Processes for preparing of glucopyranosyl-substituted (ethynyl-benzyl)-benzene derivatives and intermediates thereof

1. Process for preparing the compounds of general formula I,

wherein

R 1 denotes hydrogen, or

C 1-4 -alkyl, C 3-7 -cycloalkyl, tetrahydrofuranyl, or tetrahydropyranyl, which may be substituted with one to four substituents L2, or

an aryl-group or a 5- or 6-membered monocyclic heteroaryl-group or a 8-, 9- or 10-membered bicyclic heteroaryl-group wherein said heteroaryl-groups have 1 to 4 heteroatoms independently selected from the group consisting of N, O and S; and wherein said heteroaryl-group may possess 1 or 2 carbonyl groups as part of the mono- or bicyclic aromatic ring-system; and

wherein an N-atom of the heteroaryl ring-system may be oxidized to form the corresponding N-oxide; and

wherein one or more methine groups in said aryl- and heteroaryl-group may be substituted independently of one another with a substituent L1; and

wherein one or more imino-groups in said heteroaryl-group may be substituted independently of one another with a substituent R N ; and

R 2 denotes chlorine or methyl; and

R 3 denotes hydrogen;

R N independently of one another are selected from among C 1-3 -alkyl; and

L1 independently of one another are selected from among fluorine, chlorine, bromine, C 1-3 -alkyl, C 1-4 -alkoxy and nitro;

L2 independently of one another are selected from among fluorine, chlorine, hydroxy, hydroxyl-C 1-4 -alkyl, C 1-4 -alkoxy, trifluoromethoxy, C 1-4 -alkoxy-C 1-4 -alkyl, cyano, C 1-4 -alkyl, trifluoromethyl, amino, C 1-4 -alkyl-carbonylamino, C 1-3 -alkyl-amino and di(C 1-3 -alkyl)-amino; and

while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups, which may be mono- or polysubstituted with L1;

characterised in that in a compound of general formula II

wherein R 1 and R 2 are defined as hereinbefore and

R 4 independently of one another denote hydrogen, C 3-18 -alkenyl, (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, (C 3-18 -alkenyl)carbonyl, (C 3-18 -alkenyl)oxycarbonyl, di-(C 1-18 -alkyl)aminocarbonyl, arylcarbonyl, aryl-(C 1-3 -alkyl)-carbonyl, aryl-C 1-3 -alkyl, C 1-6 -alkoxymethyl, aryl-C 1-3 -alkoxy, C 1-4 -alkylthioethyl, arylthioethyl, C 1-4 -alkylsulfonylethyl, arylsulfonylethyl, R a R b R c Si—, —CR a R b OR c , wherein two adjacent groups R 4 may be linked with each other to form a bridging group SiR a R b , CR a R b or CR a OR b —CR a OR b and wherein each alkyl group may be substituted with up to three substituents selected from fluorine, chlorine, C 1-3 -alkyl, R a R b R c Si, C 1-4 -alkoxy, with the proviso that at least one substituent R 4 is not hydrogen;

R a , R b , R c independently of one another denote C 1-4 -alkyl, aryl or aryl-C 1-3 -alkyl, while the alkyl may be mono- or polysubstituted by halogen;

L1 and L2 are defined as hereinbefore; and

while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups, which may be mono- or polysubstituted with L1;

the protective groups R 4 not being hydrogen are cleaved.

2. Process for preparing the compounds of general formula II′,

wherein

R 1 denotes hydrogen,

C 1-4 -alkyl, C 3-7 -cycloalkyl, tetrahydrofuranyl, or tetrahydropyranyl, which may be substituted with one to four substituents L2,

an aryl-group or a 5- or 6-membered monocyclic heteroaryl-group or a 8-, 9- or 10-membered bicyclic heteroaryl-group wherein said heteroaryl-groups have 1 to 4 heteroatoms independently selected from the group consisting of N, O and S; and wherein said heteroaryl-group may possess 1 or 2 carbonyl groups as part of the mono- or bicyclic aromatic ring-system; and

wherein an N-atom of the heteroaryl ring-system may be oxidized to form the corresponding N-oxide; and

wherein one or more methine groups in said aryl- and heteroaryl-group may be substituted independently of one another with a substituent L1; and

wherein one or more imino-groups in said heteroaryl-group may be substituted independently of one another with a substituent R N ; and

R 2 denotes chlorine or methyl; and

R 4 independently of one another denote hydrogen, C 3-18 -alkenyl, (C 1-18 -alkyl)-carbonyl, (C 1-18 -alkyl)oxycarbonyl, (C 3-18 -alkenyl)carbonyl, (C 3-18 -alkenyl)oxycarbonyl, di-(C 1-18 -alkyl)aminocarbonyl, arylcarbonyl, aryl-(C 1-3 -alkyl)-carbonyl, aryl-C 1-3 -alkyl, C 1-6 -alkoxymethyl, aryl-C 1-3 -alkoxy, C 1-4 -alkylthioethyl, arylthioethyl, C 1-4 -alkylsulfonylethyl, arylsulfonylethyl, R a R b R c Si, CR a R b OR c , wherein two adjacent groups R 4 may be linked with each other to form a bridging group SiR a R b , C═O, CR a R b or CR a OR b —CR a OR b and wherein each alkyl group may be substituted with up to three substituents selected from fluorine, chlorine, C 1-3 -alkyl, R a R b R c Si, C 1-4 -alkoxy,

R 6 denotes hydrogen, para-R 7 -phenyl-, C 1-6 -alkyloxy, aryloxy, —OR 4 ; and

R 7 denotes —C≡C—R 1 , Cl, Br, I, —OSO 2 R, —CHO, —SiAlk 3 , —O—C 1-6 -alkyl, —OR 4 , —C≡C—Si(C 1-4 -alkyl) 3 , —C≡C—Si(aryl)(C 1-4 -alkyl) 2 , —C≡C—Si(biphenyl)(C 1-4 -alkyl) 2 , or —C≡C—C(OH)(C 1-4 -alkyl) 2 ; and

R denotes C 1-4 -alkyl, C 3-4 -alkenyl, C 1-4 -alkoxy, CF 3 , aryl or aryl-C 1-3 -alkyl, wherein aryl-groups may be mono- or polysubstituted with L1;

R a , R b , R c independently of one another denote C 1-4 -alkyl, aryl or aryl-C 1-3 -alkyl, while the alkyl groups may be mono- or polysubstituted by halogen;

R N independently of one another are selected from among C 1-3 -alkyl; and

L1 independently of one another are selected from among fluorine, chlorine, bromine, C 1-3 -alkyl, C 1-4 -alkoxy and nitro;

L2 independently of one another are selected from among fluorine, chlorine, hydroxy, hydroxyl-C 1-4 -alkyl, C 1-4 -alkoxy, trifluoromethoxy, C 1-4 -alkoxy-C 1-4 -alkyl, cyano, C 1-4 -alkyl, trifluoromethyl, amino, C 1-4 -alkyl-carbonylamino, C 1-3 -alkyl-amino and di(C 1-3 -alkyl)-amino; and

while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups, which may be mono- or polysubstituted with L1;

characterised in that a compound of general formula III′

wherein R 2 , R 6 and each R 4 are defined as hereinbefore and

R′ denotes hydrogen, C 1-6 -alkyl, (C 1-4 -alkyl)carbonyl, (C 1-4 -alkyl)oxycarbonyl, arylcarbonyl, aryl-(C 1-3 -alkyl)-carbonyl; while the term “aryl” is defined as hereinbefore;

is reacted with a reducing agent.

3. Process for preparing the compounds of general formula III′,

wherein R 2 , R′ and each R 4 are defined as in claim 2 ; and

R 6 denotes hydrogen, para-R 7 -phenyl-, C 1-6 -alkyloxy, aryloxy, —OR 4 ; and

R 7 denotes —C≡C—R 1 , Cl, Br, I, —OSO 2 R, —CHO, —SiAlk 3 , —O—C 1-6 -alkyl, —OR 4 , —C≡C—Si(C 1-4 -alkyl) 3 , —C≡C—Si(aryl)(C 1-4 -alkyl) 2 , —C≡C—Si(biphenyl)(C 1-4 -alkyl) 2 , or —C≡C—C(OH)(C 1-4 -alkyl) 2 ; and

R denotes C 1-4 -alkyl, C 3-4 -alkenyl, C 1-4 -alkoxy, CF 3 , aryl or aryl-C 1-3 -alkyl, wherein aryl-groups may be mono- or polysubstituted with L1;

wherein R 1 , aryl and L1 are defined as in claim 2 ;

characterised in that an organometallic compound of the formula VI

wherein R 2 and R 6 are defined as hereinbefore and M denotes Li or MgHal, wherein Hal denotes Cl, Br or I; and

or a derivative thereof obtained by transmetallation;

which compound of the formula VI may be obtained by halogen-metal exchange or by the insertion of a metal in the carbon-halogen bond of a halogen-benzylbenzene compound of general formula V

wherein R 2 and R 6 are defined as hereinbefore and X denotes Cl, Br or I;

and optionally subsequent transmetallation,

is added to a gluconolactone of general formula IV

wherein R 4 is as hereinbefore defined,

then the adduct obtained is reacted with water or an alcohol R′—OH, where R′ denotes C 1-6 -alkyl, in the presence of an acid and optionally the product obtained in the reaction with water wherein R′ denotes H is converted in a subsequent reaction with an acylating agent into the product of formula III′ wherein R′ denotes (C 1-4 -alkyl)carbonyl, (C 1-4 -alkyl)oxycarbonyl, arylcarbonyl, or aryl-(C 1-3 -alkyl)-carbonyl, wherein the term “aryl” is defined as hereinbefore.

4. Process according to claim 3 characterized in that the compound of formula III′ is reacted with a reducing agent to yield a compound of the formula II′

wherein

R 2 is chlorine or methyl

R 4 independently of one another denote hydrogen, C3-18-alkenyl, (C1 18-alkyl) carbonyl, (C1-18-alkyl)oxycarbonyl, (C3-18-alkenyl)carbonyl, (C3-18-alkenyl)oxycarbonyl, di-(C1-18-alkyl)aminocarbonyl, arylcarbonyl, aryl-(C1-3-alkyl) carbonyl, aryl-C1-3-alkyl, C1 6-alkoxymethyl, aryl-C1-3-alkoxy, C1-4-alkylthioethyl, arylthioethyl, C1-4-alkylsulfonylethyl, arylsulfonylethyl, RaRbRcSi, CRaRbORc, wherein two adjacent groups R4 may be linked with each other to form a bridging group SiRaRb, C═O, CRaRb or CRaORb—CRaORb and wherein each alkyl group may be substituted with up to three substituents selected from fluorine, chlorine, C1 3-alkyl, RaRbRcSi, C1-4-alkoxy,

R 6 denotes hydrogen, para-R7-phenyl-, C1-6-alkyloxy, aryloxy, —OR4;

R 7 denotes —C≡C—R 1 , Cl, Br, I, —OSO 2 R, —CHO, —SiAlk 3 , —O—C 1-6 -alkyl, —OR 4 , —C≡C—Si(C 1-4 -alkyl) 3 , —C≡C—Si(aryl)(C 1-4 -alkyl) 2 , —C≡C—Si(biphenyl)(C 1-4 -alkyl) 2 , or —C≡C—C(OH)(C 1-4 -alkyl) 2 .

5. Process for preparing the compounds of general formula X,

wherein R 2 and each R 4 are defined as in claim 2 ; and R 6 is defined as in claim 3 ;

characterised in that a protected D-glucal of the formula VII

wherein R 4 is defined as hereinbefore;

is metallated to yield a metallated D-glucal of the formula VIII

wherein R 4 is defined as hereinbefore and M denotes lithium or a magnesium moiety;

which is optionally transmetallated to yield a metallated D-glucal of the formula VIII, wherein M denotes a magnesium, zinc, indium, boron, tin, silicon or chromium moiety; and

the metallated or trans-metallated D-glucal of the formula VIII is reacted with an aglycon of the formula V

wherein R 2 and R 6 are defined as hereinbefore and X denotes a replaceable group;

in the presence of a transition metal catalyst

to yield a glucal derivative of the formula IX

wherein R 2 , R 6 and each R 4 are defined as hereinbefore; and

the glucal derivative of the formula IX is converted to the product of the formula X by the addition of water to the double bond of the glucal moiety, in particular by hydroboration of the double bond and subsequent cleavage of the carbon-boron bond or by epoxidation or dihydroxylation of the double bond and subsequent reduction of the resultant anomeric carbon-oxygen bond.

6. Process for preparing the compounds of general formula X

wherein

R 2 is chlorine or methyl

R 4 independently of one another denote hydrogen, C3-18-alkenyl, (C1 18-alkyl) -carbonyl, (C1-18-alkyl)oxycarbonyl, (C3-18-alkenyl)carbonyl, (C3-18-alkenyl)oxycarbonyl, di-(C1-18-alkyl)aminocarbonyl, arylcarbonyl, aryl-(C1-3-alkyl) carbonyl, aryl-C1-3-alkyl, C1 6-alkoxymethyl, aryl-C1-3-alkoxy, C1-4-alkylthioethyl, arylthioethyl, C1-4-alkylsulfonylethyl, arylsulfonylethyl, RaRbRcSi, CRaRbORc, wherein two adjacent groups R4 may be linked with each other to form a bridging group SiRaRb, C═O, CRaRb or CRaORb—CRaORb and wherein each alkyl group may be substituted with up to three substituents selected from fluorine, chlorine, C1 3-alkyl, RaRbRcSi, C1-4-alkoxy,

R 6 denotes hydrogen, para-R7-phenyl-, C1-6-alkyloxy, aryloxy, —OR4;

R 7 denotes —C≡C—R 1 , CI, Br, I, —OSO 2 R, —CHO, —SiAlk 3 , —O—C 1-6 -alkyl, —OR 4 , —C≡C—Si(C 1-4 -alkyl) 3 , —C≡C—Si(aryl)(C 1-4 -alkyl) 2 , —C≡C—Si(biphenyl)(C 1-4 -alkyl) 2 , or —C≡C—C(OH)(C 1-4 -alkyl) 2 ; and

characterised in that a protected D-glucal of the formula VII

wherein R 4 is defined as hereinbefore;

is epoxidated to yield the corresponding glucaloxide of the formula XI

wherein R 4 is defined as hereinbefore; and

the glucaloxide of the formula XI is reacted with an aglycon of the formula VI

wherein R 2 and R 6 is defined as hereinbefore and M denotes a lithium, magnesium, zinc, indium, aluminum or boron moiety;

to yield the product of the formula X.

7. Process for preparing the compounds of general formula II′,

wherein

R 2

R2 is chlorine or methyl

R4 independently of one another denote hydrogen, C3-18-alkenyl, (C1 18-alkyl) carbonyl, (C1-18-alkyl)oxycarbonyl, (C3-18-alkenyl)carbonyl, (C3-18-alkenyl)oxycarbonyl, di-(C1-18-alkyl)aminocarbonyl, arylcarbonyl, aryl-(C1-3-alkyl) -carbonyl, aryl-C1-3-alkyl, C1 6-alkoxymethyl, aryl-C1-3-alkoxy, C1-4-alkylthioethyl, arylthioethyl, C1-4-alkylsulfonylethyl, arylsulfonylethyl, RaRbRcSi, CRaRbORc, wherein two adjacent groups R4 may be linked with each other to form a bridging group SiRaRb, C═O, CRaRb or CraORb—CRaORb and wherein each alkyl group may be substituted with up to three substituents selected from fluorine, chlorine, C1 3-alkyl, RaRbRcSi, C1-4-alkoxy,

R 6 denotes hydrogen, para-R 7 -phenyl-, C1-6-alkyloxy, aryloxy, —OR4;

R 7 denotes —C≡C—R 1 , Cl, Br, I, —OSO 2 R, —CHO, —SiAlk 3 , —O—C 1-6 -alkyl, —OR 4 , —C≡C—Si(C 1-4 -alkyl) 3 , —C≡C—Si(aryl)(C 1-4 -alkyl) 2 , —C≡C—Si(biphenyl)(C 1-4 -alkyl) 2 , or —C≡C—C(OH)(C 1-4 -alkyl) 2 ;

characterised in that a glucose derivative of the formula XII

wherein R 4 is defined as hereinbefore and LG denotes F, Cl, Br, C 1-3 -alkylcarbonyloxy, C 1-3 -alkyloxycarbonyloxy, C 1-3 -alkyloxy or trichloroacetimidate;

is reacted with a metallated aglycon of the formula VI

wherein R 2 is defined as hereinbefore; and R 6 is defined as in claim 3 ; and M denotes a lithium, magnesium, zinc, indium or boron moiety;

to yield the product of the formula II′.

8. Process according to claim 5 characterized in that in the product of the formula X the hydroxyl group in 2-position of the pyranosyl-ring is protected by a group R 4 not being hydrogen to yield a compound of the formula II′

wherein R 2 , R 6 and each R 4 are defined as hereinbefore.

9. Process according to claim 3 wherein the group R 6 denotes a group of the subformula

wherein R 1 is hydrogen or

C1-4-alkyl, C3-7-cycloalkyl, tetrahydrofuranyl, or tetrahydropyranyl, which may be substituted with one to four substituents L2, or

an aryl-group or a 5- or 6-membered monocyclic heteroaryl-group or a 8-, 9- or 10-membered bicyclic heteroaryl-group wherein said heteroaryl-groups have 1 to 4 heteroatoms independently selected from the group consisting of N, O and S; and wherein said heteroaryl-group may possess 1 or 2 carbonyl groups as part of the mono- or bicyclic aromatic ring-system; and

wherein an N-atom of the heteroaryl ring-system may be oxidized to form the corresponding N-oxide; and

wherein one or more methine groups in said aryl- and heteroaryl-group may be substituted independently of one another with a substituent L1; and

wherein one or more imino-groups in said heteroaryl-group may be substituted independently of one another with a substituent RN.

10. Process for preparing compounds of the formula XXVI′

wherein

R 2 denotes chlorine or methyl; and

R 4 independently of one another denote hydrogen, C 3-18 -alkenyl, (C 1-18 -alkyl)-carbonyl, (C 1-18 -alkyl)oxycarbonyl, (C 3-18 -alkenyl)carbonyl, (C 3-18 -alkenyl)oxycarbonyl, di-(C 1-18 -alkyl)aminocarbonyl, arylcarbonyl, aryl-(C 1-3 -alkyl)-carbonyl, aryl-C 1-3 -alkyl, C 1-6 -alkoxymethyl, aryl-C 1-3 -alkoxy, C 1-4 -alkylthioethyl, arylthioethyl, C 1-4 -alkylsulfonylethyl, arylsulfonylethyl, R a R b R c Si, CR a R b OR c , wherein two adjacent groups R 4 may be linked with each other to form a bridging group SiR a R b , C═O, CR a R b or CR a OR b —CR a OR b and wherein each alkyl group may be substituted with up to three substituents selected from fluorine, chlorine, C 1-3 -alkyl, R a R b R c Si, C 1-4 -alkoxy,

R 13 denotes —CHO, —C≡C—R 1 , OH, C 1-6 -alkyloxy, —Si(C 1-6 -alkyl) 3 , —C≡C—Si(C 1-4 -alkyl) 3 , —C≡C—Si(aryl)(C 1-4 -alkyl) 2 , —C≡C—Si(biphenyl)(C 1-4 -alkyl) 2 , —C≡C—C(OH)(C 1-4 -alkyl) 2 , iodine, bromine, chlorine, or C 1-6 -alkylsulfonyloxy; wherein R 1 is defined as in claim 1 ;

characterized in that

in a compound of the formula X

wherein R 2 and each R 4 are defined hereinbefore; and

R 6 denotes hydrogen, OH, C 1-6 -alkyloxy or aryloxy

or in a compound of the formula II′

wherein R 2 , R 6 and each R 4 are defined as hereinbefore;

the group R 6 is transformed into a group Z 4 to yield a compound of the formula XXXIX

wherein R 2 and each R 4 are defined as hereinbefore; and

Z 4 denotes chlorine, bromine, iodine, C 1-6 -alkyloxy, aryloxy, C 1-6 -alkylcarbonyl-oxy, C 1-6 -alkyloxycarbonyloxy, C 1-6 -alkylsulfonyloxy, —OPO(O—C 1-6 -alkyl) 2 , or aryloxy;

and the compound of the formula XXXIX is reacted with a metalated benzene of the formula XXIII

wherein R 13 is defined as hereinbefore; and

M 3 denotes a lithium-, boron-, magnesium-, silicon-, tin-, cerium-, indium-, zinc-, or chromium-moiety;

to yield a compound of the formula XXVI′.

11. Process according to claim 10 characterized in that in the compound of the formula XXVI′ wherein the group R 13 which does not denote —C≡C—R 1 is transformed into a group —C≡C—R 1 , wherein R 1 is hydrogen, or C1-4-alkyl, C3-7-cycloalkyl, tetrahydrofuranyl, or tetrahydropyranyl, which may be substituted with one to four substituents L2, or

an aryl-group or a 5- or 6-membered monocyclic heteroaryl-group or a 8-, 9- or 10-membered bicyclic heteroaryl-group wherein said heteroaryl-groups have 1 to 4 heteroatoms independently selected from the group consisting of N, O and S; and wherein said heteroaryl-group may possess 1 or 2 carbonyl groups as part of the mono- or bicyclic aromatic ring-system; and

wherein an N-atom of the heteroaryl ring-system may be oxidized to form the corresponding N-oxide; and

wherein one or more methine groups in said aryl- and heteroaryl-group may be substituted independently of one another with a substituent L1; and

wherein one or more imino-groups in said heteroaryl-group may be substituted independently of one another with a substituent RN.

12. Process according to claim 10 characterized in that the group R 13 denotes —C≡C—R 1 .

13. Process according to claim 10 wherein product of the formula XXVI′ protective groups R 4 not being hydrogen are cleaved.

14. Process according to claim 1 characterized in that one or more of the groups R 4 independently of each other denote hydrogen, (C 1-6 -alkyl)carbonyl, (C 1-6 -alkyl)oxycarbonyl, (C 3-6 -alkenyl)oxycarbonyl, arylcarbonyl, aryl-methyl, C 1-6 -alkoxymethyl, R a R b R c Si, CR a R b OR c , wherein two adjacent groups R 4 may be linked with each other to form a bridging group SiR a R b , C═O, CR a R b or CR a OR b —CR a OR b and wherein each alkyl group may be substituted with up to three substituents selected from fluorine, chlorine, C 1-3 -alkyl, R a R b R c Si and C 1-4 -alkoxy; wherein R a , R b , R c and aryl are defined as in claim 1 .

15. Process according to claim 1 characterized in that the group R 1 denotes hydrogen or

C 1-4 -alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl, which may be substituted with one or two substituents L2.

16. Compound of general formula IX

wherein:

R 2 denotes chlorine or methyl;

R 4 independently of one another denote hydrogen, C3-18-alkenyl, (C1-18-alkyl) -carbonyl, (C1-18-alkyl)oxycarbonyl, (C3-18-alkenyl)carbonyl, (C3-18-alkenyl)oxycarbonyl, di-(C1-18-alkyl)aminocarbonyl, arylcarbonyl, aryl-(C1-3-alkyl)- carbonyl, aryl-C1-3-alkyl, C1-6-alkoxymethyl, aryl-C1-3-alkoxy, C1-4-alkylthioethyl, arylthioethyl, C1-4-alkylsulfonylethyl, arylsulfonylethyl, RaRbRcSi, CRaRbORc, wherein two adjacent R 4 groups may be linked with each other to form a bridging group SiRaRb, C═O, CRaRb or CRaORb—CRaORb and wherein each alkyl group may be substituted with up to three substituents selected from fluorine, chlorine, C1-3-alkyl, RaRbRcSi, and C1-4-alkoxy;

R 6 denotes hydrogen, para-R 7 -phenyl-, C1-6-alkyloxy, aryloxy, or OR 4 ;

R 7 denotes —C≡C—R 1 , Cl, Br, I, —OSO 2 R, —CHO, —SiAlk 3 , —O—C 1-6 -alkyl, —OR 4 , —C≡C—Si(C 1-4 -alkyl) 3 ,—C≡C—Si(aryl)(C 1-4 -alkyl) 2 ,—C≡C—Si(biphenyl)(C 1-4 -alky) 2 , or —C≡C—C(OH)(C 1-4 -alkyl) 2 ;

R 1 denotes hydrogen, C 1-4 -alkyl, C 3-7 -cycloalkyl, tetrahydrofuranyl, or tetrahydropyranyl, which may be substituted with one to four substituents L2,

an aryl-group or a 5- or 6-membered monocyclic heteroaryl-group or a 8-, 9- or 10-membered bicyclic heteroaryl-group wherein said heteroaryl-groups have 1 to 4 heteroatoms independently selected from the group consisting of N, O and S;

and wherein said heteroaryl-group may possess 1 or 2 carbonyl groups as part of the mono- or bicyclic aromatic ring-system; and,

wherein an N-atom of the heteroaryl ring-system may be oxidized to form the corresponding N-oxide; and,

wherein one or more methine groups in said aryl- and heteroaryl-group may be substituted independently of one another with a substituent L1; and,

wherein one or more imino-groups in said heteroaryl-group may be substituted independently of one another with a substituent R N ; and,

R N independently of one another are selected from among C 1-3 alkyl; and,

R denotes C 1-4 -alkyl, C 3-4 -alkenyl, C 1-4 -alkoxy, CF 3 , aryl or aryl-C 1-3 -alkyl, wherein aryl-groups may be mono- or polysubstituted with L1;

L1 independently of one another are selected from among fluorine, chlorine, bromine, C 1-3 -alkyl, C 1-4 -alkoxy, and nitro;

L2 independently of one another are selected from among fluorine, chlorine, hydroxy, hydroxyl-C 1-4 -alkyl, C 1-4 -alkoxy, trifluoromethoxy, C 1-4 -alkoxy-C 1-4 -alkyl, cyano, C 1-4 -alkyl, trifluoromethyl, amino, C 1-4 -alkyl-carbonylamino, C 1-3 -alkyl-amino and di(C 1-3 -alkyl)-amino;

while the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups, which may be mono- or polysubstituted with L1; and,

Ra, Rb, and Rc independently of one another denote C1-4-alkyl, aryl, or aryl-C1-3-alkyl, while alkyl may be mono- or polysubstituted by halogen.