Patent Application
20100048699
The present invention relates to thiourea derivatives, to processes for preparing them, to insecticidal, acaricidal, molluscicidal and nematicidal compositions comprising them and to methods of using them to combat and control insect, acarine, mollusc and nematode pests.
The present invention therefore provides a method of combating and controlling insects, acarines, nematodes or molluscs which comprises applying to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I)
wherein
R73 is hydrogen, G-, formyl, G-C(O)—, G-C(S)—, G-O—C(O)—, G-O—C(S)—, R78R79N—C(O)—, R78R79N—C(S)—, where R78 and R79 are independently H or G-, or R78 and R79 together with the N atom to which they are attached, form a group N═CRaRb, where Ra and Rb are H, C1-6 alkyl or phenyl; or R78 and R79 together with the N atom to which they are attached form a five, six or seven membered ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one to four C1-6 alkyl groups;
R10 and R72 are independently hydrogen, hydroxy, amino, cyano, formyl, G-, G-O—, G-S—, G-S—S—, G-A-, R24R25N—, G-A-NR17, R24R25N—S—, R24R25N-A-, R18N═C(R19)—, G-O-A- or G-S-A-; where R24 and R25 are independently H or G-, or R24 and R25 together with the N atom to which they are attached, form a group N═CRaRb where Ra and Rb are H, C1-6 alkyl or phenyl; or R24 and R25 together with the N atom to which they are attached form a five, six or seven membered ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one to four C1-6 alkyl groups or phenyl; R17 is H, G-, G-C(O)— or G-OC(O)—; R13 is H, OH, cyano, nitro, G-, G-O— or R38R39N—, where R33 and R39 are independently H or G-, or R38 and R39 together with the N atom to which they are attached, form a group N═CRaRb, where Ra and Rb are H, C1-6 alkyl or phenyl; or R38 and R39 together with the N atom to which they are attached form a five, six or seven membered ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one to four C1-6 alkyl groups; R19 is H, cyano, G-, G-O—, G-S— or R42R43N—, where R42 and R43 are independently H or G; or R42 and R43 together with the N atom to which they are attached, form a group N═CRaRb, where Ra and Rb are H, C1-6 alkyl or phenyl; or R42 and R43 together with the N atom to which they are attached form a five, six or seven membered ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one to four C1-6 alkyl groups or phenyl;
L is a direct bond, CR74R75 or CR74R75CR76R77, where R74, R75, R76R77 independently hydrogen, OH, halogen, COOH, cyano, formyl, G-, GO-, GS-, G-C(O)—, G-C(S)—, G-O—C(O)—, G-O—C(S)—, R80R81N—C(O)—, R80R81N—C(S)—; or the groups R74 and R75 and/or R76 and R77 together with the carbon atom to which they are attached form a three to six membered ring, containing at least 2 carbon atoms and optionally containing one or two sulphur and/or one or two non-adjacent oxygen atoms or a group NR82, S(O)2, S(O) or C(O) the ring being optionally substituted by C1-6 alkyl or phenyl, where R80 and R81 are independently H or G-, or R80 and R81 together with the N atom to which they are attached, form a group N═CRaRb, where Ra and Rb are H, C1-6 alkyl or phenyl; or R80 and R81 together with the N atom to which they are attached form a five, six or seven membered ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one to four C1-6 alkyl groups; R82 is H, OH, cyano, formyl, G-, G-O—, G-S—, G-A-, R27R28N—, R27R28N-A-, G-O-A-, G-S-A-, G-A-NR29—, R27R28N-A-NR29—, G-O-A-NR29— or G-S-A-NR29—, where R27 and R28 are independently H or G-, or R27 and R28 together with the N atom to which they are attached, form a group N═CRaRb where Ra and Rb are H, C1-6 alkyl or phenyl; or R27 and R28 together with the N atom to which they are attached form a five, six or seven membered ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one to four C1-4 alkyl groups or phenyl; R29 is H or G-; or two of the groups R74, R75, R76 and R77 attached to different atoms together with the atoms to which they are attached form a three to seven membered ring, that optionally contains one or two sulphur and/or one or two non-adjacent oxygen atoms or a group NR82, S(O)2, S(O) or C(O), the ring being optionally substituted by C1-C6 alkyl or phenyl; where R82 has the meanings assigned to it above; R43, R47, R48 and R49 are each independently hydrogen, halogen, G-, G-C(O)—, G-C(S)—, G-O—C(O)—, G-O—C(S)—, R83R84N—C(O)—, R83R84N—C(S)—; where R33 and R84 are independently H or G-, or R83 and R84 together with the N atom to which they are attached, form a group N═CRaRb where Ra and Rb are H, C1-6 alkyl or phenyl; or R83 and R84 together with the N atom to which they are attached form a five, six or seven membered ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one to four C1-6 alkyl groups or phenyl, or the groups R46 and R47 and/or R48 and R49 together with the carbon atom to which they are attached form a three to six membered ring, containing at least 2 carbon atoms and optionally containing one or two sulphur and/or one or two non-adjacent oxygen atoms or a group NR85, where R85 is H, OH, cyano, formyl, G-, G-O—, G-S—, G-A-, R27R28N—, R27R28N-A-, G-O-A-, G-S-A-, G-A-NR29—, R27R28N-A-NR29—, G-O-A-NR29— or G-S-A-NR29—, where R27 and R28 are independently H or G-, or R27 and R28 together with the N atom to which they are attached, form a group N═CRaRb where Ra and Rb are H, C1-6 alkyl or phenyl; or R27 and R28 together with the N atom to which they are attached form a five, six or seven membered ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one to four C1-6 alkyl groups or phenyl; or two of the groups R46, R47, R48, R49, R74, R75, R76 and R77 attached to different atoms together with the atoms they are attached form a three to seven membered ring, that optionally contains one or two sulphur and/or one or two non-adjacent oxygen atoms or a group NR85, where R82 and R85 have the meanings assigned to them as above, or a group S(O)2, S(O) or C(O) the ring being optionally substituted by C1-C6 alkyl or phenyl;
Y is O, S(O)m, where m is 0, 1 or 2, NR3, SO2—NR3, NR3—SO2, NR3—O or O—NR3 where R3 is H, OH, cyano, formyl, G-, G-O—, G-S—, G-A-, R27R28N—, R27R28N-A-, G-O-A-, G-S-A-, G-A-NR29—, R27R28N-A-NR29—, G-O-A-NR29— or G-S-A-NR29—, where R27, R28 and R29 have the meanings assigned to them above; or Y is CR5R6, CR5R6—CR7R8, O—CR7R8, S(O)m—CR7R8, NR3—CR7R8, CR5R6—O, CR5R6—S(O)m or CR5R6—NR3, where R3 and m have the meanings assigned to them above, and R5, R6, R7 and R8 are each independently H, OH, halogen, nitro, cyano, rhodano, carboxy, formyl, formyloxy, G-, G-O—, G-S—, G-A-, R21R22N—, R21R22N-A-, G-O-A-, G-S-A-, G-A-O—, G-A-S—, G-A-NR23, R21R22 N-A-O—R21R22N-A-S, R21R22NA NR23—, G-O-A-O—, G-O-A-S—, G-O-A-NR23—, G-S-A-O, G-S-A-NR23— or R20S(O)(═NR17)—, where R21 and R22 are independently H or G-, or R21 and R22 together with the N atom to which they are attached, form a group N═CRaRb, where Ra and Rb are H, C1-6 alkyl or phenyl; or R21 and R22 together with the N atom to which they are attached form a five, six or seven membered ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one to four C1-6 alkyl groups or phenyl; R23 is H or G- and R17 is as defined above; R20 is C1-6 alkyl, optionally substituted phenyl, optionally substituted benzyl; or two of the groups R5, R6, R7 and R8 attached to the same carbon atom are ═O, ═S, ═NR11 or ═CR12R13, where R11 is H, OH, nitro, cyano, formyl, formyloxy, G-, G-O—, G-A-, R36R37N—, G-C(O)—O—, G-C(O)—NR26—, R36R37N—C(O)O—, G-O—C(O)O—, G-O—C(O)—NR26—, where R38, R3 and R26 are independently H or G-, or R36 and R37 together with the N atom to which they are attached, form a group N═CRaRb where Ra and Rb are H, C1-6 alkyl or phenyl; or R36 and R37 together with the N atom to which they are attached form a five, six or seven membered ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one to four C1-6 alkyl groups or phenyl, and R12 and R13 are each independently H, halogen, nitro, cyano, formyl, formyloxy, G-, G-O—, G-S—, G-A-, R40R41N—, R40R41N-A-, G-O-A-, G-A-O—, R40R41N-A-O—, R40R41N-A-S—, G-O-A-O—, G-O-A-S—, G-O-A-NR30—; where R40, R41 and R30 are independently H or G-, or R40 and R41 together with the N atom to which they are attached, form a group N═CRaRb where Ra and Rb are H, C1-6 E alkyl or phenyl; or R40 and R41 together with the N atom to which they are attached form a five, six or seven membered ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one to four C1-6 alkyl groups or phenyl, or R12 and R13 together with the carbon atom to which they are attached form a 3 to 6 membered carbocyclic ring; or the groups R5 and R6 or R7 and R8 together with the carbon atom to which they are attached form a three to six membered ring, containing at least 2 carbon atoms and optionally containing one or two sulfur and/or one or two non-adjacent oxygen atoms or a group NR14, where R14 is H, OH, cyano, formyl, G-, G-O—, C—S—, C-A-, R27R28N—, R27R28N-A-, G-O-A-, G-S-A-, G-A-NR29—, R27R28 N-A-NR29—, G-O-A-NR29— or G-S-A-NR29—, where R27, R28 and R29 have the meanings assigned to them above, the ring being optionally substituted by one to four C1-C6alkyl groups or phenyl; or two of the groups R5, R6, R7 and R8 attached to different atoms together with the atoms they are attached form a three to seven membered ring, that optionally contains one or two sulfur and/or one or two non-adjacent oxygen atoms or a group NR14, where R14 is as defined above, or two of the groups R5, R6, R7 and R3 attached to adjacent atoms combine to form a bond;
the ring (T)
is a 5- or 6-membered aromatic or heteroaromatic ring;
R1 and R2 are each independently H, OH, halogen, nitro, cyano, rhodano, carboxy, formyl, formyloxy, G-, G-O—, G-S—, G-A-, R21R22N—, R21R22N-A-, G-O-A-, G-S-A-, G-A-O—, G-A-S—, G-A-NR23—, R21R22N-A-O—, R21R22N-A-S—, R21R22N-A-NR23—, G-S-A-O—, G-O-A-S—, G-O-A-NR23—, G-S-A-O—, G-S-A-NR23—, or R20S(O)(═NR17)—; where R17, R20, R21, R22 and R23 are as defined above, or two of the groups R1 and R2 attached to the same carbon atom are ═O, ═S, ═NR11 or ═CR12R13, where R11, R12 and R13 are defined as above, or the groups R1 and R2 together with the same carbon atom to which they are attached form a three to six membered ring, containing at least 2 carbon atoms and optionally containing one or two sulfur and/or one or two non-adjacent oxygen atoms or a group NR14, where R14 is as defined above, the ring being optionally substituted by C1-C6 alkyl; or two of the groups R1, R2 and R7, R8 attached to different atoms together with the atoms they are attached form a three to seven membered ring, that optionally contains one or two sulfur and/or one or two non-adjacent oxygen atoms or a group NR14, where R14 is defined as above, the ring being optionally substituted by one or four C1-C6alkyl groups or phenyl; or two of the groups R1, R2, R5, R6, R7 and R8 attached to adjacent atoms combine to form a bond;
each R4 is independently OH, halogen, nitro, cyano, azido, rhodano, isothiocyanato, carboxy, formyl, formyloxy, G-, G-O—, G-S—, G-A-, R31R32N—, R31R32N-A-, G-O-A-, G-S-A-, G-A-O—, G-A-S—, G-A-NR33—, R31R32N-A-O—, R31R32N-A-S—, R31R32N-A-NR33—, G-O-A-O—, G-O-A-S—, G-O-A-NR33—, G-S-A-O—, G-S-A-NR33—, R20S(O)(═NR17)—, R18N═C(R19)—, R44R45P(O)— or R44R45P(S)—, where R17, R18, R19 and R20 have the meanings assigned to them above, and R31, R32 and R33 are independently H or G-, or R31 and R32 together with the N atom to which they are attached, form a group N═CRaRb, where Ra and Rb are H, C1-6 alkyl or phenyl; or R31 and R32 together with the N atom to which they are attached form a five, six or seven membered ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one to four C1-6 alkyl groups or phenyl, and R44 and R45 are independently H, C1-6alkyl, C1-6-alkoxy, phenyl, phenoxy; or 2 adjacent groups R4 together with the carbon atoms to which they are attached form a 4, 5, 6 or 7 membered carbocyclic or heterocyclic ring which may be optionally substituted by C1-6alkyl or halogen; or a group R4 together with a group R3, R5, R6 or R9 and the atoms to which they are attached form a 5-7 membered ring optionally containing an NR15 group where R15 is H, OH, cyano, formyl, G-, G-O—, G-S—, G-A-, R27R28N—, R27R28N-A-, G-O-A-, G-S-A-, G-A-NR29—, R27R28N-A-NR29—, G-O-A-NR29— or G-S-A-NR29—, where R27, R28 and R29 have the meanings assigned to them above, or containing an S or O atom, the ring being optionally substituted by one to four C1-C8 alkyl groups or phenyl;
n is 0, 1, 2, 3 or 4;
R9 is H, formyl, G-, G-A-, R34R35N-A-, where R34 and R35 are independently H or G-, or R34 and R35 together with the N atom to which they are attached, form a group N═CRaRb where Ra and Rb are H, C1-6 alkyl or phenyl; or R34 and R35 together with the N atom to which they are attached form a five, six or seven membered ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one to four C1-6 alkyl groups or phenyl; or R9 is G-O-A- or G-S-A-; or R9 together with a group R1, R2, R3, R5, R6, R7 or R8 and the atoms to which they are attached may form a three to seven membered ring, that optionally may contain one or two sulfur and/or one or two non-adjacent oxygen atoms or a group NR16; where R16 is H, OH, cyano, formyl, G-, G-O—, G-S—, G-A-, R27R28N—, R27R28N-A-, G-O-A-, G-S-A-, G-A-NR29—, R27R28N-A-NR29—, G-O-A-NR29— or G-S-A-NR29—, where R27, R23 and R29 have the meanings assigned to them above,
G is optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;
or salts or N-oxides thereof,
with the proviso, that the compound of formula I is not: 1-(2-hydroxy-ethyl)-3-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-thiourea, 1-(2-hydroxy-ethyl)-3-(1,2,3,4-tetrahydro-naphthalen-1-yl)-thiourea, methoxy-acetic acid 2-[3-(1,2,3,4-tetrahydro-naphthalen-1-yl)-thioureido]-ethyl ester, acetic acid 2-[3-(7-chloro-1,2,3,4-tetrahydro-naphthalen-1-yl)-thioureido]-ethyl ester, benzoic acid 2-[3-(7-chloro-1,2,3,4-tetrahydro-naphthalen-1-yl)-thioureido]-ethyl ester, acetic acid 2-[3-(7-bromo-1,2,3,4-tetrahydro-naphthalen-1-yl)-thioureido]-ethyl ester, benzoic acid 2-[3-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-thioureido]-ethyl ester, 1-(7-bromo-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(2-hydroxy-ethyl)-thiourea, 1S-benzoic acid 2-(3-indan-1-yl-thioureido)-ethyl ester, nicotinic acid 2-(3-indan-1-yl-thioureido)-ethyl ester, nicotinic acid 2-(1-acetyl-3-indan-1-yl-thioureido)-ethyl ester, isonicotinic acid 2-(3-indan-1-yl-thioureido)-ethyl ester, pyridine-2-carboxylic acid 2-(3-indan-1-yl-thioureido)-ethyl ester, methoxy-acetic acid 2-(3-indan-1-yl-thioureido)-ethyl ester, 1-(2-hydroxy-ethyl)-3-indan-1-yl-thiourea, 1R-benzoic acid 2-(3-indan-1-yl-thioureido)-ethyl ester, acetic acid 2-[3-(6-methoxy-indan-1-yl)-thioureido]-ethyl ester, acetic acid 2-[3-(4-chloro-indan-1-yl)-thioureido]-ethyl ester, benzoic acid 2-[3-(4-chloro-indan-1-yl)-thioureido]-ethyl ester, 1-indan-1-yl-3-[2-(thiazol-2-yloxy)-ethyl]-thiourea, 4,5-dihydro-thiazole-2-carboxylic acid 2-(3-indan-1-yl-thioureido)-ethyl ester, 5-chloro-thiophene-2-carboxylic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, furan-2-carboxylic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, 3-trifluoromethyl-benzoic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, 2-ethylsulfanyl-nicotinic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, 2-methylsulfanyl-nicotinic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, 3-cyano-benzoic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, phenyl-acetic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, 2-acetoxy-benzoic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, diphenyl-acetic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, 3-(2-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, 2-phenyl-butyric acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, cyclopentanecarboxylic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, 3-methyl-butyric acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, naphthalene-2-carboxylic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, 2,2-dimethyl-propionic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, 3-phenyl-propionic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, thiophen-2-yl-acetic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, propionic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, 3-methylsulfanyl-propionic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, phenoxy-acetic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester, or 3,5-dimethyl-isoxazole-4-carboxylic acid 2-((S)-3-indan-1-ylthioureido)-ethyl ester.
The compounds of formula (I) as defined herein are novel and as such form a further aspect of the invention.
The compounds of formula (I) may exist as different geometric or optical isomers or in different tautomeric forms. One or more centres of chirality may be present, for example on the chiral carbon atoms CR1R2, CR46R47, CR48R49 and CR9 or a chiral carbon unit in the group G, or a chiral —S(O)— unit, in which case compounds of the formula (I) may be present as pure enantiomers, mixtures of enantiomers, pure diastereomers or mixtures of diastereomers. There may be double bonds present in the molecule, such as C═C or C═N bonds, in which case compounds of formula (I) may exist as single isomers of mixtures of isomers. Centres of tautomerisation may be present. This invention covers all such isomers and tautomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds.
Suitable acid addition salts include those with an inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, or an organic carboxylic acid such as oxalic, tartaric, lactic, butyric, toluic, hexanoic and phthalic acids, or sulphonic acids such as methane, benzene and toluene sulphonic acids. Other examples of organic carboxylic acids include haloacids such as trifluoroacetic acid.
N-oxides are oxidised forms of tertiary amines or oxidised forms of nitrogen containing heteroaromatic compounds. They are described in many books for example in “Heterocyclic N-oxides” by Angelo Albini and Silvio Pietra, CRC Press, Boca Raton, Fla., 1991.
Each alkyl moiety either alone or as part of a larger group (such as G, or alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl) is a straight or branched chain and is, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl or neo-pentyl. The alkyl groups are suitably C1 to C12 alkyl groups, but are preferably C1-C10, more preferably C1-C8, even more preferably C1-C6 and most preferably C1-C4 alkyl groups.
Ring or chain forming alkylen, alkenylen and alkinyl groups can optionally be further substituted by one or more halogen, C1-3alkyl and/or C1-3-alkoxy group.
When present, the optional substituents on an alkyl moiety (alone or as part of a larger group such as G, alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl) include one or more of halogen, nitro, cyano, rhodano, isothiocyanato, C3-7 cycloalkyl (itself optionally substituted with C1-6 alkyl or halogen), C5-7 cycloalkenyl (itself optionally substituted with C1-6 alkyl or halogen), hydroxy, C1-10 alkoxy, C1-10 alkoxy(C1-10)alkoxy, tri(C1-4)alkylsilyl(C1-6)alkoxy, C1-6 alkoxycarbonyl(C1-10)alkoxy, C1-10 haloalkoxy, aryl(C1-4)-alkoxy (where the aryl group is optionally substituted), C3-7 cycloalkyloxy (where the cycloalkyl group is optionally substituted with C1-6 alkyl or halogen), C2-10 alkenyloxy, C2-10 alkynyloxy, mercapto, C1-10 alkylthio, C1-10 haloalkylthio, aryl(C1-4)alkylthio (where the aryl group is optionally substituted), C3-7 cycloalkylthio (where the cycloalkyl group is optionally substituted with C1-6 alkyl or halogen), tri(C1-4)alkylsilyl(C1-6)alkylthio, arylthio (where the aryl group is optionally substituted), C1-6 alkylsulfonyl, C1-6 haloalkylsulfonyl, C1-6 alkylsulfinyl, C1-6 haloalkylsulfinyl, arylsulfonyl (where the aryl group may be optionally substituted), tri(C1-4)alkylsilyl, aryldi (C1-4)alkylsilyl, (C1-4)alkyldiarylsilyl, triarylsilyl, formyl, C1-10 alkylcarbonyl, HO2C, C1-10 alkoxycarbonyl, aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6 alkyl)aminocarbonyl, N—(C1— alkyl)-N—(C1-3 alkoxy)aminocarbonyl, C1-8 alkylcarbonyloxy, arylcarbonyloxy (where the aryl group is optionally substituted), di(C1-6)alkylaminocarbonyloxy, aryl (itself optionally substituted), heteroaryl (itself optionally substituted), heterocyclyl (itself optionally substituted with C1-6 alkyl or halogen), aryloxy (where the aryl group is optionally substituted), heteroaryloxy, (where the heteroaryl group is optionally substituted), heterocyclyloxy (where the heterocyclyl group is optionally substituted with C1-6 alkyl or halogen), amino, C1-6 alkylamino, di(C1-6)alkylamino, C1-6 alkylcarbonylamino, N—(C1-6)alkylcarbonyl-N—(C1-6)alkylamino, C2-6 alkenylcarbonyl, C2-6 alkynylcarbonyl, C3-6 alkenyloxycarbonyl, C3-6 alkynyloxycarbonyl, aryloxycarbonyl (where the aryl group is optionally substituted) and arylcarbonyl (where the aryl group is optionally substituted). Furthermore a CH2 moiety, which is part of the alkyl group may be substituted to an oxime or oximether such as —NOalkyl, —NOhaloalkyl and ═NOaryl (itself optionally substituted).
Alkenyl and alkynyl moieties can be in the form of straight or branched chains, and the alkenyl moieties, where appropriate, can be of either the (E)- or (Z)-configuration. Examples are vinyl, allyl and propargyl. Alkenyl and alkynyl moieties can contain one or more double and/or triple bonds in any combination. It is understood that allenyl and alkylinylalkenyl, as well as alkenylalkinyl, are included in these terms.
When present, the optional substituents on alkenyl or alkynyl include those optional substituents given above for an alkyl moiety.
In the context of this specification acyl is optionally substituted C1-6 alkylcarbonyl (for example acetyl), optionally substituted C2-6 alkenylcarbonyl, optionally substituted C3-6 cycloalkylcarbonyl (for example cyclopropylcarbonyl, optionally substituted C2-6 alkynylcarbonyl, optionally substituted arylcarbonyl (for example benzoyl) or optionally substituted heteroarylcarbonyl.
Halogen is fluoro, chlorine, bromine or iodine.
Haloalkyl groups are alkyl groups which are substituted with one or more of the same or different halogen atoms and are, for example, CF3, CF2Cl, CF2H, CCl2CH, FCH2, ClCH2, BrCH2, CH3CHF, (CH3)2CF, CF3CH2 or CHF2CH2.
In the context of the present specification the terms “aryl”, “aromatic ring” and “aromatic ring system” refer to ring systems which may be mono-, bi- or tricyclic. Examples of such rings include phenyl, naphthalenyl, anthracenyl, indenyl or phenanthrenyl. A preferred aryl group is phenyl. In addition, the terms “heteroaryl”, “heteroaromatic ring” or “heteroaromatic ring system” refer to an aromatic ring system containing at least one heteroatom and consisting either of a single ring or of two or more fused rings. Preferably, single rings will contain up to three and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulphur. Examples of such groups include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzofuryl, benzisofuryl, benzothienyl, benzisothienyl, indolyl, isoindolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, 2,1,3-benzoxadiazole, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, benzotriazinyl, purinyl, pteridinyl and indolizinyl. Preferred examples of heteroaromatic radicals include pyridyl, pyrimidyl, triazinyl, thienyl, furyl, oxazolyl, isoxazolyl, 2,1,3-benzoxadiazole and thiazolyl.
The terms heterocycle and heterocyclyl refer to a non-aromatic preferably monocyclic or bicyclic ring systems containing up to 10 atoms including one or more (preferably one or two) heteroatoms selected from O, S and N. Examples of such rings include 1,3-dioxolane, oxetane, tetrahydrofuran, morpholine, thiomorpholin and piperazine.
When present, the optional substituents on heterocyclyl include C1-6 alkyl and C1-6 haloalkyl as well as those optional substituents given above for an alkyl moiety.
Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkylalkyl is preferentially cyclopropylmethyl. Cycloalkenyl includes cyclopentenyl and cyclohexenyl. Carbocyclic rings include aryl, cycloalkyl, and cycloalkenyl groups.
When present, the optional substituents on cycloalkyl or cycloalkenyl include C1-3 alkyl as well as those optional substituents given above for an alkyl moiety.
When present, the optional substituents on aryl or heteroaryl are selected independently, from halogen, nitro, cyano, rhodano, isothiocyanato, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy-(C1-6)alkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C3-7 cycloalkyl (itself optionally substituted with C1-6 alkyl or halogen), C5-7 cycloalkenyl (itself optionally substituted with C1-6 alkyl or halogen), hydroxy, C1-10 alkoxy, C1-10 alkoxy(C1-10)alkoxy, tri(C1-4)alkyl-silyl(C1-6)alkoxy, C1-6 alkoxycarbonyl(C1-10)alkoxy, C1-10 haloalkoxy, aryl(C1-4)alkoxy (where the aryl group is optionally substituted with halogen or C1-6 alkyl), C3-7 cycloalkyloxy (where the cycloalkyl group is optionally substituted with C1-6 alkyl or halogen), C2-10 alkenyloxy, C2-10 alkynyloxy, mercapto, C1-10 alkylthio, C1-10 haloalkylthio, aryl(C1-4)alkylthio, C3-7 cycloalkylthio (where the cycloalkyl group is optionally substituted with C1-6 alkyl or halogen), tri(C1-4)-alkylsilyl(C1-6)alkylthio, arylthio, C1-6 alkylsulfonyl, C1-6 haloalkylsulfonyl, C1-6 alkylsulfinyl, C1-6 haloalkylsulfinyl, arylsulfonyl, tri(C1-4)alkylsilyl, aryldi(C1-4)-alkylsilyl, (C1-4)alkyldiarylsilyl, triarylsilyl, C1-10 alkylcarbonyl, HO2C, C1-10 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(C1-6 alkyl)-aminocarbonyl, N—(C1-3 alkyl)-N—(C1-3 alkoxy)aminocarbonyl, C1-6 alkylcarbonyloxy, arylcarbonyloxy, di(C1-6)alkylamino-carbonyloxy, aryl (itself optionally substituted with C1-6 alkyl or halogen), heteroaryl (itself optionally substituted with C1-6 alkyl or halogen), heterocyclyl (itself optionally substituted with C1-6 alkyl or halogen), aryloxy (where the aryl group is optionally substituted with C1-6 alkyl or halogen), heteroaryloxy (where the heteroaryl group is optionally substituted with C1-6 alkyl or halogen), heterocyclyloxy (where the heterocyclyl group is optionally substituted with C1-6 alkyl or halogen), amino, C1-6 alkylamino, di(C1-6)alkylamino, C1-6 alkylcarbonylamino, N—(C1-6)alkylcarbonyl-N—(C1-6)alkylamino, arylcarbonyl, (where the aryl group is itself optionally substituted with halogen or C1-6 alkyl) or two adjacent positions on an aryl or heteroaryl system may be cyclised to form a 5, 6 or 7 membered carbocyclic or heterocyclic ring, itself optionally substituted with halogen or C1-6 alkyl. Further substituents for aryl or heteroaryl include aryl carbonyl amino (where the aryl group is substituted by C1-6 alkyl or halogen), (C1-6)alkyloxycarbonylamino (C1-6)alkyloxycarbonyl-N—(C1-6)alkylamino, aryloxycarbonylamino (where the aryl group is substituted by C1-6 alkyl or halogen), aryloxycarbonyl-N—(C1-6)alkylamino, (where the aryl group is substituted by C1-6 alkyl or halogen), arylsulphonylamino (where the aryl group is substituted by C1-6 alkyl or halogen), arylsulphonyl-N—(C1-6)alkylamino (where the aryl group is substituted by C1-6 alkyl or halogen), aryl-N—(C1-6)alkylamino (where the aryl group is substituted by C1-6 alkyl or halogen), arylamino (where the aryl group is substituted by C1-6 alkyl or halogen), heteroaryl amino (where the heteroaryl group is substituted by C1-6 alkyl or halogen), heterocyclylamino (where the heterocyclyl group is substituted by C1-6 alkyl or halogen), aminocarbonylamino, C1-6 alkylaminocarbonyl amino, di(C1-6)alkylaminocarbonyl amino, arylaminocarbonyl amino (where the aryl group is substituted by C1-6 alkyl or halogen), aryl-N—(C1-6)alkylaminocarbonylamino (where the aryl group is substituted by C1-6 alkyl or halogen), C1-6 alkylaminocarbonyl-N—(C1-6)alkyl amino, di(C1-6)alkylaminocarbonyl-N—(C1-6)alkyl amino, arylaminocarbonyl-N—(C1-6)alkyl amino (where the aryl group is substituted by C1-6 alkyl or halogen) and aryl-N—(C1-6)alkylaminocarbonyl-N—(C1-6)alkyl amino (where the aryl group is substituted by C1-6 alkyl or halogen).
For substituted phenyl moieties, heterocyclyl and heteroaryl groups it is preferred that one or more substituents are independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy(C1-6)alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylthio, C1-6 haloalkylthio, C1-6 alkylsulfinyl, C1-6 haloalkylsulfinyl, C1-6 alkylsulfonyl, C1-6 haloalkylsulfonyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C3-7 cycloalkyl, nitro, cyano, CO2H, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, aryl, heteroaryl, R50R51N or R52R53NC(O), wherein R50, R51, R52 and R53 are, independently, hydrogen or C1-6 alkyl.
Haloalkenyl groups are alkenyl groups which are substituted with one or more of the same or different halogen atoms.
It is to be understood that dialkylamino substituents include those where the dialkyl groups together with the N atom to which they are attached form a five, six or seven-membered heterocyclic ring which may contain one or two further heteroatoms selected from O, N or S and which is optionally substituted by one or two independently selected (C1-6)alkyl groups. When heterocyclic rings are formed by joining two groups on an N atom, the resulting rings are suitably pyrrolidine, piperidine, thiomorpholine and morpholine each of which may be substituted by one or two independently selected (C1-6) alkyl groups.
Preferably the optional substituents on an alkyl moiety include one or more of halogen, nitro, cyano, HO2C, C1-10 alkoxy (itself optionally substituted by C1-10 alkoxy), aryl(C1-4)alkoxy, C1-10 alkylthio, C1-10 alkylcarbonyl, C3-5 cycloalkylcarbonyl, C1-10 alkoxycarbonyl, C1-6 alkylaminocarbonyl, di(C1-6 alkyl)aminocarbonyl, (C1-6)alkylcarbonyloxy, optionally substituted phenyl, heteroaryl, aryloxy, arylcarbonyloxy, heteroaryloxy, heterocyclyl, heterocyclyloxy, C3-7 cycloalkyl (itself optionally substituted with (C1-6)alkyl or halogen), C3-7 cycloalkyloxy, C5-7 cycloalkenyl, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, tri(C1-4)alkylsilyl, tri(C1-4)alkylsilyl(C1-6)alkoxy, aryldi(C1-4)alkylsilyl, (C1-4)alkyldiarylsilyl and triarylsilyl.
Preferably the optional substituents on alkenyl or alkynyl include one or more of halogen, aryl, and C3-7 cycloalkyl.
A preferred optional substituent for heterocyclyl is C1-3 alkyl.
Preferably the optional substituents for cycloalkyl include halogen, cyano and C1-6 alkyl.
The optional substituents for cycloalkenyl preferably include C1-3 alkyl, halogen and cyano.
Y is preferably O, S, S(O), SO2, NR3 or CR5R6, where R3, R5 and R6 are defined above. R3 is especially hydrogen, formyl, C1-6 alkylcarbonyl, cyclopropylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylsulfonyl, C1-6 alkyl, C1-6 haloalkyl, C3-4 alkenyl, C3-4 haloalkenyl, C3-4 alkynyl, benzyl or phenyl (where the phenyl containing groups are optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN or NO2). Especially-R5 and R6 are independently hydrogen, hydroxy, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy(C1-6)alkyl, phenyl(C1-3)alkyl (wherein the phenyl group may be optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NO2, aryl, heteroaryl, amino, dialkylamino, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl, or two adjacent positions on the phenyl ring may be cyclised to form a 5, 6 or 7 membered carbocyclic or heterocyclic ring, itself optionally substituted with halogen), C3-5 cycloalkyl, 1,3-dioxolan-2-yl, phenyl (which may be optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NO2, aryl, heteroaryl, amino, dialkylamino, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl, or two adjacent positions on the phenyl ring may be cyclised to form a 5, 6 or 7 membered carbocyclic or heterocyclic ring, itself optionally substituted with halogen), C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkenyloxy, C1-6 alkynyloxy, C1-3 alkoxy(C1-3)alkoxy, benzyloxy (wherein the phenyl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NO2), C1-6 alkylthio, C1-6 haloalkylthio, NR54R55 (where R54 and R55 are independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-4 alkoxy(C1-4)alkyl, formyl, C2-6 alkylcarbonyl or phenylcarbonyl (where the phenyl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NO2)), or R5 and R6 together with the carbon atom to which they are attached form a three to six membered ring, that optionally may contain one or two sulfur or one or two not adjacent oxygen atoms or a group NR56 (where R56 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-4 alkoxy(C1-4)alkyl, formyl, C2-6 alkylcarbonyl, or when R5 together with R1 forms a bond, or either R5 or R6 together with R1 or R2 and the carbon atom they are attached form a three to six membered ring, that optionally may contain one or two not adjacent oxygen atoms, or R5 and R6 together form ═O, ═S, ═NR57 or ═CR58R59, wherein R57 is OH, optionally substituted C1-6 alkoxy or C1-4 alkylcarbonylamino, and R58 and R59 are independently H or C1-5 alkyl.
More preferably Y is O or CR5R6, where R5 and R6 are hydrogen, hydroxy, fluoro, chloro, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkenyloxy, C1-6 alkynyloxy, C1-3 alkoxy(C1-3)alkoxy or benzyloxy, or R5 and R6 together with the carbon atom to which they are attached form a three to six membered carbocyclic ring, or R5 and R1 together form a bond, or R5 together with R1 and the carbon atoms to which they are attached form a three to six membered carbocyclic ring, or R5 and R6 together form ═CR58R59, wherein R58 and R59 are independently H or C1-6 alkyl.
Most preferably Y is CR5R6, where R5 and R6 are independently hydrogen, fluoro or methyl, especially hydrogen.
Preferably each R1 and R2 group is independently hydrogen, hydroxy, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy(C1-6)alkyl, phenyl(C1-3)alkyl (wherein the phenyl group may be optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NO2, aryl, heteroaryl, amino, dialkylamino, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl), C3-5 cycloalkyl, 1,3-dioxolan-2-yl, phenyl (which may be optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NO2, aryl, heteroaryl, amino, dialkylamino, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl), C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyloxy, C2-6 alkinyloxy, C1-6 alkylthio, C1-6 haloalkylthio, formyl, C2-6 alkylcarbonyl, phenylcarbonyl (where the phenyl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NO2), or R1 and R2 together are ═O, ═S, ═NR11 or ═CR12R13, wherein R11 is OH, C1-6 alkoxy or C1-6 alkylcarbonylamino, and R12 and R13 are independently H, C1-6 alkyl, or C1-6 haloalkyl; or R1 and R9 together with the carbon atom they are attached form a three to six membered ring, that optionally may contain one or two not adjacent oxygen atoms; or R1 and R2 together form a three to six membered ring, that optionally may contain one or two non-adjacent oxygen atoms. A preferred subset of this grouping of substituents excludes C1-6 cyanoalkyl and C1-6 hydroxyalkyl.
More preferably each R1 and R2 group is independently hydrogen, hydroxy, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkenyloxy, C1-6 alkynyloxy, C1-3 alkoxy(C1-3)alkoxy or benzyloxy. A preferred subset of this grouping of substituents excludes C1-6hydroxyalkyl.
Even more preferably each R1 and R2 group is independently hydrogen, hydroxy, fluoro or methyl. Most preferably each R1 and R2 group is independently hydrogen or methyl.
R9 is preferably hydrogen, C1-6 alkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C3-7 cycloalkyl(C1-4)alkyl, C1-6 alkoxy(C1-6)alkyl, aryl(C1-6)alkyl (wherein the aryl group may be optionally substituted by halo, nitro, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylthio, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, arylcarbonyl), C2-6 alkylcarbonyl, phenylcarbonyl (where the phenyl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NO2, aryl, heteroaryl, amino or dialkylamino), C1-6 alkoxycarbonyl, C(O)NR34R35 (where R34 and R35 are independently hydrogen, C1-6 alkyl or C1-6 haloalkyl or C1-6 alkoxy(C1-6)alkyl or R34 and R35 together with the N atom to which they are attached form a five, six or seven-membered ring containing an O or S atom); or R9 and R1 together with the carbon atoms to which they are attached form a three to six membered ring, that may optionally contain one or two sulphur and/or one or two non-adjacent oxygen atoms.
More preferably R9 is independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl(C1-4)alkyl, C1-6 alkoxy(C1-6)alkyl, aryl(C1-6)alkyl (wherein the aryl group may be optionally substituted by halo, nitro, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy), C2-6 alkylcarbonyl, phenylcarbonyl (where the phenyl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl), C1-6 alkoxycarbonyl; or R9 and R1 together with the carbon atoms to which they are attached form a three to six membered ring.
Most preferably R9 is independently hydrogen or methyl.
Preferably each R4 is independently halogen, nitro, cyano, C1-8 alkyl, C1-8 haloalkyl, cyano(C1-6)alkyl, C1-3 alkoxy(C1-3)alkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-3 alkyl-(C3-6)cycloalkyl, C3-6 cycloalkyl-(C1-3)alkyl, phenyl (optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NO2, aryl, heteroaryl, amino or dialkylamino), heterocyclyl (optionally substituted by halo, nitro, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy or C1-6 haloalkoxy), formyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylthiocarbonyl, C1-6 alkoxythionocarbonyl, carbamoyl, C1-6 alkylaminocarbonyl, di-C1-6 alkylaminocarbonyl, thiocarbamoyl, C1-6 alkylaminothionocarbonyl, di-C1-6 alkylaminothionocarbonyl, C1-8 alkoxy, C1-6 haloalkoxy, phenoxy (optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NO2, phenyl), heteroaryloxy (optionally substituted by halo, nitro, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or C1-3 haloalkoxy), C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyloxy, C1-6 alkylaminocarbonyloxy, di-C1-6 (alkylaminocarbonyloxy, C1-6 alkylaminothionocarbonyloxy, di-C1-6 alkylaminothionocarbonyloxy, C1-6 alkylthio, C1-6 haloalkylthio, arylthio or heteroarylthio (where the aryl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CN, NO2 or phenyl), C1-6 alkylcarbonylthio, C1-6 alkylaminocarbonylthio, di-C1-6 alkylaminocarbonylthio, di(C1-8)alkylamino, C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkylaminocarbonylamino, di-C1-6 alkylaminocarbonylamino, aminothionocarbonylamino, C1-6 alkylaminothionocarbonylamino, di-C1-6 alkylaminothionocarbonylamino; or 2 adjacent groups R4 together with the carbon atoms to which they are attached form a 4, 5, 6 or 7 membered carbocyclic or heterocyclic ring which may be optionally substituted by halogen; and n is 0, 1, 2 or 3, preferably 1, 2, or 3.
More preferably each R4 is independently halogen, nitro, cyano, C1-8 alkyl, C1-8 haloalkyl, cyano(C1-6)alkyl, C1-6 alkoxy(C1-6)alkyl, C2-6 alkynyl, heterocyclyl (optionally substituted by C1-6 alkyl), C1-8 alkoxy, C1-6 haloalkoxy, phenoxy (optionally substituted by halo, cyano, C1-3 alkyl or C1-3 haloalkyl), heteroaryloxy (optionally substituted by halo, cyano, C1-3 alkyl or C1-3 haloalkyl), C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkylthio, C1-3 haloalkylthio, C1-3 alksulfonyl, di(C1-8)alkylamino, or 2 adjacent groups R4 together with the carbon atoms to which they are attached form a 4, 5, 6 or 7 membered carbocyclic or heterocyclic ring which may be optionally substituted by halogen; and n is 0, 1, 2 or 3, preferably 1, 2 or 3, more preferably 1 or 2.
Even more preferably each R4 is independently fluoro, chloro, bromo, C1-4 alkyl or C1-4 haloalkyl, most preferably fluoro, C1-4 alkyl or C1-4 haloalkyl; and n is 0, 1, 2 or 3, preferably 1 or 2.
Preferably at least one group R4 is positioned adjacent to the group Y. In particularly preferred embodiments this R4 group is selected from fluoro, fluoromethyl, difluoromethyl, trifluoromethyl and methyl.
In some embodiments R73 is hydrogen, C1-4 alkoxy-C1-4 alkyl, C1-4 haloalkoxy-C1-4 alkyl, cyano-C1-4 alkyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, vinyl, cinnamyl (wherein the phenyl group is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, aryl, heteroaryl, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl), C3-6 alkenyl, C3-6 alkinyl, aryldi(C1-4)alkylsilyl, (C1-4)alkyldiarylsilyl, formyl, C1-12 alkylcarbonyl, where the alkyl group may be substituted by one or more halogen, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C3-6 cycloalkyl, phenyl or phenoxy (wherein the phenyl group is optionally substituted by halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, cyano, nitro); C2-12 alkenylcarbonyl, where alkenyl may be substituted by Halogen, C1-6alkoxycarbonyl or phenyl (that itself may be substituted by halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, cyano or nitro); C1-6 alkylthiocarbonyl, C3-6 cycloalkylcarbonyl, adamantylcarbonyl, arylcarbonyl or heteroarylcarbonyl (wherein aryl or heteroaryl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano or nitro); C1-6 alkoxycarbonyl, C1-6 alkylthiocarbonyl, C1-6 alkoxythionocarbonyl, C1-6 alkylthiothionocarbonyl, benzyloxycarbonyl, phenoxycarbonyl or phenylthiocarbonyl (wherein the phenyl group is optionally substituted by halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, cyano, nitro); R78R79N—C(O)— or R78R79N—C(S)—, wherein R78 and R79 are independently hydrogen, C1-6 alkyl, C3-6 alkenyl, C3-6 alkinyl or phenyl (which is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, aryl, heteroaryl, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl.
In some embodiments R73 is preferably C1-4 alkoxy-C1-4 alkyl, C1-4 haloalkoxy-C1-4 alkyl, cyano-C1-4 alkyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, cinnamyl (wherein the phenyl group is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, aryl, heteroaryl, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl); aryldi(C1-4)alkylsilyl, C1-4 alkyldiarylsilyl, C1-12 alkylcarbonyl, where the alkyl group is substituted by C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C3-6 cycloalkyl, phenyl or phenoxy (wherein phenyl group a are optionally substituted by halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3alkoxy, cyano or nitro); C3-6 cycloalkylcarbonyl, adamantylcarbonyl, arylcarbonyl or heteroarylcarbonyl (wherein aryl or heteroaryl is substituted by C1-4 haloalkyl, C1-4 haloalkylthio, di-C1-4-alkylamino, benzoyloxymethyl, phenyl or phenylsulfonyl (wherein the phenyl group is optionally substituted by halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, cyano or nitro); naphthylcarbonyl, (2,3-dihydro-benzofuranyl)carbonyl, (2,2-difluoro-benzo[1,3]dioxolyl)carbonyl, phenoxycarbonyl or phenylthiocarbonyl (wherein phenyl groups are optionally substituted by halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, cyano or nitro); C2-12 alkenylcarbonyl, where alkenyl is substituted by C1-6alkoxycarbonyl or phenyl (wherein the phenyl group is optionally substituted by halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3alkoxy, cyano or nitro); benzyloxycarbonyl (wherein the phenyl group is optionally substituted by halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, cyano or nitro); R71R79N—C(O)— or R73R79N—C(S)—, wherein R78 and R79 are independently hydrogen, C3-6 alkenyl or phenyl (wherein the phenyl group is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, aryl, heteroaryl, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl); or R78 and R79 together with the N atom to which they are attached form a five, six or seven membered ring which may contain one or two further hetero atoms selected from O, N or S and which may be optionally substituted by one to four C1-6 alkyl groups.
Preferably R73 is hydrogen, C3-6 alkenyl, C3-6 alkinyl, formyl, C1-6 alkylcarbonyl, C1-6 alkylthiocarbonyl, aryl- or heteroarylcarbonyl (where aryl or heteroaryl are optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano or nitro), C1-6 alkoxycarbonyl, C1-6 alkylthiocarbonyl, C1-6 alkoxythionocarbonyl, C1-6 alkylthiothionocarbonyl, R78R79N—C(O)— or R78R79N—C(S)—, wherein R78 and R79 are independently hydrogen, C1-6 alkyl, C3-6 alkenyl, C3-6 alkinyl or phenyl (which is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, aryl, heteroaryl, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl);
More preferably R73 is hydrogen, formyl, C1-6 alkylcarbonyl, phenylcarbonyl (where phenyl is optionally substituted by halogen, C1-4 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, cyano or nitro), C1-6 alkoxycarbonyl, R78R79N—C(O)— or R78R79N—C(S)—, wherein R78 and R79 are independently hydrogen, C1-6 alkyl, C3-6 alkenyl, C3-6 alkinyl or phenyl (which is optionally substituted by halogen, C1-4 alkyl, C1 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, cyano, nitro, C1— alkylsulfonyl or C1-3 alkoxycarbonyl);
Most preferably R73 is hydrogen.
In some embodiments R10 and R72 are independently hydrogen, hydroxy, amino, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy(C1-6)alkyl, C3-6-alkenyl, C3-6alkinyl, aryl(C1-3)alkyl or heteroaryl(C1-3)alkyl (wherein aryl or heteroaryl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, C1-4 alkylsulfonyl or C1-6 to alkoxycarbonyl); C3-5 cycloalkyl-C1-3alkyl, C3-5 cycloalkyl, aryl or heteroaryl (wherein aryl or heteroaryl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, C1-6 alkylsulfonyl and C1-6 alkoxycarbonyl), C1-6 alkylthio, C1-6 haloalkylthio, C1-6 alkyldithio, C1-6 alkylthiosulfinyl, formyl, C1-12 alkylcarbonyl, C2-12 alkenylcarbonyl, where alkenyl is substituted by C1-12 alkoxycarbonyl or phenyl (wherein the phenyl group is optionally substituted by halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, cyano and/or nitro); C3-6 cycloalkylcarbonyl, aryl- or heteroarylcarbonyl (wherein aryl or heteroaryl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano and/or nitro), napthylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylthiocarbonyl, C1-6 alkylcarbonylamino, R24R25N—, R24R25N—S— or R24R25N-A-, wherein R24 and R25 are preferably hydrogen or C1-6alkyl and A is SO2, C(O) or C(S);
In some embodiments R10 and R72 are independently preferably hydroxy, amino, phenyl(C2-3)alkyl (wherein the phenyl group is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, C1-6 alkylsulfonyl and/or C1-6 alkoxycarbonyl), heteroaryl(C1-3)alkyl (wherein heteroaryl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, C1-5 alkylsulfonyl or C1-6 alkoxycarbonyl); C3-5 cycloalkyl-C1-3alkyl, heteroaryl (wherein heteroaryl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl), C1-6 alkylthio, C1-6 haloalkylthio, C1-6 alkyldithio, C1-6 alkylthiosulfinyl, C7-12 alkylcarbonyl, C7-12 alkenylcarbonyl, cinnamylcarbonyl, (wherein the phenyl group is optionally substituted by halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, cyano and/or nitro); aryl- or heteroarylcarbonyl (wherein aryl or heteroaryl is substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano and/or nitro); napthylcarbonyl, (2,2-difluoro-benzo[1,3]dioxolyl)-carbonyl, C1-6 alkylcarbonylamino, R24R25N—, R24R25N—S— or R24R25N-A-, wherein R24 and R25 are preferably hydrogen or C1-6alkyl and A is SO2 or C(S).
Preferably R10 and R72 are independently hydrogen, hydroxy, amino, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy(C1-6)alkyl, C3-6-alkenyl, C3-6alkinyl, phenyl(C1-3)alkyl (wherein the phenyl group is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl), C3-5 cycloalkyl-C1-3alkyl, C3-5 cycloalkyl, aryl or heteroaryl (wherein aryl or heteroaryl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl), C1-6 alkylthio, C1-6 haloalkylthio, C1-6 alkyldithio, C1-6 alkylthiosulfinyl, formyl, C1-6 alkylcarbonyl, aryl- or heteroarylcarbonyl (wherein aryl or heteroaryl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano or nitro), C1-6 alkoxycarbonyl, C1-6 alkylthiocarbonyl, C1-6 alkylcarbonylamino, R24R25N—, R24R25N—S— or R24R25N-A-, wherein R24 and R25 are preferably hydrogen or C1-6alkyl and A is SO2, C(O) or C(S);
More preferably one of R10 or R72 is hydrogen and the other is hydrogen, amino, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy(C1-3)alkyl, C3-6 alkenyl, C3-6 alkinyl, phenyl-(C1-12) alkyl (wherein phenyl is optionally substituted by halogen, C1-4 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, cyano, nitro, C1-3 alkylsulfonyl or C1-4 alkoxycarbonyl), C3-5 cycloalkyl-(C1-3)alkyl, C3-5 cycloalkyl, furyl, phenyl (which may be optionally substituted by halogen, C1-4 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, cyano, nitro, C1-3 alkylsulfonyl, or C1-4 alkoxycarbonyl), C1-6 alkylthio, C1-6 haloalkylthio, C1-6 alkyldithio, C1-6 alkylthiosulfinyl, formyl, C1-6 alkylcarbonyl, phenylcarbonyl (where phenyl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano or nitro), C1-6 alkoxycarbonyl, C1-6 alkylthiocarbonyl, C1-6 alkylcarbonylamino, R24R25N—, R24R25N—S— or R24R25N-A-, wherein R24 and R25 are preferably hydrogen or C1-6 alkyl and A is SO2, C(O) or C(S).
Most preferably R10 and R72 are both hydrogen.
Preferably L is a direct bond, CR74CR75 or CR74R75CR76R77, wherein R74, R75, R76 and R77 are independently hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, hydroxyl(C1-6)alkyl, C1-6 alkoxy(C1-6)alkyl, phenyl(C1-3)alkyl (wherein the phenyl group may be optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano; nitro, aryl, heteroaryl, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl), C3-6 cycloalkyl-C1-3alkyl, C3-6 cycloalkyl, 1,3-dioxolan-2-yl, phenyl (which is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, C1-5 alkylsulfonyl or C1-6 alkoxycarbonyl), C1-6 alkoxy, C1-6 haloalkoxy, C3-6 alkenyloxy, C3-6 alkinyloxy, C1-3 alkoxy(C1-3)alkoxy, benzyloxy (wherein phenyl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano or nitro), C1-6 alkylthio, C1-6 haloalkylthio, formyl, C1-6 alkylcarbonyl, phenylcarbonyl (wherein phenyl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano or nitro), C1-6 alkoxycarbonyl, C1-6 alkylthiocarbonyl, R80R81N—C(O)— or R80R81N—C(S)—, wherein R80 and R81 are independently hydrogen, C1-6 alkyl, C3-6 alkenyl C3-6 alkinyl or phenyl (which is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, aryl, heteroaryl, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl); or the groups R74 and R75 and/or R76 and R77 together with the carbon atom to which they are attached form a three to six membered ring, containing at least 2 carbon atoms and optionally containing a sulphur atom, an oxygen atom, S(O), S(O)2 or a group NR82, wherein R82 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 alkinyl or benzyl (which may be optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl); the ring being optionally substituted by one or two C1-3alkyl groups; or two of the groups R74, R75, R75 and R77 attached to different atoms together with the atoms to which they are attached form a three to six membered ring, that optionally contains a sulphur atom, an oxygen atom, S(O), S(O)2, C(O) or a group NR82, and the ring being optionally substituted by one or two C1-3 alkyl groups.
More preferably L is a direct bond or CR74R75, wherein each R74 and R75 are independently hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, hydroxyl(C1-6)alkyl, C1-6 alkoxy(C1-6)alkyl, phenyl(C1-2)alkyl (wherein phenyl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl), C3-6cycloalkyl-C1-3alkyl, C3-5 cycloalkyl, 1,3-dioxolan-2-yl, phenyl (which is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl; C1-4 haloalkoxy, cyano, nitro, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl), C1-6 alkoxy, C1-6 haloalkoxy, C3-6 alkenyloxy, C3-6 alkinyloxy, C1-3 alkoxy(C1-3)alkoxy, benzyloxy (wherein phenyl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano or nitro), C1-6 alkylthio, C1-6 haloalkylthio, formyl, C1-6 alkylcarbonyl, phenylcarbonyl (where phenyl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano or nitro), C1-6 alkoxycarbonyl, C1-6 alkylthiocarbonyl, R80R81N—C(O)— or R80R81N—C(S)—, wherein R80 and R81 are independently hydrogen, C1-6 alkyl, C3-6alkenyl C3-6 alkinyl or phenyl (which is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl); or the groups R74 and R75 together with the carbon atom to which they are attached form a three to six membered ring, containing at least 2 carbon atoms and optionally containing a sulphur atom, an oxygen atom, S(O), S(O)2, C(O) or a group NR82, wherein R82 is hydrogen, C1-6 alkyl, C2-6-alkenyl, C3-6-alkinyl or benzyl (where phenyl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl); the ring being optionally substituted by one or two C1-3 alkyl groups;
Even more preferably L is a direct bond or CH2. Most preferably L is a direct bond.
Preferably R46, R47, R48 and R49 are independently hydrogen, fluoro, C1-6 alkyl, C1-6 haloalkyl, hydroxy(C1-6)alkyl, C1-6 alkoxy(C1-6)alkyl, phenyl(C1-3)alkyl (wherein phenyl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl), C1-3 cycloalkyl(C1-3)alkyl, C3-5 cycloalkyl, 1,3-dioxolan-2-yl, phenyl (which may be optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, aryl, heteroaryl, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl), C1-6 alkylcarbonyl, phenylcarbonyl (where phenyl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano or nitro), C1-6 alkoxycarbonyl, C1-6 alkylthiocarbonyl, R83R84N—C(O)— or R83R84N—C(S)—, wherein R83 and R84 are independently hydrogen, C1-6 alkyl, C3-6 alkenyl C3-6 alkinyl or phenyl (which may be optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, aryl, heteroaryl, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl); or the groups R46 and R47 and/or R48 and R49 together with the carbon atom to which they are attached form a three to six membered ring, containing at least 2 carbon atoms and optionally containing one or two sulphur and/or one or two non-adjacent oxygen atoms or a group S(O), S(O)2, C(O) or NR85, wherein R85 is hydrogen, C1-6-alkyl, C2-6-alkenyl, C3-6-alkinyl or benzyl (which is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, nitro, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl); the ring being optionally substituted by one or two C1-3-alkyl groups; or two of the groups R46, R47, R48 and R49 attached to different atoms together with the atoms to which they are attached form a three to six membered ring, that optionally contains one or two sulphur and/or one or two non-adjacent oxygen atoms or a group S(O), S(O)2, C(O) or NR85, the ring being optionally substituted by one or two C1-3-alkyl groups.
More preferably R46, R47, R48 and R49 are independently hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, hydroxyl(C1-6)alkyl, C1-6 alkoxy(C1-6)alkyl, phenyl(C1-2)alkyl (wherein phenyl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl), C3-6 cycloalkyl(C1-3)alkyl, C3-5 cycloalkyl, phenyl (which is substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, cyano, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl), C1-6 alkylcarbonyl, phenylcarbonyl (where phenyl is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl or C1-4 haloalkoxy), C1-6 alkoxycarbonyl, C1-6 alkylthiocarbonyl, R83R84N—C(O)— or R83R84N—C(S)—, wherein R83 and R84 are independently hydrogen, C1-6 alkyl, C3-6 alkenyl, C3-6 alkinyl or phenyl (which is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl); or the groups R46 and R47 and/or R48 and R49 together with the carbon atom to which they are attached form a three to six membered ring, the ring being optionally substituted by one or two C1-3 alkyl groups; or two of the groups R46, R47, R44 and R49 attached to different atoms together with the atoms to which they are attached form a three to five membered ring, the ring being optionally substituted by one or two C1-3 alkyl groups.
Most preferably R46, R47, R48 and R49 are hydrogen.
It is preferred that the ring
is a 6-membered aromatic ring or is a 5 or 6 membered heteroaromatic ring, wherein the ring members are each independently CH, S, N, NR4, O or CR4, wherein R4 is as defined herein, provided that there are no more than one O or S atoms present in the ring. In a particularly preferred group of compounds T is a 6-membered aromatic ring, n is 1, 2, or 3 and at least one substituent R4 is selected from fluoro, methyl, fluoromethyl, difluoromethyl, and trifluoromethyl.
More preferably the ring
is a benzene, thiophene, furan, pyridine, pyrimidine, pyrazine, pyridazine, triazine, pyrrole, imidazole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, [1,2,3]triazole, [1,2,3]oxadiazole or [1,2,3]thiadiazole ring.
Most preferably the ring
is a benzene, pyridine or thiophene ring, especially a benzene ring.
Preferably T and Y complete an indane ring system. A particularly preferred group of compounds wherein T and Y form an indane ring system are those wherein at least one of R10 and R72 is hydrogen.
Another especially preferred group of compounds are those compounds of formula (IA)
where the chirality on the R9 bearing carbon atom is that shown in the structure above, and L, T, Y, R1, R2, R4, R9, R10, R46, R47, R48, R49, R72, R73 and n are as defined in relation to formula (I).
Another preferred group of compounds are those of formula I wherein T is phenyl, Y is CR5R6 or CR5R6CR7R8, L is a direct bond, each of R46, R47, R48, and R49 are hydrogen, and R1, R2, R4, R5, R6, R7, R8, R9, R10, R72 and R73 are as defined herein.
Another preferred group of compounds of formula I are those wherein Y is O, S(O)m, NR3, SO2—NR3, NR3SO2, NR3—O, O—NR3, O—CR7R8, S(O)m—CR7R8, NR3—CR7R8, CR5R6—O, CR5R6—S(O)m or CR5R6—NR3 wherein R3, R5, R6, R7 and R8 are as defined herein, and wherein L, T, R4, R9, R10, R46, R47, R48, R49, R72 and R73 are as defined herein.
Another preferred group of compounds are those of formula I wherein T is a benzene ring, Y is CH2 or CH2CH2, L is a direct bond, and R1, R2, R9, R46, R47, R48 and R49 are each hydrogen.
Another preferred group of compounds are those of formula I wherein at least one of R1, R2, R5, R6, R7, R8 or R9 is other than hydrogen.
In highly preferred compounds of formula I, L is a direct bond, R46, R47, R48, R49 are hydrogen, and least one of R10 and R72 is hydrogen.
The compounds in Tables 1 to 11 below illustrate the compounds of the invention.
a)S-Enantiomer.
b)R-Enantiomer.
c)Single diastereoisomer (anti).
a) The retention times (Ret) were obtained on an analytical HPLC column as follows:
b) iBu = CH2—CH(CH3)2.
c) 3-THF = 3-tetrahydrofuranyl.
a) Ret = Retention time in minutes. HPLC-data were performed with a Waters 2795 HPLC using an Atlantis dC18 3 μm, 3 × 20 mm column. Eluent-system: 80% water, 20% acetonitril, 0.1% formic acid, linear gradient from 20% acetonitril to 100% acetonitril within 2.5 mm. The flow rate was 1.7 ml/min. Compounds were detected by UV using a diode array measuring wavelengths from 200 nm to 400 nm.
b) 2-THP = 2-tetrahydo-pyranyl.
a) Ret = HPLC-retention time in minutes, for experimental details see table 2.
a) Retention time, for further experimental details see table 3.
The compounds of the invention may be made by a variety of methods.
Compounds of formula (I) can be prepared by treatment of an amine of formula (IIa) with thiophosgene to afford an intermediate compound of formula (IIIa), which is then further reacted with an amine of formula (IVa) as outlined in the reaction scheme below (see Houben-Weyl 1983, E4, 484 and Chem. Ber. 1970, 103, 133).
Furthermore, reaction of the isothiocyanates of formula (III) shown below with amine derivatives of formula (IVa) lead to thioureas of formula (Ia) wherein R10 is hydrogen (see Tetrahedron Letters 2003, 44, 795 and Bull. Kor. Chem. Soc. 2000, 21, 919).
The isothiocyanates of formula (III) can be prepared in various ways. For example many methods for the preparation of isothiocyanates are reviewed by Sharma (Sulfur Reports 1988, 8, 327). Isothiocyanates (III) can be prepared from the amines (IIa) (J. Am. Chem. Soc. 2004, 126, 7450, Bioorg. & Med. Chem., 2003, 11, 4189 and Rec. Trav. Chim 1926, 45, 421), alcohols (IIb) (Chemistry Letters, 2006, 35(11), 1262 and Synthesis 2004 (1), 92) and azides (IIc) (Carbohyd. Res. 2002, 337, 2329) as shown in the reaction scheme below. They can be prepared by addition of thiocyanate to indene (IIf) (Tet. Lett. 1992, 33(25), 3599-3602).
Further methods involve treating of an activated precursor (IId) (X=leaving group e.g. halogen, tosylate or mesylate) with Bu4N+SCN− (see i.e. J. Comb. Chem. 2001, 3, 90) or by rearrangement of the corresponding thiocyanato derivatives (IIe) (see Tetrahedron 1988, 44, 1619 or Synthesis 1986, 817).
Amines of the formula (IIa), wherein R9 is hydrogen, can be prepared in various ways. One method starts from ketones (IV). Transformation involves reduction of the ketone with NaBH4/MeOH in the known manner and conversion to the corresponding azide according to WO 95/01970. Subsequent reduction with PPh3/H2O (e.g. J. Med. Chem. 2005, 48, 485) or in the presence of SnCl2/MeOH (e.g. Synthetic Commun. 1991, 21, 733) leads to the desired amines (IIa).
Amines of the formula (IIa) can also be prepared from carboxylic acids (V) by a Curtius degradation, e.g. using (PhO)2P(O)N3 as reagent (e.g. Tetrahedron Letters 1997, 38, 1681) as shown below.
Amines of formula IIa, wherein Y is oxygen are partially known or may be prepared by the known methods as described in Chimica Acta Turica, 13(3), 403-412 (1985) and Farmaco, Edizione Scientifica, 43(7-8), 643-655 (1988).
The compounds of formula (I) can be used to combat and control infestations of insect pests such as Lepidoptera, Diptera, Hemiptera, Thysanoptera, Orthoptera, Dictyoptera, Coleoptera, Siphonaptera, Hymenoptera and Isoptera and also other invertebrate pests, for example, acarine, nematode and mollusc pests. Insects, acarines, nematodes and molluscs are hereinafter collectively referred to as pests. The pests which may be combated and controlled by the use of the invention compounds include those pests associated with agriculture (which term includes the growing of crops for food and fibre products), horticulture and animal husbandry, companion animals, forestry and the storage of products of vegetable origin (such as fruit, grain and timber); those pests associated with the damage of man-made structures and the transmission of diseases of man and animals; and also nuisance pests (such as flies).
Examples of pest species which may be controlled by the compounds of formula (I) include: Myzus persicae (aphid), Aphis gossypii (aphid), Aphis fabae (aphid), Lygus spp. (capsids), Dysdercus spp. (capsids), Nilaparvata lugens (planthopper), Nephotettixc incticeps (leafhopper), Nezara spp. (stinkbugs), Euschistus spp. (stinkbugs), Leptocorisa spp. (stinkbugs), Frankliniella occidentalis (thrip), Thrips spp. (thrips), Leptinotarsa decemlineata (Colorado potato beetle), Anthonomus grandis (boll weevil), Aonidiella spp. (scale insects), Trialeurodes spp. (white flies), Bemisia tabaci (white fly), Ostrinia nubilalis (European corn borer), Spodoptera littoralis (cotton leafworm), Heliothis virescens (tobacco budworm), Helicoverpa armigera (cotton bollworm), Helicoverpa zea (cotton bollworm), Sylepta derogata (cotton leaf roller), Pieris brassicae (white butterfly), Plutella xylostella (diamond back moth), Agrotis spp. (cutworms), Chilo suppressalis (rice stem borer), Locusta migratoria (locust), Choffiocetes terminifera (locust), Diabrotica spp. (rootworms), Panonychus ulmi (European red mite), Panonychus citri (citrus red mite), Tetranychus urticae (two-spotted spider mite), Tetranychus cinnabarinus (carmine spider mite), Phyllocoptruta oleivora (citrus rust mite), Polyphagotarsonemus latus (broad mite), Brevipalpus spp. (flat mites), Boophilus microplus (cattle tick), Dermacentor variabilis (American dog tick), Ctenocephalides felis (cat flea), Liriomyza spp. (leafminer), Musca domestica (housefly), Aedes aegypti (mosquito), Anopheles spp. (mosquitoes), Culex spp. (mosquitoes), Lucillia spp. (blowflies), Blattella germanica (cockroach), Periplaneta americana (cockroach), Blatta orientalis (cockroach), termites of the Mastotermitidae (for example Mastotermes spp.), the Kalotermitidae (for example Neotermes spp.), the Rhinotermitidae (for example Coptotermes formosanus, Reticulitermes flavipes, R. speratu, R. virginicus, R. hesperus, and R. santonensis) and the Termitidae (for example Globitermes sulphureus), Solenopsis geminata (fire ant), Monomorium pharaonis (pharaoh's ant), Damalinia spp. and Linognathus spp. (biting and sucking lice), and Deroceras reticulatum (slug).
The invention therefore provides a method of combating and controlling insects, acarines, or molluscs which comprises applying an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I), or a composition containing a compound of formula (I), to a pest, a locus of pest, or to a plant susceptible to attack by a pest, The compounds of formula (I) are preferably used against insects or acarines.
The term “plant” as used herein includes seedlings, bushes and trees.
In order to apply a compound of formula (I) as an insecticide, acaricide, nematicide or molluscicide to a pest, a locus of pest, or to a plant susceptible to attack by a pest, a compound of formula (I) is usually formulated into a composition which includes, in addition to the compound of formula (I), a suitable inert diluent or carrier and, optionally, a surface active agent (SFA). SFAs are chemicals which are able to modify the properties of an interface (for example, liquid/solid, liquid/air or liquid/liquid interfaces) by lowering the interfacial tension and thereby leading to changes in other properties (for example dispersion, emulsification and wetting). It is preferred that all compositions (both solid and liquid formulations) comprise, by weight, 0.0001 to 95%, more preferably 1 to 85%, for example 5 to 60%, of a compound of formula (I). The composition is generally used for the control of pests such that a compound of formula (I) is applied at a rate of from 0.1 g to 10 kg per hectare, preferably from 1 g to 6 kg per hectare, more preferably from 1 g to 1 kg per hectare.
When used in a seed dressing, a compound of formula (I) is used at a rate of 0.0001 g to 10 g (for example 0.001 g or 0.05 g), preferably 0.005 g to 10 g, more preferably 0.005 g to 4 g, per kilogram of seed.
In another aspect the present invention provides an insecticidal, acaricidal, nematicidal or molluscicidal composition comprising an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I) and a suitable carrier or diluent therefor. The composition is preferably an insecticidal, acaricidal, nematicidal or molluscicidal composition.
In a still further aspect the invention provides a method of combating and controlling pests at a locus which comprises treating the pests or the locus of the pests with an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a composition comprising a compound of formula (I). The compounds of formula (I) are preferably used against insects, acarines or nematodes.
The compositions can be chosen from a number of formulation types, including dustable powders (DP), soluble powders (SP), water soluble granules (SG), water dispersible granules (WG), wettable powders (WP), granules (GR) (slow or fast release), soluble concentrates (SL), oil miscible liquids (OL), ultra low volume liquids (UL), emulsifiable concentrates (EC), dispersible concentrates (DC), emulsions (both oil in water (EW) and water in oil (EO)), micro-emulsions (ME), suspension concentrates (SC), aerosols, fogging/smoke formulations, capsule suspensions (CS) and seed treatment formulations. The formulation type chosen in any instance will depend upon the particular purpose envisaged and the physical, chemical and biological properties of the compound of formula (I).
Dustable powders (DP) may be prepared by mixing a compound of formula (I) with one or more solid diluents (for example natural clays, kaolin, pyrophyllite, bentonite, alumina, montmorillonite, kieselguhr, chalk, diatomaceous earths, calcium phosphates, calcium and magnesium carbonates, sulphur, lime, flours, talc and other organic and inorganic solid carriers) and mechanically grinding the mixture to a fine powder.
Soluble powders (SP) may be prepared by mixing a compound of formula (I) with one or more water-soluble inorganic salts (such as sodium bicarbonate, sodium carbonate or magnesium sulphate) or one or more water-soluble organic solids (such as a polysaccharide) and, optionally, one or more wetting agents, one or more dispersing agents or a mixture of said agents to improve water dispersibility/solubility. The mixture is then ground to a fine powder. Similar compositions may also be granulated to form water soluble granules (SG).
Wettable powders (WP) may be prepared by mixing a compound of formula (I) with one or more solid diluents or carriers, one or more wetting agents and, preferably, one or more dispersing agents and, optionally, one or more suspending agents to facilitate the dispersion in liquids. The mixture is then ground to a fine powder. Similar compositions may also be granulated to form water dispersible granules (WG).
Granules (GR) may be formed either by granulating a mixture of a compound of formula (I) and one or more powdered solid diluents or carriers, or from pre-formed blank granules by absorbing a compound of formula (I) (or a solution thereof, in a suitable agent) in a porous granular material (such as pumice, attapulgite clays, fuller's earth, kieselguhr, diatomaceous earths or ground corn cobs) or by adsorbing a compound of formula (I) (or a solution thereof, in a suitable agent) on to a hard core material (such as sands, silicates, mineral carbonates, sulphates or phosphates) and drying if necessary. Agents which are commonly used to aid absorption or adsorption include solvents (such as aliphatic and aromatic petroleum solvents, alcohols, ethers, ketones and esters) and sticking agents (such as polyvinyl acetates, polyvinyl alcohols, dextrins, sugars and vegetable oils). One or more other additives may also be included in granules (for example an emulsifying agent, wetting agent or dispersing agent).
Dispersible Concentrates (DC) may be prepared by dissolving a compound of formula (I) in water or an organic solvent, such as a ketone, alcohol or glycol ether. These solutions may contain a surface active agent (for example to improve water dilution or prevent crystallisation in a spray tank).
Emulsifiable concentrates (EC) or oil-in-water emulsions (EW) may be prepared by dissolving a compound of formula (I) in an organic solvent (optionally containing one or more wetting agents, one or more emulsifying agents or a mixture of said agents). Suitable organic solvents for use in ECs include aromatic hydrocarbons (such as alkylbenzenes or alkylnaphthalenes, exemplified by SOLVESSO 100, SOLVESSO 150 and SOLVESSO 200; SOLVESSO is a Registered Trade Mark), ketones (such as cyclohexanone or methylcyclohexanone) and alcohols (such as benzyl alcohol, furfuryl alcohol or butanol), N-alkylpyrrolidones (such as N-methylpyrrolidone or N-octylpyrrolidone), dimethyl amides of fatty acids (such as C8-C10 fatty acid dimethylamide) and chlorinated hydrocarbons. An EC product may spontaneously emulsify on addition to water, to produce an emulsion with sufficient stability to allow spray application through appropriate equipment. Preparation of an EW involves obtaining a compound of formula (I) either as a liquid (if it is not a liquid at room temperature, it may be melted at a reasonable temperature, typically below 70° C.) or in solution (by dissolving it in an appropriate solvent) and then emulsifiying the resultant liquid or solution into water containing one or more SFAs, under high shear, to produce an emulsion. Suitable solvents for use in EWs include vegetable oils, chlorinated hydrocarbons (such as chlorobenzenes), aromatic solvents (such as alkylbenzenes or alkylnaphthalenes) and other appropriate organic solvents which have a low solubility in water.
Microemulsions (ME) may be prepared by mixing water with a blend of one or more solvents with one or more SFAs, to produce spontaneously a thermodynamically stable isotropic liquid formulation. A compound of formula (I) is present initially in either the water or the solvent/SFA blend. Suitable solvents for use in MEs include those hereinbefore described for use in ECs or in EWs. An ME may be either an oil-in-water or a water-in-oil system (which system is present may be determined by conductivity measurements) and may be suitable for mixing water-soluble and oil-soluble pesticides in the same formulation. An ME is suitable for dilution into water, either remaining as a microemulsion or forming a conventional oil-in-water emulsion.
Suspension concentrates (SC) may comprise aqueous or non-aqueous suspensions of finely divided insoluble solid particles of a compound of formula (I). SCs may be prepared by ball or bead milling the solid compound of formula (I) in a suitable medium, optionally with one or more dispersing agents, to produce a fine particle suspension of the compound. One or more wetting agents may be included in the composition and a suspending agent may be included to reduce the rate at which the particles settle. Alternatively, a compound of formula (I) may be dry milled and added to water, containing agents hereinbefore described, to produce the desired end product.
Aerosol formulations comprise a compound of formula (I) and a suitable propellant (for example n-butane). A compound of formula (I) may also be dissolved or dispersed in a suitable medium (for example water or a water miscible liquid, such as n-propanol) to provide compositions for use in non-pressurised, hand-actuated spray pumps.
A compound of formula (I) may be mixed in the dry state with a pyrotechnic mixture to form a composition suitable for generating, in an enclosed space, a smoke containing the compound.
Capsule suspensions (CS) may be prepared in a manner similar to the preparation of EW formulations but with an additional polymerisation stage such that an aqueous dispersion of oil droplets is obtained, in which each oil droplet is encapsulated by a polymeric shell and contains a compound of formula (I) and, optionally, a carrier or diluent therefor. The polymeric shell may be produced by either an interfacial polycondensation reaction or by a coacervation procedure. The compositions may provide for controlled release of the compound of formula (I) and they may be used for seed treatment. A compound of formula (I) may also be formulated in a biodegradable polymeric matrix to provide a slow, controlled release of the compound.
A composition may include one or more additives to improve the biological performance of the composition (for example by improving wetting, retention or distribution on surfaces; resistance to rain on treated surfaces; or uptake or mobility of a compound of formula (I)). Such additives include surface active agents, spray additives based on oils, for example certain mineral oils or natural plant oils (such as soy bean and rape seed oil), and blends of these with other bio-enhancing adjuvants (ingredients which may aid or modify the action of a compound of formula (I)).
A compound of formula (I) may also be formulated for use as a seed treatment, for example as a powder composition, including a powder for dry seed treatment (DS), a water soluble powder (SS) or a water dispersible powder for slurry treatment (WS), or as a liquid composition, including a flowable concentrate (FS), a solution (LS) or a capsule suspension (CS). The preparations of DS, SS, WS, FS and LS compositions are very similar to those of, respectively, DP, SP, WP, SC and DC compositions described above. Compositions for treating seed may include an agent for assisting the adhesion of the composition to the seed (for example a mineral oil or a film-forming barrier).
Wetting agents, dispersing agents and emulsifying agents may be surface SFAs of the cationic, anionic, amphoteric or non-ionic type.
Suitable SFAs of the cationic type include quaternary ammonium compounds (for example cetyltrimethyl ammonium bromide), imidazolines and amine salts.
Suitable anionic SFAs include alkali metals salts of fatty acids, salts of aliphatic monoesters of sulphuric acid (for example sodium lauryl sulphate), salts of sulphonated aromatic compounds (for example sodium dodecylbenzenesulphonate, calcium dodecylbenzenesulphonate, butylnaphthalene sulphonate and mixtures of sodium di-isopropyl- and tri-isopropyl-naphthalene sulphonates), ether sulphates, alcohol ether sulphates (for example sodium laureth-3-sulphate), ether carboxylates (for example sodium laureth-3-carboxylate), phosphate esters (products from the reaction between one or more fatty alcohols and phosphoric acid (predominately mono-esters) or phosphorus pentoxide (predominately di-esters), for example the reaction between lauryl alcohol and tetraphosphoric acid; additionally these products may be ethoxylated), sulphosuccinamates, paraffin or olefine sulphonates, taurates and lignosulphonates.
Suitable SFAs of the amphoteric type include betaines, propionates and glycinates.
Suitable SFAs of the non-ionic type include condensation products of alkylene oxides, such as ethylene oxide, propylene oxide, butylene oxide or mixtures thereof, with fatty alcohols (such as oleyl alcohol or cetyl alcohol) or with alkylphenols (such as octylphenol, nonylphenol or octylcresol); partial esters derived from long chain fatty acids or hexitol anhydrides; condensation products of said partial esters with ethylene oxide; block polymers (comprising ethylene oxide and propylene oxide); alkanolamides; simple esters (for example fatty acid polyethylene glycol esters), amine oxides (for example lauryl dimethyl amine oxide); and lecithins.
Suitable suspending agents include hydrophilic colloids (such as polysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose) and swelling clays (such as bentonite or attapulgite).
A compound of formula (I) may be applied by any of the known means of applying pesticidal compounds. For example, it may be applied, formulated or unformulated, to the pests or to a locus of the pests (such as a habitat of the pests, or a growing plant liable to infestation by the pests) or to any part of the plant, including the foliage, stems, branches or roots, to the seed before it is planted or to other media in which plants are growing or are to be planted (such as soil surrounding the roots, the soil generally, paddy water or hydroponic culture systems), directly or it may be sprayed on, dusted on, applied by dipping, applied as a cream or paste formulation, applied as a vapour or applied through distribution or incorporation of a composition (such as a granular composition or a composition packed in a water-soluble bag) in soil or an aqueous environment.
A compound of formula (I) may also be injected into plants or sprayed onto vegetation using electrodynamic spraying techniques or other low volume methods, or applied by land or aerial irrigation systems.
Compositions for use as aqueous preparations (aqueous solutions or dispersions) are generally supplied in the form of a concentrate containing a high proportion of the active ingredient, the concentrate being added to water before use. These concentrates, which may include DCs, SCs, ECs, EWs, MEs SGs, SPs, WPs, WGs and CSs, are often required to withstand storage for prolonged periods and, after such storage, to be capable of addition to water to form aqueous preparations which remain homogeneous for a sufficient time to enable them to be applied by conventional spray equipment. Such aqueous preparations may contain varying amounts of a compound of formula (I) (for example 0.0001 to 10%, by weight) depending upon the purpose for which they are to be used.
A compound of formula (I) may be used in mixtures with fertilisers (for example nitrogen-, potassium- or phosphorus-containing fertilisers). Suitable formulation types include granules of fertiliser. The mixtures suitably contain up to 25% by weight of the compound of formula (I).
The invention therefore also provides a fertiliser composition comprising a fertiliser and a compound of formula (I).
The compositions of this invention may contain other compounds having biological activity, for example micronutrients or compounds having fungicidal activity or which possess plant growth regulating, herbicidal, insecticidal, nematicidal or acaricidal activity.
The compound of formula (I) may be the sole active ingredient of the composition or it may be admixed with one or more additional active ingredients such as a pesticide, fungicide, synergist, herbicide or plant growth regulator where appropriate. An additional active ingredient may: provide a composition having a broader spectrum of activity or increased persistence at a locus; synergise the activity or complement the activity (for example by increasing the speed of effect or overcoming repellency) of the compound of formula (I); or help to overcome or prevent the development of resistance to individual components. The particular additional active ingredient will depend upon the intended utility of the composition. Examples of suitable pesticides include the following:
a) Pyrethroids, such as permethrin, cypermethrin, fenvalerate, esfenvalerate, deltamethrin, cyhalothrin (in particular lambda-cyhalothrin), bifenthrin, fenpropathrin, cyfluthrin, tefluthrin, fish safe pyrethroids (for example ethofenprox), natural pyrethrin, tetramethrin, s-bioallethrin, fenfluthrin, prallethrin or 5-benzyl-3-furylmethyl-(E)-(1R,3S)-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropane carboxylate;
b) Organophosphates, such as, profenofos, sulprofos, acephate, methyl parathion, azinphos-methyl, demeton-s-methyl, heptenophos, thiometon, fenamiphos, monocrotophos, profenofos, triazophos, methamidophos, dimethoate, phosphamidon, malathion, chlorpyrifos, phosalone, terbufos, fensulfothion, fonofos, phorate, phoxim, pirimiphos-methyl, pirimiphos-ethyl, fenitrothion, fosthiazate or diazinon;
c) Carbamates (including aryl carbamates), such as pirimicarb, triazamate, cloethocarb, carbofuran, furathiocarb, ethiofencarb, aldicarb, thiofurox, carbosulfan, bendiocarb, fenobucarb, propoxur, methomyl or oxamyl;
d) Benzoyl ureas, such as diflubenzuron, triflumuron, hexaflumuron, flufenoxuron or chlorfluazuron;
e) Organic tin compounds, such as cyhexatin, fenbutatin oxide or azocyclotin;
f) Pyrazoles, such as tebufenpyrad and fenpyroximate;
g) Macrolides, such as avermectins or milbemycins, for example abamectin, emamectin benzoate, ivermectin, milbemycin, spinosad or azadirachtin;
h) Hormones or pheromones;
i) Organochlorine compounds such as endosulfan, benzene hexachloride, DDT, chlordane or dieldrin;
j) Amidines, such as chlordimeform or amitraz;
k) Fumigant agents, such as chloropicrin, dichloropropane, methyl bromide or metam;
l) Chloronicotinyl compounds such as imidacloprid, thiacloprid, acetamiprid, nitenpyram or thiamethoxam;
m) Diacylhydrazines, such as tebufenozide, chromafenozide or methoxyfenozide;
n) Diphenyl ethers, such as diofenolan or pyriproxifen;
In addition to the major chemical classes of pesticide listed above, other pesticides having particular targets may be employed in the composition, if appropriate for the intended utility of the composition. For instance, selective insecticides for particular crops, for example stemborer specific insecticides (such as cartap) or hopper specific insecticides (such as buprofezin) for use in rice may be employed. Alternatively insecticides or acaricides specific for particular insect species/stages may also be included in the compositions (for example acaricidal ovo-larvicides, such as clofentezine, flubenzimine, hexythiazox or tetradifon; acaricidal motilicides, such as dicofol or propargite; acaricides, such as bromopropylate or chlorobenzilate; or growth regulators, such as hydramethylnon, cyromazine, methoprene, chlorfluazuron or diflubenzuron).
Examples of fungicidal compounds which may be included in the composition of the invention are (E)-N-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-iminoacetamide (SSF-129), 4-bromo-2-cyano-N,N-dimethyl-6-trifluoromethylbenzimidazole-1-sulphonamide, α-[N-(3-chloro-2,6-xylyl)-2-methoxyacetamido]-γ-butyrolactone, 4-chloro-2-cyano-N,N-dimethyl-5-p-tolylimidazole-1-sulfonamide (IKF-916, cyamidazosulfamid), 3-5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide (RH-7281, zoxamide), N-allyl-4,5-dimethyl-2-trimethylsilylthiophene-3-carboxamide (MON65500), N-(1-cyano-1,2-dimethylpropyl)-2-(2,4-dichlorophenoxy)propionamide (AC382042), N-(2-methoxy-5pyridyl)-cyclopropane carboxamide, acibenzolar (CGA245704), alanycarb, aldimorph, anilazine, azaconazole, azoxystrobin, benalaxyl, benomyl, biloxazol, bitertanol, blasticidin S, bromuconazole, bupirimate, captafol, captan, carbendazim, carbendazim chlorhydrate, carboxin, carpropamid, carvone, CGA41396, CGA41397, chinomethionate, chlorothalonil, chlorozolinate, clozylacon, copper containing compounds such as copper oxychloride, copper oxyquinolate, copper sulphate, copper tallate and Bordeaux mixture, cymoxanil, cyproconazole, cyprodinil, debacarb, di-2-pyridyl disulphide 1,1′-dioxide, dichlofluanid, diclomezine, dicloran, diethofencarb, difenoconazole, difenzoquat, diflumetorim, O,O-di-iso-propyl-S-benzyl thiophosphate, dimefluazole, dimetconazole, dimethomorph, dimethirimol, diniconazole, dinocap, dithianon, dodecyl dimethyl ammonium chloride, dodemorph, dodine, doguadine, edifenphos, epoxiconazole, ethirimol, ethyl(Z)-N-benzyl-N([methyl(methyl-thioethylideneaminooxycarbonyl)amino]thio)-β-alaninate, etridiazole, famoxadone, fenamidone (RPA407213), fenarimol, fenbuconazole, fenfuram, fenhexamid (KBR2738), fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumetover, fluoroimide, fluquinconazole, flusilazole, flutolanil, flutriafol, folpet, fuberidazole, furalaxyl, furametpyr, guazatine, hexaconazole, hydroxyisoxazole, hymexazole, imazalil, imibenconazole, iminoctadine, iminoctadine triacetate, ipconazole, iprobenfos, iprodione, iprovalicarb (SZX0722), isopropanyl butyl carbamate, isoprothiolane, kasugamycin, kresoxim-methyl, LY186054, LY211795, LY248908, mancozeb, maneb, mefenoxam, mepanipyrim, mepronil, metalaxyl, metconazole, metiram, metiram-zinc, metominostrobin, myclobutanil, neoasozin, nickel dimethyldithiocarbamate, nitrothal-isopropyl, nuarimol, ofurace, organomercury compounds, oxadixyl, oxasulfuron, oxolinic acid, oxpoconazole, oxycarboxin, pefurazoate, penconazole, pencycuron, phenazin oxide, phosetyl-Al, phosphorus acids, phthalide, picoxystrobin (ZA1963), polyoxin D, polyram, probenazole, prochloraz, procymidone, propamocarb, propiconazole, propineb, propionic acid, pyrazophos, pyrifenox, pyrimethanil, pyroquilon, pyroxyfur, pyrrolnitrin, quaternary ammonium compounds, quinomethionate, quinoxyfen, quintozene, sipconazole (F-155), sodium pentachlorophenate, spiroxamine, streptomycin, sulphur, tebuconazole, tecloftalam, tecnazene, tetraconazole, thiabendazole, thifluzamid, 2-(thiocyanomethylthio)benzothiazole, thiophanate-methyl, thiram, timibenconazole, tolclofos-methyl, tolylfluanid, triadimefon, triadimenol, triazbutil, triazoxide, tricyclazole, tridemorph, trifloxystrobin (CGA279202), triforine, triflumizole, triticonazole, validamycin A, vapam, vinclozolin, zineb and ziram.
The compounds of formula (I) may be mixed with soil, peat or other rooting media for the protection of plants against seed-borne, soil-borne or foliar fungal diseases.
Examples of suitable synergists for use in the compositions include piperonyl butoxide, sesamex, safroxan and dodecyl imidazole.
Suitable herbicides and plant-growth regulators for inclusion in the compositions will depend upon the intended target and the effect required.
An example of a rice selective herbicide which may be included is propanil. An example of a plant growth regulator for use in cotton is PIX™.
Some mixtures may comprise active ingredients which have significantly different physical, chemical or biological properties such that they do not easily lend themselves to the same conventional formulation type. In these circumstances other formulation types may be prepared. For example, where one active ingredient is a water insoluble solid and the other a water insoluble liquid, it may nevertheless be possible to disperse each active ingredient in the same continuous aqueous phase by dispersing the solid active ingredient as a suspension (using a preparation analogous to that of an SC) but dispersing the liquid active ingredient as an emulsion (using a preparation analogous to that of an EW). The resultant composition is a suspoemulsion (SE) formulation.
The invention is illustrated by the following Examples:
Mass spectra data were obtained for selected compounds of the following examples using LCMS: LC5: 254 nm—gradient 10% A to 100% B A=H2O+0.01% HCOOH B═CH3CN/CH3OH+0.01% HCOOH positive electrospray 150-1000 m/z.
A mixture of 2.3 ml (27.1 mmol) thiophosgene in 20 ml dichloromethane is cooled to 0° C. after which a cold (0° C.) solution of 3.1 g (22.5 mmol) K2CO3 in 22 ml water is added. The mixture is stirred for 10 min and 3 ml (22.5 mmol) indan-1-ylamine is then added dropwise with vigorous stirring at 0° C. After an additional 10 min a cold solution of 2.5 g KOH in 22 ml water is added in one portion with cooling. The organic layer and three extracts (Et2O) are combined, dried over MgSO4, filtered and concentrated to give 3.9 g of crude 1-isothiocyanato-indane as a brown liquid. The product is used directly without further purification.
1H-NMR (ppm, CDCl3): 2.20-2.30 (m, 1H); 2.50-2.60 (m, 1H); 2.85-2.95 (m, 1H); 3.05-3.15 (m, 1H); 5.20 (t, 1H); 7.20-7.35 (m, 3H); 7.40-7.50 (m, 1H).
300 mg (1.7 mmol) 1-isothiocyanato-indane is dissolved in 6 ml THF at room temperature under argon. Then 0.103 ml (1.7 mmol) 2-amino-ethanol is added slowly. The reaction mixture is stirred for 2 hours at room temperature. THF is removed under reduced pressure to give the crude product, which is purified by column chromatography on silica gel, eluting with EtOAc/hexane (1:3). The title compound 1-(2-hydroxy-ethyl)-3-indan-1-yl-thiourea is obtained in 96% yield as a beige powder (Mp 119-121° C.).
1H-NMR (ppm, DMSO): 1.70-1.80 (m, 1H); 2.40-2.50 (m, 1H); 2.75-2.85 (m, 1H); 2.85-2.95 (m, 1H); 3.50 (brs, 4H); 4.75 (brs, 1H); 5.8 (brs, 1H); 7.15-7.30 (m, 4H); 7.40 (brs, 1H); 7.85 (d, 1H).
15.0 g (102.6 mmol) 4-methyl-indan-1-one is dissolved in 125 ml MeOH. The solution is cooled to 0-5° C. and 4.3 g (112.9 mmol) NaBH4 is added portionwise while maintaining the temperature between 0-8° C. After the addition of NaBH4 the cool-bath is removed and the reaction mixture is stirred till TLC indicates completion of the reaction. The reaction mixture is poured into water and extracted three times with EtOAc. The collected organic layers are washed with water and brine, dried over MgSO4 and filtered. After evaporation of EtOAc 4-methyl-indan-1-ol is isolated in 98% yield. The crude material may be used directly without further purification.
1H-NMR (ppm, CDCl3): 1.95-2.03 (m, 1H); 2.30 (s, 3H); 2.45-2.55 (m, 1H); 2.70-2.80 (m, 1H); 2.95-3.05 (m, 1H); 5.25-5.30 (dd, 1H); 7.12 (d, 1H); 7.18 (t, 1H); 7.28 (d, 1H).
4.34 g (29.28 mmol) 4-methyl-indan-1-ol and 7.8 ml (35.14 mmol) diphenylphosphoryl azide are dissolved in dry THF at room temperature under argon. To this mixture is added slowly 5.0 ml (35.14 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction is stirred for 6 h at room temperature (TLC monitoring). Then the mixture is poured into water and extracted three times with toluene. The organic layers are combined, dried over MgSO4 and concentrated in vacuo. Purification using silica gel chromatography (hexane/EtOAc 9:1) affords pure 1-azido-4-methyl-indane in 80% yield as light orange liquid.
1H-NMR (ppm, CDCl3): 2.05-2.15 (m, 1H); 2.25 (s, 3H); 2.35-2.45 (m, 1H); 2.72-3.02 (m, 1H); 4.82-4.88 (dd, 1H); 7.10 (d, 1H); 7.15 (t, 1H); 7.22 (d, 1H).
1.0 g (5.8 mmol) 1-azido-4-methyl-indane is treated with 4.54 g (17.3 mmol) triphenylphosphine in 26 ml THF and 1.4 ml H2O at room temperature overnight. Completion of the reaction is achieved by heating up the mixture for additional 2.5 hours. The reaction mixture is then cooled to room temperature and diluted with water. The pH is adjusted to 2 by adding cold (ca 0° C.) aqueous HCl (1M). After extraction with EtOAc the aqueous layer is separated, basified with NaOH (2M) and extracted into EtOAc. The organic layer is then dried (MgSO4) and concentrated in vacuo to give 0.61 g (72%) 4-methyl-indan-1-yl-amine as a light yellow liquid.
1H-NMR (ppm, CDCl3): 1.55 (brs, 1H); 1.60-1.70 (m, 1H); 2.25 (s, 3H); 2.45-2.52 (m, 1H); 2.62-2.72 (m, 1H); 2.85-2.94 (m, 1H); 4.33 (t, 1H); 6.98-7.05 (m, 1H); 7.10-7.15 (m, 2H).
A mixture of 0.36 ml (4.32 mmol) thiophosgene in 4 ml dichloromethane is cooled to 0° C. after which a cold (0° C.) solution of 0.5 g (3.60 mmol) K2CO3 in 4 ml water is added. The mixture is stirred for 10 min and 0.53 g (3.60 mmol) indan-1-ylamine is then added drop wise with vigorous stirring at 0° C. After an additional 10 min a cold solution of 0.40 g (7.20 mmol) KOH in 4 ml water is added in one portion with cooling. The organic layer and three extracts (Et2O) are combined, dried over MgSO4, filtered and concentrated to give 0.68 g of crude 1-isothiocyanato-4-methyl-indane as an orange brown liquid. The product is used directly without further purification.
1H-NMR (ppm, CDCl3): 2.18-2.28 (m, 1H); 2.28 (s, 3H); 2.50-2.60 (m, 1H); 2.75-2.85 (m, 1H); 2.95-3.05 (m, 1H); 5.19 (t, 1H), 7.11 (d, 1H); 7.18 (t, 1H); 7.25 (d, 1H).
680 mg (3.59 mmol) 1-isothiocyanato-4-methyl-indane is dissolved in 13 ml THF at room temperature under argon. Then 0.21 ml (3.59 mmol) 2-amino-ethanol is added slowly. The reaction mixture is stirred at room temperature overnight. After completion of the reaction as indicated by TLC the solvent is removed under reduced pressure to give the crude product. Subsequent purification by column chromatography on silica gel (CH2Cl2/MeOH 15:1) and stirring in Et2O affords the title compound 1-(2-hydroxy-ethyl)-3-(4-methyl-indan-1-yl)-thiourea in 82% yield as a white powder (Mp 90-93° C.).
1H-NMR (ppm, CDCl3): 1.85-1.95 (m, 1H); 2.25 (s, 3H); 2.55 (br s, 1H); 2.60-2.70 (m, 1H); 2.71-2.81 (m, 1H); 2.86-2.99 (m, 1H); 3.62 (br s, 2H); 3.78 (t, 2H); 5.67 (br s, 1H); 6.47 (br s, 1H), 6.11 (br s, 1H); 7.07 (d, 1H); 7.12 (t, 1H); 7.18 (d, 1H).
A mixture of 0.304 g (2 mmol) 4-fluoro-indan-1-ol and 0.233 g (2.4 mmol) potassium rhodanide were heated in the presence of 0.180 g (2 mmol) oxalic acid, 0.400 g (2.4 mmol) potassium iodide and 0.051 (0.4 mmol) iodine in 5 ml nitromethane to 90° C. and held over night. The cold reaction mixture was then filtered through Hyflo®, extracted with ethylacetate against water and brine and evaporated. The crude material was purified by silica chromatography (eluent ethyl acetate/n-heptane 1:9) and almost pure 4-fluoro-1-isothiocyanato-indane was obtained.
1H-NMR (ppm, CDCl3): 2.23-2.33 (m, 1H); 2.55-2.65 (m, 1H); 2.85-2.95 (m, 1H); 3.08-3.18 (m, 1H); 5.19 (t, 1H); 7.00 (m, 1H); 7.15-7.30 (m, 2H).
509 mg (2.0 mmol) 1-(2-hydroxy-ethyl)-3-(4-fluoro-indan-1-yl)-thiourea and 646 mg (5.0 mmol) Hünig's base (N,N′-diisopropylethylamine) are dissolved in 10 ml THF at room temperature. Then 0.36 ml (5.0 mmol) acetyl chloride is added dropwise keeping the temperature below 20° C. The reaction mixture is then stirred at room temperature overnight. After completion of the reaction (indicated by TLC) the mixture is diluted with water. After extraction with EtOAc the organic layer is separated, washed (H2O) and dried over Na2SO4. The crude material is purified by silica chromatography (eluent ethylacetate/n-heptane 1:7 at p=1.3 bar) and 135 mg carbonic acid 2-[3(4-fluoro-indan-1-yl)-thioureido]-ethyl methylester are obtained (Mp.: 137-138° C.).
1H-NMR (ppm, CDCl3): 1.95-2.05 (m, 1H); 2.07 (s, 3H); 2.68-2.78 (m, 1H); 2.88-2.2.98 (m, 1H); 3.05-3.16 (m, 1H); 3.80 (br t, 2H); 4.29 (t, 2H); 5.71 (brs, 1H); 6.98 (t, 1H); 7.15-7.25 (m, 2H).
As a byproduct 65 mg of the corresponding bis acetyl compound (=compound 10.032) were isolated as a colourless oil. 1H-NMR data of carbonic acid 2-[1-acetyl-3-(4-fluoro-indan-1-yl)-thioureido]-ethyl methylester is shown below:
1H-NMR (ppm, CDCl3): 1.86-1.98 (m, 1H); 2.0 (s, 3H); 2.48 (s; 3H); 2.69-2.88 (m, 2H); 2.95-3.05 (m, 1H); 4.35 (t, 2H), 4.55 (t, 2H); 5.90 (q, 1H); 6.82-6.91 (m, 1H); 7.07-7.15 (m, 2H); 11.5 (s, 1H).
A further product (compound=10.033) obtained is carbonic acid 2-[3-acetyl]-3-(4-fluoro-indan-1-yl)-thioureido]-ethyl methylester (355 mg).
1H-NMR (ppm, CDCl3): 2.05 (s, 3H); 2.1 (s, 3H); 22.30-2.42 (m, 1H); 2.6-2.75 (m, 1H); 2.38-3.0 (m, 1H), 2.85-3.0 (m, 1H); 3.1-3.22 (m, 1H); 3.75-3.92 (m, 2H); 4.12-4.28 (m, 2H); 6.65 (t, 1H); 6.92 (t, 1H); 7.05 (d, 1H); 7.15-7.22 (m, 1H).
This Example illustrates the pesticidal/insecticidal properties of compounds of formula (I). Test against were performed as follows:
Eggs (0-24 h old) were placed in 24-well microtiter plate on artificial diet and treated with test solutions at an application rate of 200 ppm by pipetting. After an incubation period of 4 days, samples were checked for egg mortality, larval mortality, and growth regulation.
The following compounds gave at least 80% control of Heliothis virescens:
1.050; 1.073; 1.088; 3.082; 11.023; 11.031; 11.034; 11.046; 11.051.
Sunflower leaf discs were placed on agar in a 24-well microtiter plate and sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs were infested with an aphid population of mixed ages. After an incubation period of 6 DAT, samples were checked for mortality.
The following compounds gave at least 80% control of Myzus persicae:
1.001; 1.012; 1.027; 1.050, 1.073, 1.088; 1.092; 1.118; 1.205; 1.422; 1.424; 1.425; 2.091; 2.201; 3.004; 3.010; 3.020; 3.031; 3.035; 3.038; 3.040; 3.043; 3.046; 3.064; 3.065; 3.066; 3.067; 3.068; 3.069; 3.070; 3.071; 3.072; 3.073; 3.074; 3.076; 3.080; 3.081; 3.082; 3.083; 3.084; 3.086; 3.087; 3.089; 3.090; 3.094; 3.095; 3.096; 3.097; 3.099; 3.100; 3.101; 3.102; 3.103; 3.104; 3.105; 3.106; 3.107; 3.108; 3.110; 3.111; 3.112; 3.113; 3.115; 3.116; 3.117; 4.003; 6.001; 8.002; 9.001; 10.007; 10.009; 10.010; 10.014; 10.015; 10.016; 10.017; 10.018; 10.019; 10.020; 10.021; 10.022; 10.024; 10.025; 10.026; 10.027; 10.028; 10.030; 10.032; 10.033; 10.034; 11.001; 11.003; 11.005; 11.006; 11.007; 11.009; 11.010; 11.011; 11.012; 11.013; 11.014; 11.015; 11.016; 11.018; 11.023; 11.024; 11.027; 11.028; 11.030; 11.031; 11.034; 11.035; 11.039; 11.040; 11.041; 11.043; 11.044; 11.045; 11.046; 11.047; 11.048; 11.049; 11.051; 11.052; 11.053; 11.054; 11.055; 11.058; 11.059; 11.060; 11.062; 11.063; 11.064; 11.065; 11.067; 11.068; 11.070; 11.072.
Roots of pea seedlings, infested with an aphid population of mixed ages, were placed directly in the test solutions of 24 ppm. 6 days after introduction, samples were checked for mortality.
The following compounds gave at least 80% control of Myzus persicae:
1.001, 1.012; 1.027; 1.050, 1.073, 1.088; 1.092; 1.118; 1.422; 1.424; 1.425; 3.004; 3.010; 3.020; 3.031; 3.035; 3.038; 3.040; 3.043; 3.046; 3.064; 3.065; 3.066 3.067; 3.068; 3.069; 3.070; 3.071; 3.072; 3.073; 3.074; 3.076; 3.080; 3.081; 3.082; 3.083; 3.084; 3.086; 3.087; 3.089; 3.090; 3.094; 3.095; 3.096; 3.097; 3.099; 3.100; 3.101; 3.102; 3.103; 3.104; 3.105; 3.106; 3.107; 3.110; 3.112; 3.113; 3.116; 3.117; 10.007; 10.009; 10.010; 10.014; 10.017; 10.018; 10.019; 10.020; 10.021; 10.022; 10.030; 10.032; 11.003; 11.005; 11.006; 11.007; 11.009; 11.010; 11.011; 11.012; 11.013; 11.014; 11.016; 11.018; 11.023; 11.024; 11.028; 11.030; 11.031; 11.034; 11.035; 11.040; 11.044; 11.045; 11.047; 11.048; 11.049; 11.051; 11.053; 11.054; 11.055; 11.058; 11.059; 11.060; 11.062; 11.063; 11.065; 11.070.
Bean leaf discs on agar in 24-well microtiter plates were sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs are infested with mite populations of mixed ages. 8 days later, discs are checked for egg mortality, larval mortality, and adult mortality.
The following compounds gave at least 80% control of Tetranychus urticae:
1.050, 1.073, 1.088; 1.092; 1.422; 1.424; 1.425; 3.004; 3.020; 3.031; 3.038; 3.040; 3.043; 3.046; 3.066; 3.069; 3.072; 3.074; 3.080; 3.081; 3.082; 3.084; 3.086; 3.087; 3.089; 3.090; 3.095; 3.096; 3.097; 3.099; 3.100; 3.101; 3.102; 3.103; 3.104; 3.105; 3.106; 3.107; 3.108; 3.110; 3.111; 3.112; 3.113; 3.115; 3.116; 3.117; 10.007; 10.009; 10.010; 10.012; 10.017; 10.018; 10.019; 10.024; 10.025; 10.028; 10.030; 10.032; 11.001; 11.003; 11.005; 11.006; 11.007; 11.009; 11.010; 11.011; 11.012; 11.013; 11.014; 11.016; 11.018; 11.023; 11.024; 11.028; 11.030; 11.035; 11.040; 11.041; 11.043; 11.044; 11.046; 11.047; 11.048; 11.051; 11.052; 11.053; 11.055; 11.058; 11.059; 11.060; 11.062; 11.063; 11.064; 11.065; 11.067; 11.068; 11.070; 11.072.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0614552.8 | Jul 2006 | GB | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/GB2007/002456 | 6/29/2007 | WO | 00 | 9/16/2009 |
