulphonyl, R2 represents hydrogen and Hal represents halogen.

8. 6(7)-Amino-substituted quinoline-5,8-quinones of the formula (Ib) (Ib) in which R1 represents substituted C1-C6-alkyl or optionally substituted cycloalkylalkyl, cycloalkyl, aralkyl or aryl, substituents which may be mentioned being halogen, nitro, alkyl, alkylamino, aminoaryl, aryl, aryloxy, arylthio, aralkyl, halogenoalkyl, alkoxy, halogenoalkoxy, alkylthio, halogenoalkyl-thio, alkylsulphinyl, halogenoalkylsulphinyl, alkylsulphonyl or halogenoalkylsulphonyl, R2 represents hydrogen or alkyl, or R1 and R2, together with the adjacent N atom, represent a carbocyclic 5-, 6- or 7-membered ring, which can optionally also be interrupted by 0, N
or S and is optionally substituted by C1-4-alkyl and R4 represents alkyl.

9. A process for preparing a 6(7)-amino-substituted quinoline-5,8-quinone of formula (I) as defined in claim 6, which process comprises:
(a) for preparing a compound of formula (I) in which R3 represents halogen, reacting a compound of the formula (II) (II) in which Hal represents halogen, with an amino compound of the formula (III) (III) in which R1 and R2 are as defined in claim 6 for the case where R3 represents halogen; or (b) for preparing a compound of formula (I) in which R3 represents halogen, reacting a compound of the formula (IV) (IV) in which Hal represents halogen and Alk represents lower alkyl, with an amino compound of formula (III) (III) in which R1 and R2 are as defined in claim 6 for the case where R3 represents halogen; or (c) for preparing a compound of formula (I) in which R3 represents alkylthio, reacting a compound of formula (Ia) (Ia) in which Hal represents halogen and R1 and R2 are as defined in claim 6 for the case where R3 represents alkylthio, with an alkali metal sulphide of the formula (V) M2S (V) wherein M represents a monovalent alkali metal cation, to form an alkali metal salt of formula (VI) (VI) and reacting the alkali metal salt of formula (VI) with an alkylating agent of formula (VII) R4-E (VII) in which R4 represents alkyl and E represents an electron-withdrawing leaving group; or (d) a compound of formula (Ia) (Ia) in which Hal represents halogen and R1 and R2 are as defined in claim 6 for the case where R3 represents alkylthio, with a thiol or an alkali metal salt thereof, of formula (VIII) R4-S-M+ (VIII) in which M represents hydrogen or one metal cation equivalent bonded in salt form and R4 represents alkyl.

10. An endoparasiticidal agent which comprises a 6(7)-amino-substituted quinoline-5,8-quinone of formula (I) as defined in any one of claims 1 to 8, together with a suitable diluent or carrier.

11. A process for preparing an endoparasiticidal agent which comprises admixing a 6(7)-amino-substituted quinoline-5,8-quinone of formula (I) as defined in any one of claims 1 to 8, together with a suitable diluent or carrier.

12. A commercial package containing as active pharma-ceutical ingredient a 6(7)-amino-substituted quinoline-5,8-quinone of formula (I) as defined in any one of claims 1 to 8, together with instructions for its use in combating endoparasites.