WO2014044615A1

WO2014044615A1 - Dihydroquinolinone derivatives

Info

Publication number: WO2014044615A1
Application number: PCT/EP2013/069027
Authority: WO
Inventors: Noëlle GAUVRY; Christoph Kempter; François PAUTRAT; Ulrich Roos
Original assignee: Novartis Ag
Priority date: 2012-09-18
Filing date: 2013-09-13
Publication date: 2014-03-27

Abstract

The present invention relates to new dihydroquinolinone derivatives as defined in formula (I), as well as to a new process for the manufacture of dihydroquinolinone derivatives. The invention further relates to the use of said dihydroquinolinone derivatives as pesticide.

Description

DIHYDROQUINOLINONE DERIVATIVES

The present invention relates to new dihydroquinolinone derivatives, as well as to a new process for the manufacture of dihydroquinolinone derivatives.

The invention further relates to the use of said dihydroquinolinone derivatives as pesticides, in particular for combating ectoparasites, including insects, particularly acarina and especially ticks, on non-human animals. The invention further relates to compositions containing said dihydroquinolinone derivatives, a method of controlling ectoparasites, whereby an effective amount of at least one dihydroquinolinone derivative of formula (I) is administered to the habitat of the parasites.

Dihydroquinolinone derivatives generally are known natural compounds that have been published under a variety of different names, such as Dihydroquinolinones, Quinolinones, Penigequinolones, Peniprequinolone, Yaequinolones, Aspoquinolones or FKI-2140 derivatives. In the following the name dihydroquinolinone derivatives will be used.

Dihydroquinolinone derivatives generally can be prepared in accordance with the preparation processes described in the literature. Certain Dihydroquinolinone derivatives were isolated from the culture broth of Penicillium sp. FKI-2140 (Ryuji Uchida et al., 'Yaequinolones, New Insecticidal Antibiotics Produced by Penicillium sp. FKI-2140', J.

Antibiot. 59(10): 646-658 (2006); and WO2006/059400) or by the fungus Penicillium cf. simplicissimum (Miyako Kusano et al., 'Nematicidal Alkaloides and Related Compounds Produced by the Fungus Penicillium cf. simplicissimum. Biosci. Biotechnol. Biochem., 64 (12), 2559-2568 (2000)). Others were produced by the fungus Aspergillus nidulans

(DE102006006893).

It was reported in various articles and in patent literature that some dihydroquinolinones exhibit a pronounced biological activity against Artemia salina, which is the brine shrimp.

PCT application WO2002/26713 very generally discloses quinolinone compounds, which are structurally different from dihydroquinolinone compounds, to be useful in the

manufacture of a pharmaceutical composition for the treatment or prophylaxis of infections caused by helminths or arthropod ectoparasites. PCT application PCT/EP2008/065033 (unpublished) describes the use of particular dihydroquinolinone derivatives of the formula (A) below and the stereoisomers thereof, for combating ectoparasites on non-human animals, and especially for combating ticks on farm animals or pet animals.

wherein

OR14 is OH or OCH₃;

R1 is H or OH;

R2 is H or one of the following side chains G1 , G16, G15, G14, G13 G12, G1 1 , G10, G9

OH, CH₀ O

H₃C- :C C ; H,C— C— C=C or μ C— C— C=C

H H„ H H ³ H H or the group R1 and the substituent R2 form together with the carbon atoms a and b of the phenyl group to which they are attached the following substituent H3

whereby said compounds of formula (A) are in free form or salt form.

The following dihydroquinolone compounds, referring with their substituents to general formula (A), are known in the art:

Table 1

Although the harmful effects of a tick infestation on animals have been known for years, and enormous progress has been made using tick-control programs, until now no completely satisfactory methods of controlling or eliminating these parasites have been found. In addition, ticks have often developed resistance to chemical active ingredients. The present invention now relates to new dihydroquinolinone derivatives of formula (I) and the stereoisomers thereof, whereby said compounds of formula (I) are in free form or salt form in accordance with independent claim 1 .

Preferably, the present invention relates to new dihydroquinolinone derivatives of formula (II) or (III) and the stereoisomers thereof, whereby said compounds of formula (II) or (III) are in free form or salt form in accordance with the dependent claims.

The present invention further relates to a process for the manufacture of dihydroquinolinone derivatives of formula (I), as well as to processes for the manufacture of starting materials, and to intermediates used in said process.

Further, the present invention relates to the use of compounds of the formula (I) as pesticides, in particular as acaricides or insecticides.

Salts of compounds of the formula (I) may be produced in known manner. Acid addition salts, for example, are obtainable from compounds of formula (I) by treating with a suitable acid or a suitable ion exchange reagent, and salts with bases are obtainable by treating with a suitable base or a suitable ion exchange reagent.

Salts of compounds of the formula (I) can be converted into the free compounds by the usual means, acid addition salts e.g. by treating with a suitable basic composition or with a suitable ion exchange reagent, and salts with bases e.g. by treating with a suitable acid or a suitable ion exchange reagent.

Salts of compounds of the formula (I) can be converted into other salts of compounds in a known manner; acid addition salts can be converted for example into other acid addition salts, e.g. by treating a salt of an inorganic acid, such as a hydrochloride, with a suitable metal salt, such as a sodium, barium, or silver salt, of an acid, e.g. with silver acetate, in a suitable solvent, in which a resulting inorganic salt, e.g. silver chloride, is insoluble and thus precipitates out from the reaction mixture. Depending on the method and/or reaction conditions, compounds of the formula (I) with salt-forming characteristics can be obtained in free form or in the form of salts.

Specific but non-limiting examples of compounds according to the invention of the formula (I) are the compounds B1 to B21 , C1 to C3, D1 to D26, E1 , E2, H1 and H2 shown in table 2.

The group of compounds D1 to D26 as well as each individual compound D1 to D26 within the group are preferred embodiments of the present invention.

The compounds B2, B18, B19, C1 , C3, D16 and D26 are individually preferred because of their pesticidal activity. The compounds D16 and D26 are individually most preferred because of their pesticidal activity.

The compounds of the formula (I) contain several asymmetric carbon atoms or stereo centers. Consequently, these compounds may be optionally present as optical and/or geometric isomers or as a mixture thereof. The invention relates both to the pure isomers and to all possible isomeric mixtures, and is hereinbefore and hereinafter understood as doing so, even if stereochemical details are not specifically mentioned.

Diastereoisomeric mixtures of compounds of the formula (I) , which are obtainable, may be separated in known manner, on the basis of the physical-chemical differences in their components, into the pure diastereoisomers, for example by fractional crystallization, distillation and/or chromatography.

Splitting of mixtures of enantiomers, that are obtainable accordingly, into the pure isomers, may be achieved by known methods, for example by recrystallization from an optically active solvent, by chromatography on chiral adsorbents, e.g. high-pressure liquid chromatography (HPLC) on acetyl cellulose, with the assistance of appropriate microorganisms, by cleavage with specific immobilized enzymes, through the formation of inclusion compounds, e.g. using chiral crown ethers, whereby only one enantiomer is complexed. According to the invention, apart from separation of corresponding isomer mixtures, generally known methods of diastereoselective or enantioselective synthesis can also be applied to obtain pure diastereoisomers or enantiomers, e.g. by carrying out the method of the invention using educts with correspondingly suitable stereochemistry.

It is advantageous to isolate or synthesize the biologically more active isomer, e.g.

enantiomer, provided that the individual components have differing biological efficacy.

It has now surprisingly been found that the compounds of formula (I) and the individual representatives as defined above exhibit a pronounced pesticidal activity, in particular against a series of ectoparasites on non-human animals, for example against

representatives of the order acarina including ticks and mites, especially against ticks. They also exhibit a decent activity against blood-sucking insects, in particular fleas such as dog and cat fleas.

The good pesticidal activity of the compounds of formula (I) according to the invention corresponds to a mortality rate of at least 50-60% of the pests mentioned, more preferably to a mortality rate over 90%, most preferably to 95-100%.

The compounds of formula (I) are preferably employed internally and externally in unmodified form or preferably together with the adjuvants conventionally used in the art of formulation and may therefore be processed in a known manner to give, for example, liquid formulations (e.g. spot-on, pour-on, spray-on, emulsions, suspensions, solutions, emulsifiable concentrates, solution concentrates), semi-solid formulations (e.g. creams, ointments, pastes, gels, liposomal preparations) and solid preparations (e.g. food additives tablets including e. g. capsules, powders including soluble powders, granules, embeddings of the active ingredient in polymeric substances, like implants and microparticles). As with the compositions, the methods of application are selected in accordance with the intended objectives and the prevailing circumstances.

The formulation, i.e. preparations containing the active ingredient of formula (I) , or combinations of these active ingredients with other active ingredients, and optionally a solid, semi-solid or liquid adjuvant, are produced in a manner known per se, for example by intimately mixing, kneading or dispersing the active ingredients with compositions of excipients, whereby the physiological compatibility of the formulation excipients must be taken into consideration. The solvents in question may be, for example: alcohols (aliphatic and aromatic), such as benzylalcohol, ethanol, propanol, isopropanol or butanol, fatty alcohols, such as oleyl alcohol and glycols and their ethers and esters, such as glycerin, propylene glycol, dipropylene glycol ether, ethylene glycol, ethylene glycol monomethyl or -ethyl ether and butyl dioxytol, ketones, such as propylene carbonate, cyclohexanone, isophorone or diacetanol alcohol and polyethylene glycols, such as PEG 300. In addition, the

compositions may comprise strong polar solvents, such as N-methyl-2-pyrrolidone, dimethyl sulfoxide or dimethylformamide, or water, fatty acid esters, such as ethyl oleate or isopropylpalmitate, vegetable oils, such as rape, castor, coconut, or soybean oil, synthetic mono-, di-, triglycerides like e.g. glyceryl monostearate and medium chain triglycerides and also, if appropriate, silicone oils. The mentioned ingredients may also serve as carrier for particulate application forms.

As ointment base resp. structure building ingredients the following excipients may be used: Petroleum based substances, such as Vaseline or paraffines, bases made from wool fat, like e.g. lanolin or lanolin alcohols, polyethylene glycols like e.g. macrogols and lipid bases like e.g. phospholipids or triglycerids, such as hydrogenated vegetable oils.

The use of emulsifiers, wetting agents and spreading agents may also be required, in general, lecithins like soy lecithin, salts of fatty acids with alkaline earth and alkali metals, alkyl sulfates like sodium cetylstearyl sulphate, cholates, fatty alcohols like cetyl alcohol, sterols like cholesterol, polyoxyethylene sorbitan fatty acid esters like polysorbate 20, sorbitan fatty acid esters like sorbitan mono laureate, fatty acid esters and fatty alcohol ethers of polyoxyethylene like poloxyl oleyl ether, polyoxypropylene polyoxyethylene block copolymers as e.g. Pluronic™ , saccharose esters like saccharose distearate, polyglyceryl fatty acid esters like polyglycerol oleate and fatty acid esters like e.g. ethyl oleate or isopropylmyristate.

The formulations may also include gelifying and stiffening agents, like e.g. polyacrylic acid derivatives, cellulose ethers, polyvinyl alcohols, polyvinylpyrrolidone and fine disperse silicium dioxide.

As polymeric agents with controlled release properties, may be applied derivatives made by e.g. polylactic acid, polylactic coglycolic acid, poly orthoester, polyethylene carbonate, poly anhydrids and starch and PVC based matrices.

The addition of penetration enhancers like ketons, sulfoxids, amids, fatty acid esters and fatty alcohols may be necessary. Also preservatives like sorbic acid, benzyl alcohol and parabenes, and antioxidants as e.g. alpha tocopherol may be added. The active ingredient or combinations of the active ingredient may be also applied in capsules, like hard gelatin capsules or soft capsules.

The binders for tablets and boli may be chemically modified polymeric natural substances that are soluble in water or in alcohol, such as starch, cellulose or protein derivatives (e.g. methyl cellulose, carboxymethyl cellulose, ethylhydroxyethyl cellulose, proteins such as zein, gelatin and the like), as well as synthetic polymers, such as polyvinyl alcohol, polyvinyl pyrrolidone etc. The tablets also contain fillers (e.g. starch, microcrystalline cellulose, sugar, lactose etc.), glidants (e.g. magnesium stearate) and disintegrants (e.g. cellulose derivatives) and acid resistant coatings, like e.g. acrylic acid esters.

The compounds of formula (I) according to the invention may be used alone or in combination with other biocides. They may be combined with pesticides having the same sphere of activity e.g. to increase activity, or with substances having another sphere of activity e.g. to broaden the range of activity. It can also be sensible to add so-called repellents. By combining the compounds of the formula (I) with other suitable parasiticides not only the parasiticidal activity can be enhanced but the greatest part of those parasites that produce great economic damage will be covered. Moreover, this action will contribute substantially to avoiding the formation of resistance. Many combinations may also lead to synergistic effects, i.e. the total amount of active ingredient can be reduced, which is desirable from an ecological point of view.

Suitable combination partners in the mixture may be biocides, e.g. the insecticides and acaricides with a varying mechanism of activity, which are named in the following and have been known to the person skilled in the art for a long time, e.g. chitin synthesis inhibitors, growth regulators; active ingredients which act as juvenile hormones; active ingredients which act as adulticides; broad-band insecticides, broad-band acaricides and nematicides; and also the well known anthelminthics and insect- and/or acarid-deterring substances, said repellents or detachers.

As a rule, the pesticidal compositions according to the invention contain 0.1 to 99 % by weight, especially 0.1 to 95 % by weight of active ingredient of formula (I), or mixtures thereof, 99.9 to 1 % by weight, especially 99.8 to 5 % by weight of a solid or liquid admixture.

Application of the compounds and compositions according to the invention to the animals to be treated may take place topically, perorally, parenterally or subcutaneously, the composition being present in the form of solutions, emulsions, suspensions, (drenches), powders, tablets, boli, capsules, collars, ear tags and pour-on formulations.

Preferred topical formulations are understood to refer to a ready-to-use solution in form of a spot-on, pour-on or spray-on formulation often consisting of a dispersion or suspoemulsion or a combination of active ingredient and spreading auxiliaries. The expression spot-on or pour-on method is understood to refer to a ready-to-use concentrate intended to be applied topically and locally on the animal. This sort of formulation is intended to be applied directly to a relatively small area of the animal, preferably on the animal's back and breech or at one or several points along the line of the back and breech. It is applied as a low volume of 0.05 to 1 ml per kg, preferably about 0.1 ml per kg, with a total volume from 1 to 100 ml per animal, preferably limited to a maximum of about 50 ml. However, it goes without saying that the total volume has to be adapted to the animal that is in need of the treatment and will clearly be different, for example, in young cats and in cattle. These pour-on and spot-on formulations are designed to spread all around the animal giving protection or treatment to almost any part of the animal. Even so the administration is carried out by applying a swab or spray of the pour-on or spot-on formulation to a relatively small area of the coat, one observes that from the active substance is dispersed almost automatically over wide areas of the fur owing to the spreading nature of the components in the formulation and assisted by the animal's movements.

Pour-on or spot-on formulations suitably contain carriers, which promote rapid distribution over the skin surface or in the coat of the host animal, and are generally regarded as spreading oils. Suitable carriers are e.g. oily solutions; alcoholic and isopropanolic solutions such as solutions of 2-octyldodecanol or oleyl alcohol; solutions in esters of monocarboxylic acids, such as isopropyl myristate, isopropyl palmitate, lauric acid oxalate, oleic acid oleyl ester, oleic acid decyl ester, hexyl laurate, oleyl oleate, decyl oleate, capric acid esters of saturated fat alcohols of chain length Ci₂-Ci₈; solutions of esters of dicarboxylic acids, such as dibutyl phthalate, diisopropyl isophthalate, adipic acid diisopropyl ester, di-n-butyl adipate or also solutions of esters of aliphatic acids, e.g. glycols. It may be advantageous for a dispersing agent to be additionally present, such as one known from the pharmaceutical or cosmetic industry. Examples are 2-pyrrolidone, 2-(N-alkyl)pyrrolidone, acetone,

polyethylene glycol and the ethers and esters thereof, propylene glycol or synthetic triglycerides.

The oily solutions include e.g. vegetable oils such as olive oil, groundnut oil, sesame oil, pine oil, linseed oil or castor oil. The vegetable oils may also be present in epoxidised form. Paraffins and silicone oils may also be used.

A pour-on or spot-on formulation generally contains 1 to 40 %, preferably 10 to 25% by weight of a compound of formula (I), 0 to 50 % by weight of dispersing agent and 10 to 99 %, preferably 45 to 90% by weight of solvent. The pour-on or spot-on method is especially advantageous for use on herd animals such as cattle, horses, sheep or pigs, in which it is difficult or time-consuming to treat all the animals orally or by injection. Because of its simplicity, this method can of course also be used for all other animals, including individual domestic animals or pets, and is greatly favored by the keepers of the animals, as it can often be carried out without the specialist presence of the veterinarian.

Whereas it is preferred to formulate commercial products as concentrates, the end user will often use dilute formulations. However, this depends on the mode of administration. Orally administered products are most often used in diluted form or as feed additives, whereas commercial pour-on and spot-on formulations are normally ready-to-use concentrates.

Such compositions may also contain further additives, such as stabilizers, anti-foaming agents, viscosity regulators, binding agents or tackifiers, as well as other active ingredients, in order to achieve special effects. Pesticidal compositions of this type, which are used by the end user, similarly form a constituent of the present invention.

In each of the processes according to the invention for pest control or in each of the pest control compositions according to the invention, the active ingredients of formula (I) can be used in all of their steric configurations or in mixtures thereof. Preferably the active ingredient is used in the steric configuration represented by formula (I^*).

The invention also includes a method for prophylactically protecting animals, especially productive livestock, domestic animals and pets, against parasites which is characterized in that the active ingredients of formula (I) or the active ingredient composition prepared therefrom are administered to the animals as an additive to the feed, or to the drinks or also in solid or liquid form, orally, as pour-on or spot-on, by injection or parenterally. The invention also includes the compounds of formula (I) according to the invention for usage in one of the said processes.

Preferred embodiments within the present invention are:

I.) Compounds of the formula (I) and the stereoisomers thereof, whereby said compounds are in the free form or a salt form, characterized in that formula (I) is

wherein

R1 is H, OH, halogen, d-C₆-alkyl, CrC₆-haloalkyl, CrC₆-alkoxy (preferably methoxy), C C₆-haloalkoxy, CrC₆-alkylthio, CrC₆-haloalkylthio, CrC₆-alkylsulfinyl, CrC₆- haloalkylsulfinyl, CrC₆-alkylsulfonyl, CrC₆-haloalkylsulfonyl, SF₅, N-(Ci-C₆-alkyl)amino, N,N-di-(Ci-C₆-alkyl)amino, N-(Ci-C₆-haloalkyl)amino, N,N-di-(Ci-C₆-haloalkyl)amino, C₂- C₆-haloalkoxycarbonyl, C₂-C₆-alkoxycarbonyl, cyano, formyl, nitro, phenyl (which may be substituted with 1 to 4 halogen atoms and/or 1 to 3 methoxy groups or which may be unsubstituted) or a 5- to 6-membered heterocycle (which have from 1 to 3 oxygen atoms, 1 to 3 nitrogen atoms and/or 1 to 3 sulfur atoms in the heterocycle, and which may be substituted or unsubstituted), or tris-(CrC₆-alkyl)-silyl (preferably t-butyl-di- methyl-silyl);

or -O-CH₂-X; wherein X is, CrC₆-alkenyl, CrC₆-alkinyl, CrC₆-alkoxy (preferably methoxy), CO-NR'R" (wherein R' and R" independently are hydrogen or CrC₆-alkyl or R' and R" together form a ring, which is either an N-morpholino or N-pyrrolidino ring), COOR'" (wherein R'" is CrC₄-alkyl, preferably is CH₃), phenyl (which may be substituted by H, OH, halogen (preferably chloro), CrC₆-alkyl (preferably methyl), d- C₆-haloalkyl (preferably trifluoromethyl), CrC₆-alkoxy (preferably methoxy), Ci-C₆- haloalkoxy, CrC₆-alkylthio, CrC₆-haloalkylthio, CrC₆-alkylsulfinyl, CrC₆- haloalkylsulfinyl, CrC₆-alkylsulfonyl, SF₅, CrC₆-haloalkylsulfonyl, N-(Ci-C₆-alkyl)amino, N,N-di-(Ci-C₆-alkyl)amino, N-(Ci-C₆-haloalkyl)amino, N,N-di-(Ci-C₆-haloalkyl)amino, C₂- C₆-haloalkoxycarbonyl, C₂-C₆-alkoxycarbonyl, acetamido, cyano, formyl, nitro or tris-(Ci- C₆-alkyl)-silyl (preferably t-butyl-di-methyl-silyl)) or a 5- to 6-membered heterocycle (which have from 1 to 3 oxygen atoms, 1 to 3 nitrogen atoms and/or 1 to 3 sulfur atoms in the heterocycle, and which may be substituted as the phenyl above or unsubstituted);

or -0-Si-(Y)₃, wherein each Y, indepedent of each other, is CrC₆-alkyl, CrC₆-alkenyl, CrC₆-haloalkyl, phenyl, benzyl;

is H, halogen (preferably bromo or chloro), formyl, CrC₆-alkyl (preferably methyl or propyl), CrC₆-alkylen (preferably 2-propylen), or phenyl (which may be substituted with 1 to 4 halogen atoms and/or 1 to 3 methoxy groups or which may be unsubstituted) or one of the following side chains G1 to G25

or the group R1 and the substituent R2 form together with the carbon atoms a and b of the phenyl group to which they are attached one of the following substituents H 1 , H2 or H3

H1 H2 H3

R3 and R4 independently of each other are hydrogen, CrC₆-alkyl, CrC₆-haloalkyl, CrC₆- alkoxy, CrC₆-haloalkoxy, CrC₆-alkylthio, CrC₆-haloalkylthio, CrC₆-alkylsulfinyl, CrC₆- haloalkylsulfinyl, CrC₆-alkylsulfonyl, CrC₆-haloalkylsulfonyl, SF₅, N-(Ci-C₆-alkyl)amino, N,N-di-(Ci-C₆-alkyl)amino, N-(Ci-C₆-haloalkyl)amino, N,N-di-(Ci-C₆-haloalkyl)amino, C₂- C₆-alkoxycarbonyl, C₂-C₆-haloalkoxycarbonyl, cyano, OH; preferably H;

R10 is hydrogen, CrC₆-alkyl; preferably H;

OR14 is -Ci-C₃-alkoxy, preferably -OCH₃;

R12 is H, an alkyl-alkoxy type prodrug moiety or a carbamate type prodrug moiety,

preferably H, -CH₂-0-(CrC₆-alkyl) ,-CH(CH₃)-0-(Ci-C₆-alkyl) or

-COO-CH₂-0-(Ci-C₆-alkyl), more preferably H;

R13 is phenyl which may be substituted or unsubstituted (preferably substituted with one methoxy group, most preferably one methoxy group in para position), or thiophen which may be substituted or unsubstituted, wherein the subtituents for phenyl and thiophen are selected from H, OH, halogen (preferably chloro), CrC₆-alkyl (preferably methyl), CrC₆-haloalkyl (preferably trifluoromethyl), CrC₆-alkoxy (preferably methoxy), Ci-C₆- haloalkoxy, CrC₆-alkylthio, CrC₆-haloalkylthio, CrC₆-alkylsulfinyl, CrC₆- haloalkylsulfinyl, CrC₆-alkylsulfonyl, CrC₆-haloalkylsulfonyl, SF₅, N-(Ci-C₆-alkyl)amino, N,N-di-(Ci-C₆-alkyl)amino, N-(Ci-C₆-haloalkyl)amino, N,N-di-(Ci-C₆-haloalkyl)amino, C₂- C₆-haloalkoxycarbonyl, C₂-C₆-alkoxycarbonyl, acetamido, cyano, formyl, nitro, phenyl (which may be substituted with 1 to 4 halogen atoms and/or 1 to 3 methoxy groups or which may be unsubstituted) or a 5- to 6-membered heterocycle (which have from 1 to 3 oxygen atoms, 1 to 3 nitrogen atoms and/or 1 to 3 sulfur atoms in the heterocycle, and which may be substituted as the phenyl above or which may be unsubstituted), or tris-(CrC₆-alkyl)-silyl (preferably t-butyl-di-methyl-silyl);

R15 is H or -CrC₆-alkyl, tris-(CrC₆-alkyl)-silyl, preferably H or t-butyl-di-methyl-silyl, most preferably H;

with the proviso that R1 is not H, for compounds of formula (I) wherein

R2, R3, R4, R10, R12 and R15 are H;

OR14 is -OCHs,

R13 is 4-methoxyphenyl, and with the proviso that R1 is not OH, for compounds of formula (I) wherein

R2 is H, or one of the side chains G1 , G9, G10, G1 1 , G12, G13, G14, G15 or G16,

R3, R4, R10, R12 and R15 are H; OR14 is -OCHs,

R13 is 4-methoxyphenyl, and with the proviso that for compounds of formula (I) wherein

R3, R4, R10, R12 and R15 are H;

OR14 is -OCHs,

R13 is 4-methoxyphenyl, and

the group R1 and the substituent R2 together with the carbon atoms a and b of the phenyl group to which they are attached do not form the following substituent

H3

II.) Compounds of formula (II)

wherein

R1 , R2, R3, R4, R10, R14 and R15 are defined as in the preceding claim; and

R5, R6, R7, R8 and R9, independently of each other, are H, OH, halogen (preferably chloro), CrC₆-alkyl (preferably methyl), CrC₆-haloalkyl (preferably trifluoromethyl), d-C₆-alkoxy (preferably methoxy), CrC₆-haloalkoxy, Ci-C₆- alkylthio, CrC₆-haloalkylthio, CrC₆-alkylsulfinyl, CrC₆-haloalkylsulfinyl, CrC₆- alkylsulfonyl, CrC₆-haloalkylsulfonyl, SF₅, N-(Ci-C₆-alkyl)amino, N,N-di-(C C₆- alkyl)amino, N-(Ci-C₆-haloalkyl)amino, N,N-di-(Ci-C₆-haloalkyl)amino, C₂-C₆- haloalkoxycarbonyl, C₂-C₆-alkoxycarbonyl, acetamido, cyano, formyl, nitro, phenyl (which may be substituted with 1 to 4 halogen atoms and/or 1 to 3 methoxy groups or which may be unsubstituted) or a 5- to 6-membered heterocycle (which have from 1 to 3 oxygen atoms, 1 to 3 nitrogen atoms and/or 1 to 3 sulfur atoms in the heterocycle, and which may be substituted as the phenyl above or which may be unsubstituted), or tris-(CrC₆-alkyl)-silyl (preferably t-butyl-di-methyl-silyl); preferably H, OH, -CrC₃-alkyl or -Ci-C₃- alkoxy, most preferably R5,R6,R8 and R9 are H and R7 is methoxy;

R12 is H, -CH₂-0-(CrC₆-alkyl) ,-CH(CH₃)-0-(Ci-C₆-alkyl) or

-COO-CH₂-0-(Ci-C₆-alkyl), preferably H. Compounds of formul

wherein

R7 is H, OH or -CrC₃-alkoxy, preferably methoxy

R12 is H, -CH₂-0-(CrC₆-alkyl) ,-CH(CH₃)-0-(Ci-C₆-alkyl) or

-COO-CH₂-0-(Ci-C₆-alkyl), preferably H;

R14 is Methyl;

R15 is H or t-butyl-di-methyl-silyl, preferably H;

R1 is halogen, CrC₆-alkyl, CrC₆-haloalkyl, d-C₆-alkoxy (preferably methoxy), Ci-C₆- haloalkoxy, CrC₆-alkylthio, CrC₆-haloalkylthio, CrC₆-alkylsulfinyl, CrC₆- haloalkylsulfinyl, CrC₆-alkylsulfonyl, CrC₆-haloalkylsulfonyl, SF₅, N-(CrC₆- alkyl)amino, N,N-di-(Ci-C₆-alkyl)amino, C₂-C₆-alkoxycarbonyl, cyano, formyl, nitro, phenyl (which may be substituted with 1 to 4 halogen atoms and/or 1 to 3 methoxy groups or which may be unsubstituted) or a 5- to 6-membered heterocycle (which have from 1 to 3 oxygen atoms, 1 to 3 nitrogen atoms and/or 1 to 3 sulfur atoms in the heterocycle, and which may be substituted as the phenyl above or which may be unsubstituted),

or -O-CH₂-X, wherein X is, CrC₆-alkenyl, CrC₆-alkinyl, CrC₆-alkoxy (preferably methoxy), CO-NR'R" (wherein R' and R" independently are hydrogen or CrC₆- alkyl or R' and R" together form a ring, which is either an N-morpholino or N- pyrrolidino ring), COOR'" (wherein R'" is CrC₄-alkyl, preferably is CH₃), phenyl (which may be substituted by H, OH, halogen (preferably chloro), CrC₆-alkyl (preferably methyl), CrC₆-haloalkyl (preferably trifluoromethyl), CrC₆-alkoxy (preferably methoxy), CrC₆-haloalkoxy, CrC₆-alkylthio, CrC₆-haloalkylthio, Ci-C₆- alkylsulfinyl, CrC₆-haloalkylsulfinyl, CrC₆-alkylsulfonyl, CrC₆-haloalkylsulfonyl, SF₅, N-(CrC₆-alkyl)amino, N,N-di-(Ci-C₆-alkyl)amino, N-(Ci-C₆-haloalkyl)amino, N,N-di-(Ci-C₆-haloalkyl)amino, C₂-C₆-haloalkoxycarbonyl, C₂-C₆-alkoxycarbonyl, acetamido, cyano, formyl, nitro or tris-(Ci-C₆-alkyl)-silyl (preferably t-butyl-di- methyl-silyl)) or a 5- to 6-membered heterocycle (which have from 1 to 3 oxygen atoms, 1 to 3 nitrogen atoms and/or 1 to 3 sulfur atoms in the heterocycle, and which may be substituted as the phenyl above or which may be unsubstituted); or -0-Si-(Y)₃, wherein each Y, indepedent of each other, is CrC₆-alkyl, Ci-C₆- alkenyl, CrC₆-haloalkyl, phenyl, benzyl;

R2 is H, halogen (preferably chloro), formyl, d-C₆-alkyl (preferably methyl or propyl), CrC₆-alkylen (preferably 2-propylen), or phenyl (which may be substituted with 1 to 4 halogen atoms and/or 1 to 3 methoxy groups or which may be unsubstituted); or one of the side chains G1 to G24 as defined as in claim 1 ;

or the group R1 and the substituent R2 form together with the carbon atoms a and b of the phenyl group to which they are attached one of the following substituents H1 or

H2 as defined in claim 1.

Preferred compounds of formula (III) are compounds wherein R7 is methoxy; R12 is H;

R14 is Methyl; R15 is H or t-butyl-di-methyl-silyl, preferably H;

R1 is -O-CH₂-X, wherein X is, CrC₆-alkenyl, CrC₆-alkinyl, CrC₆-alkoxy (preferably methoxy), CO-NR'R" (wherein R' and R" independently are hydrogen or CrC₆- alkyl or R' and R" together form a ring, which is either an N-morpholino or N- pyrrolidino ring), COOR'" (wherein R'" is CrC₄-alkyl, preferably is CH₃), phenyl (which may be substituted by H, OH, halogen (preferably chloro), CrC₆-alkyl (preferably methyl), CrC₆-haloalkyl (preferably trifluoromethyl), CrC₆-alkoxy (preferably methoxy), CrC₆-haloalkoxy, CrC₆-alkylthio, CrC₆-haloalkylthio, Ci-C₆- alkylsulfinyl, CrC₆-haloalkylsulfinyl, CrC₆-alkylsulfonyl, CrC₆-haloalkylsulfonyl, SF₅, N-(Ci-C₆-alkyl)amino, N,N-di-(Ci-C₆-alkyl)amino, N-(Ci-C₆-haloalkyl)amino, N,N-di-(Ci-C₆-haloalkyl)amino, C₂-C₆-haloalkoxycarbonyl, C₂-C₆-alkoxycarbonyl, acetamido, cyano, formyl, nitro or tris-(CrC₆-alkyl)-silyl (preferably t-butyl-di- methyl-silyl)) or a 5- to 6-membered heterocycle (which have from 1 to 3 oxygen atoms, 1 to 3 nitrogen atoms and/or 1 to 3 sulfur atoms in the heterocycle, and which may be substituted or unsubstituted);

or -0-Si-(Y)₃, wherein each Y, indepedent of each other, is CrC₆-alkyl, Ci-C₆- alkenyl, CrC₆-haloalkyl, phenyl, benzyl;

R2 is H, halogen (preferably chloro), CrC₆-alkyl (preferably methyl or propyl), CrC₆- alkylen (preferably 2-propylen), or phenyl (which may be substituted with 1 to 4 halogen atoms and/or 1 to 3 methoxy groups or which may be unsubstituted); or one of the following side chains G1 to G25 as defined as in the preceding claims.

V. ) Most preferred compound of formula (I), (I^*), (II), (III) and (III^*) are compounds wherein

R2 is one of the side chains G1 or G12 as defined above.

VI. ) Particularly preferable are compounds selected from the group consisting of the

compounds C1 to C3, B1 to B21 , D1 to D26, E1 , E2, H1 and H2 of table 2.

VII. ) Especially preferred compounds have the stereochemical configuration (I^*)

VIII). Further especially preferred compounds have the stereochemical configuration (III^*)

In another aspect the present invention relates to a process for the manufacture of dihydroquinolinone derivates characterized by the following reaction step

wherein R1 to R4 and R10 to R14 are as defined above in I.) to VIII).

The invention further relates to a process according to IX.) wherein the ortho- aminoketones as starting materials are provided by the following reaction step

wherein R1 to R4 and R10 to R14 are as defined above in I.) to VIII).

XI.) In yet another aspect the present invention relates to ortho-aminoketone compounds for the use as starting material in a process according to IX.), wherein said compounds are of the formula

wherein R1 , R2, R3, R4, R10, R12, R13 and R14 are as defined above in I.) to VIII). XII. ) In still another aspect the present invention relates to the use of a compound according to any one of I.) to VIII.) as pesticides, preferably to the use as acaricides or insecticides.

XIII. ) A further embodiment of the present invention is a composition comprising a

compound as defined in I.) to VIII.) together with a carrier or diluent that is

physiologically acceptable to non-human animals.

XIV. ) Another embodiment of the present invention is the use of compounds according to any one of I.) to VIII.) for combating ectoparasites on non-human animals, in particular acarina, preferably ticks.

XV. ) In still another embodiment the present invention relates to a method of controlling ectoparasites, in particular acarina, preferably ticks, on non-human animals, characterized in that an effective amount of at least one compound as defined in any one of I.) to VIII.) is administered to the habitat of the parasites.

The following examples serve to illustrate the invention. The starting substances used may be produced by methods described in literature or are commercially available.

Preparation of compound A11

The filamentous fungus Penicillium scabrosum (e.g. CBS-305.97) is grown in 500 ml flasks containing 250 ml of a liquid medium consisting of malt extract (20 g/L), Glucose (20 g/L) and Peptone (1 g/L). After 3 days of incubation at 24°C at 150 rpm, these cultures are used to inoculate production flasks containing Rice grains or a liquid medium. The liquid medium consist of Soymeal (20 g/L) and Mannitol (20 g/L) and is adjusted to a pH7 prior to sterilisation. Cultivation is carried out at 24 °C for 10 to 30 days without agitation. The fermentation broth is harvested and subsequently extracted with an organic solvent like Methanol or Ethylacetate. The raw extract is purified via silica gel chromatography using Heptan and Ethylacetate (50:50). The fractions containing the compound of formula A1 1 is evaporated to dryness and reconstituted in Acetonitril. Final purification is done via chromatography on a C18 reversed phase column using a Water Acetonitril gradient. The compounds B7-B10 were produced and isolated analogously from this fermentation broth.

Compounds of formula (I) according to the invention, in particular compounds wherein R1 is OH and R2 is the side chain G1 , can be obtained starting from the known compound A1 1 .

Derivatives of A1 1 generally can be generated by synthetic or semi-synthetic routes or by so-called biotransformation with a microorganism in an aqueous nutritional broth under aerobic conditions or with an enzyme extract or by one or several enzymes isolated from said extract.

A number of microorganisms are known and have been described in literature as being able to modify natural and synthetic compounds. Especially filamentous fungi, gram positive bacteria and gram negative bacteria have been used for biotransformation.

For the biotransformation of dihydroquinolinone derivatives, filamentous fungi and gram positive bacteria are particularly useful. Especially useful are gram positive bacteria from the genus Streptomyces and filamentous fungi of the genus Mortierella.

Biotransformation Route

For example, the compounds B1 1 , B12, B13, B14, B15, E1 and E2 of table 2 below were produced by growing microorganisms in a fermentation medium under aerobic conditions from A1 1 . Typically, fermentation media contain a carbon source and a nitrogen source. The fermentation is performed at temperatures supporting growth of the organisms, typically between 20 and 35 °C. The biotransformation can be done in culture tubes, shake flasks or in stirred fermenters. Biotransformation products can be purified from the culture broth by standard isolation techniques.

Media preparation:

ISP-2 medium:

per liter: 4 g yeast extract; 4 g glucose; 10 g malt extract; pH 7.3.

RM24 medium:

per liter: 2 g glucose; 10 g malt extract; 4 g yeast extract; 0.5 g KH₂P0₄; 0.5 g NH₄CI;

20 g MOPS, pH 5.9.

The media were sterilized at 121 °C for 20 minutes at 1 .1 bar before use. Biotransformation with Streptomyces sp. DSM-40865.

A seed culture of the strain was grown in 100 ml of Medium ISP-2 in a 500 ml shake flask with baffles and grown on a rotary shaker at 28°C for 3 days at a shaking speed of 150 rpm. To inoculate the biotransformation culture, 5 ml of the seed -culture was added to 100 ml of medium ISP-2 and incubated under the same conditions as the seed culture. On day three, 1 ml of a stock solution of 5 mg/ml of A1 1 in methanol was added to the culture. After 17 days the culture broth was extracted twice by addition of an equal volume of ethyl acetate.

Biotransformation with Mortierella ramanniana. DSM-62752.

A seed culture of the strain was grown in 100 ml of Medium RM24 in a 500 ml shake flask and grown on a rotary shaker at 24°C for 3 days at a shaking speed of 150 rpm. To inoculate the biotransformation culture, 5 ml of the seed -culture was added to 100 ml of medium RM24 and incubated under the same conditions as the seed culture. On day three, 1 ml of a stock solution of 5 mg/ml of A1 1 in methanol was added to the culture. After 17 days the culture broth was extracted twice by addition of an equal volume of ethyl acetate. The compounds of interest were then isolated by standard high performance liquid chromatography techniques.

Synthetic or Semi-synthetic Routes

B2 can be obtained by standard hydrogenation of the double bond of A1 1 , for example with Pd/C and HC0₂NH₄ in refluxing EtOH.

D2, and D1 1 to D25 can be obtained from A1 1 by standard phenol alkylation methods, for example in the presence of a base (such as K₂C0₃ or tBuOK), in a solvent (such as MeOH or THF), a commercially available electrophile (such as Mel, Hal-CH₂Aryl (wherein Hal is CI , Br or I), allylbromide, CICH₂COY (wherein Y is OMe or NR₂).

When these where not commercially available, these where synthesized according to the procedure described in Heterocycles 32, (5), 1991 , p.969)) and eventually addition of Nal. These conditions also produced compound D3 and D4 when CICH₂C0₂Me was used as electrophile.

B3 was synthesized from A1 1 by standard double bond oxidation procedure using a peracid (such as mCPBA) in a chlorinated solvent (such as dichloromethane). These conditions also produces compounds B5 and B16.

B4 was synthesized from A1 1 by standard double bond dihydroxylation procedure using the system Os0₄ / NMMO in tBuOH. These conditions also produces compound B21 (with or without subsequent addition of Nal0₄).

An alternative route to obtain compounds of formula (I) having R1 =OH and OR15 = OH is based on the deprotection of compounds wherein the OH in the R1 position is protected, for instance with a benzyl group. The deprotection uses standard hydrogenation procedures, for example:

This procedure was used for B18, B19 and A3.

B17 can be synthesized from B19 by direct standard bromination conditions (e.g as described in 1993 Bull. Chem Soc. Jpn. 66(5)1576-1579, with only 1 eq. of NBS and 0.1 eq. of iPr₂NH). These conditions also produces the dibrominated compound "B17bis" for which R1 =OH, R2=R4=Br, R3=R5=R6=R8=R9=R10=R12=R15=H, R7=OR14=OMe as defined in formula (II) below.

D26 can be synthesized from A1 1 by using standard sililation conditions (for instance 1 eq tBuMe₂SiCI + 1 eq tBuOK in THF). These conditions also produce the compound B1 .

A general route to access dihydroquinolones with OR15 = OH is based, as a starting point, on the procedure described for example in Tetrahedron 59 (2003) 7301-7306 or Tetrahedron Letters 44 (2003) 4271-4273. Surprisingly it has been found that applying said general route to dihydroquinolone derivatives according to the present invention, the following process provides the desired compounds of formula (I):

This procedure was applied, for example, to synthesize C1 , C2, C3, D1 , D5, D6, D7, D8, D9 and D10. The above cyclization is usually highly diastereoselective and provides mainly the following diastereoisomer of formula (I^*):

For optimal pesticidal activity of the compounds of the invention it is important, that OR14 and OR15 (which in the above formula is OH) are stereochemically on the same side of the compound.

The starting materials for the above cyclization can be obtained from the respective ortho- aminoketones as follows:

This procedure was applied for example for starting materials for C1 , C2, D1 and D5:

The cyclization precursor for compound D7 (which may further be derivatized to B18) was prepared according to the following reaction scheme using standard reaction conditions:

Standard epoxidation conditions (for instance mCPBA) of the precursor of D7 provid cyclization precursor of D10.

For compounds with R1 = OH, the Fries rearrangement is a suitable alternative route:

For example used for starting materials for B19:

The UV irradiation (hv) was performed using a 400 Watt medium pressure mercury lamp filtted on a UK Photochemical Reactors Ltd. RQ400 quarz immersion well reactor.

Using 2-methoxyphenylboronic acid instead of 3-methoxyphenylboronic acid provided compounds D9 and B20.

The required ortho-aminoketones as starting materials for the process of the present invention are generally available through standard ortho-lithiation of the respective functionalized aromatic rings as follows:

For example the ortho-aminoketones for the synthesis of C1 , D1 and D5 are available as follows:

The side chain G1 generally can be obtained using the following strategy:

or alternativel

For synthetic route compound A1 1 , the side chain G1 has been synthesized as follows:

or alternatively:

All exemplified compounds in table 2 referred to below are represented with their substituents with regard to general formula (III)

The compounds A1 to A13 in table 2 are comparative Examples of table 1 above.

Definition of "route":

1 . Isolation from the fermentation broth after extraction and chromatography as described above for preparation of A1 1 .

2. Chemical derivatization from the natural products obtained in 1.) especially A1 1 (i.e. Semi-synthetic route).

3. Chemical synthesis from commercially available chemicals at room temperature if not stated otherwise (i.e. Synthetic route).

4. Biotransformation.

The compounds of table 2 were isolated by standard high performance liquid chromatography techniques.

Analysis of the purified samples is done using one of the following Methods (M1 to M6):

M1 : Waters Autopurification (HPLC/MS) system with a reversed phase column (Daisogel SP-120-ODS-AP δμηι, 150X3mm) from Bischoff, Leonberg, Germany. The samples are characterized by m/z and retention time. The above-given retention times relate in each case to the use of a solvent system comprising two different solvents, solvent A: H₂0 + 0.01 % HCOOH, and solvent B: CH₃CN + 0.01 % HCOOH). Said two solvents A and B are employed at a flow rate of 2.00 ml/min with a time-dependent gradient as given in the Table:

M2: Waters Alliance 2795 system equipped with a 2996 DAD detector and Waters

Micromass Quattro micro MS detector with a reversed phase column (Discovery C18, δμηη, 150X3mm) from Supelco Inc., Bellefonte, USA. The samples are characterized by m/z and retention time. The above-given retention times relate in each case to the use of a solvent system comprising two different solvents, solvent A: water + 1 % methanol + 0.01 % acetic acid, and solvent B: methanol + 1 % water + 0.01 % acetic acid. Said two solvents A and B are employed at a flow rate of 0.45 ml/min with a time-dependent gradient as given in the Table:

M3: Waters Alliance 2795 system equipped with a 2996 DAD detector and Waters Micromass Quattro micro MS detector with a reversed phase column (Discovery C18, 5μηι, 150X3mm) from Supelco Inc., Bellefonte, USA. The samples are characterized by m/z and retention time. The above-given retention times relate in each case to the use of a solvent system comprising two different solvents, solvent A: water + 1 % acetonitril + 0.01 % TFA, and solvent B: acetonitril + 1 % water + 0.01 % TFA. Said two solvents A and B are employed at a flow rate of 0.45 ml/min with a time-dependent gradient as given in the Table:

M4: Waters Alliance 2795 system equipped with a 2996 DAD detector and Waters

Micromass Quattro micro MS detector with a reversed phase column (Zorbax SB-Phenyl, 5μηι, 150X3mm) from Agilent Technologies, USA. The samples are characterized by m/z and retention time. The above-given retention times relate in each case to the use of a solvent system comprising two different solvents, solvent A: water + 1 % acetonitril + 0.01 % TFA, and solvent B: acetonitril + 1 % water + 0.01 % TFA. Said two solvents A and B are employed at a flow rate of 0.45 ml/min with a time-dependent gradient as given in the Table:

M5: Waters Alliance 2795 system equipped with a 2996 DAD detector and Waters

Micromass Quattro micro MS detector with a reversed phase column (Discovery C18, 5μηι, 150X3mm) from Supelco Inc., Bellefonte, USA. The samples are characterized by m/z and retention time. The above-given retention times relate in each case to the use of a solvent system comprising two different solvents, solvent A: water + 1 % methanol + 0.01 % acetic acid, and solvent B: methanol + 1 % water + 0.01 % acetic acid. Said two solvents A and B are employed at a flow rate of 0.45 ml/min with a time-dependent gradient as given in the Table:

M6: Waters Alliance 2795 system equipped with a 2996 DAD detector and Waters

The results of the analysis are represented in table 3 below.

Table 3

Compound Calc. monoisotopic Method Observed m/z Observed

No molecular weight (ES- or ES+) Retention

(g/mol) Time

(min)

A3 315 M1 314 2.6

B1 581 M1 580 5.5

B2 469 M1 468 4.2

B3 483 M1 482 3.9

B4 483 M3 466(-H₂0) 9.8

B7 465 M3 466 7.5/8.1

B8 465 M3 466 9.1

B9 497 M5 498 14.3

B10 449 M3 432(-H₂0) 13.8

B1 1 483 M2 484 10.8

B12 483 M2 484 9.9

B13 499 M2 482(-H₂0) 8.1

B14 499 M2 482(-H₂0) 9.9

B15 483 M2 484 10.3/1 1 .3

B16 499 M4 482(-H₂0) 10.9/1 1 .3

B17bis 471 M1 470 3.3

B17 3.93 M1 392 2.8

B18 357 M1 356 3.3

B19 421 M1 420 3.1

B20 421 M1 420 3.1

B21 343 M4 344 6.9

C1 451 M1 450 3.5

C2 333 M1 332 3.1

C3 313 M1 296(-H₂0) 3.1

D1 329 M1 312(-H₂0) 2.9 D2 481 M1 480 4.6

D5 359 M1 358 2.9

D6 405 M1 404 3.0

D7 445 M1 444 3.7

D8 51 1 M1 510 3.7

D9 51 1 M1 510 3.6

D10 461 M1 444(-H₂0) 3.0

D1 1 557 M1 556 4.3

D12 591 M1 590 4.5

D13 591 M1 590 4.6

D14 591 M1 590 4.6

D15 587 M1 586 4.2

D16 587 M1 586 4.1

D17 617 M1 616 4.1

D18 539 M1 538 3.4

D19 608 M1 607 3.8

D20 578 M1 577 3.1

D21 594 M1 593 2.9

D22 571 M1 570 4.7

D23 641 M1 640 4.6

D24 614 M1 613 3.2

D25 507 M1 506 4.2

D26 581 M1 580 5.4

E1 453 M2 454 12.0

E2 469 M2 470 8.8/9.9

H1 381 M6 382 10.0

H2 465 M3 466 5.0 Biological Examples (Control of animal parasites)

The following test methods are employed in investigating the pesticidal (acaricidal and insecticidal) action of the compounds of the formula I.

1 . Activity in vitro against Ctenocephalides felis (Cat flea).

A mixed adult population of fleas is placed in a suitably formatted 96-well plate allowing fleas to access and feed on treated blood via an artificial feeding system. Each compound is tested by serial dilution in order to determine its minimal effective dose (MED). Fleas are fed on treated blood for 24 hours, after which the compound's effect is recorded.

Insecticidal activity is determined on the basis of the number of dead fleas recovered from the feeding system. For example compound C1 , C3, B18, B19 and D26 showed at least 80% mean efficacy in this test at 100 ppm.

2. Activity in vitro against Rhipicephalus sanguineus (Dog tick).

A clean adult tick population is used to seed a suitably formatted 96-well plate containing the test substances to be evaluated for antiparasitic activity. Each compound is tested by serial dilution in order to determine its minimal effective dose (MED). Ticks are left in contact with the test compound for 10 minutes and are then incubated at 28°C and 80% relative humidity for 7 days, during which the test compound's effect is monitored. Acaricidal activity is confirmed if adult ticks are dead. For example compound B2, D16 and D26 showed a mean efficacy of at least 80% at 640 ppm in this test.

3. In-vivo test against Rhipicephalus sanguineus nymphs on Mongolian gerbils (Meriones unguiculatus)

On day 0, gerbils are treated with the test compound at a given dose by spray (or spot-on) application. 2 days later, the animals are infested with nymphs of R. sanguineus. Ticks are left on the animals until full repletion. Seven days after infestation nymphs dropped off fully engorged are collected and counted. They are kept until molting to also evaluate growth regulating activity of the test compound. Efficacy in killing (and growth regulating) is expressed as a tick number (and molted tick number) reduction in comparison with a placebo treated group, using the Abbot's formula. A tick number reduction of more than 60 %, in particular more than 70 %, is regarded as a minimum prerequisite for a commercial development of a compound. In addition, said killing efficacy should be put into practice with the minimal dose for safety and environmental reasons. For example compound D16 showed in this test at 32 mg/kg a mean efficacy of 87%.

Claims

What is claimed is:

1 . A compound of the formula (I) and the stereoisomers thereof, whereby said

compound is in the free form or a salt form, characterized in that formula (I) is

wherein

R1 is H, OH, halogen, CrC₆-alkyl, CrC₆-haloalkyl, CrC₆-alkoxy, CrC₆-haloalkoxy, d- C₆-alkylthio, CrC₆-haloalkylthio, CrC₆-alkylsulfinyl, CrC₆-haloalkylsulfinyl, CrC₆- alkylsulfonyl, CrC₆-haloalkylsulfonyl, SF₅, N-(Ci-C₆-alkyl)amino, N,N-di-(C C₆- alkyl)amino, N-(Ci-C₆-haloalkyl)amino, N,N-di-(Ci-C₆-haloalkyl)amino, C₂-C₆- haloalkoxycarbonyl, C₂-C₆-alkoxycarbonyl, cyano, formyl, nitro, phenyl (which may be substituted with 1 to 4 halogen atoms and/or 1 to 3 methoxy groups or which may be unsubstituted) or a 5- to 6-membered heterocycle (which have from 1 to 3 oxygen atoms, 1 to 3 nitrogen atoms and/or 1 to 3 sulfur atoms in the heterocycle, and which may be substituted or unsubstituted), or tris-(CrC₆-alkyl)-silyl; or -O-CH₂-X; wherein X is, C C₆-alkenyl, C C₆-alkinyl, C C₆-alkoxy, CO-NR'R" (wherein R' and R" independently are hydrogen or CrC₆-alkyl or R' and R" together form a ring, which is either an N-morpholino or N-pyrrolidino ring), COOR'" (wherein R'" is CrC₄-alkyl), phenyl (which may be substituted by H, OH, halogen, CrC₆-alkyl, CrC₆-haloalkyl, CrC₆-alkoxy, CrC₆-haloalkoxy, CrC₆- alkylthio, CrC₆-haloalkylthio, CrC₆-alkylsulfinyl, CrC₆-haloalkylsulfinyl, CrC₆- alkylsulfonyl, SF₅, CrC₆-haloalkylsulfonyl, N-(Ci-C₆-alkyl)amino, N,N-di-(C C₆- alkyl)amino, N-(Ci-C₆-haloalkyl)amino, N,N-di-(Ci-C₆-haloalkyl)amino, C₂-C₆- haloalkoxycarbonyl, C₂-C₆-alkoxycarbonyl, acetamido, cyano, formyl, nitro or tris- (CrC₆-alkyl)-silyl) or a 5- to 6-membered heterocycle (which have from 1 to 3 oxygen atoms, 1 to 3 nitrogen atoms and/or 1 to 3 sulfur atoms in the heterocycle, and which may be substituted as the phenyl above or unsubstituted); or -0-Si-(Y)₃, wherein each Y, indepedent of each other, is CrC₆-alkyl, Ci-C₆- alkenyl, CrC₆-haloalkyl, phenyl, benzyl;

R2 is H, halogen, formyl, CrC₆-alkyl, CrC₆-alkylen, or phenyl (which may be

substituted with 1 to 4 halogen atoms and/or 1 to 3 methoxy groups or which may be unsubstituted), or one of the following side chains G1 to G25

H1 H2 H3

R3 and R4 independently of each other are hydrogen, CrC₆-alkyl, CrC₆-haloalkyl, d- C₆-alkoxy, CrC₆-haloalkoxy, CrC₆-alkylthio, CrC₆-haloalkylthio, CrC₆- alkylsulfinyl, CrC₆-haloalkylsulfinyl, CrC₆-alkylsulfonyl, CrC₆-haloalkylsulfonyl, SF₅, N-(Ci-C₆-alkyl)amino, N,N-di-(Ci-C₆-alkyl)amino, N-(Ci-C₆-haloalkyl)amino, N,N-di-(Ci-C₆-haloalkyl)amino, C₂-C₆-alkoxycarbonyl, C₂-C₆- haloalkoxycarbonyl, cyano, OH;

R10 is hydrogen, CrC₆-alkyl;

OR14 is -Ci-C₃-alkoxy;

R12 is H, an alkyl-alkoxy type prodrug moiety or a carbamate type prodrug moiety;

R13 is phenyl which may be substituted or unsubstituted, or thiophen which may be substituted or unsubstituted, wherein the subtituents for phenyl and thiophen are selected from H, OH, halogen, CrC₆-alkyl, CrC₆-haloalkyl, CrC₆-alkoxy, Ci-C₆-haloalkoxy, CrC₆-alkylthio, CrC₆-haloalkylthio, CrC₆-alkylsulfinyl, CrC₆- haloalkylsulfinyl, CrC₆-alkylsulfonyl, CrC₆-haloalkylsulfonyl, SF₅, N-(CrC₆- alkyl)amino, N,N-di-(Ci-C₆-alkyl)amino, N-(Ci-C₆-haloalkyl)amino, N,N-di-(Ci- C₆-haloalkyl)amino, C₂-C₆-haloalkoxycarbonyl, C₂-C₆-alkoxycarbonyl, acetamido, cyano, formyl, nitro, phenyl (which may be substituted with 1 to 4 halogen atoms and/or 1 to 3 methoxy groups or which may be unsubstituted) or a 5- to 6-membered heterocycle (which have from 1 to 3 oxygen atoms, 1 to 3 nitrogen atoms and/or 1 to 3 sulfur atoms in the heterocycle, and which may be substituted as the phenyl above or which may be unsubstituted), or tris-(Ci- C₆-alkyl)-silyl;

R15 is H or -d-Ce-alkyl, tris-(CrC₆-alkyl)-silyl; with the proviso that R1 is not H, for compounds of formula (I) wherein

R2, R3, R4, R10, R12 and R15 are H;

OR14 is -OCHs,

R13 is 4-methoxyphenyl, and

with the proviso that R1 is not OH, for compounds of formula (I) wherein

R3, R4, R10, R12 and R15 are H;

OR14 is -OCHs,

R13 is 4-methoxyphenyl, and

with the proviso that for compounds of formula (I) wherein

R3, R4, R10, R12 and R15 are H;

OR14 is -OCHs,

R13 is 4-methoxyphenyl, and

2. Compound according to claim 1 , characterized in that the compound is of formula (II)

wherein

R1 , R2, R3, R4, R10, R14 and R15 are defined as in the preceding claim; and

R5, R6, R7, R8 and R9, independently of each other, are H, OH, halogen, d-C₆-alkyl, CrC₆-haloalkyl, CrC₆-alkoxy, CrC₆-haloalkoxy, CrC₆-alkylthio, CrC₆- haloalkylthio, CrC₆-alkylsulfinyl, CrC₆-haloalkylsulfinyl, CrC₆-alkylsulfonyl, d- Ce-haloalkylsulfonyl, SF₅, N-(Ci-C₆-alkyl)amino, N,N-di-(Ci-C₆-alkyl)amino, N- (Ci-C₆-haloalkyl)amino, N,N-di-(Ci-C₆-haloalkyl)amino, C₂-C₆- haloalkoxycarbonyl, C₂-C₆-alkoxycarbonyl, acetamido, cyano, formyl, nitro, phenyl (which may be substituted with 1 to 4 halogen atoms and/or 1 to 3 methoxy groups or which may be unsubstituted) or a 5- to 6-membered heterocycle (which have from 1 to 3 oxygen atoms, 1 to 3 nitrogen atoms and/or 1 to 3 sulfur atoms in the heterocycle, and which may be substituted as the phenyl above or which may be unsubstituted), or tris-(CrC₆-alkyl)-silyl;

R12 is H, -CH₂-0-(CrC₆-alkyl) ,-CH(CH₃)-0-(Ci-C₆-alkyl) or

-COO-CH₂-0-(CrC₆-alkyl).

3. Compound according to claim 1 , characterized in that the compound is of formula (III)

wherein

R7 is H, OH or -Ci-C₃-alkoxy;

R12 is H, -CH₂-0-(CrC₆-alkyl) ,-CH(CH₃)-0-(Ci-C₆-alkyl) or

-COO-CH₂-0-(CrC₆-alkyl);

R14 is Methyl;

R15 is H or t-butyl-di-methyl-silyl;

R1 is halogen, CrC₆-alkyl, CrC₆-haloalkyl, CrC₆-alkoxy, CrC₆-haloalkoxy, CrC₆- alkylthio, CrC₆-haloalkylthio, CrC₆-alkylsulfinyl, CrC₆-haloalkylsulfinyl, CrC₆- alkylsulfonyl, CrC₆-haloalkylsulfonyl, SF₅, N-(Ci-C₆-alkyl)amino, N,N-di-(C C₆- alkyl)amino, C2-C₆-alkoxycarbonyl, cyano, formyl, nitro, phenyl (which may be substituted with 1 to 4 halogen atoms and/or 1 to 3 methoxy groups or which may be unsubstituted) or a 5- to 6-membered heterocycle (which have from 1 to 3 oxygen atoms, 1 to 3 nitrogen atoms and/or 1 to 3 sulfur atoms in the heterocycle, and which may be substituted as the phenyl above or which may be unsubstituted),

or -0-CH₂-X;

wherein X is, CrC₆-alkenyl, CrC₆-alkinyl, CrC₆-alkoxy, CO-NR'R" (wherein R' and R" independently are hydrogen or CrC₆-alkyl or R' and R" together form a ring, which is either an N-morpholino or N-pyrrolidino ring), COOR'" (wherein R'" is CrC₄-alkyl,), phenyl (which may be substituted by H, OH, halogen, d-C₆-alkyl, CrC₆-haloalkyl, CrC₆-alkoxy, CrC₆-haloalkoxy, CrC₆-alkylthio, CrC₆- haloalkylthio, CrC₆-alkylsulfinyl, CrC₆-haloalkylsulfinyl, CrC₆-alkylsulfonyl, CrC₆- haloalkylsulfonyl, SF₅, N-(CrC₆-alkyl)amino, N,N-di-(Ci-C₆-alkyl)amino, N-(C C₆- haloalkyl)amino, N,N-di-(Ci-C₆-haloalkyl)amino, C2-C₆-haloalkoxycarbonyl, C₂-C₆- alkoxycarbonyl, acetamido, cyano, formyl, nitro or tris-(CrC₆-alkyl)-silyl) or a 5- to 6-membered heterocycle (which have from 1 to 3 oxygen atoms, 1 to 3 nitrogen atoms and/or 1 to 3 sulfur atoms in the heterocycle, and which may be substituted as the phenyl above or which may be unsubstituted);

R2 is H, halogen, formyl, CrC₆-alkyl, CrC₆-alkylen, or phenyl (which may be

substituted with 1 to 4 halogen atoms and/or 1 to 3 methoxy groups or which may be unsubstituted);

or one of the side chains G1 to G24 as defined as in claim 1 ; or the group R1 and the substituent R2 form together with the carbon atoms a and b of the phenyl group to which they are attached one of the following substituents H1 or H2 as defined in claim 1 .

4. Compound according to claim 1 , characterized in that the compound is of formula (III)

wherein

R7 is methoxy;

R12 is H;

R14 is Methyl; R15 is H or t-butyl-di-methyl-silyl;

R1 is -O-CH₂-X, wherein X is, C C₆-alkenyl, C C₆-alkinyl, C C₆-alkoxy, CO-NR'R" (wherein R' and R" independently are hydrogen or CrC₆-alkyl or R' and R" together form a ring, which is either an N-morpholino or N-pyrrolidino ring), COOR'" (wherein R'" is CrC₄-alkyl,), phenyl (which may be substituted by H, OH, halogen, CrC₆-alkyl, CrC₆-haloalkyl, CrC₆-alkoxy, CrC₆-haloalkoxy, CrC₆- alkylthio, CrC₆-haloalkylthio, CrC₆-alkylsulfinyl, CrC₆-haloalkylsulfinyl, CrC₆- alkylsulfonyl, CrC₆-haloalkylsulfonyl, SF₅, N-(Ci-C₆-alkyl)amino, N,N-di-(C C₆- alkyl)amino, N-(Ci-C₆-haloalkyl)amino, N,N-di-(Ci-C₆-haloalkyl)amino, C₂-C₆- haloalkoxycarbonyl, C₂-C₆-alkoxycarbonyl, acetamido, cyano, formyl, nitro or tris- (CrC₆-alkyl)-silyl) or a 5- to 6-membered heterocycle (which have from 1 to 3 oxygen atoms, 1 to 3 nitrogen atoms and/or 1 to 3 sulfur atoms in the heterocycle, and which may be substituted or unsubstituted);

or -0-Si-(Y)₃ , wherein each Y, indepedent of each other, is CrC₆-alkyl, Ci-C₆- alkenyl, CrC₆-haloalkyl, phenyl, benzyl.

R2 is H, halogen, CrC₆-alkyl, CrC₆-alkylen, or phenyl (which may be substituted with 1 to 4 halogen atoms and/or 1 to 3 methoxy groups or which may be

unsubstituted); or one of the following side chains G1 to G25 as defined as in the preceding claims.

5. Compound according to any one of the preceding claims characterized in that

R2 is one of the side chains G1 or G12.

6. Compound according to any one of the preceding claims characterized in that the compound is selected from the group consisting of the compounds designated as C1 to C3, B1 to B21 , D1 to D26, E1 , E2, H 1 and H2 in table 2.

7. Compound according to any one of the preceding claims wherein the compound of formula (I) has the following stereochemical configuration (I^*)

8. Compound according to any one of the preceding claims 3 to 6 wherein the

compound of formula (III) has the following stereochemical configuration (III^*)

9. Process for the manufacture of dihydroquinolinone derivates characterized by the following reaction step

wherein R1 to R4 and R10 to R14 are defined as in any one of claims 1 to 8.

10. Process according to claim 9 wherein the ortho-aminoketones as starting materials for the process according to claim 9 are provided by the following reaction step

wherein R1 to R4 and R10 to R14 are defined as in any one of claims 1 to 8.

1 1 . Compound for the use as starting material in a process according to claim 9, wherein said compound is of the following formula

wherein R1 , R2, R3, R4, R10, R12, R13 and R14 are defined as in any one of claims 1 to 8, respectively.

12. Use of a compound according to any one of claims 1 to 8 as pesticide.

13. Composition comprising a compound as defined in any one of claims 1 to 8 together with a carrier or diluent that is physiologically acceptable to non-human animals.

14. Use of compounds according to any one of claims 1 to 8 for combating ectoparasites on non-human animals.

15. Method of controlling ectoparasites on non-human animals, characterized in that an effective amount of at least one compound as defined in any one of claims 1 to 8 is administered to the habitat of the parasites.