Login| Sign Up| Help| Contact|

Patent Searching and Data


Title:
BENZOYLISOXAZOLES AND 2-CYANO-1,3-DIONE DERIVATIVES AND THEIR USE AS HERBICIDES
Document Type and Number:
WIPO Patent Application WO/1997/028136
Kind Code:
A1
Abstract:
The invention relates to 4-benzoylisoxazole derivatives of formula (Ia), 5-phenylisoxazole derivatives of formula (Ib) and 2-cyano-1,3-dione derivatives of formula (Ic), wherein R1, R2, R3, X and n are as defined in the description, and to their use as herbicides.

Inventors:
, GO.
Atsushi, Kudo
Sachio, Murata
Tetsuya, Morris
John, Lambert
Claude, Itoh
Masahito, Mukaida
Hidesi, Geach
Neil, Araki
Koichi, Brett
Takako OE.
Yukiko
Application Number:
PCT/EP1997/000330
Publication Date:
August 07, 1997
Filing Date:
January 24, 1997
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
RHONE-POULENC AGRICULTURE LTD
MITSUBISHI CHEMICAL CORPORATION GO, Atsushi KUDO, Sachio MURATA, Tetsuya MORRIS, John LAMBERT, Claude ITOH, Masahito MUKAIDA, Hidesi GEACH, Neil ARAKI, Koichi BRETT, Takako OE, Yukiko.
International Classes:
A01N37/42; A01N43/80; C07C49/792; C07C49/813; C07C49/84; C07C63/72; C07C69/76; C07C225/16; C07C255/40; C07C317/24; C07C323/22; C07C323/56; C07C323/62; C07D261/08; (IPC1-7): C07D261/08; C07C255/40; A01N43/80; A01N37/34; C07D261/18; C07C323/32; C07C225/16; C07C225/18; C07C323/19
Foreign References:
EP0625505A21994-11-23
EP0418175A21991-03-20
EP0580439A11994-01-26
EP0524018A11993-01-20
US2765305A1956-10-02
Other References:
JEAN RIGAUDY ET AL: "Cétones dérivées du dibenzo[a,d]cycloheptadiéne.", BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE, 1959, PARIS FR, pages 638 - 643, XP002028874
CHARLES DUFRAISSE ET AL: "Acide diméthoxy-2',4'benzyl-2benzoique et corps apparentés", BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE, 1947, PARIS FR, pages 701 - 705, XP002028875
KAZUO SUZUKI ET AL: "Derivatives of 3-fluorofluorene by the Pschorr synthesis", JOURNAL OF ORGANIC CHEMISTRY, vol. 26, no. 7, July 1961 (1961-07-01), EASTON US, pages 2239 - 2242, XP002028876
ANDREW J,G. BAXTER ET AL: "Azoalkene route to methyl 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate and analogues", SYNTHESIS, February 1994 (1994-02-01), STUTTGART DE, pages 207 - 211, XP002028877
LOUIS E.BENJAMIN ET AL: "2-Benzazepines.2.Thiazolo[5,4-d][2]benzazepines", JOURNAL OF MEDICINAL CHEMISTRY, vol. 26, no. 1, January 1983 (1983-01-01), WASHINGTON US, pages 100 - 103, XP002028878
FOUCHE J ET AL: "Recherches dans le domaine des produits à activité psychotrope", BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE, no. 8, 1 January 1972 (1972-01-01), pages 3113 - 3130, XP000560355
WILSON BAKER ET AL: "Eight and higher-membered ring compounds", JOURNAL OF THE CHEMICAL SOCIETY, 1952, LETCHWORTH GB, pages 1452 - 1457, XP002028879
ERNST D.BERGMANN ET AL: "1:1'-Difluorodianthron-9-ylidene and an attempted synthesis of 4:4'-dibromodianthron-9-ylidene", JOURNAL OF THE CHEMICAL SOCIETY, 1953, LETCHWORTH GB, pages 2572 - 2574, XP002028880
E.D. BERGMANN ET AL: "Fulvénes et éthylénes thermochromes.", BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE, 1952, PARIS FR, pages 66 - 72, XP002028881
Download PDF:
Claims:
CLAΓMS
1. A 4benzoylisoxazole derivative of formula (Ia), a 5phenylisoxazole derivative of formula (Ib) or a 2cyano 1,3 dione derivative of formula (Ic): (Ia) (lb) (Ic) wherein: R represents hydrogen or CO2R^; R1 represents: a straight or branched chain alkyl group containing up to six carbon atoms which is optionally substituted by one or more halogen atoms; or a cycloalkyl group containing from three to six carbon atoms optionally substituted by one or more groups selected from R12 and halogen; R2 represents: halogen; a straight or branched chain alkyl group containing up to six carbon atoms which is substituted by one or more groups OR5; a cycloalkyl group containing from three to six carbon atoms; or a group selected from nitro, cyano, CO2R5, NR5R6, S(O)pR7, O(CH2)mOR5, COR5, N(R8)SO2R7, OR7, OH, OSO2R7, (CR9R10)tS(O)qR7, CONR5R6, N(R8)C(Z)=Y, C^R^NRSR1 ! and R12; or two groups R2, together with adjacent carbon atoms of the phenyl ring, may form a 1,3benzodioxole ring which is optionally substituted by one or two halogen atoms at the 2 position of the 1,3 benzodioxole ring; n represents zero or an integer from one to three; where n is greater than one the groups R2 may be the same or different; X represents (CR15R16)rCRl3R14(CR15aR16a)s; R represents : phenyl optionally substituted by one or more groups selected from halogen, nitro, cyano, CO2R5, S(O)pR7 , NR5R6, OR7, OH, CH2S(O)pR7, CONR5R6, R12, SO2NR5R6, CH2OR12, N(R5)SO2R12, N(R5)C(Z)=Y, CH N(R5)SO2R12; CH2N(R5)C(V)=Y, CH2P(OR17)(OR18)=O, and CH^19; or two groups on R^ together with adjacent carbon atoms of the phenyl ring may form a 1,3benzodioxole ring which is optionally substituted by one or two halogen atoms at the 2position of the 1,3 benzodioxole ring; m represents one, two or three; p represents zero, one or two; q represents zero, one or two; t represents one, two, three or four; r and s each represent zero, one or two, with the proviso that the combined value of r and s is not greater than two; R4 represents a straight or branched chain alkyl group containing up to six carbon atoms optionally substituted by one or more groups selected from halogen, OR5, CO2R5, S(O)nR7, phenyl and cyano; or phenyl optionally substituted by one or more halogen atoms, OR5 or R12; R5 and R^ which may be the same or different, each represents hydrogen or R12; R7 and R7a independently represent R12 or a cycloalkyl group containing from three to six carbon atoms; or a group (CH2)w[phenyl optionaUy substituted by from one to five groups R2^ which may be the same or different]; w represents zero or one; R8 represents : hydrogen; a straight or branched chain alkyl, aikenyl or alkynyl group containing up to ten carbon atoms optionaUy substituted by one or more halogen atoms; a cycloalkyl group containing from three to six carbon atoms; (CH2) [phenyl optionally substituted by from one to five groups R ^ which may be the same or different]; or a group OR21; R9 and R1^ independently represent hydrogen or a straight or branched chain alkyl group containing up to six (preferably up to three) carbon atoms optionally substituted by one or more halogen atoms; R1 ! represents S(O)qR7 or C(Z)=Y; R1 represents a straight or branched chain alkyl, aikenyl or alkynyl group containing up to six carbon atoms optionally substituted by one or more halogen atoms; R13, R15, R15a, R16 and R16a independently represent: hydrogen or a straight or branched chain alkyl, aikenyl or alkynyl group containing up to six carbon atoms optionally substituted by one or more halogen atoms; R14 represents R5, cyano, OR12, S(O)pR12 or halogen; R17 and R18 independently represents hydrogen or R12; R19 represents a Nlinked pyrazole, imidazole or 1,2,4triazole ring optionally substituted by one or more groups selected from halogen and R12; R represents: a halogen atom; a straight or branched chain alkyl group containing up to three carbon atoms optionally substituted by one or more halogen atoms; or a group selected from nitro, cyano, S(O)pR2 and OR5; R21 represents a straight or branched chain alkyl group containing up to six carbon atoms optionally substituted by one or more halogen atoms; V represents R12, OR12 or SR12; Y represents oxygen or sulphur; Z represents R12, NR8R22, NR8NR22R23, SR7 or OR7; R22 and R23 independently represent R8; or an agricυlturaUy acceptable salt or metal complex thereof.
2. A compound according to claim 1 which is a compound of formula (Ia).
3. A compound according to claim 1 or 2 in which the 2 position of phenyl is substituted.
4. A compound according to claim I, 2 or 3 in which the XR3 group is at the 2 or 3 position of phenyl.
5. A compound according to any one of the preceding claims in which X represents CHR14, CHR14CH2, CH2CHR14 or (CH2)3.
6. A compound according to claim 5 in which X represents CH2.
7. A compound according to any one of the preceding claims in which the 6 position of phenyl is unsubstituted.
8. A compound according to any one of the preceding claims in which R1 represents a straight or branched chain alkyl group containing up to three carbon atoms which is optionally substituted by one or more halogen atoms; or cyclopropyl or 1methylcyclopropyl.
9. A compound according to claim 8 in which R1 represents cyclopropyl.
10. A compound according to any one of the preceding claims in which R2 represents : halogen; a straight or branched chain alkyl or aikenyl group containing up to four carbon atoms optionally substituted by one or more halogen atoms; or a group selected from nitro, cyano, S(O)pR7, OR7 and OH.
11. A compound according to any one of the preceding claims in which n represents zero, one or two.
12. A compound according to any one of the preceding claims in which R3 represents phenyl optionally substituted by S(O)pR7a or halogen.
13. A compound according to any one of the preceding claims in which R7 represents a straight or branched chain alkyl group containing up to six carbon atoms which is optionally substituted by one or more halogen atoms. SUBSTTTUTE SHEET (RULE 26) .
14. A compound of formula (Ia) according to claim 1 having one or more of the following features : R represents hydrogen or CO2R4; R1 represents cyclopropyl or 1 methylcyclopropyl; R2 represents : halogen; a straight or branched chain alkyl group containing up to three carbon atoms optionally substituted by one or more halogen atoms; or a S(O)pR7 group; or when XR3 is attached to the 2position of the phenyl ring, two groups R2 together with the carbon atoms at the 3 and 4 positions of the phenyl ring form a 1,3benzodioxole ring substituted by one or two chlorine or fluorine atoms at the 2position of the 1,3benzodioxole ring. n represents zero, one or two; X represents CHR14, CHR14CH2, CH2CHR14 or (CH2)3; XR3 is attached to the 2 or 3 position of the phenyl ring; R3 represents : phenyl optionally substituted by one or two groups selected from halogen, S(O)pR7a NR5R6, OR7, CH2S(O)pR7, R12, SO2NR5R6, CH2OR12, N(R5)SO2R12, N(R5)C(Z)=Y, CH2N(R5)SO2R12, CH2N(R5)C(V)=Y, CH2P(OR17)(OR18)=O and CH2R19; R4 represents a straight or branched chain alkyl group containing from one to three carbon atoms; R5, R6, R7, R8 and R12 independently represent methyl or ethyl optionally substituted by one or more halogen atoms; R17 and R1 independently represent hydrogen, or methyl or ethyl optionaUy substituted by one or more halogen atoms; V and Z represent methyl, ethyl, methoxy or ethoxy, which may be substituted by one or more halogen atoms; and Y represents oxygen.
15. A compound according to claim 1 in which: R1 represents cyclopropyl; R2 represents : halogen; methyl or ethyl optionally substituted by one or more halogen atoms; or S(O)pR7; n represents zero, one or two; when n is one or two the R2 groups are attached to the 3 and/or 4 positions of the phenyl ring; X represents CHR14, CH2CHR14 or (CH2)3; XR3 is attached to the 2position of the phenyl ring; R3 represents phenyl optionally substituted by a group selected from halogen, methyl optionally substituted by one or more halogen atoms, and S(O)pR7a; R4 represents methyl or ethyl; R7 represents a methyl ethyl which is optionally substituted by one or more halogen atoms; R7a represents a straight or branched chain alkyl group containing from one to three carbon atoms optionally substituted by one or more halogen atoms; and R14 represents hydrogen, methyl or S(O)pCH3.
16. A compound according to claim 1 in which: R1 represents cyclopropyl, 1methylcyclopropyl or tbutyl; R2 represents : halogen; methyl or ethyl optionally substituted by one or more halogen atoms; or S(O)pR7; n represents zero, one or two; when n is one or two the R2 groups are attached to the 3, 4 or 5 positions of the phenyl ring; X represents CHR14, CH2CHR14 or (CH2)3, XR3 is attached to the 2 or 3 position of the phenyl ring; R3 represents phenyl optionally substituted by one to three groups selected from halogen, methyl optionally substituted by one or more halogen atoms, S(O)pR7a CH2S(O)pR7, CH2OR12 and OR7; or two groups on R3 together with adjacent carbon atoms of the phenyl ring form a 1,3benzodioxole ring which is optionaUy substituted by one or two halogen atoms at the 2position of the 1,3benzodioxole ring; R4 represents methyl, ethyl or isopropyl; R7 represents methyl or ethyl which is optionally substituted by one or more halogen atoms; R7a represents a straight or branched chain alkyl group containing from one to three carbon atoms optionally substituted by one or more halogen atoms; R12 represents optionally halogenated methyl; and R14 represents hydrogen, methyl or S(O)pCH3.
17. A composition comprising a herbicidally effective amount of a compound of formula (Ia), (Ib) or (Ic) as defined in any one of claims 1 to 16, or an agriculturally acceptable salt or metal complex thereof in association with an agriculturally acceptable diluent or carrier and/or surfaceactive agent.
18. A method for the control of weeds at a locus which comprises applying to said locus a herbicidally effective amount of a compound of formula (Ia), Ib) or (Ic) as defined in any one of claims 1 to16 or an agriculturally acceptable salt or metal complex thereof; or a composition according to claim 17.
19. A process for the preparation of a compound of formula (Ia), (Ib) or (Ic) as defined in claim 1, said process comprising: (a) where the compound is of formula (Ia) or (Ib) in which R represents hydrogen and R1, R2, R3, X and n are as defined in claim 1, reacting a compound of formula (II): (II) wherein L is a leaving group and R1, R2, R3, n and X are as defined in claim 1, with hydroxylamine or a salt of hydroxylamine; (b) where the compound is of formula (Ia) in which R represents hydrogen and R1, R2, R3, X and n are as defined in claim 1, reacting a compound of formula (III). (III) wherein R1 is as defined in claim 1 and Y represents a carboxy group or a reactive derivative thereof or a cyano group, with an organometallic reagent; (c) where the compound is of formula (Ia) wherein R represents a group CO2R4 and R , R2, R3, X and n are as defined in claim 1, reacting a compound of formula (IV): (rN) wherein R1, R2, R3, X and n are as defined in claim 1 and P1 is a leaving group, with a compound of formula R4O2CC(Z1)=NOH wherein R4 is as defined in claim 1 and Z is a halogen atom; (d) where the compound is of formula (Ia) in which R represents a group CO2R4 and R1, R2, R3, X and n are as defined in claim 1, reacting a compound of formula (V): (N) wherein R , R2, R3, X and n are as defined in claim 1, with a compound of formula R4O2CC(Z1)=NOH wherein Z1 and R4 are as defined above; (e) where the compound is of formula (Ia) or (Ib) wherein R represents CO2R4 and R1, R2, R3, R4, X and n are as defined in claim 1, reacting a salt of a compound of formula (VI): (VI) wherein R1, R2, R3, X and n are as defined in claim 1 with a compound of formula R4O2CC(Z1)=NOH wherein R4 and Z1 are as defined above; (f) where the compound is of formula (Ib) in which R, R1, R2, R3, X and n are as defmed in claim 1, metallating a compound of formula (Nil) wherein R, R2, R3,X and n are as defined in claim 1 and A is a halogen atom, followed by reaction of the compound thus obtained with an acid chloride of formula R COC1, wherein R1 is as defined in claim 1; (g) where the compound is of formula (Ib) in which R, R1 , R2, R3, X and n are as defined in claim 1, oxidising a compound of formula ( I): which R, R1, R2, R3, X and n are as defined in claim 1, to convert the hydroxy group to a ketone group; (h) where the compound is of formula (Ib) in which R represents hydrogen and R1, R2, R3, X and n are as defined in claim 1, reacting a compound of formula (IX): in which D represents a carboxy group or a reactive derivative thereof or a cyano group, with an organometallic reagent, to introduce a group COR1 into the 4position of the isoxazole ring; (i) where the compound is of formula (Ib) in which R represents a CO R4 group and R1, R2, R3, R4, X and n are as defined in claim 1, reacting a compound of formula (X): (X) wherein P1 is as defined above and R1, R2, R3, X and n are as defined in claim 1, with a compound of formula R4O2CC(Z1)=NOH wherein Z1 and R4 are as defined above; (j) where the compound is of formula (Ib) in which R represents a group CO2R4 and R1, R2, R3, R4, X and n are as defined in claim 1, (XI) with a compound of general formula R4O2CC(Z1)=NOH wherein Z1 and R4 are as defined above; (k) where the compound is of formula (Ia) or (Ib) in which X represents CR13R14(CR15 R16a)s or (CR15R16)rCR13R14 and R, Rl, R2, R3, R13, R15, R15a, R16, R16a, r, s and n are as defined in claim 1 and R14 represents halogen, reacting the conesponding compound of formula (Ia) or (Ib) in which X represents CHR13(CR15aR16a)s or (CR15R16)rCHR13 respectively with a halogenating agent; (1) where the compound is of formula (Ia) or (Ib) in which R, R1, R2, R3, R12, R13, R15, R15a, R16, R16a, r, s and n are as defined in claim 1 and R14 represents SR12, reacting the conesponding compound of formula (Ia) or (Ib) in which R14 represents halogen, with a. compound of formula R12SM, wherein R1 is as defined above and M is hydrogen or an alkali metal; (m) where the compound is of formula (Ic), reacting the conesponding compound of formula (Ia) or (Ib) in which R is as defined above, with a base; (n) where the compound is of formula (Ic), performing a hydrolytic reaction on the conesponding compound of formula (Ia) or (Ib) in which R represents CO2R4, or in which R is replaced by amide or nitrile; (o) where the compound is of formula (Ic), reacting a benzoyi chloride of formula (XII): (xπ) wherein R2, R3, X and n are as defined in claim 1, with a betaketonitrile of formula (xm) wherein R1 is as defined in claim 1; (p) where the compound is of formula (Ic), reacting an acid chloride of formula R^OCl wherein R is as defined in claim 1, with a betaketonitrile of formula (XIV): (X1N) wherein R2, R3, X and n are as defined in claim 1 ; (q) where p or q is one or two, oxidising the sulphur atom of the conesponding compound of formula (I), (Ib) or (c) in which p or q is O or l; (r) where the compound is of formula (Ia) or (Ib) in which R1 , R2, R3, X and n are as defined in claim 1 and R represents CO2R4a in which R4a represents a straight or branched chain alkyl group containing up to six carbon atoms optionally substituted by one or more groups selected from halogen, OR5, CO2R5, S(O)pR7, phenyl or cyano, reacting the conesponding compound of formula (Ia) or (Ib) in which R represents CO2R4, by reaction with an alcohol of formula (XXX): R aOH (XXX) wherein R a is as defined above; (s) where the compound is of formula (Ia) or (Ib) in which R1, R2, R3 and n are as defined in claim 1 and X represents CR1 R14, reacting the conesponding compound of formula (Ia) or (Ib) in which XR3 is replaced by CR1 R14hal in which hal represents bromine or iodine, with a compound of formula (XXXI): R3B(OH)2 (XXXI) wherein R3 is as defined in claim 1 ; optionaUy followed by the conversion of the compound of formula (Ia), (b) or (c) thus obtained into an an agriculturally acceptable salt or metal complex thereof.
20. A compound of formula (II), (IV), (V), (VI), (VII), (WI), (ix), (X), (xi), (xiv), (xx), (xxiv), (xxv), (xxvπi), (xxrx), (XXVI or (XXVII) : (II) (IV) (V) (Ni) (NH) (vm) (XI) (XTN) (XX) (XXIV) (xxvπi) (XXLX) wherein R1, R2, R3, X and n are as defined in claim 1, L is alkoxy, or N,Ndialkylamino, P1 is N,Ndialkylamino, A is a halogen atom, D represents a carboxy group, or a reactive derivative thereof or a cyano group, D1 is CO2alkyl or CN, and Q represents hydrogen or a bromine or iodine atom. (xπ) (XXI) (xxm) wherein R2, R3, X and n are as defined in claim 1 and and R2^ represents a straight or branched chain alkyl group containing up to six carbon atoms.
Description:
BENZOYLISOXAZOLES AND 2-CYANO- 1 ,3-DIONE DERIVATIVES AND THEIR USE AS HERBI¬ CIDES

This invention relates to novel 4-benzoylisoxazole derivatives, 5-phenyiisoxazole derivatives and 2-cyano- 1,3 -dione derivatives, compositions containing them, processes for their preparation, intermediates in their preparation and their use as herbicides.

Herbicidal 4-benzoylisoxazoles are described in European Patent Publication Numbers 0418175, 0487357, 0527036, 0527037, 0560482 and 0560483. Herbicidal 2-cyano-l,3-diones are described in European Patent Publication Numbers 0213892, 0496630 and 0496631, and International Patent Publication No. WO 95/25099. Herbicidal 5-phenylisoxazoles are described in European Patent Publication Number 0524018. However, none of the above publications disclose or suggest the presence of a benzene ring linked to a hydrocarbon group as a substituent on the phenyl ring.

The present invention provides 4-beπzoylisoxazole derivatives of formula (Ia), 5-phenyIisoxazole derivatives of formula (Ib) and 2-cyano- 1,3 -dione derivatives of formula (Ic):

(Ia) (Ib) (Ic) wherein:

R represents hydrogen or -CO2 ^;

R.1 represents:- a straight- or branched- chain alkyl group containing up to six carbon atoms which is optionally substituted by one or more halogen atoms; or a cycloalkyl group containing from three to six carbon atoms optionally substituted by one or more groups selected from R^ and halogen;

R2 represents :-

halogen; a straight- or branched- chain alkyl group containing up to six carbon atoms which is substituted by one or more groups -OR-'; a cycloalkyl group containing from three to six carbon atoms; or a group selected from nitro, cyano, -CO2R 5 , -NR 5 R 6 , -S(O) p R 7 ,

-O(CH 2 ) m OR 5 , -COR 5 , -N(R8)SO 2 R 7 , -OR 7 , -OH, -OSO 2 R 7 , -(CR 9 R 10 ) t S(O) q R 7 , -CONR 5 R 6 , -N(R 8 )-C(Z)=Y, -C(R 9 R 10 )NR 8 R n and R 12 ; or two groups R 2 , together with adjacent carbon atoms of the phenyl ring, may form a 1,3-benzodioxole ring which is optionally substituted by one or two halogen (preferably chlorine or fluorine) atoms at the 2- position of the 1,3-benzodioxole ring; n represents zero or an integer from one to three; where n is greater than one the groups R 2 may be the same or different; X represents -(CR 15 R 16 ) r CRl 3Rl4 -(CR I 5a R 16a ) s -,

R3 represents: - phenyl optionally substituted by one or more groups selected from halogen, nitro, cyano, -CO 2 R 5 , -S(O)pR 7a , -NR 5 R 6 , -OR 7 , -OH, -CH 2 S(O) p R 7 , -CONR 5 R 6 , R 2 , -SO 2 NR 5 R 6 , -CH 2 OR 12 , -N(R 5 )SO 2 R 12 , -N(R 5 )-C(Z)=Y, -CH 2 N(R 5 )SO 2 R 12 ;

-CH 2 N(R 5 )-C(V)=Y, -CH 2 P(OR 17 )(OR 18 )=O, and -CH 2 R 19 ; or two of the above groups together with adjacent carbon atoms of the phenyl ring may form a 1,3-benzodioxole ring which is optionally substituted by one or two halogen (preferably chlorine or fluorine) atoms at the 2-position of the 1,3-benzodioxole ring; m represents one, two or three; p represents zero, one or two; q represents zero, one or two; t represents one, two, three or four (preferably one); r and s each represent zero, one or two, with the proviso that the combined value of r and s is not greater than two;

R represents a straight- or branched- chain alkyl group containing up to six carbon atoms optionally substituted by one or more groups selected from halogen, -OR 5 , -CO 2 R 5 , -S(O) p R 7 , phenyl and cyano; or phenyl optionally substituted by one or more halogen atoms, -OR 5 or

Rl 2 ;

R 5 and R> which may be the same or different, each represents hydrogen or R^ 2 ;

SUBSTTTUTE SHEET (RULE 26)

- J

R 7 and R 7a independently represent R^ 2 or a cycloalkyl group containing from three to six carbon atoms; or a group -(CH 2 ) w -[phenyl optionally substituted by from one to five groups R 2 ^ which may be the same or different]; w represents zero or one;

R 8 represents :- hydrogen; a straight- or branched- chain alkyl, aikenyl or alkynyl group containing up to ten carbon atoms optionally substituted by one or more halogen atoms; a cycloalkyl group containing from three to six carbon atoms; -(CH 2 ) -[phenyl optionally substituted by from one to five groups R 2 ^ which may be the same or different]; or a group -OR 1; R 9 and R*-^ independently represent hydrogen or a straight- or branched- chain alkyl group containing up to six (preferably up to three) carbon atoms optionally substituted by one or more halogen atoms; R 1 ] represents -S(O) q R 7 or -C(Z)=Y; R 12 represents a straight- or branched- chain alkyl, aikenyl or alkynyl group containing up to six carbon atoms optionally substituted by one or more halogen atoms;

R 13 , R 15 , R l 5a , R 16 and R l6a independently represent:- hydrogen or a straight- or branched- chain alkyl, aikenyl or alkynyl group containing up to six carbon atoms optionally substituted by one or more halogen atoms;

R 14 represents R 5 , cyano, -OR 12 , -S(O)pR 12 or halogen; R' 7 and R^ independently represents hydrogen or R* 2 ; Rl 9 represents a N-linked pyrazole, imidazole or 1,2,4-triazole ring optionally substituted by one or more groups selected from halogen and R 12 ;

R 2u represents :- a halogen atom; a straight- or branched- chain alkyl group containing up to three carbon atoms optionally substituted by one or more halogen atoms; or a group selected from nitro, cyano, -S(O) p R 21 and -OR 5 ;

R 21 represents a straight- or branched- chain alkyl group containing up to six carbon atoms optionally substituted by one or more halogen atoms;

V represents R 12 , -OR 12 or -SR 12 ;

Y represents oxygen or sulphur (preferably Y represents oxygen); Z represents R 12 , -NR 8 R 22 , -NR 8 -NR 22 R 23 , -SR 7 or -OR 7 ; R 22 and R 23 independently represent R 8 ; and agriculturally acceptable salts and metal complexes thereof, which possess valuable herbicidal properties.

Compounds of formula (Ic) may exist in enolic tautomeric forms that may give rise to geometric isomers around the enolic double bond.

Furthermore in certain cases the substituents R, R 1 , R 2 , R 3 , R4, R 5 , R6, R 7 , R 7 * R 8 , R 9 , RlO, R l 1, R 12 R 13 > R 14 > R 15 > R 15a R 16 ? R 16a

R 17 , R 18 , R 20 , R 21 , R 22 , R 23 , X and Z may contribute to optical isomerism and/or stereoisomerism. All such forms are embraced by the present invention.

It will be understood that in the description that follows, reference to compounds of formula (I) means reference to a compound of formula

(Ia), (Ib) or (Ic).

It will also be understood that the proviso that the combined maximum value of r and s is to be not greater than two is for reasons of biological interest. It is also to be understood that the -(CR 1 R 1 ^) r - terminus of X is attached to the benzoyi ring, whilst the -(CR 15a R 16a ) s - terminus is attached to the R 3 group.

By the term "agriculturally acceptable salts" is meant salts the cations or anions of which are known and accepted in the art for the formation of salts for agricultural or horticultural use. Preferably the salts are water-soluble. Suitable salts with bases include alkali metal (e.g. sodium and potassium), alkaline earth metal (eg. calcium and magnesium), ammonium and amine (eg. diethanolamine, triethanolamine, octylamine, morpholine and dioctylmethylamine) salts. Suitable acid addition salts, formed by compounds of formula (I) containing an amino group, include salts with inorganic acids, for example hydrochlorides, sulphates, phosphates and nitrates and salts with organic acids, for example acetic acid.

By the term "metal complexes" is meant compounds in which one or both of the oxygen atoms of the 1,3-dione of formula (Ic) act as chelating agents to a metal cation. Examples of such cations include zinc, manganese, cupric, cuprous, ferric, ferrous, titanium and aluminium.

SUBSTTTUTE SHEET (RULE 26)

The compounds of the invention, in certain aspects of their properties, for example their control of Echinochloa orvzicola and their selectivity in paddy rice, show advantages over known compounds. Compounds of formula (Ia) above are preferred. Compounds in which the 2-position of phenyl is substituted are also preferred.

Compounds in which the -XR 3 group is at the 2- or 3- position of phenyl are preferred; most preferably it is at the 2- position.

Compounds in which X represents -CHR 14 -, -CHR 14 -CH 2 -, -CH CHR 14 - or -(CH 2 )3- are preferred; more preferably X represents

-CHR 14 - and most preferably X represents -CH -.

Preferably the 6- position of phenyl is unsubstituted. Preferably R 1 represents a straight- or branched- chain alkyl group containing up to three carbon atoms which is optionally substituted by one or more halogen atoms; or cyclopropyl or 1-methylcyclopropyl.

Most preferably R 1 represents cyclopropyl. Preferably R 2 represents :- halogen; a straight- or branched- chain alkyl or aikenyl group containing up to four carbon atoms optionally substituted by one or more halogen atoms; or a group selected from nitro, cyano, -S(O)pR 7 , -OR 7 and -OH. Preferably n represents zero, one or two. Preferably R 3 represents phenyl optionally substituted by -S(O) p R 7 or halogen.

Preferably R 7 represents a straight- or branched- chain alkyl group containing up to six carbon atoms which is optionally substituted by one or more halogen atoms.

A particularly preferred class of compounds of formula (Ia) above are those having one or more of the following properties: -

R represents hydrogen or -CO R 4 ; R 1 represents cyclopropyl or 1-methylcyclopropyl; R 2 represents:- halogen; a straight- or branched- chain alkyl group containing up to three carbon atoms optionally substituted by one or more halogen atoms; or a -S(O)pR 7 group;

or when -XR 3 is attached to the 2-ρosition of the phenyl ring, two groups R 2 together with the carbon atoms at the 3- and 4- positions of the phenyl ring form a 1,3-benzodioxole ring substituted by one or two chlorine or fluorine atoms at the 2-position of the 1,3-benzodioxole ring. n represents zero, one or two;

X represents -CHR 14 -, -CHR 14 -CH 2 -, -CH 2 CHR 14 - or

-(CH 2 ) 3 .;

-XR 3 is attached to the 2- or 3- position of the phenyl ring; R 3 represents: - phenyl optionally substituted by one or two groups selected from halogen, -S(O) p R 7a , -NR 5 R 6 , -OR 7 , -CH 2 S(O)pR 7 , R 12 , -SO 2 NR 5 R 6 , -CH OR 12 -N(R 5 )SO 2 R 12 , -N(R 5 )-C(Z)=Y, -CH 2 N(R 5 )SO 2 R 12 , -CH 2 N(R 5 )-C(V)=Y, -CH 2 P(OR 17 )(OR 18 )=O and -CH 2 R 19 ; R 4 represents a straight- or branched- chain alkyl group containing from one to three carbon atoms;

R 5 , R6, R 7 , R 8 and R 2 independently represent methyl or ethyl optionally substituted by one or more halogen atoms;

R 17 and R 1 independently represent hydrogen, or methyl or ethyl optionally substituted by one or more halogen atoms;

V and Z independently represent methyl, ethyl, methoxy or ethoxy, which may be substituted by one or more halogen atoms;

Y represents oxygen.

Another particularly preferred class of compounds of formula (I) are those wherein: -

R 1 represents cyclopropyl; R 2 represents:- halogen; methyl or ethyl optionally substituted by one or more halogen atoms; or -S(O) j -,R 7 ; n represents zero, one or two; when present the R 2 groups are attached to the 3 and/or 4 positions of the phenyl ring; X represents -CHR 14 , -CH 2 -CHR 14 - or -(CH 2 )3S -XR 3 is attached to the 2-position of the phenyl ring; R 3 represents phenyl optionally substituted by a group selected from halogen, methyl optionally substituted by one or more halogen atoms, and -S(O) p R 7a ;

R 4 represents methyl or ethyl;

SUBSTTTUTE SHEET (RULE 26)

R 7 represents methyl or ethyl which is optionally substituted by one or more halogen atoms;

R 7a represents a straight- or branched- chain alkyl group containing from one to three carbon atoms optionally substituted by one or more halogen atoms;

R 14 represents hydrogen, methyl or -S(O) p CH3. Another particularly preferred class of compounds of formula (I) are those wherein: -

R 1 represents cyclopropyl, 1-methylcyclopropyl or t-butyl; R 2 represents :- halogen; methyl or ethyl optionally substituted by one or more halogen atoms; or -S(O)pR 7 ; n represents zero, one or two; when present the R 2 groups being attached to the 3, 4 or 5 -positions of the phenyl ring; X represents -CHR 14 -, -CH 2 -CHR 14 - or -(CH ) 3 -;

-XR 3 is attached to the 2 or 3 -position of the phenyl ring; R 3 represents phenyl optionally substituted by one to three groups selected from halogen, methyl optionally substituted by one or more halogen atoms, -S(O) p R 7a , -CH 2 S(O)pR 7 , -CH 2 OR 12 and -OR 7 ; or two of the above groups together with adjacent carbon atoms of the phenyl ring form a 1,3-benzodioxole ring which is optionally substituted by one or two halogen (preferably chlorine or fluorine) atoms at the 2-position of the 1,3-benzodioxole ring; R 4 represents methyl, ethyl or isopropyl; R 7 represents methyl or ethyl which is optionally substituted by one or more halogen atoms;

R 7a represents a straight- or branched- chain alkyl group containing from one to three carbon atoms optionally substituted by one or more halogen atoms; R 2 represents optionally halogenated methyl; and

R 14 represents hydrogen, methyl or -S(O) p CH3-

Particularly important compounds of formula (I), in which the compound numbers are for reference purposes only, include the following:

1. 4-[2-benzyl-4-(ethylthio)benzoyl]-5-cyclopropylisoxazole;

2. 4-[2-benzyl-4-(methylthio)benzoyl]-5-cyclopropylisoxazole;

3. 4-(2-benzylbenzoyl)-5-cyclopropylisoxazole;

- 8 -

4. 4-[2-(4-chlorobenzyl)-4-fluoro-3-methylbenzoyl]-5- cyclopropylisoxazole;

5. 5-cyclopropyl-4-[4-fluoro-2-(4-fluorobeπzyl)-3 - methylbenzoyl]isoxazole; 6. 5-cyclopropyl-4-[2-(4-fluorobenzyl)-3-methyl-4-

(methylthio)benzoyl]isoxazole;

7. 5 -cyclopropyl-4-[4-fluoro-2- ( 1 -methylbenzyl)benzoyl]isoxazole;

8. 5-cyclopropyl-4-[2-( 1 -methylbenzyl)-4-(methylthio)benzoyl] isoxazole;

9. 5-cyclopropyl-4-[2-( 1 -methyltbiobenzyl)benzoyl]isoxazole;

10. 5 -cyclopropyl-4-[2-(2-methylthiobenzyl)benzoyl]isoxazole;

11. 5-cyclopropyl-4-[2-(3-methylthiobenzyl)benzoyl]isoxazole;

12. 5-cyclopropyl-4-[2-(4-methylthiobenzyl)benzoyl]isoxazole; 13. 4-[4-chloro-2-(2-methylthiobenzyl)berιzoyl]-5- cyclopropylisoxazole;

14. 4-[5-chloro-2-(2-methylthiobenzyl)benzoyl]-5- cyclopropylisoxazole;

15. 5-cyclopropyl-4-[2-(2-ethylthiobenzyl)benzoyl]isoxazole; 16. 5-cyclopropyl-4-[2-(2-isopropylthiobenzyl)benzoyl] isoxazole;

17. 5-cyclopropyl* -[4-fluoro-2-(2-methylthiobenzyl)- benzoyl]isoxazole;

18. 5 -cyclopropyl-4-[4-fluoro-2-(2-phenylethyl)benzoyl] isoxazole;

19. 5-cyclopropyl-4-[2-(2-phenylethyl)-4- (methylthio)benzoyl]isoxazole;

20. 5-cyclopropyl-4-{2-[2-(2- methylthiophenyl)ethyl]benzoyl)isoxazole; 21. 4-[4-bromo-2-(2-methylsulphonyl-2-phenylethyl)benzoyl]-

5-cyclopropylisoxazole;

22. 5-cyclopropyl-4-[2-(2-methylsulphonyl-2-phenylethyl)-4- (methylthio)benzoyl]isoxazole;

23. 4-[2-(4-chlorobenzyl)-3 -methyl-4-(methylthio)benzoyl]-5- cyclopropylisoxazole;

24. 5-cyclopropyl-4-[4-methylthio-2-(2- methylthiobenzyl)benzoyl] isoxazole;

25. 4-[2-(2-chlorobenzyl)-4-fluorobenzoyl]-5- cyclopropylisoxazole;

26. 4-[2-(2-chlorobenzyl)-4-(methylthio)benzoyl]-5- cyclopropylisoxazole; 27. 4-[2-(4-chlorobenzyl)-4-(methylthio)benzoyl]-5- cyclopropylisoxazole;

28. 4-[2-(3-chlorobenzyl)-4-fluorobenzoyl]-5- cyclopropylisoxazole;

29. 4-[2-(3-chlorobenzyl)-4-(methylthio)benzoyl]-5- cyclopropylisoxazole;

30. 4-(2-benzyl-4-ethylthio-3-methylbenzoyl)-5- cyclopropylisoxazole;

31. 4-(2-benzyl-4-fluoro-3-methylbenzoyl)-5- cyclopropylisoxazole; 32. 4-[2-benzyl-3-methyl-4-(methylthio)benzoyl]-5- cyclopropylisoxazole;

33. 5-cyclopropyl-4[4-fluoro-3-methyl-2-(4- methylbenzyl)benzoyl]isoxazole;

34. 4-(2-benzy l-4-chloro-3 -(methylthio)benzoyl)-5 - cyclopropylisoxazole;

35. 4-[2-(4-chlorobenzyl)-4-fluorobenzoyl]-5- cyclopropylisoxazole;

36. 4-[4-chloro-3-methylthio-2-(2-methylthiobenzyl)benzoyl]- 5 -cyclopropylisoxazole; 37. 5-cyclopropyl-4-[2-(2-phenylethyl)benzoyI]isoxazole;

38. 4-[2-benzyl-4-chloro-3-(methylsulphinyl)benzoyl]-5- cyclopropylisoxazole;

39. 4-[2-ber-zyl-4-(etiylsulpbinyl)benzoyl]-5- cyclopropylisoxazole; 40. 4-[2-benzyl-4-(ethylsulphonyl)benzoyl]-5- cyclopropylisoxazole;

41. 4-[2-benzyl-4-(methylsulpbinyl)benzoyl]-5- cyclopropylisoxazole;

42. 4-[2-benzyl-4-(methylsulphonyl)benzoyI]-5- cyclopropylisoxazole

43. 4-[2-(2-chlorobenzyl)-4-(methylsulphinyl)benzoyl]-5- cyclopropylisoxazole;

44. 4-[2-(2-chlorobenzyl)-4-(methylsulphonyl)benzoyl]-5- cyclopropylisoxazole;

45. 4-[2-(4-chlorobenzyl)-4-(methylsulphinyl)benzoyl]-5- cyclopropylisoxazole; 46. 4-[2-(4-chlorobenzyl)-4-(methylsuIphonyl)benzoyl]-5- cyclopropylisoxazole;

47. 4-[2-(3-chlorobenzyl)-4-(methylsulphinyl)benzoyl]-5- cyclopropylisoxazole;

48. 4-[2-(3-chlorobenzyl)-4-(methylsulphonyl)benzoyl]-5- cyclopropylisoxazole;

49. 4-(2-benzyl-4-ethylsulphinyl-3-methylbenzoyl)-5- cyclopropylisoxazole;

50. 4-[2-benzyl-3-methyl-4-(methylsulphinyl)benzoyl]-5- cyclopropylisoxazole; 51. 5-cyclopropyl-4-[4-fluoro-2-(2- methylsulphinylbenzyl)benzoyl]isoxazole;

52. 5-cyclopropyl-4-[4-fluoro-2-(2- methylsulphonylbenzyl)benzoyl]isoxazole;

53. 4-[2-benzyl-3-methyl-4-(methylsulphonyl)benzoyl]-5- cyclopropylisoxazole;

54. 4-(2-benzyl-4-ethylsulphonyl-3-methylbenzoyl)-5- cyclopropylisoxazole;

55. 4-[2-(4-chlorobenzyl)-3 -methyl-4- (methylsulphinyl)benzoyl]-5-cyclopropylisoxazole; 56. 4-[2-(4-chlorobenzyl)-3-methyl-4-

(methylsulphonyl)benzoyl]-5-cyclopropylisoxazole;

57. 5 -cyclopropyl-4-[2-(4-fluorobenzyl)-3 -methyl-4- (methylsulphinyl)benzoyl]isoxazole;

58. 5 -cyclopropyl-4-[2-(4-fluorobenzyl)-3 -methyl-4- (methylsulphonyl)benzoyl]isoxazole;

59. 5 -cyclopropyl-4-[2-( 1 -methylbenzyl)-4- (methylsulphinyl)benzoyl]isoxazole;

60. 5-cyclopropyl-4-[2-( 1 -methylbenzyl)-4- (methylsulphonyl)benzoyl]isoxazole; 61. 5-cyclopropyl-4-[2-(l- methylsulphinylbenzyl)benzoyl]isoxazole;

62. 5-cyclopropyl-4-[2-(l- methylsulphonylbenzyl)benzoyl]isoxazole;

63. 5-cyclopropyl-4-[2-(2- methylsulphinylbenzyl)benzoyl]isoxazole;

64. 5-cyclopropyl-4-[2-(2- methylsulphonylbenzyl)benzoyl]isoxazole; 65. 5-cyclopropyl-4-[2-(4- methylsulphinylbenzyl)benzoyl]isoxazole;

66. 5-cyclopropyl-4-[2-(4- methylsulphonylbenzyl)benzoyl]isoxazole;

67. ethyl 5-cyclopropyl-4-[2-(2- methylsulphinylbenzyl)benzoyl]isoxazole-3 -carboxylate;

68. ethyl 5-cyclopropyl-4-[2-(2- methylsulphonylbenzyl)benzoyl]isoxazole-3-carboxylate;

69. 5-cyclopropyl-4-[2-(2-ethylsulphinylbenzyl)benzoyl] isoxazole; 70. 5-cyclopropyl-4-[2-(2-ethylsulphonylbenzyl)benzoyl] isoxazole;

71. ethyl 5-cyclopropyl-4-[4-fluoro-2-(2- methylsulphinylbenzyl)benzoyl]isoxazole-3-carboxylate;

72. ethyl 5-cyclopropyl-4-[4-fluoro-2-(2- methylsulphonylbenzyl)benzoyl]isoxazole-3-carboxylate;

73. 4-[2-benzyl-4-chloro-3-(methylsulphonyl)benzoyl]-5- cyclopropylisoxazole;

74. 5-cyclopropyl-4-(4-methylsulphonyl-2-(2- phenylethyl)benzoyl]isoxazole; 75. 5-cyclopropyl-4-[4-methylsulphinyl-2-(2- phenylethyl)benzoyl] isoxazole;

76. ethyl 5-cyclopropyl-4-[4-methylsulphonyl-2-(2- phenylethyl)benzoyl]isoxazole-3-carboxylate;

77. 5-cyclopropyl-4-{2-[2-(2- methylsulphonylphenyl)ethyl]benzoyl}isoxazole;

78. 5-cyclopropyl-4-{2-[2-(2- methylsulphinylphenyl)ethyl]benzoyl} isoxazole;

79. 5-cyclopropyl-4-[4-methylsulphonyl-2-(2-methylsulphonyl-2- phenylethyl)benzoyl]isoxazole; 80. 5-cyclopropyl-4-[4-methylsulphinyl-2-(2-methylsulphonyl-2- phenylethyl)benzoyI]isoxazole;

81. ethyl 5-cyclopropyl-4-[4-fluoro-2-(2- methylthiobenzyl)benzoyl]isoxazole-3-carboxylate;

82 ethyl 5-cyclopropyl-4-[2-(2-methylthιobenzyi)benzoyl] ιsoxazole-3 -carboxylate,

83 ethyl 5-cyclopropyl-4-[4-fluoro-2-(2-phenylethyl)benzoyl] ιsoxazole-3 -carboxylate, 84 5-[2-benzyl-3-methyl-4-(methylthιo)ρhenyl]-4- cyclopropylcarbonyhsoxazole,

85 1 -(2-benzylphenyl)-2-cyano-3-cyclopropylpropan- 1 ,3-dιone,

86 1 -[2-benzyl-4-(ethylthio)phenyl]-2-cyano-3- cyclopropylpropan- 1 , 3 -dione, 87 l-[2-benzyl-4-(methylthio)phenyl]-2-cyano-3- cyclopropylpropan- 1 ,3-dione,

88 5-cyclopropyl-4-[2-(4-fluoro-2- methylthiobenzyl)benzoyl]isoxazole,

89 5-cyclopropyl-4-[2-(4-fluoro-2- methylsulphιnylbenzyl)benzoyl]ιsoxazole,

90 5-cyclopropyl-4-[2-(4-fluoro-2- methylsulphonylbenzyl)benzoyl]isoxazole,

91 4-[2-(2-chloro-6-methylthiobenzyl)benzoyl]-5- cyclopropylisoxazole, 92 4-[2-(6-chloro-2-methylsulphinylbenzyl)benzoyl]-5- cyclopropylisoxazole;

93 4-[2-(6-chloro-2-methylsulphonylbenzyl)benzoyl]-5- cyclopropylisoxazole,

94 4-[2-(5-chloro-2-methylthiobenzyl)benzoyl]-5- cyclopropylisoxazole,

95 4-[2-(5-chloro-2-methylsulphinylbenzyl)benzoyl]-5- cyclopropylisoxazole;

96 4-[2-(5-chloro-2-methylsulphonylbenzyl)benzoyl]-5- cyclopropylisoxazole; 97 4-[2-(4-chloro-2-methylthiobenzyl)benzoyl]-5- cyclopropylisoxazole;

98 4-[2-(4-chloro-2-methylsulphιnylbenzyl)benzoyl]-5- cyclopropylisoxazole,

99 4-[2-(4-chloro-2-methylsulphonylbenzyl)benzoyl]-5- cyclopropyhsoxazole,

103 4-[2-(3 ,4-dichloro-2-methylthiobenzyl)benzoyl]-5- cyclopropylisoxazole,

106 5-cyciopropyl-4-[2-(2-methylthio-4- trifluoromethylbenzyl)benzoyl]isoxazole;

107 5-cyclopropyl-4-[2-(2-methylsulphinyl-4- trifluoromethyIbenzyl)benzoyl]isoxazole; 108 5-cyclopropyl-4-[2-(2-methylsulphonyl-4- trifluoromethylbenzyl)benzoyl]isoxazoie;

117 5-cyclopropyl-4-[2-(2, 6-difiuorobenzyl)benzoyl]isoxazole; 120 5-cyclopropyl*4-[2-(2-methyl-4- methylthiobenzyl)benzoyl]isoxazole; 121 5-cyclopropyl*4-[2-(2-methyl-4- methylsulphinylbenzyl)benzoyl3isoxazole;

122 5-cyclopropyl-4-[2-(2-methyl-4- methylsulphonylbenzyl)benzoyl]isoxazole;

136 4-[4-bromo-2-(2-methylthiobenzyi)benzoyl]-5- cyclopropylisoxazole;

141 4-[4-bromo-2-(2-methylsulphinylbenzyl)benzoyl]-5- cyclopropylisoxazole;

146 4-[4-bromo-2-(2-methylsulphonyIbenzyl)benzoyl]-5- cyclopropylisoxazole; 153 ethyl 5-cyclopropyl-4-[3,4-dichloro-2-(2- methylthiobenzyl)benzoyl]isoxazole-3-carboxylate;

165 5-cyclopropyl-4-{2-[2-(methoxymethyl)benzyl]-4- (methylt io)benzoyl} isoxazole;

166 5-cyclopropyl-4- { 2-[2-(methoxymethyl)benzyl]-4- (methylsulphonyl)benzoyl ) isoxazole;

167 5-cyclopropyl-4-{2-[2-(methoxymethyl)benzyl]-4- (methylsulphinyl)benzoyl}isoxazole;

168 5-cyclopropyl-4-{4-fluoro-2-[2- (methyltlιiomethyl)benzyl]benzoyl} isoxazole; 170 5-cyclopropyl-4-{4-fluoro-2-[2-

(methyisulphonylmethyl)benzyI]benzoyl } isoxazole;

172 5-cyclopropyl-4-[2-(2-methylbenzyl)-4- methylthiobenzoyl]isoxazole;

173 5-cyclopropyl-4-[2-(2-methylbenzyl)-4- methylsulphinylbenzoyl]isoxazole;

174 5-cyclopropyl-4-[2-(2-methylbenzyl)-4- methylsulphonylbenzoyl]isoxazole;

212 5 -cyclopropyl-4- [2-(3 -fluoro-2- methylthiobenzyl)benzoyl]isoxazole;

213 5-cyclopropyl-4-[2-(2,4-bis- methylthiobenzyl)benzoyl]isoxazole; 214 5-cyclopropyl-4-[2-(2,4-bis- methylsulphonylbenzyl)benzoyl]isoxazole;

215 ethyl 5-cyclopropyl-4-[2-(2,4-bis(methylthio)benzyl}benzoyl] isoxazole-3 -carboxylate;

216 ethyl 5-cyclopropyl-4-[2-(2,4-bis- methylsulphonylbenzyl)benzoyl]isoxazole-3-carboxylate;

217 4-[2-benzyl-3-(methylthio)benzoyl]-5-cyclopropylisoxazole;

218 5 -cyclopropyl-4- { 2-[ 1 -methyl-2- (methylthio)benzyl]benzoyl}isoxazole;

219 5-cyclopropyl-4-{2-[2,2-(difluorobenzodioxol-4- yl)methyl]benzoyl } isoxazole;

220 5-cyclopropyl-4-[2-(2-methylthiobenzyl>4- trifluoromethylbenzoyl]isoxazole;

221 5-cyclopropyl-4-[2-(2- trifluoromethylbenzyl)benzoyl]isoxazole; 222 5-cyclopropyl 4-[2-(2-methylthio-4- trifluoromethoxybenzyι)benzoyl]isoxazole;

223 5-cyclopropyl-4-[2-(2,6-bis- methylthiobenzyl)benzoyl]isoxazole;

224 5-cyclopropyl-4-[2-(2-fluoro-6- methylthiobenzyl)benzoyl] isoxazole;

225 4-[2-(2-chloro-4-methylthiobenzyl)benzoyl]-5- cyclopropylisoxazole;

226 5-cyclopropyl-4-[2-(2-methylthio-3- trifluoromethylbenzyl)benzoyl]isoxazole; 227 5-cyclopropyl-4-[2-(2-methyl-3- methylthiobenzyl)benzoyl]isoxazole;

228 5-cyclopropyl-4-[2-(5-fluoro-2,3-bis- methylthiobenzyl)benzoyl]isoxazole;

229 5 -cyclopropyl-4-[4-methyl-2-(2- methylthiobenzyl)benzoyl]isoxazole;

230 5-cyclopropyl-4-[2-(2-methylthio-6- trifluoromethylbenzyl)benzoyl]isoxazole;

231 4-[2-(2-methylthiobenzyl)benzoyl]-5-( 1 - methylcyclopropyl)isoxazole ;

232 4-[5-bromo-2-(2-methylthiobenzyl)benzoyl]-5- cyclopropylisoxazole; 233 5-cyclopropyl-4-[4-methylthio-2-(2- trifluoromethylbenzyl)benzoyl]isoxazole;

234 5-cyclopropyl-4-[2-(2-methylbenzyl)benzoyl]isoxazole;

235 5-cyclopropyl-4-(2-benzyl-4- trifluoromethylbenzoyl)isoxazole; 236 5-cyclopropyl-4-[2-(3,5-dichloro-2- methylthiobenzyl)benzoyl]isoxazole;

237 5-cyclopropyl-4-[2-(2-methylbenzyl)-4- trifluoromethylbenzoyrjisoxazole;

238 5-t-butyl-4-[2-(2-methylthiobenzyl)benzoyl]isoxazole; 239 5-cyclopropyl-4-{3-(2-methylthiobenzyl)benzoyl]isoxazole;

240 5-cyclopropyl-4-[2-(2-ethylbenzyl)benzoyl]isoxazole;

241 5 -cyclopropyl-4-[2-(2-methylbenzyl)-4- fluorobenzoyl]isoxazole;

242 4-[2-benzyl-3 -(methylsulphinyl)benzoyl]-5- cyclopropylisoxazole;

243 4-[2-benzyl-3 -(methylsulphonyl)benzoyl]-5- cyclopropylisoxazole;

244 5-cyciopropyl-4-{2-[l-methyl-2- (methylsulphinyl)benzyl]benzoyl } isoxazole; 245 5-cyclopropyl-4-(2-[l-methyl-2-

(methylsulphonyl)benzyl]benzoyl}isoxazole;

246 5-cyclopropyl-4-[2-(3-fluoro-2- methylsulphinylbenzyl)benzoyl]isoxazole;

247 5-cyclopropyl-4-[2-(3-fluoro-2- methylsulphonylbenzyl)benzoyl]isoxazole;

248 ethyl 5-cyclopropyl-4-[2-(3-fluoro-2- methylsulphinylbenzyl)benzoyl]isoxazole-3-carboxylate;

249 ethyl 5-cyclopropyl-4-[2-(3-fluoro-2- methylsulphonylbenzyl)benzoyl3isoxazole-3-carboxylate; 250 5-cyclopropyl-4-[2-(2-methylsulphinyl-4- trifluoromethoxybenzyl)benzoyl]isoxazole;

251 5-cyclopropyl-4-[2-(2-methylsulphonyl-4- trifluoromethoxybenzyl)benzoyl]isoxazole;

252 4-[2-(2-chloro-4-methylsulphinylbenzyl)benzoyl]-5- cyclopropylisoxazole;

253 4-[2-(2-chloro-4-methylsulphonylbenzyl)benzoyl]-5- cyclopropylisoxazole; 254 5-cyclopropyl-4-[2-(2-fluoro-6- methylsulphinylbenzyl)benzoyl]isoxazole;

255 5-cyclopropyl-4-[2-(2-fluoro-6- methylsulphonylbenzyl)benzoyl]isoxazole;

256 5-cyclopropyl-4-[2-(2-methyl-3- methylsulphinylbenzyl)benzoyl]isoxazole;

257 5-cyclopropyl-4-[2-(2-methyl-3- methylsulphonylbenzyl)benzoyl]isoxazole;

258 5-cyclopropyl-4-[4-methyl-2-(2- methylsulphinylbenzyl)benzoyl]isoxazole; 259 5-cyclopropyl-4-(4-methyl-2-(2- methylsulphonylbenzyl)benzoyl]isoxazole;

260 5-cyclopropyl-4-[2-(2- fluoromethylsulphinylbenzyl)benzoyl]isoxazole;

261 5-cyclopropyl-4-[2-(2- fluoromethylsulphonylbenzyl)benzoyl]isoxazole;

262 5-cyclopropyl-4-[2-(2-methylsulphinyl-6- trifluoromethylbenzyl)benzoyl]isoxazole;

263 5 -cyclopropyl-4-[2-(2-methylsulphonyl-6- trifluoromethylbenzyl)benzoyl]isoxazole; 264 ethyl 5-cyclopropyl-4-[2-(2- fluoromethylsulphinylbenzyl)benzoyl]isoxazole-3-carboxylate;

265 ethyl 5-cyclopropyl-4-[2-(2- fluoromethylsulphonylbenzyl)benzoyl]isoxazole-3-carboxylate;

266 methyl 5-cyclopropyl-4-[2-(2- methylsulphmylbenzyl)benzoyl]isoxazole-3-carboxylate;

267 methyl 5-cyclopropyl-4-[2-(2- methylsulphonylbenzyl)benzoyl]isoxazole-3-carboxylate;

268 iso-propyl 5-cyclopropyl-4-[2-(2- methylsulphinylbenzyl)benzoyl]isoxazole-3-carboxylate; 269 iso-propyl 5-cyclopropyl-4-[2-(2- methylsulphonylbenzyl)benzoyl]isoxazole-3-carboxylate; 270 4-[2-(2-methylsulphinylbenzyl)benzoyl]-5-( 1 - methylcyclopropyl)isoxazole;

271 4-[2-(2-raethylsulphonylbenzyl)benzoyl]-5-( 1 - methylcyclopropyl)isoxazole;

272 5-cyclopropyl-4-[4-methylsuiphinyl-2-(2- trifluoromethylbenzyl)benzoyl]isoxazole; 273 5-cyclopropyl-4-[4-methylsulphonyl-2-(2- trifluoromethylbenzyl)benzoyl]isoxazole;

274 ethyl 4-[2-(2-methylthiobenzyl)benzoyl]-5-(l- methylcyclopropyl)isoxazole-3-carboxylate;

275 ethyl 4-[2-(2-methylsulphinylbenzyl)benzoyl]-5-(l- methylcyclopropyl)isoxazole-3 -carboxylate;

276 ethyl 4-[2-(2-methylsulphonylbenzyl)benzoyl]-5-(l- methylcyclopropyl)isoxazole-3-carboxylate;

277 5-cyclopropyl-4-[2-(3 , 5-dichloro-2- methylsuipbinylbenzyl)benzoyl]isoxazole; 278 5-cyclopropyl-4-[2-(3,5-dichloro-2- methylsulphonylbenzyi)benzoyl]isoxazole;

279 5-cyclopropyl-4-[5-bromo-2-(2- methylsulphinylbenzyl)benzoyl]isoxazole;

280 5-cyclopropyl-4-[5-bromo-2-(2- methylsulphonylbenzyl)benzoyl]isoxazole;

281 5-cyclopropyl-4-[3-(2- methylsulphinylbenzyl)benzoyl]isoxazole;

282 5-cyclopropyl-4-[3-(2- methyisulphonylbenzyl)benzoyl]isoxazole; 283 ethyl 5-cyclopropyl-4-[2-(2- isopropylthiobenzyl)benzoyl]isoxazole-3-carboxylate;

284 ethyl 5-cyclopropyl-4-[2-(2-methvltbio-3- fluorobenzyl)benzoyl3isoxazole-3-carboxylate;

285 ethyl 5-cyclopropyl-4-[2-{2- trifluoromethylbenzyl)benzoyl]isoxazole-3-carboxylate;

286 ethyl 5-cyclopropyl-4-[2-(2-methylbenzyl)benzoyl3isoxazole- 3-carboxylate;

287 5-[2-(2-chloro-4-(methylthio)benzyl}phenyl3-4- cyclopropylcarbonyiisoxazole; 288 5-[2-{4-fluoro-2-(methyltbio)benzyl}phenyl3-4- cyciopropylcarbonylisoxazole,

289 5-[2-{ 2-methyl-3-(methylthio)benzyl)phenyl]-4- cyciopropyicarbonyiisoxazole;

290 ethyl 5-[2-(2-methylthiobenzyl)phenyl3-4- cyclopropylcarbonylisoxazole-3-carboxylate;

291 5-[2-benzyl-4-trifluoromethylphenyl]-4- cyclopropylcarbonylisoxazole; 292 l-[2-(2-methylthiobenzyl)phenyl]-2-cyano-3- cyclopropylpropan- 1 , 3 -dione;

293 1 -[2-(2-methylsulphinylbenzyl)phenyl]-2-cyano-3- cyclopropylpropan- 1 ,3-dione;

294 1 -[2-(2-methylsulphonylbenzyl)phenyl]-2-cyano-3- cyclopropylpropan-l,3-dione;

295 1 -[2-(2-methylbenzyl)phenyl]-2-cyano-3-cyclopropylpropan- 1,3 -dione;

296 1 -[4-fluoro-2-(2-methylbenzyl)phenyl3-2-cyano-3- cyclopropylpropan- 1 ,3-dione; 297 5-cyclopropyl-4-[2-(2- fluoromethylthiobenzyl)benzoyl3isoxazole;

298 ethyl 5-cyclopropyl-4-[2-(2- fluoromethylthiobenzyl)benzoyl3isoxazole-3-carboxylate;

299 4-[3 -fluoro-2-(2-methylthiobenzyl)benzoyl3-5-cyclopropyl isoxazole;

300 ethyl 5-cyclopropyl-4-[3-chloro-2-(2- methylthiobenzyl)benzoyl]isoxazole-3-carboxylate;

301 methyl 5-cyclopropyl-4-[2-(2- methylthiobenzyl)benzoyl] isoxazole-3 -carboxylate; 302 isopropyl 5 -cyclopropyl-4-[2-(2- methylthiobenzyl)benzoyl3isoxazole-3-carboxylate; and

303 4-cyclopropylcarbonyl-5-{2-[2,2-(difluorobenzodioxol-4- yl)methyl]phenyl}isoxazole.

The following compounds of formula (Ia) in which X is attached to the 2-position of the phenyl ring form part of the present invention.

In the Table that follows Me means methyl, Pr means propyl, cPr means cyclopropyl, Ph means phenyl, Et means ethyl. Where subscripts do not appear in the Table it is understood that in appropriate cases they are present (for example 'CF3' is understood to mean '-CF3'; 'SO2Me' means '-SO 2 CH 3 ' etc.).

Compounds of formula (I) may be prepared by the application or adaptation of known methods (i.e. methods heretofore used or described in the literature), for example as hereinafter described.

In the following description where symbols appearing in formulae are not specifically defined, it is to be understood that they are "as hereinbefore defined" in accordance with the first definition of each symbol in the specification.

It is to be understood that in the descriptions of the following processes the sequences may be performed in different orders, and that suitable protecting groups may be required to achieve the compounds sought.

It is understood that when a process of the invention leads to the formation of a mixture of (Ia) and (Ib), these compounds may be separated by known methods.

According to a feature of the present invention compounds of formula (Ia) or (Ib) in which R represents hydrogen and R 1 , R 2 , R 3 , X and n are as defined above may be prepared by the reaction of a compound of formula (II)

(II) wherein L is a leaving group and R 1 , R 2 , R 3 , n and X are as hereinbefore defined, with hydroxylamine or a salt of hydroxylamine. Hydroxylamine hydrochloride is generally preferred. Generally L is alkoxy, for example ethoxy, or N,N-dialkylamino, for example dimethylamino. The reaction is generally carried out in an organic solvent such as ethanol or acetonitrile or a mixture of a water-miscible

organic solvent and water, preferably in a ratio of organic solvent: water of from 1 :99 to 99: 1, optionally in the presence of a base or acid acceptor such as triethylamine or sodium acetate at a temperature from room temperature to the boiling point of the solvent. According to a further feature of the present invention compounds of formula (Ia) in which R represents hydrogen and R 1 , R 2 , R 3 , X and n are as defined above may be prepared by the reaction of a compound of formula (III):

(ni) wherein R 1 is as hereinbefore defined and Y' represents a carboxy group or a reactive derivative thereof (such as a carboxylic acid chloride or carboxylic ester), or a cyano group, with an appropriate organometallic reagent such as a Grignard reagent or an organolithium reagent. The reaction is generally carried out in an inert solvent such as ether or tetrahydrofuran at a temperature from 0°C to the reflux temperature of the mixture.

According to a further feature of the present invention compounds of formula (Ia) wherein R represents a group -CO 2 R^ and R 1 , R 2 , R 3 , X and n are as defined above, may be prepared by the reaction of a compound of formula (IV):

(IV) wherein R 1 , R 2 , R 3 , X and n are as hereinbefore defined and P 1 is a leaving group such as N,N-dialkylamino, with a compound of formula

R O 2 CC(Z 1 )=NOH wherein R 4 is as hereinbefore defined and Z 1 is a halogen atom. Generally Z 1 is chlorine or bromine. The reaction is generally performed in an inert solvent such as toluene or dichloromethane either in the presence of a base such as triethylamine or a catalyst such as a 4 Angstrom molecular sieve or fluoride ion.

According to a further feature of the present invention compounds of formula (Ia) in which R represents a group -CO 2 R 4 and R 1 , R 2 , R 3 ,

X and n are as defined above may be prepared by the reaction of a compound of formula (N):

(V) wherein R 1 , R 2 , R 3 , X and n are as hereinbefore defined, with a compound of formula R 4 O 2 CC(Z 1 )=ΝOH wherein Z and R 4 are as hereinbefore defined. The reaction is generally performed in an inert solvent such as toluene or dichloromethane optionally in the presence of a base such as triethylamine or a catalyst such as a 4 Angstrom molecular sieve or fluoride ion. The reaction is preferably carried out at a temperature between room temperature and the reflux temperature of the mixture.

According to a further feature of the present invention compounds of formula (Ia) or (Ib) wherein R represents -CO 2 R 4 and R 1 , R 2 , R 3 , X and n are as defined above, may be prepared by the reaction of a salt of compounds of formula (NI):

(Ni) wherein R 1 , R 2 , R 3 , X and n are as hereinbefore defined with a compound of formula R 4 O 2 CC(Z 1 )=ΝOH wherein R 4 and Z 1 are as hereinbefore defined. Preferred salts include sodium or magnesium salts. The reaction is generally performed in an inert solvent such as dichloromethane or acetonitrile at a temperature between room temperature and the reflux temperature of the mixture. The salt of a compound of formula (VI) is generally prepared in situ by treating the compound of formula (VI) with a base. Examples of suitable bases include alkaline earth metal alkoxides such as magnesium methoxide.

According to a feature of the present invention compounds of formula (Ib) in which R, R 1 , R 2 , R 3 ,X and n are as defined above, may be prepared by the metallation of a compound of formula (VE):

wherein A is a halogen atom, followed by reaction of the compound thus obtained with an acid chloride of formula R^OCl. Generally A is bromine or iodine and the reaction performed with for example n-butyllithium in an inert solvent such as ether or tetrahydrofuran at a temperature from -78°C to 0°C.

According to a further feature of the present invention compounds of formula (Ib) in which R, R 1 , R 2 , R 3 , X and n are as defined above may be prepared by the oxidation of a compound of formula (VIII):

to convert the hydroxy group to a ketone group. The reaction is generally performed using an appropriate oxidising agent, for example, a mixture prepared from chromium trioxide and aqueous sulphuric acid.

According to a further feature of the present invention compounds of formula (Ib) in which R represents hydrogen and R 1 , R 2 , R 3 , X and n are as defined above may be prepared by the reaction of a compound of formula (IX):

(IX) in which D represents a carboxy group, or a reactive derivative thereof (such as a carboxylic acid chloride or carboxylic ester), or a cyano group, with an appropriate organometallic reagent such as a Grignard reagent or an organolithium reagent. The reaction is generally

carried out in an inert solvent such as ether or tetrahydrofuran, at a temperature from 0°C to the reflux temperature of the solvent.

According to a further feature of the present invention compounds of formula (Ib) in which R represents a -CO R 4 group and R 1 , R 2 , R 3 , X and n are as defined above, may be prepared by the reaction of a compound of formula (X):

(X) wherein P 1 is as defined above, with a compound of general formula R 4 O CC(Z 1 )=NOH wherein Z and R 4 are as hereinbefore defined. Generally Z 1 is chlorine or bromine. The reaction is preferably performed in an inert solvent such as toluene or dichloromethane either in the presence of a base such as triethylamine or a catalyst such as a 4 Angstrom molecular sieve or fluoride ion.

According to a further feature of the present invention compounds of formula (Ib) in which R represents a group -CO 2 R 4 and R 1 , R 2 , R 3 ,

X and n are as defined above may be prepared by the reaction of a compound of formula (XI):

(XI) with a compound of formula R 4 O 2 CC(Z 1 )=NOH wherein Z 1 and R 4 are as hereinbefore defined. Generally Z 1 is chlorine or bromine. The reaction is preferably performed in an inert solvent such as toluene or dichloromethane, either in the presence of a base such as triethylamine, or a catalyst such as a 4 Angstrom molecular sieve or fluoride ion.

According to a further feature of the present invention compounds of formula (Ia) or (Ib) in which X represents -CR 13 R 14 -(CR 15a R 16a ) s - or -(CR 15 R 16 ),-CR 13 R 14 - and R, R 1 , R 2 , R 3 , R 13 , R 15 , R 15a , R 16 , R 1 ^ 3 , r, s and n are as defmed above, and R 4 represents halogen, may be prepared by the reaction of the corresponding compound of formula (Ia) or (Ib) in which X represents -CHR 13 -(CR 15a R 16a ) s - or

-(CR 15 R 16 ) r -CHR 13 - respectively with a halogenating agent. The reaction is generally performed using a halogenating agent such as N- bromosuccinimide or N-chlorosuccinimide in an inert solvent, preferably carbon tetrachloride and in the presence of a radical initiator e.g. benzoyi peroxide, with irradiation by light from a Tungsten lamp at a temperature from ambient to the reflux temperature.

According to a further feature of the present invention compounds of formula (Ia) or (Ib) in which R, R 1 , R 2 , R 3 , R 13 , R 15 , R 15 R 16 , R 1 ( > a , r, s and n are as defined above and R 14 represents cyano, may be prepared by the reaction of the corresponding compound of formula (Ia) or (Ib) in which R 14 represents halogen (preferably bromine or chlorine) with an alkali metal cyanide. The reaction is generally performed using sodium cyanide or potassium cyanide, in an inert solvent e.g. dimethylsulfoxide at a temperature from 10°C to 100°C. According to a further feature of the present invention compounds of formula (Ia) or (Ib) in which R, R 1 , R 2 , R 3 , R 12 , R 13 , R 15 , R 15a R 16 Rlόa ^ r5 s and n are as defined above, and R 14 represents -OR 12 , may be prepared by the reaction of the corresponding compound of formula (Ia) or (Ib) in which R 14 represents halogen (preferably bromine or chlorine) with a compound of formula R 1 OM where M represents hydrogen or an alkali metal (e.g. sodium, potassium or lithium). The reaction is generally performed in an inert solvent e.g. acetonitrile or N,N-dimethylformamide, optionally in the presence of a base e.g. sodium hydride, at a temperature from ambient to the reflux temperature. According to a further feature of the present invention compounds of formula (Ia) or (Ib) in which R, R 1 , R 2 , R 3 , R 12 R 13 , R 15 , R 15a R 1 ^, R^a rj s and n are as defined above, and R 14 represents -SR 12 may be prepared by the reaction of the corresponding compound of formula (Ia) or (Ib) in which R 1 represents halogen (preferably bromine or chlorine) by the same procedure as used for the compounds above wherein R 14 represents an OR 12 group, by replacing the compound R 12 OM by a compound R 12 SM.

According to a further feature of the present invention compounds of formula (Ia) or (Ib) in which X represents -CR 13 R 1 -(CR 15a R 16a ) s -, and R, R 1 , R 2 , R 3 , R 12 , R 13 , R 15a , R 16a , n and p are as defined above, s represents one or two, and R 1 represents cyano, -OR 12 or -S(O) R 12 , may be prepared by the reaction of the corresponding compound (Ia) or (Ib) in which XR3 is replaced by a group -CHR 3 R 14 ,

with a compound of formula Z 1 -(CR 15a R 16a ) s -R 3 in which s represents one or two and Z represents halogen as defined above. The reaction is generally performed in the presence of a base, e.g. sodium hydride, in an inert solvent e.g. N,N-dimethylformamide, at a temperature from 0°C to 100°C.

According to a further feature of the present invention compounds of formula (Ia) or (Ib) in which R, R 1 , R 2 , R 3 , R 12 , R 13 , R 15 , R 1 a R 1 , n and p are as defined above, X represents -(CR 15 R 16 ) r -CR 13 R 14 -, and R 14 represents R 5 , cyano, -OR 12 or -S(O)pR 12 , and r represents one or two, may be prepared by the reaction of the corresponding compound (Ia) or (Ib) in which -XR 3 is replaced by a group -(CR^R^ j -Z 1 in which Z 1 is halogen as defined above, with a compound of formula HCR 1 R 4 R 3 .

The reaction is generally performed using a base, e.g. sodium hydride, in an inert solvent e.g. N,N-dimethylformamide, at a temperature from 0°C to 100°C.

According to a feature of the present invention compounds of formula (Ic) may be prepared from the corresponding compound of formula (Ia) or (Ib) in which R is as defined above, or in which R is replaced by an amide or nitrile. Where R represents a hydrogen atom the reaction is preferably carried out by treatment with a base. Examples of suitable bases include alkali or alkaline earth metal hydroxides, alkoxides such as sodium ethoxide or organic bases such as triethylamine. Where R represents -CO 2 R 4 , or where R is replaced by amide or nitrile, the conversion is generally carried out by a hydrolytic reaction. The hydrolytic reaction may be performed in the presence of an acid or base. Acidic hydrolysis may be achieved for example using aqueous hydrochloric acid. Basic hydrolysis may be achieved for example using sodium hydroxide in a mixture of alcohol and water. The reactions are preferably carried out at a temperature between room temperature and the reflux temperature of the mixture. Compounds of formula (Ia) or (Ib) in which R is replaced by amide or nitrile are novel and thus constitute a further feature of the invention.

According to a further feature of the present invention, compounds of formula (Ic) in which R 1 , R 2 , R 3 , X and n are as defined above may also be prepared by the reaction of a benzoyi chloride of formula (XTJ):

(XII) wherein R 2 , R 3 , X and n are as hereinbefore defined, with a beta-ketonitrile of formula (XIII):

(Xffl) wherein R 1 is as hereinbefore defined. The reaction is generally performed in the presence of a base, in a solvent or solvent mixture. Suitable bases include metal hydrides, hydroxides or alkoxides (e.g. sodium or lithium hydride, sodium hydroxide, potassium hydroxide, magnesium ethoxide or magnesium methoxide). Suitable solvents include for example tetrahydrofuran; hydrocarbons such as toluene; or halogenated hydrocarbons such as dichloromethane. The reaction is generally performed at a temperature from 0°C to the reflux temperature. A number of compounds of formula (XII) are novel and thus form a further feature of the invention.

According to a further feature of the present invention, compounds of formula (Ic) in which R 1 , R 2 , R 3 , X and n are as defined above may also be prepared by the reaction of an acid chloride of formula R^OCl wherein R 1 is as hereinbefore defined, with a beta-ketonitrile of formula

(xrv) wherein R 2 , R 3 , X and n are as hereinbefore defined. The reaction is generally performed under the same conditions as described above for the reaction of compounds of formula (XTI) with compounds of formula

(xm).

According to a further feature of the present invention compounds of formula (Ic) in which R 1 , R 2 , R 3 , X and n are as defined above may also be prepared by the reaction of a benzoyi chloride of formula (XH) above wherein R 2 , R 3 , X and n are as hereinbefore defined, with a beta- ketonitrile of formula (Xϋl) wherein R 1 is as hereinbefore defined, via an intermediate of formula (XN):

(XN) wherein R 1 , R 2 , R 3 , X and n are as hereinbefore defined. The formation of the intermediate of formula (XN) may be carried out in the presence of a mild base such as an organic base e.g. triethylamine, in an inert solvent such as acetonitrile or dichloromethane at a temperature between room temperature and the reflux temperature of the mixture. The rearrangement of the intermediate of formula (XV) to a compound of formula (Ic) is generally carried out in situ in an inert solvent such as acetonitrile or dichloromethane in the presence of a catalyst such as a source of cyanide. Examples of such sources of cyanide are acetone cyanohydrin or an alkali metal cyanide such as potassium cyanide, optionally in the presence of a crown ether such as 18-crown-6.

According to a further feature of the present invention compounds of formula (Ic) in which R 1 , R 2 , R 3 , X and n are as defined above, may be prepared by the reaction of an acid chloride of formula R^OCl wherein R 1 is as hereinbefore defined, with a beta-ketonitrile of formula

(XTV) wherein R 2 , R 3 , X and n are as hereinbefore defined via an intermediate of formula (XVI):

wherein R 1 , R 2 , R 3 , X and n are as hereinbefore defined. The formation and rearrangement of the intermediate of formula (XVI) is

generally carried out under the same conditions as described above for the formation and rearrangement of compounds of formula (XV).

Intermediates in the preparation of compounds of formula (Ia), (lb) and (Ic) may be prepared by the application or adaptation of known methods.

Intermediates of formula (Ia) or (Ib) in which R is replaced by an amide or nitrile may be prepared by the reaction of a salt of a compound of formula (VI) with a compound of formula P 2 C(Z 1 )=NOH in which P 2 is amide or nitrile. The reaction is performed using the same conditions as described for the preparation of compounds of formula (Ia) or (Ib) in which R is -CO 2 R 4 from compounds of formula (VI).

Compounds of formula (II) may be prepared by the reaction of compounds of formula (VI) with either a trialkyl orthoformate such as triethyl orthoformate or a dimethylformamide dialkyi acetal such as dimethylformamide dimethyl acetal.

The reaction with a trialkyl orthoformate can be carried out in the presence of acetic anhydride at the reflux temperature of the mixture and the reaction with dialkylformamide dialkyi acetal is carried out optionally in the presence of an inert solvent at a temperature from room temperature to the reflux temperature of the mixture.

Compounds of formula (IV) may be prepared by the reaction of a compound of formula (XVϋ) with a benzoyi chloride of formula (XH):

R 1 C(P 1 H:H2 (XVΠ) wherein R 1 and P 1 are as defined above.

The reaction is generally carried out in the presence of an organic base such as triethylamine in an inert solvent such as toluene or dichloromethane at a temperature between -20°C and room temperature. Compounds of formula (V) may be prepared by the metallation of the appropriate acetylene of formula (XVOT):

R Ϊ CsCH (XVBT) followed by reaction of the metal salt thus obtained with a benzoyi chloride of formula (XII). The metallation is generally performed using n-butyl lithium in an inert solvent such as ether or tetrahydrofuran at a temperature from -78°C to 0°C. The subsequent reaction with the benzoyi chloride is carried out in the same solvent at a temperature between -78°C and room temperature.

Compounds of formula (VI) may be prepared by the reaction of an acid chloride of formula (XII) with the metal salt of a compound of formula (XTX):

O O

R 1 ' v OtBu

(XTX) wherein R is as hereinbefore defined, to give a compound of formula (XX):

(XX) wherein R 1 , R 2 R 3 , X and n are as hereinbefore defined, which is subsequently decarboxylated to give a compound of formula (VI). Generally the reaction to produce the compound of formula (XX) is performed in a solvent such as a lower alcohol, preferably methanol, in the presence of a metal, preferably magnesium. The reaction may also be performed using a pre-prepared metal salt of a compound of formula

(XIX). The decarboxylation is generally performed by refluxing the compound of formula (XX) in the presence of a catalyst, such as para-toluenesulphonic acid or trifiuoroacetic acid, in an inert solvent e.g. toluene or 1,2-dichloroethane. Compounds of formula (VI) may also be prepared by the reaction of a benzoic acid ester of formula (XXI):

(XXI)

wherein R 2 , R 3 , X and n are as hereinbefore defined and R 2 ^ represents a lower alkyl group (generally of one to six carbon atoms), with a compound of formula (XXII):

R!-C(O)-CH 3 (XXΠ) wherein R 1 is as hereinbefore defined. The reaction is generally performed in a solvent such as ether, tetrahydrofuran or N,N-

SUBSTTTUTE SHEET (RULE 26)

dimethylformamide, in the presence of a base, preferably an alkali metal base such as sodium hydride, at a temperature from 0°C to the reflux temperature.

Intermediates of formula (Ia) or (Ib) wherein XR 3 is replaced by a group -CHR 13 R 14 , or -(CR^R 16 )*-^ 1 , and r represents one or two may be prepared by any of the processes described above for the preparation of a compound of formula (Ia) or (Ib) from the corresponding compound of formula (II), (III), (IV), (V), (VI), (VH),

(vπi), (rx), (X) or (xi). Intermediates of formula (Ia) or (Ib) wherein XR 3 is replaced by a group -(CR^R 16 )^ 1 and R, R 1 , R 2 , R 15 , R 16 , Z 1 and n are defmed above, may be prepared by the reaction of the corresponding compound of formula (Ia) or (Ib) wherein XR 3 is replaced by a group - (CR 15 R^)-H, with a halogenating agent e.g. N-bromosuccimmide or N-chlorosuccinimide, in an inert solvent preferably carbon tetrachloride and in the presence of a radical initiator e.g. benzoyi peroxide, with irradiation by light from a Tungsten lamp at a temperature from ambient to the reflux temperature.

Acid chlorides of formula (XH) may be prepared by the reaction of a benzoic acid of formula (XXDI):

(xxm) with a chlorinating agent, for example thionyl chloride at the reflux temperature of the mixture. In some cases the benzoyi chlorides may also be prepared by reaction of the benzoic acid with oxalyl chloride in a solvent such as 1,2-dichloroethane at from ambient to reflux temperature.

A number of the benzoic acids of formula (XXHI) and esters of formula (XXI) are novel and as such constitute further features of the present invention.

Esters of formula (XXI) may be prepared from acids of formula (XXDT) by known methods.

Compounds of formula (VOT) may be prepared by metallation of compounds of formula (VII) wherein A represents bromine or iodine with for example n-butyllithium in an inert solvent such as ether or

tetrahydrofuran at a temperature from -78°C to 0°C, followed by reaction with an aldehyde of formula R CHO.

Compounds of formula (IX) wherein D is -CO 2 -alkyl or -CN may be prepared by the reaction of compounds of formula (XXTV):

(XXIV) wherein D' represents -CO 2 -alkyl or -CN and L is as hereinbefore defined, with a salt of hydroxylamine such as hydroxylamine hydrochloride, in a solvent such as ethanol or acetonitrile, optionally in the presence of a base or acid acceptor such as triethylamine or sodium acetate.

Compounds of formula (IX) in which D represents a carboxylic acid or carboxylic acid chloride may be prepared from the corresponding compound of formula (IX) in which D represents a carboxylic ester group by the hydrolysis of said ester group and conversion, as necessary, of the acid thus obtained to the acid chloride, e.g. by heating with thionyl chloride.

Compounds of formula (XXTV) may be prepared by the reaction of a beta-ketonitrile of formula (XIV) above or a ketoester of formula (XXV):

(XXV) with either triethyl orthoformate in the presence of acetic anhydride at the reflux temperature of the mixture or with dimethylformamide dimethylacetal optionally in an inert solvent such as toluene at a temperature from room temperature to the reflux temperature of the mixture.

Compounds of formula (X) may be prepared by the reaction of a compound of formula (XXVI):

(XXVI) wherein P 1 is as hereinbefore defined, with an acid chloride of formula R^OCl in an inert solvent such as dichloromethane or toluene, in the presence of a base such as triethylamine.

Compounds of formula (XI) may be prepared by the metallation of the appropriate phenylacetylene of formula (XXVTI):

(xxvπ) wherein Q represents hydrogen or a bromine or iodine atom, using for example n-butyllithium in an inert solvent such as ether or tetrahydrofuran at a temperature from -78°C to 0°C, followed by treatment with an acid chloride of formula R1COC1.

Compounds of formula (VII) may be prepared by the halogenation of compounds of formula (XXViπ):

(xxvm) for example by heating with bromine or iodine in the presence of concentrated nitric acid.

Compounds of formula (XXVUI) may be prepared by the reaction of compounds of formula (XXIX):

(XXIX) with a salt of hydroxylamine such as hydrochloride, in a solvent such as ethanol or acetonitrile, optionally in the presence of a base or acid acceptor such as triethylamine or sodium acetate.

Beta-ketonitriles of formula (XIII) may be prepared from acid chlorides of formula R-COC1 by a number of methods well known in the chemical literature. For example, see Krauss, et al, Synthesis, 1983, 308, or Muth, et al, J. Org. Chem, 1960, 25, 736. Alternatively beta- ketonitriles of formula (XIII) may be prepared by the reaction of an ester of formula R 1 -CO 2 Et, wherein R 1 is as hereinbefore defined, with acetonitrile. This reaction is described in the literature, for example see the article by Abramovitch and Hauser, J.Am. Chem. Soc, 1942, 64, 2720. Beta-ketonitriles of formula (XIV) may be prepared from benzoyi chlorides of formula (XII) or from conesponding ethyl benzoates in a manner analogous to the preparation of beta-ketonitriles of formula (XIII) set forth above.

Benzoic acids of formula (XXIII) in which R 2 , R 3 , X and n are as defined above, and XR 3 is at the 2- position, may be prepared by the reaction of the conesponding compound of formula (XXIII) in which the carboxylic acid is protected preferably as the oxazoline and R 3 is replaced by a fluorine atom, with an organometallic reagent R 3 X-M where M represents a metallic group, preferably magnesium bromide, followed by deprotection by known methods.

Those skilled in the art will appreciate that some compounds of formula (I) may be prepared by the interconversion of other compounds of formula (I) and such interconversions constitute yet more features of the present invention. According to a further feature of the present invention compounds in which p or q is one or two may be prepared by the oxidation of the sulphur atom of the conesponding compounds in which p or q is 0 or 1. The oxidation of the sulphur atom is generally carried out using for example 3-chloroperoxybenzoic acid in an inert solvent such as dichloromethane at a temperature from -40°C to room temperature.

According to a further feature of the present invention compounds of formula (Ia) or (Ib) in which R 1 , R 2 , R 3 , X and n are as defined above and R represents -CO 2 R 4a in which R 4a represents a straight- or branched- chain alkyl group containing up to six carbon atoms optionally substituted by one or more groups selected from halogen, -OR 5 ,

"CO 2 R 5 , -S(O) p R 7 , phenyl or cyano may be prepared from another compound of formula (Ia) or (Ib) in which R represents -CO 2 R 4 , by reaction with an alcohol of formula (XXX):

R 4a OH (XXX)

The reaction is generally performed in the presence of an excess of the alcohol (XXX) and a catalytic amount of a base such as R a ONa optionally in the presence of another solvent such as toluene and optionally with distillation to facilitate removal of the undesired alohol component R 4 OH, and at a temperature from 0°C to the reflux temperature.

According to a further feature of the present invention compounds of formula (Ia) or (Ib) in which R, R 1 , R 2 , R 3 and n are as defined above and X represents -CHR 13 - in which R 13 is defined above may be prepared by the reaction of the conesponding compound of formula (Ia) or (Ib) in which -XR 3 is replaced by -CHR 13 -hal in which hal represents bromine or iodine, with a compound of formula (XXXI): R 3 B(OH) 2 (XXXI) The reaction is generally performed in a solvent such as toluene or dimethoxyethane in the presence of a palladium catalyst such as tetrakis triphenylphosphine palladium(0) and a base for example aqueous sodium carbonate at a temperature of from 50 tol20°C.

Compounds of formulae (II), (IV), (V), (VI), (VII), (VTII), (IX), (X), (XI), (XIV), (XX), (XXTV) and (XXV), (XXVUI), (XXIX),

(XXVI) and (XXVTI) are novel and as such constitute further features of the present invention.

Intermediates of formula (IH), (XVII), (XVffl), (XTX), (XXII), (XXV), (XXVI), (XXVII), (XXIX), (XXX) and (XXXI), Z 1 -(CR 15a R! 6 ) s -R 3 and HCR 13 R 14 R 3 are known or may be prepared by the application or adaptation of known methods.

The following non-limiting Examples illustrate the preparation of compounds of formula (I) and the Reference Examples illustrate the preparation of intermediates in their synthesis. NMR Spectra are proton

NMR spectra recorded as δ (ppm) in deuterochloroform as solvent.

Example 1

Hydroxylamine hydrochloride (2.44 g) was added to a stined solution of 1 -[2-benzyl-4-(ethylthio)phenyl]-3-cyclopropyl-2- dimethylaminopropan-l,3-dione (11.5 g) in ethanol. The mixture was stirred for 2 hours, water added and the mixture extracted with dichloromethane. The extract was washed (water), dried (magnesium

sulphate) and evaporated to give a gum. This was purified by chromatography eluting with hexane/ethyl acetate (9: 1) to give 4-[2- benzyl-4-(ethylthio)benzoyl]-5-cyclopropylisoxazole as a yellow gum (Compound 1, 7.8 g), NMR l . l(m,2H), 1.2(m,2H), 1.3(q,3H), 2.5(m, lH), 3.0(q,2H), 4.1(s,2H), 7.2(m,8H), 8.1(s, lH).

By proceeding in a similar manner the following compounds were prepared:

4-[2-benzyl-4-(methylthio)benzoyl)-5-cyclopropylisoxazole (Compound 2), NMR l . l(m,2H), 1.2(m,2H), 2.5(m,4H), 4.1(s,2H), 7.2(m,8H), 8.1(s, lH);

4-(2-benzylbenzoyl)-5-cyclopropylisoxazole (Compound 3), NMR l . l-1.3(m,4H), 2.45(m, lH), 4.12(s,2H), 7.04-7.47(m,9H), 8.1(s, lH);

4-[2-(4-chlorobenzyl)-4-fluoro-3-methylbenzoyl3-5- cyclopropylisoxazole (Compound 4), NMR 1.12-1.33(m,4H), 2.16(d,3H), 2.54(m, lH), 4.11(s,2H), 6.92-7.2 l(m,6H), 8.11(s, lH);

5 -cyclopropyl-4-[4-fluoro-2-(4-fluorobenzyl)-3 - methylbenzoyl3isoxazole (Compound 5), NMR 1.13-1.32(m,4H), 2.18(d,3H), 2.55(m, lH), 4.12(s,2H), 6.85-7.18(m,6H), 8.11(s, lH); 5 -cyclopropyl-4-[2-(4-fluorobenzyl)-3 -methyl-4- (methylthio)benzoyl]isoxazole (Compound 6), NMR 1.14-1.32(m,4H),

2.21(s,3H), 2.5(s,3H), 2.59(m, lH), 4.14(s,2H), 6.83-7.2(m,6H), 8.15(s,lH);

5-cyclopropyl-4-[4-fluoro-2-(l-methylbenzyl)benzoyl]isoxa zole (Compound 7), NMR l. l l-1.28(m,4H), 1.63(d,3H), 2.39(m,lH), 4.63(q, lH), 6.91-7.3(m,8H), 8.05(s, lH);

5-cyclopropyl-4-[2-( 1 -methylbenzyl)-4-(methylthio)benzoyl3 isoxazole (Compound 8), NMR l. l-1.38(m,4H), 1.61(d,3H), 2.43(m,lH), 2.48(s,3H), 4.65(q, lH), 7.05-7.26(m,8H), 8.05(s,lH); 5-cyclopropyl-4-[2-( 1 -methylthiobenzyl)benzoyrjisoxazole (Compound 9), NMR l.l-1.35(m,4H), 2.04(s,3H), 2.4-2.48(m,lH),

5.62(s, lH), 7.15-7.72(m,9H), 8.14(s,lH);

5-cyclopropyl-4-[2-(2-methylthiobenzyl)benzoyl]isoxazole (Compound 10), NMR 1.15-1.43(m,4H), 2.37(s,3H), 2.52-2.6(m, lH), 4.22(s,2H), 7.0-7.42(m,8H), 8.2(s,lH); 5-cyclopropyl-4-[2-(3-methylthiobenzyl)benzoyl3isoxazole

(Compound 11), NMR l . l l-1.32(m,4H), 2.39(s,3H), 2.38-2.49(m,lH), 4.12(s,2H), 6.82-7.49(m,8H), 8.1(s,lH);

SUBSTTTUTE SHEET (RULE 26)

5-cyclopropyl-4-[2-(4-methylthiobenzyl)benzoyl3isoxazole (Compound 12), NMR 1.13-1.29(m,4H), 2.41(s,3H), 2.4-2.5(m, lH), 4.09(s,2H), 7.0 and 7 l(dd,4H), 7.26-7.45(m,4H), 8.12(s,lH); 4-[4-chloro-2-(2-methylthiobenzyl)benzoyl3-5- cyclopropylisoxazole (Compound 13), NMR 1.19-1.35(m,4H),

2.38(s,3H), 2.54-2.6(m, lH), 4.2(s,2H), 7.05-7.35(m,7H), 8.2(s,lH);

4-[5-chloro-2-(2-methylthiobenzyl)benzoyl3-5- cyclopropylisoxazole (Compound 14), NMR 1.15-1.29(m,4H), 2.29(s,3H), 2.43-2.54(m, lH), 4.09(s,2H), 6.95-7.28(m,7H), 8.13(s,lH); 5-cyclopropyl-4-[2-(2-ethylthiobenzyl)benzoyl]isoxazole

(Compound 15), NMR 1.15-1.32(m,4H), 1.22(t,3H), 2.6(m,lH), 2.83(q,2H), 4.26(s,2H), 7.07-7.38(m,8H), 8.22(s,lH);

5-cyclopropyl-4-[2-(2-isopropylthiobenzyl)benzoyl3isoxazo le (Compound 16), NMR 1.15-1.33(m,4H), 1.19(d,6H), 2.6(m,lH), 3.28(1H), 4.31(s,2H), 7.1-7.4(m,8H), 8.23(s, lH);

5-cyclopropyl-4-[4-fluoro-2-(2-methylthiobenzyl)benzoyl3 isoxazole (Compound 17), m.p. 64.5-66°C;

5-cyclopropyl-4-[4-fluoro-2-(2-phenylethyl)benzoyl]isoxaz ole (Compound 18), m.p. 110-111°C; 5-cyclopropyl-4-[2-(2-phenylethyl)-4-(methylthio)benzoyl] isoxazole (Compound 19), m.p. 121-122°C;

5 -cyclopropyl-4- { 2-[2-(2-methylthiophenyl)ethyl]benzoyl } isoxazole (Compound 20), m.p. 107-109°C;

4-[4-bromo-2-(2-methylsulphonyI-2-phenylethyl)benzoyl]-5- cyclopropylisoxazole (Compound 21) m.p. 174.5-175.5°C;

5-cyclopropyl-4-[2-(2-methylsulphonyl-2-phenylethyl)-4- (methylthio)benzoyl]isoxazole (Compound 22), m.p. 132.5-134°C;

4- [2-(4-chlorobenzyl)-3 -methyl-4-(methylthio)benzoyl]-5 - cyclopropylisoxazole (Compound 23), NMR 1.15-1.32(m,4H), 2.21(s,3H), 2.52(s,3H), 2.59(m,lH), 4.15(s,2H), 6.94-7.3 l(m,6H),

8.17(s,lH);

4-[2-benzyl-3-(methylthio)benzoyl]-5-cyclopropylisoxazole (Compound 217), NMR 1.11-1.18 (m, 2H), 1.22-1.30 (m, 2H), 2.40- 2.52 (m, IH), 2.49 (s, 3H), 4.30 (s, 2H), 7.03-7.41 (m, 8H), 8.03 (s, IH);

5-cyclopropyl-4-( 2-[ 1 -methyl-2- (methylthio)benzy!3benzoyl} isoxazole (Compound 218),

NMR 1.15-1.31 (m, 4H), 1.71 (d, 3H), 2.30 (s, 3H), 2.68 (m, IH), 4.10 (q, IH), 7.06-7.42 (m, 8H), 8.09 (s, IH);

5 -cyclopropyl-4- { 4-fluoro-2-[2- (methylthiomethyl)benzyl]benzoyl} isoxazole (Compound 168), NMR 1.17 - 1.38 (4H, m), 1.99 (3H, s), 2.52 - 2.63 (IH, m), 3.60 (2H, s), 4.29

(2H, s), 6.87 (IH, dd), 6.97 - 7.06 (2H, m), 7.11 - 7.22 (3H, m), 7.42 (lH, dd), 8.18 (lH, s);

5-cyclopropyl-4-{2-[2,2-(difluorobenzodioxol-4- yl)methyl]benzoyl} isoxazole (Compound 219), NMR 1.13 - 1.36 ( , 4H), 2.48 - 2.58 (IH, m), 4.20 (2H, s), 6.78 - 6.93 (3H, m), 7.31 - 7.50

(4H, m), 8.15 (lH, s);

5-cyclopropyl-4-{2-[2-(methoxymethyl)benzyl]-4- (methylthio)benzoyl) isoxazole (Compound 165), NMR 1.12 - 1.23 (4H, m), 2.44 (3H, s), 2.50 - 2.62 (IH, m), 3.32 (3H, s), 4.21 (2H, s), 4.39 (2H, s), 6.94 - 7.00 (IH, m), 7.01 (IH, d), 7.11 - 7.20 (3H, m), 7.27 -

7.33 (IH, m), 7.36 (IH, d), 8.17 (IH, s);

5-cyclopropyl-4-[2-(2-methylthiobenzyl)-4- trifluoromethylbenzoyl]isoxazole (Compound 220), NMR, 1.2-1.35(4H) 2.36(s,3H) 2.6(m, IH) 4.26(s,2H) 7.0-7.6(7H) 8.12(s, IH); 5-cyclopropyl-4-[2-(2,4-bis-methylthiobenzyl)benzoyl]isoxazo le

(Compound 213), NMR, l. l-1.45(m,4H) 2.38(s,3H) 2.46(s,3H) 2.59(m, lH) 4.17(s,2H) 6.95-7.40(m,7H) 8.20(s,lH);

5-cyclopropyl-4-[2-(2-methylthio-4- trifluoromethylbenzyl)benzoyl]isoxazole (Compound 106), NMR 1.1- 1.4(4H) 2.44(s,3H) 2.60(m, IH) 4.24(s,2H) 7.08-7.20(2H) 7.28-

7.48(5H) 8.20(s,lH);

4-[2-(2-chloro-6-methylthiobenzyl) benzoyi]- 5-cyclopropyl isoxazole (Compound 91), NMR 1.23(m,2H) 1.36(m,2H) 2.37(s,3H) 2.67(m, lH) 4.45(s,2H) 6.90(d,lH) 7.10-7.60(6H) 8.31(s,lH); 4-[2-(5-chloro-2-methylthiobenzyl) benzoyl]-5-cyclopropyl isoxazole (Compound 94), NMR 1.2(m,2H) 1.32(m,2H) 2.37(s,3H) 2.59(m, lH) 4.21(s,2H) 7.01(1H) 7.08(1H) 7.13-7.25(2H) 7.30-7.48(3H) 8.21(s,lH);

4-[2-(4-chloro-2-methylthiobenzyl) benzoyi]- 5-cyclopropyl isoxazole (Compound 97), NMR 1.17-1.34(4H) 2.39(s,3H) 2.59(m, lH)

4.16(s,2H) 6.93-7.42(7H) 8.20(s,lH);

5-cyclopropyl 4-[2-(3-fluoro-2-methylthiobenzyl) benzoyi ]isoxazole (Compound 212), NMR 1.19-1.34(4H) 2.28(s,3H) 2.6(m,lH) 4.4(s,2H) 6.9-7.42(7H) 8.21(s,lH);

5-cyclopropyl-4-[2-(2-methyl-4-methylthiobenzyl)benzoyl] isoxazole (Compound 120), NMR 1.15-1.35(4H) 2.14(s,3H) 2.43(s,3H)

2.57(m, lH) 4.08(s,2H) 6.88(d, lH) 6.92-7.53(6H) 8.13(s,lH);

4-[4-bromo-2-(2-methylthiobenzyl)benzoyl]- 5-cyclopropyl isoxazole (Compound 136), NMR 1.20(m,2H) 2.32(m,2H) 2.37(s,3H) 2.58(m,lH) 4.19(s,2H) 7.00-7.50(7H) 8.18(s,lH); 5-cyclopropyl-4-[2-(2-trifluoromethylbenzyl)benzoyl ]isoxazole

(Compound 221), NMR 1.2-1.35(4H) 2.61(m,lH) 4.34(s,2H) 7.08- 7.65(8H) 8.22(s, lH);

5-cyclopropyl 4-[2-(2-methylthio-4- trifluoromethoxybenzyl)benzoyl]isoxazole (Compound 222), NMR 1.18(m,2H) 1.30(m,2H) 2.39(s,3H) 2.59(m,lH) 4.17(s,2H) 6.88(d,lH)

6.97(d,lH) 7.00(d,lH) 7.19(d,lH) 7.28-7.46(3H) 8.20(s,lH);

5-cyclopropyl-4-[2-(2,6-bis-methylthiobenzyl)benzoyl]isox azole (Compound 223), NMR 1.2-1.4(4H) 2.38(s,6H) 2.68(m,lH) 4.46(s,2H) 6.98-7.4(7H) 8.33(s,lH); 5-cyclopropyl-4-[2-(2-fluoro-6- methylthiobenzyl)benzoyl]isoxazole (Compound 224), NMR 1.2-1.4(4H) 2.35(s,3H) 2.7(m,lH) 4.31(s,2H) 6.7-7.4(7H) 8.29(s,lH);

5-cyclopropyl-4-[2-(2,6-difluorobenzyl)benzoyl]isoxazole (Compound 117), NMR 1.13-1.35(4H) 2.45(m, lH) 4.13(s,2H) 6.95- 7.42(8H) 8.19(s,lH);

4-[2-(2-chloro-4-methylthiobenzyl)benzoyl]- 5-cyclopropyl isoxazole (Compound 225), NMR 1.15(m,2H) 1.28(m,2H) 2.42(s,3H) 2.52(m,lH) 4.17(2H) 6.99(2H) 7.14-7.42(5H) 8.16(s,lH);

5-cyclopropyl-4-[2-(2-methylthio-3- trifluoromethylbenzyl)benzoyl]isoxazole (Compound 226), NMR 1.15-

1.35(4H) 2.19(s,3H) 2.6(m,lH) 4.54(s,2H) 7.05-7.55(7H) 8.18(s,lH);

5 -cyclopropyl-4-[2-(4-fluoro-2- methylthiobenzyl)benzoyl]isoxazole (Compound 88), NMR 1.18(m,2H) l.30(m,2H) 2.42(s,3H) 2.50(ra,lH) 4.1 l(s,2H) 6.8-6.9(2H) 7.00(t,lH) 7.25-7.46(4H) 8.17(s, lH);

5-cyclopropyl-4-[2-(2-methyl-3- methylthiobenzyl)benzoyl]isoxazole (Compound 227), NMR 1.17(m,2H) 1.30(m,2H) 2.32(s,3H) 2.38(s,3H) 2.59(m, lH) 4.21(s,2H) 6.96- 7.20(6H) 7.30(d, lH) 8.22(s,lH); 5 -cyclopropyl-4-[2-( 5-fluoro-2,3 -bis- methylthiobenzyl)benzoyl]isoxazole (Compound 228), NMR 1.17- 1.37(4H) 2.36(s,3H) 2.47(s,3H) 2.64(m,lH) 4.23(s,2H) 6.78-7.39(6H) 8.26(s,lH);

4-[2-(3,4-dichloro-2-methylthiobenzyl)benzoyl] 5-cyclopropyl isoxazole (Compound 103), NMR 1.22(m,2H) 1.35(m,2H) 2.39(s,3H)

2.55(m,lH) 5.30(s,lH) 7.17(d,lH) 7.10-7.45(4H) 7.56(d,lH) 8.11(s, lH);

5-cyclopropyl-4-[4-methyl-2-(2- methylthiobenzyl)benzoyl]isoxazole (Compound 229), NMR 1.18(m,2H) 1.30(m,2H) 2.32(s,3H) 2.58(m,lH) 2.38(s,3H) 4.21(s,2H) 6.97-

7.13(4H) 7.15-7.20(2H) 7.30(d,lH) 8.22(s, lH);

5-cyclopropyl-4-[2-(2-methylthio-6- trifluoromethylbenzyl)benzoyl]isoxazole (Compound 230), NMR 1.24(m,2H) 1.37(m,2H) 2.36(s,3H) 2.70(m,lH) 4.45(s,2H) 6.70(1H) 7.23-7 58(6H) 8.32(s,lH);

4-[2-(2-methylthiobenzyl)benzoyl]-5-( 1 - methylcyclopropyl)isoxazole (Compound 231), NMR 0.89(m,2H) 1.27(m,2H) 1.46(s,3H) 2.37(s,3H) 4.24(s,2H) 7.00-7.10(2H) 7.12- 7.20(3 H) 7.25-7.43(3H) 8.11 (s,lH); 4-[5-bromo-2-(2-methylthiobenzyl)benzoyl]-5- cyclopropylisoxazole (Compound 232), NMR 1.19-1.26(m,2H), 1.3- 1.35(m,2H), 2.37(s,3H), 2.57(m,lH), 4.14(s,2H), 7.03-7.1(3H), 7.15- 7.26(2H), 7.48-7.53(2H), 8.21(1H);

5-cyclopropyl-4-[4-methylthio-2-(2- trifluoromethylbenzyl)benzoyl)isoxazole (Compound 233), NMR 1.15-

1.35(4H) 2.43(s,3H) 2.6(m,lH) 4.35(s,2H) 6.9-7.65(7H) 8.23(s,lH);

5-cyclopropyl-4-[2-(2-methylbenzyl)benzoyl3isoxazole (Compound 234), NMR 1.15-1.32(4H) 2.17(s,3H) 2.65(m,lH) 4.12(s,2H) 6.95- 7.4(8H) 8.14(s, lH);

SUBSTTTUTE SHEET (RULE 26)

5-cyclopropyl-4-(2-benzyl-4-trifluoromethylbenzoyl)isoxazole (Compound 235), NMR 1.15-1.3(4H) 2.48(m, lH) 4.16(s,2H) 7.0- 7.58(8H) 8.0(s,lH);

5-cyclopropyl-4-[2-(3,5-dichloro-2- methylthiobenzyl)benzoyl]isoxazole (Compound 236), NMR 1.17-

1.35(4H) 2.2(s,3H) 2.6(m,lH) 4.45(s,2H) 7.02-7.45(6H) 8.20(s, lH);

5-cyclopropyl-4-[2-(2-methylbenzyl)~4- methylthiobenzoyl]isoxazole (Compound 172), NMR 1.15-1.32(4H) 2.19(s,3H) 2.42(s,3H) 2.55(m,lH) 4.14(s,2H) 6.9-7.35(7H) 8.17(s,lH); 5-cyclopropyl-4-[2-(2-methylbenzyl)-4- trifluoromethylbenzoyl]isoxazole (Compound 237), NMR 1.2-1.33(4H) 2.17(s,3H) 2.58(m,lH) 4.14(s,2H) 6.89-7.58(7H) 8.03(s,lH);

5-t-butyl-4-[2-(2-methythiobenzyl)benzoyl]isoxazole (Compound 238), NMR 1.49(s,9H) 2.36(s,3H) 4.21(s,2H) 7.00-7.42(8H) 8.02(s, lH); 5-cyclopropyl-4-[3-(2-methyIthiobenzyl)benzoyl]isoxazole

(Compound 239), NMR 1.20(2H) 1.40(2H) 2.44(s,3H) 2.73(m,lH) 4.15(s,2H) 7.10(2H) 7.25(2H) 7.38-7.68(4H) 8.33(s,lH);

5-cyclopropyl-4-[2-(2-ethylbenzyl)benzoyl]isoxazole (Compound 240), NMR l . l(t,3H) 1.15-1.35(4H) 2.54(q,2H) 2.58(m,lH) 4.16(s,2H) 6.9-7.4(8H) 8.14(s,lH);

5-cyclopropyl-4-[2-(2-methylbenzyl)-4-fluorobenzoyl]isoxa zole (Compound 241), NMR 1.18-1.35(4H) 2.16(s,3H) 2.58(m,lH) 4.14(s,2H) 6.75-7.63(7H) 8.16(s,lH); and ethyl-4-[2-(2-methylthiobenzyl)benzoyl]-5-( 1 - methylcyclopropyl)isoxazole-3 -carboxylate (Compound 274), NMR

0.82(2H) 1.15(t,3H) 1.20(2H) l.33(s,3H) 2.46(s,3H) 4.18(q,2H) 4.52(s,2H) 6.98-7.12(3H) 7.20-7.30(3H) 7.40(t,lH) 7.50(d,lH)

By proceeding as above but in the additional presence of sodium acetate was prepared: 5-cyclopropyl-4-[4-methylthio-2-(2-methylthiobenzyl)benzoyl] isoxazole (Compound 24), m.p. 102-104°C. Example 2

Hydroxylamine hydrochloride (0.63g) and sodium acetate (0.75g) were added to a stined solution of l-[2-(2-chlorobenzyl)-4- fluorophenyl]-3 -cyclopropyl-2-ethoxymethylenepropan- 1 , 3 -dione

(2.33g) in ethanol. After 2 hours water was added and the mixture extracted (dichloromethane), dried (magnesium sulphate) and evaporated to dryness. Purification by chromatography eluting with ethyl acetate/hexane (5:95) gave 4-[2-(2-chlorobenzyl)-4-fluorobenzoyl]-5- cyclopropylisoxazole (Compound 25, 1.43g), NMR 1.15-1.35(m,4H),

2.55(m,lH), 4.28(s,2H), 6.85(dd,lH), 7.0(m, lH), 7.15(m,3H), 7.32(m, lH), 7.42(dd,lH), 8.2(s,lH).

By proceeding in a similar manner the following compounds were prepared: 4-[2-(2-chlorobenzyl)-4-(methylthio)benzoyl]-5- cyclopropylisoxazole (Compound 26), NMR 1.15-1.33(m,4H), 2.45(s,3H), 2.54(m, lH), 4.25(s,2H), 7.01(d,lH), 7.15(m,2H), 7.3- 7.4(m,4H), 8.21(s, lH);

4-[2-(4-chlorobenzyl)-4-(methylthio)benzoyl]-5- cyclopropylisoxazole (Compound 27), NMR 1.15-1.35(m,4H),

2.5(s,4H), 4.12(s,2H), 7 0-7.25(m,6H), 7.37(d,lH), 8.15(s, lH);

4-[2-(3-chlorobenzyl)-4-fluorobenzoyl]-5-cyclopropylisoxa zole (Compound 28), NMR 1.15-1.3(m,4H), 2.47(m, lH), 4.12(s,2H), 6.97- 7.2(m,6H), 7.4(dd,lH), 8.1(s,lH); -| ( 3 -chlorobenzyl)-4-(methylthio)benzoyl]-5- cyclopropylisoxazole (Compound 29), m.p. 76.8-77.6°C;

4-(2-benzyl-4-ethylthio-3-methylbenzoyl)-5-cyclopropyliso xazole (Compound 30), m.p. 102.5-104°C;

4-(2-benzyl-4-fluoro-3 -methyIbenzoyl)-5 -cyclopropylisoxazole (Compound 31), NMR l.l-1.2(m,4H), 2.1(d,4H), 2.5(m,lH), 4.1(s,2H),

6.9-7.2(m,7H), 8.05(s,lH);

4-[2-benzyl-3-methyl-4-(methylthio)benzoyl]-5- cyclopropylisoxazole (Compound 32), m.p. 94-95°C; 5-cyclopropyl-4[4-fluoro-3-methyl-2-(4- methylbenzyl)benzoyl]isoxazole (Compound 33), m.p. 77-78°C;

4-(2-benzyl-4-chloro-3-(methylthio)benzoyl)-5- cyclopropylisoxazole (Compound 34), m p. 85.8-88.8°C;

4-[2-(4-chlorobenzyl)-4-fluorobenzoyl3-5-cyclopropylisoxa zole (Compound 35), NMR 1.08-1.28(m,4H), 2.4(m,lH), 4.04(s,2H), 6.85- 7.2(m,6H), 7.35(dd,lH), 8.1(s,lH);

4-[4-chloro-3-methylthio-2-(2-methylthiobenzyl)benzoyl3-5 - cyclopropylisoxazole (Compound 36), NMR 1.2-1.32(m,4H),

2.25(s,3H), 2.48(s,3H), 2.58(m,lH), 4.58 ' (s,2H), 6.6(d,lH), 6.92(m, lH), 7.12(m,2H), 7.28(d, lH), 7.52(d,lH), 8.02(s,lH);

5-cyclopropyl-4-[2-(2-phenylethyl)benzoyl]isoxazole (Compound 37), m.p. 88-90 O C. Example 3 m-Chloroperbenzoic acid (0.6g of 50-65% w/w) was added to a stined solution of 4-[2-benzyl-4-chloro-3-(methylthio)benzoyl]-5- cyclopropylisoxazole (l.Og) in dichloromethane at -20°C. After 1.5 hours the mixture was warmed to room temperature and left overnight. The mixture was cooled to -20°C, filtered and the filtrate washed with sodium metabisulphite solution, dried (magnesium sulphate) and evaporated. The residue was purified by chromatography eluting with ethyl acetate/petroleum ether (1:5) to give 4-[2-benzyl-4-chloro-3- (methylsulphinyl)benzoyl]-5-cyclopropylisoxazole (Compound 38, 0.85g), m.p. 123-124°C.

By proceeding in a similar manner the following compounds were prepared using the appropriate quantity of m-chloroperbenzoic acid: 4-[2-benzyl-4-(ethylsulphinyl)benzoyl]-5-cyclopropylisoxazol e (Compound 39), NMR 1.2(m,7H), 2.4(m, lH), 3.1(q,2H), 4.1(s,2H), 7.0(d,2H), 7.1(m,3H), 7.5(d,lH), 7.9(m,2H), 8.0(s,lH), and

4-[2-benzyl-4-(ethylsulphonyl)benzoyl]-5-cyclopropylisoxa zole (Compound 40), m.p. 98.2-99.6°C;

4-[2-benzyl-4-(methylsulphinyl)benzoyl]-5-cyclopropylisox azole (Compound 41), NMR 1.2(m,2H), 1.3(m,2H), 2.4(m,lH), 2.7(s,3H), 4.1(s,2H), 7.1(m,5H), 7.5(d,lH), 7.6(m,2H), 8.0(s,lH), and 4-[2-benzyl-

4-(methylsulphonyl)benzoyl]-5-cyclopropylisoxazole (Compound 42), NMR 1.2(m,4H), 2.4(m,lH), 3.0(s,3H), 4.2(s,2H), 7.1(m,5H), 7.5(d,lH), 7.9(m,2H), 8.0(s,lH);

4-[2-(2-chlorobenzyl)-4-(methylsulphinyl)benzoyl]-5- cyclopropylisoxazole (Compound 43), NMR l. l-1.3(m,4H),

2.42(m,lH), 2.65(s,3H), 4.21(s,2H), 7.05(m,3H), 7.2(m,lH), 7.38(s,lH), 7.48 and 7.59 (dd,2H), 8.09(s,lH), and

4-[2-(2-chlorobenzyl)-4-(methylsulphonyl)benzoyl]-5- cyclopropylisoxazole (Compound 44), NMR l.l-1.3(m,4H), 2.46(m,lH), 2.97(s,3H), 4.2(s,2H), 7.03(m,3H), 7.2(m,lH), 7.44(d,lH),

7.72(s,lH), 7.81(d,lH), 8.0(s,lH);

4-[2-(4-chlorobenzyl)-4-(methylsulphinyl)benzoyl]-5- cyclopropylisoxazole (Compound 45), NMR l. l-1.4(m,4H), 2.4(m, lH),

2 7(s,3H), 4 l(s,2H), 6 98 and 7 l l(2d,4H), 7 44-7 53(m,3H), 8 0(s, lH), and

4-[2-(4-chlorobenzyl)-4-(methylsulphonyl)benzoyl]-5- cyclopropylisoxazole (Compound 46), NMR 1 1-1 3(m,4H), 2 4(m, lH), 3 l(s,3H , 4 l(s,2H), 6 95 and 7 15(2d,4H), 7 5(d, lH), 7 88(m,2H),

7 95(s, lH),

4-[2-(3-chlorobenzyl)-4-(methylsulphιnyl)benzoyl]-5- cyclopropy soxazole (Compound 47), NMR 1 15-1 4(m,4H), 2 4(m,lH), 3 02(s,3H), 4 l(s,2H), 6 85-7 l(m,4H), 7 46(d,lH), 7 82- 7 9(m,2H), 7 92(s, IH), and

4-[2-(3-chlorobenzyl)-4-(methylsulphonyl)benzoyl]-5- cyclopropy soxazole (Compound 48), NMR 1 1-1 28(m,4H), 2 4(m,lH), 2 7(s,3H), 4 l(s,2H), 6 88-7 l(m,4H), 7 45(m, lH), 7 52(m,2H), 7 9(s,lH), 4-(2-benzyl-4-ethylsulphmyl-3-methylbenzoyl)-5- cyclopropyhsoxazole (Compound 49), m p 93-95°C,

4-[2-benzyl-3-methyl-4-(methylsulphιnyl)benzoyl]-5- cyclopropy soxazole (Compound 50), m p 116-118°C,

5-cyclopropyl-4-[4-fluoro-2-(2-methylsulphιnylbenzyl)ben zoyl] isoxazole (Compound 51), NMR 1 2-1 38(m,4H), 2 6(m,lH),

2 62(s,3H), 4 28(s,2H), 6 89(dd,lH), 7 03(m,2H), 7 38(m,lH), 7 45(m,2H), 8 0(d,lH), 8 15(s,lH), and

5 -cyclopropyl-4- [4-fluoro-2-(2-methylsulphonylbenzyl)benzoy 1] isoxazole (Compound 52) m p 53-56 5°C, 4-[2-benzyl-3-methyl-4-(methylsulphonyl)benzoyl]-5- cyclopropy soxazole (Compound 53), m p 178-180°C, 4-(2-benzyl-4-ethylsulphonyl-3-methylbenzoyl)-5- cyclopropylisoxazole (Compound 54), m p 136°C,

4-[2-(4-chlorobenzyl)-3-methyl-4-(methylsulphmyl)benzoyl] -5- cyclopropylisoxazole (Compound 55), NMR 1 19-1 32(m,4H),

2 23(s,3H), 2 6(m,lH), 2 7(s,3H), 4 12(d,2H), 6 96(d,2H), 7 18(d,2H), 7 53(d,lH), 8 05(d,lH), 8 l(s,lH),

4-[2-(4-chlorobenzyl)-3-methyl-4-(methylsulphonyl)benzoyl ]-5- cyclopropyhsoxazole (Compound 56), NMR 1 2-1 36(m,4H), 2 58(m,lH), 2 63(s,3H), 3 13(s,3H), 4 12(s,2H), 6 96(d,2H),

7 19(d,2H), 7 42(d, lH), 8 05(s,lH), 8 16(d,lH),

5-cyclopropyl-4-[2-(4-fluorobenzyl)-3-methyl-4- (methylsulphmyl)benzoyl]isoxazole (Compound 57), NMR 1 19-

1.32(m,4H), 2.24(s,3H), 2.58(m,lH), 2.7(s,3H), 4.11(d,2H), 6.87- 7.0(m,4H), 7.51(d, lH), 8.05(d,lH), 8.09(s,lH);

5-cyclopropyl-4-[2-(4-fluorobenzyl)-3-methyl-4- (methylsulphonyl)benzoyl]isoxazole (Compound 58), NMR 1.2- 1.37(m,4H), 2.58(m, IH), 2.64(s,3H), 3.12(s,3H), 4.12(s,2H), 6.83-

7.01(m,4H), 7.41(d,lH), 8.05(s,lH), 8.16(d,lH);

5-cyclopropyl-4-[2-( 1 -methylbenzyl)-4- (methylsulphinyl)benzoyl]isoxazole (Compound 59), NMR 1.14- 1.3(m,4H), 1.67(dd,3H), 2.4(m,lH), 2.76(d,3H), 4.6(m, lH), 7.05- 7.8(m,8H), 7.92(d,lH), and

5-cyclopropyl-4-[2-( 1 -methylbenzyl)-4- (methylsulphonyl)benzoyl]isoxazole (Compound 60), NMR 1.2- 1.81(m,4H), 1.68(d,3H), 2.4(m,lH), 3.09(s,3H), 4.58(q,lH), 7.01- 7.85(m,8H), 8.05(d,lH); 5-cyclopropyl-4-[2-( 1 -methylsuiphinylbenzyl)benzoyl]isoxazole

(Compound 61), NMR 1.15-1.4(m,4H), 2.45(s,3H), 2.48-2.6(m, lH), 5.7(s,lH), 7.28-7.9(m,9H), 8.28(s,lH), and

5-cyclopropyl-4-[2-( 1 -methylsulphonylbenzyl)benzoyl]isoxazole (Compound 62), NMR l. l l-1.4(m,4H), 2.47-2.58(m,lH), 2.82(s,3H), 6.28(s, lH), 7.35-8.05(m,9H), 8.27(s,lH);

5-cyclopropyl-4-[2-(2-methylsulphinylbenzyl)benzoyl]isoxa zole (Compound 63), NMR 1.2-1.38(m,4H), 2.6(s,3H), 2.59-2.68(m,lH), 4.27(d,2H), 7.01-8.03(m,8H), 8.16(s,lH), and

5-cyclopropyl-4-[2-(2-methylsulphonylbenzyl)benzoyl]isoxa zole (Compound 64), NMR 1.16-1.35(m,4H), 2.55-2.65(m,lH), 3.07(s,3H),

4.64(s,2H), 7.09-8.1 l(m,8H), 8.23(s,lH);

5-cyclopropyl-4-[2-(4-methylsulphinylbenzyl)benzoyl]isoxa zole (Compound 65), NMR 1.18-1.3(m,4H), 2.48-2.57(m,lH), 2.65(s,3H), 4.21(s,2H), 7.27-7.5 l(m,8H), 8.09(s,lH), and 5 -cyclopropyl-4-[2-(4-methylsulphonylbenzyl)benzoyl]isoxazole

(Compound 66), NMR 1.2-1.32(m,4H), 2.5-2.59(m,lH), 2.99(s,3H), 4.24(s,2H), 7.33-7.8(m,8H), 8.1(s,lH); ethyl 5-cyclopropyl-4-[2-(2-methylsulphinylbenzyl)benzoyl] isoxazole-3 -carboxylate (Compound 67), NMR 1.15-1.32(m,4H), 1.2(t,3H), 2.25(m,lH), 2.68(s,3H), 4.13(q,2H), 4.37(d,2H), 7.1(d,2H),

7.27-7.5(m,5H), 8.05(d,lH); ethyl 5-cyclopropyl-4-[2-(2-methylsulphonylbenzyl)benzoyl] isoxazole-3 -carboxylate (Compound 68), NMR 1.13-1.3(m,4H),

1.2(t,3H), 2.21(m,lH), 3.17(s,3H), 4.14(q,2H), 4.75(s,2H), 7.15- 7.54(m,7H), 8.09(d,lH);

5-cyclopropyl-4-[2-(2-ethylsuIphinylbenzyl)benzoyl]isoxaz ole (Compound 69), NMR 1.18-1.3 (m,4H), 1.2(t,3H), 2.66(m,lH), 2.75(q,2H), 4.23(q,2H), 7.0-7.9(m,8H), 8.16(s,lH);

5-cyclopropyl-4-[2-(2-ethylsulphonylbenzyl)benzoyl]isoxaz ole (Compound 70), NMR 1.18-1.32(m,4H), 1.25(t,3H), 2.6(m, lH), 3.16(q,2H), 4.61(s,2H), 7.1-7.5(m,7H), 8.02(d,lH), 8.23(s,lH); ethyl 5-cyclopropyl-4-[4-fluoro-2-(2- methylsulphinylbenzyl)benzoyl]isoxazole-3-carboxylate (Compound 71 ), m.p. 155.5-157°C; ethyl 5-cyclopropyl-4-[4-fluoro-2-(2- methylsulphonylbenzyl)benzoyl]isoxazole-3-carboxylate (Compound 72), m.p. 131-132°C; 4-[2-benzyl-4-chloro-3-(methylsulphonyl)benzoyl]-5- cyclopropylisoxazole (Compound 73), m.p. l26-127°C;

5-cyclopropyl-4-[4-methylsulphonyl-2-(2- phenylethyl)benzoyl]isoxazole (Compound 74), m.p. 136-137°C; 5-cyclopropyl-4-[4-methylsulphinyl-2-(2- phenylethyl)benzoyl]isoxazole (Compound 75), m.p. 120-121°C, ethyl 5-cyclopropyl-4-[4-methylsulphonyl-2-(2- phenylethyl)benzoyl]isoxazole-3-carboxylate (Compound 76), m.p. 99- 101°C;

5 -cyclopropyl-4- { 2- [2-(2-methylsulphonylphenyl)ethyl]benzoyl } - isoxazole (Compound 77), m.p. 113-114°C;

5-cyclopropyl-4-{2-[2-(2-methylsulphinylphenyl)ethyl]benz oyl} isoxazole (Compound 78), m.p. 105-107°C;

5-cyclopropyl-4-[4-methylsulphonyl-2-(2-methyisulphonyl-2 - phenylethyl)benzoyl]isoxazole (Compound 79), m.p. 97°C (dec); 5-cyclopropyl-4-[4-methylsulphinyl-2-(2-methylsulphonyl-2- phenylethyl)benzoyl]isoxazole (Compound 80), m.p. 80°C (dec);

4-[2-benzyl-3-(methylsulphinyl)benzoyl]-5-cyclopropylisox azole (Compound 242) NMR 1.15-1.22 (m, 2H), 1.25-1.31 (m, 2H), 2.35 (s, 3H), 2.40-2.49 (m, IH), 4.22 (q, 2H), 7.03-7.26 (m, 5H), 7.50 (d, IH), 7.66 (t, IH), 8.06 (s, IH), 8.24 (d, IH);

4- [2-benzyl-3 -(methylsulphonyl)benzoyl] -5 -cyclopropylisoxazole (Compound 243) NMR 1.11-1.29 (m, 4H), 2.32-2.41 (m, IH), 2.90 (s,

3H), 4.69 (s, 2H), 7.01-7.18 (m, 5H), 1.52-1.60 (m, 2H), 7.88 (s, IH), 8.31 (d, IH);

5-cyclopropyl-4-{2-[l-methyl-2-(methylsulphinyl)benzyl]be nzoyl}- isoxazole (Compound 244), m.p.149-151°C; 5-cyclopropyl-4-{2-[l-methyl-2-(methylsulphonyl)benzyl]benzo yl} isoxazole (Compound 245), m.p.51-54°C;

5-cyclopropyl-4-{4-fluoro-2-[2-(methylsulphonylmethyl)ben zyl]- benzoyl) isoxazole (Compound 170), NMR 1.10 - 1.30 (4H, m), 2.41 - 2.52 (IH, m), 2.82 (3H, s), 4.23 (2H, s), 4.30 (2H, s), 6.84 (IH, dd), 6.91 - 7.06 (2H, m), 7.13 - 7.40 (4H, m), 8.06 (IH, s);

5-cyclopropyl-4-{2-[2-(methoxymethyl)benzyl]-4- (methylsulphonyl)benzoyl} isoxazole (Compound 166), NMR 1.19-1.38 (4H,m), 2.51-2.63(lH,m), 3.07(3H,s), 3.38(3H,s), 4.25(2H,s), 4.33(2H,s), 6.92-6.99(1 H,m), 7.12-7.19(2H,m), 7.23-7.29(lH,m), 7.52(lH,d), 7.83(lH,d), 7.91(lH,dd), 8.02(lH,s);

5 -cyclopropyl-4- { 2- [2-(methoxymethyl)benzyl]-4- (methylsulphinyl)benzoyl}isoxazole (Compound 167), NMR 1.10-1.29 (4H, m), 2.47-2.58 (IH, m), 2.65 (3H, s), 3.21 (3H, s), 4.18 (2H, s), 4.39 (2H, s), 6.85-6.91 (IH, m), 7.07-7.14 (2H, m), 7.18-7.23 (IH, m), 7.37 (IH, d), 7.46 (IH, d), 7.59 (IH, dd), 8.01 (IH, s);

5-cyclopropyl-4-[2-(2-methylsulphinyl-4- trifluoromethylbenzyl)benzoyl]isoxazole (Compound 107) NMR 1.19- 1.37(4H) 2.63(m,lH) 2.67(s,3H) 4.27(q,2H) 7.14(d,lH) 7.21(d,lH) 7.4- 7.6(4H) 8.17(s,lH) 8.29(s,lH); 5 -cyclopropyl-4-[2-(2-methylsulphonyl-4-trifluoromethylbenzyl )- benzoyl]isoxazole (Compound 108), NMR 1.17-1.23(m,2H) 1.34- 1.39(m,2H) 2.59(m,lH) 3.15(s,lH) 4.67(s,2H) 7.22-7.30(2H) 7.40- 7.60(3H) 7.70(d,lH) 8.23(s,lH) 8.35(s,lH);

4-[2-(6-chloro-2-methylsulphinylbenzyl)benzoyl]-5- cyclopropylisoxazole (Compound 92), NMR 1.26(m,2H) 1.38(m,2H)

2.54(s,3H) 2.67(m,lH) 4.40(q,2H) 6.83(d, lH) 7.3-7.6(5H) 8.01(d,lH) 8.28(s,lH);

4-[2-(6-chloro-2-methylsulphonylbenzyl)benzoyl]-5- cyclopropylisoxazole (Compound 93), NMR 1.23(m,2H) 1.37(m,2H) 2.67(m, IH) 2.96(s,3H) 4.79(s,2H) 6.79(d, IH) 7.26-7.47(2H) 7.42-

7.50(2H) 7.69(d,lH) 8.11(d,lH) 8.31(s,lH);

4-[2-(5-chloro-2-methylsulphinylbenzyl)benzoyl]-5- cyclopropylisoxazole (Compound 95), NMR 1.15-1.35(4H) 2.57(m, lH) 2.60(s,3H) 4.18(d, lH) 4.22(d,lH) 6.95(1H) 7.23(d,lH) 7.35-7.50(4H) 7.90(d, lH) 8.14(s, lH); 4-[2-(5-chloro-2-methylsulphonylbenzyl)benzoyl]-5- cyclopropylisoxazole (Compound 96), NMR 1.15-1.35(4H) 2.55(m, lH) 3.03(s,3H) 4.60(s,2H) 7.04(1H) 7.25-7.58(5H) 7.99(d, lH) 8.22(s,lH);

5-cyclopropyl-4-[2-(2,4-bis- methylsulphonylbenzyl)benzoyl]isoxazole (Compoimd 214), NMR 1.16- 1.38(4H) 2.60(m,lH) 3.09(s,3H) 3.18(s,3H) 4.70(s,2H) 7.27-7.61(5H)

7.99(dd,lH) 8.23(s,lH) 8.65(d,lH); ethyl 5-cyclopropyl-4-[2-(2,4-bis- methylsulphonylbenzyl)benzoyl]isoxazole-3- carboxylate, (Compound 216) NMR 1.1-1.32(4H) 1.20(t,3H) 2.23(m,lH) 3.10(s,3H) 3.30(s,3H) 4.13(q,2H) 4.83(s,2H) 7.3-7.9(6H) 8.65(d, lH);

4-[2-(4-chloro-2-methylsulphinylbenzyl)benzoyl]-5- cyclopropylisoxazole (Compound 98), NMR 1.22-1.34(4H) 2.63(m, lH) 2.63(m,lH) 4.18(d,2H) 6.94-7.97(7H) 8.16(s,lH);

4-[2-(4-chloro-2-methylsulphonylbenzyl)benzoyl]-5- cyclopropylisoxazole (Compound 99), NMR 1.18-1.35(4H) 2.59(m, IH)

3.09(s,3H) 4.58(s,2H) 7.05-7.54(6H) 8.07(d,lH) 8.22(s,lH);

5-cyclopropyl-4-[2-(3-fluoro-2-methylsulphinylbenzyl)- benzoyl]isoxazole (Compound 246), NMR 1.2-1.33(4H) 2.62(m,lH) 2.91(s,3H) 4.5(q,2H) 6.9-7.48(7H) 8.18(s,lH); 5-cyclopropyl*4-[2-(3-fluoro-2-methylsulphonylbenzyl)benzoyl ]- isoxazole (Compound 247), NMR 1.18-1.32(4H) 2.78m, IH) 3.14(s,3H) 4.69(s,2H) 7.04-7.46(7H) 8.23(s,lH) ethyl 5-cyclopropyl-4-[2-(3-fluoro-2-methylsulphinylbenzyl)- benzoyl]isoxazole-3-carboxylate (Compound 248), NMR 1.14-1.30(4H) 1.2(t,3H) 2.21(m,lH) 3.01(s,3H) 4.13(q,2H) 4.6(q,2H) 6.93-7.49(7H); ethyl 5-cyclopropyl-4-[2-(3-fluoro-2-methylsulphonylbenzyl)- benzoyl]isoxazole-3-carboxylate (Compound 249), NMR 1.09-1.28(4H) 1.2(t,3H) 2.11(m,lH) 3.26(s,3H) 4.17(q,2H) 4.18(s,2H) 6.98-7.54(7H);

5-cyclopropyl-4-[2-(2-methyl-4-methylsulphinylbenzyl)- benzoyljisoxazole (Compound 121), NMR 1.15-1.35(4H) 2.28(s,3H) 2.57(m, lH) 2.67(s,3H) 4.18(s,2H) 7.03-7.48(7H) 8.12(s,lH);

5-cyclopropyl-4-[2-(2-methyl-4-methylsulphonylbenzyl)- benzoy soxazole (Compound 122), NMR 1.17-1 34(4H) 2.3 l(s,3H)

2.60(m, lH) 3.00(s,3H) 4.20(s,2H) 7.10-7.65(6H) 7.70(s,lH) 8.12(s, lH);

4-[4-bromo-2-(2-methylsulphinylbenzyl)benzoyl]- 5- cyclopropylisoxazole (Compound 141), NMR 1.20-1.35(4H) 2.60(m, lH) 2.63(s,3H) 4.22(q,2H) 7.05(d,lH) 7.32-7.56(5H)

8.00(d,lH) 8.12(s,lH);

4-[4-bromo-2-(2-methylsulphonylbenzyl)benzoyl]- 5- cyclopropylisoxazole (Compound 146), NMR 1.18-1.38(4H) 2.68(m,lH) 3.05(s,3H) 4.60(s,2H) 7.25(s,lH) 7.35-7.55(5H) 8.08(d,lH) 8.22(s,lH);

5-cyclopropyl-4-[2-(2- methylsulphinyl-4- trifluoromethoxybenzyl)benzoyl]isoxazole (Compound 250), NMR 1.25(m,2H) 1.32(m,2H) 2.48-2.68(4H) 4.20(q,2H) 7.05(d,lH) 7.13- 7.28(2H) 7.38-7.52(3H) 7.86(1H) 8.15(s,lH); 5-cyclopropyl-4-[2-(2- methylsulphonyl-4- trifluoromethoxybenzyl)benzoyl]isoxazole (Compound 251), NMR 1.20(m,2H) 1.32(m,2H) 2.58(mlH) 3.13(s,3H) 4.61(s,2H) 7.16(d,lH) 7.25-7.34(2H) 7.42(t,lH) 7.47-7.58(2H) 7.93(1H) 8.22(s, lH);

4-[2-(2-chloro-4-methylsulphinylbenzyl)benzoyl]-5-cyclopr opyl isoxazole (Compound 252), NMR 1.22(m,2H) 1.32(m,2H) 2.56(m,lH)

2.70(s,3H) 4.30(s,2H) 7.20-7.40(2H) 7.42-7.49(2H) 7.65(1H) 8.19(s,lH);

4-[2-(2-chloro-4-methylsulphonylbenzyl)benzoyl]-5-cyclopr opyl isoxazole (Compound 253), NMR 1.22(m,2H) 1.31(m,2H) 2.56(m,lH) 3.03(s,3H) 4.32(s,2H) 7.19-7.30(2H) 7.40(t,lH) 7.43-7.50(2H)

7.69(d,lH) 7.91(s,lH) 7.19(s,lH);

5-cyclopropyl-4-[2-(2-fluoro-6- methylsulphinylbenzyl)benzoyl]isoxazole (Compound 254), NMR 1.2- 1.35(4H) 2.54(s,3H) 2.65(m,lH) 4.25(d,2H) 6.95-7.8(7H) 8.2(s,lH);

5 -cyclopropyl-4-[2-(2-fluoro-6- methylsuiphonylbenzyl)- benzoyl]isoxazole (Compound 255), NMR 1 2-1 4(4H) 2 75(m, lH) 2.91(s,3H) 4 65(s,2H) 6 85(7H) 8 32(s, lH),

5 -cyciopropyl-4-[2-(4-fluoro-2- methylsulphinylbenzyl)- benzoyl]isoxazole (Compound 89), NMR1 15-1 35(4H) 2 52(m, lH)

2.67(s,3H) 4 21(s,2H) 7 18-7 50(7H) 8 15(s, lH),

5-cyclopropyl-4-[2-(4-fluoro-2- methylsulphonylbenzyl)- benzoyl]isoxazole (Compound 90), NMR 1 25(m,2H) 1.35(m,2H) 2 59(m,lH) 3 05(s,3H) 4 27(s,2H) 7 30-7 65(7H) 8 19(s,lH); 5-cyclopropyl-4-[2-(2-methyl-3- methylsulphinylbenzyl)- benzoyl]isoxazole (Compound 256), NMR 1.15(m,2H) 1.28(m,2H) 2 17(s,3H) 2.29(s,3H) 2.54(m,lH) 4 15(s,2H) 7 04-7 12(2H) 7.27- 7 45(4H) 7 80(d,lH) 8 l l(s,lH);

5-cyclopropyl-4-[2-(2-methyl-3- methylsulphonylbenzyl)- benzoyl]isoxazole (Compound 257), NMR 1.22(m,2H) 1.32(m,2H)

2.55-2.65(4H) 3 08(s,3H) 4 24(s,2H) 7 10(d,lH) 7.23-7 30(2H) 7 32- 7 49(3H) 7 96(d,lH) 8.17(s,lH);

5 -cyclopropyl-4- [4-methyl-2-(2-methyisulphinylbenzyl)- benzoyl]isoxazole (Compound 258), NMRl 20(m,2H) 1 29(m,2H) 2 34(s,3H) 2.66(m,lH) 2.61(s,3H) 4 23(s,2H) 6 98-7.03(2H) 7 16(d,lH)

7 30-7 48(3H) 7 98(d,lH) 8 16(s,lH);

5-cyclopropyl-4-[4-methyl-2-(2-methylsulphonylbenzyl)benz oyl]- isoxazole (Compound 259), NMRl 18(2H) 1 30(2H) 2.37(s,3H) 2.58(m,lH) 3.11(s,3H) 4.63(s,2H) 7.05-7 10(2H) 7 18(d,lH) 7 34- 7 49(3H) 8 07(d,lH) 8.23(s,lH),

5-cyclopropyl-4-[2-(2-fluoromethylsulphinylbenzyl)benzoyl ]- isoxazole (Compound 260), NMR 1.15-1.33(4H), 2.60(m,lH), 4 26(q,2H) 5.59(dq,2H) 7 05(d,lH) 7 32-7 50(5H) 7 93(d,lH) 8.13(s,lH); 5-cyclopropyl-4-[2-(2-fluoromethylsulphonylbenzyl)benzoyl]- isoxazole (Compound 261), NMR 1.119(2H), 1.28(2H) 2 60(m,lH), 4 60(s,2H) 5 20(d,2H,J=46.9Hz) 7.16(d,lH) 7.22(d, lH) 7 34-7 55(5H) 8 06(d,lH) 8.19(s,lH);

5-cyclopropyl-4-[2-(2-methylsulphinyl-6- trifluoromethylbenzyl)benzoyl]isoxazole (Compound 262),

NMR1.25(2H) 1.40(2H) 2.49(s,3H) 2.70(q,lH) 4.50(s,2H) 6.70(1H) 7.34(2H) 7.50(1H) 7.71(t, lH) 7.90(d,lH) 8.30(s.lH) 8.32(d,lH);

5-cyclopropyl-4-[2-(2-methylsulphonyl-6- trifluoromethylbenzyl)benzoyl]isoxazole (Compound 263), NMR1.25(2H) 1.45(2H) 2.70(m,lH) 2.78(s,3H) 4.85(bs,2H) 6.55(1H)

7.30(2H) 7.50(1H) 7.65(t,lH) 8.05(d,lH) 8.29(s.lH) 8.40(d,lH); ethyl 5-cyclopropyl-4-[2-(2-fluoromethylsulphinylbenzyl)- benzoyl]isoxazole-3 -carboxylate (Compound 264), NMR 1.13-1.34(4H), 1.19(t,3H) 2.24(m,lH), 4.13(q,2H) 4.73(s,2H) 5.26(d,2H) 7.11- 7.58(7H) 8.1(d,lH); ethyl 5-cyclopropyl-4-[2-(2-fluoromethylsulphonylbenzyl)- benzoyl]isoxazole-3 -carboxylate (Compound 265), NMR 1.13-1.3(4H) 1.18(t,3H) 2.23(m,lH), 4.13(q,2H) 4.73(s,2H) 5.26(d,2H) 7.17- 7.56(7H) 8.11(d,lH); methyl 5-cyclopropyl-4-[2-(2-methylsulphinylbenzyl)- benzoyl]isoxazole-3 -carboxylate (Compound 266), NMR 1.15-1.45(4H) 2.25(m,lH) 2.67(s,3H), 3.66(s,3H) 4.38(d,2H) 7.05-7.52(7H) 8.05(d,lH); methyl 5-cyclopropyl-4-[2-(2-methylsulphonylbenzyl)benzoyl]- isoxazole-3 -carboxylate (Compound 267), NMR 1.15-1.32(4H)

2.23(m,lH) 3.16(s,3H), 3.68(s,3H) 4.76(s,2H) 7.13-7.5 (7H) 8. l(d,lH); iso-propyl 5-cyclopropyl-4-[2-(2-methylsulphinylbeπzyl)- benzoyl]isoxazole-3 -carboxylate (Compound 268), NMR 1.15-1.3 (4H) 1.18(dd,6H) 2.23(m,lH) 2.68(s,3H), 4.38(d,2H) 5.0(sep, lH) 7.08-7.54 (7H) 8.05(d,lH); iso-propyl 5-cyclopropyl-4-[2-(2-methylsulphonylbenzyl)- benzoyl]isoxazole-3 -carboxylate (Compound 269) NMR 1.11-1.29 (4H) 1.17(d,6H) 2.17(m,lH) 3.18(s,3H), 4.76(s,2H) 5.02(sep,lH) 7.23-7.53 (7H) 8.1(d,lH); 4-[2-(2-methylsulphinylbenzyl)benzoyl]-5-( 1 -methylcyclopropyl)- isoxazole (Compound 270), NMR 0.86(2H) 1.20(2H) 1.41(s,3H) 2.60(s,3H) 4.27(s,2H) 7.00(d,lH) 7.17(d,lH) 7.30-7.38(2H) 7.40- 7.50(3H) 7.98(d,lH) 8.06(s,lH);

4-[2-(2-methylsulphonylbenzyl)benzoyl]-5-( 1 - metiiylcyclopropyOisoxazole (Compound 271), NMR 0.95(2H) 1.20(2H)

1.40(s,3H) 3.08(s,3H) 4.67(s,2H) 7.10(d, lH) 7.25(d,lH) 7.35-7.52(5H) 8.07(d,lH) 8.16(s,lH);

5-cyclopropyl-4-[4-methylsulphinyl-2-(2-trifluoromethylbenzy i)- benzoyl]isoxazole (Compound 272), NMR 1.2-1.38(4H) 2.63(m, lH) 2.71(s,3H) 4.38(s,2H) 7.1-7.7(7H) 8.17(s,lH);

5-cyclopropyl-4-[4-methylsulphonyl-2-(2-trifluoromethylbe nzyl)- benzoyl]isoxazole (Compound 273), NMR 1.22-1.4(4H) 2.64(m,lH)

3.04(s,3H) 4.37(s,2H) 7.1-7.9(7H) 8.12(s,lH); ethyl 4-[2-(2-methylsulphinylbenzyl)benzoyl]-5-(l- methylcyclopropyl)isoxazole-3-carboxylate (Compound 275), NMR 0.85(2H) 1.18(t,3H) 1.21(2H) 1.32(s,3H) 2.70(s,3H) 4.20(q,2H) 4.52(q,2H) 7.03-7 08(2H) 7.28(t, lH) 7.35-7.53(4H) 8.07(d,lH); ethyl 4-[2-(2-methylsulphonylbenzyl)benzoyl]-5-( 1 - methylcyclopropyl)isoxazole-3-carboxylate (Compound 276), NMR 0.82(m,2H), 1.17(t,3H), 1.18(m,2H), 1.27(s,3H), 3.26(s,3H), 4.19(q,2H), 4.87(s,2H), 6.98(d,lH), 7.25-7.56(6H), 8.12(d,lH); 5-cyclopropyl-4-[2-(3 , 5-dichloro-2-methylsulphinylbenzyl)- benzoyl3isoxazole (Compound 277), NMR 1.20-1.38(4H) 2.6(m,lH) 2.88(s,3H) 4.67(q,2H) 7.00(s, lH)7.22-7.52(5H) 8.20(s,lH);

5-cyclopropyl-4-[2-(3,5-dichloro-2-methylsulphonylbenzyl) - benzoy soxazole (Compound 278), NMR 1.10-1.28(4H) 2.50(m,lH) 3.11(s,3H) 4.64(s,2H) 7.01(d,lH)7.03(s,lH)7.24-7.45(4H) 8.14(s,lH),

5-cyclopropyl-4-[5-bromo-2-(2-methylsulphinylbenzyl)- benzoyl]isoxazole (Compound 279), NMR 1.26(2H) 1.32(2H) 2.55(m, lH) 2.62(s,3H) 4.18(q,2H) 7.00(d,lH) 7.08(d,lH) 7.34(t, lH) 7.45(t, lH) 7.55-7.60(lH) 7.58(s,lH) 7.98(d, lH) 8.17(s,lH); 5-cyclopropyl-4-[5-brorao-2-(2-methylsulphonylbenzyl)- benzoyl]isoxazole (Compound 280), NMR 1.23(2H) 1.35(2H) 2.55(m,lH) 3.06(s,3H) 4.55(s,2H) 7.10(d,lH) 7.14(d,lH) 7.36- 7.65(4H) 8.05(1H) 8.26(s, lH);

5-cyclopropyl-4-[2-(2-raethylbenzyl)-4-methylsulphinyl- benzoyl]isoxazole (Compound 173), NMR 1.19-1.33(4H) 2.16(s,3H)

2.55(m,lH) 2.72(s,3H) 4.16(s,2H) 6.92-7.65(7H) 8.06(s,lH);

5-cyclopropyl-4-[2-(2-methylbenzyl)-4-methylsulphonyl- benzoyl]isoxazole (Compound 174), NMR 1.21-1.33(4H) 2.17(s,3H) 2.53(m,lH) 3.06(s,3H) 4.16(s,2H) 6.87-7.93(7H) 7.99(s,lH);

5-cyclopropyl-4-[3-(2-methylsulphinylbenzyl)benzoyl3isoxazol e (Compound 281), NMR 1.23(2H) 1.35(2H) 2.49(s,3H) 2.64(m,lH) 4.20(q,2H) 7.23(d,lH) 7.38-7.68(6H) 8.04(d,lH) 8.30(s,lH); and

5-cyclopropyl-4-[3-(2-methylsulphonylbenzyl)benzoyl3isoxa zole (Compound 282), NMR 1.25(2H) 1.33(2H) 2.75(m,lH) 2.91(s,3H)

4 60(s,2H) 7.32(d,lH) 7.42-7.70(6H) 8.10(d,lH) 8.36(s,lH);

Example 4

Magnesium turnings (0.09g) and methanol were heated under reflux until dissolved, and a suspension of 3-cyclopropyl-l-[4-fluoro-2-

(2-methylthiobenzyl)phenyl3propan-l,3-dione (l.lόg) in methanol was added at room temperature. Acetonitrile was added and the mixture heated under reflux for four hours. The solvent was evaporated and the residue dissolved in dichloromethane. A solution of ethyl chloroximidoacetate (0.62g) in dichloromethane was added and the mixture stined overnight. Hydrochloric acid (2 M) was added and the organic layer was washed (water), dried (anhydrous magnesium sulphate) and the solvent evaporated. The residue was purified by chromatography eluting with ethyl acetate/hexane to give ethyl 5- cyclopropyl-4-[4-fluoro-2-(2-methylthiobenzyl)benzoyl]isoxaz ole-3- carboxylate as a colourless gum (Compound 81, 0.98g), NMR 1.05- 1.3(m,4H), 1.2(t,3H), 2.1(m,lH), 2.38(s,3H), 4.17(q,2H), 4.3(s,2H), 6.72(d,lH), 6.86(m,lH), 7.06(m,2H), 7.2(m,2H), 7.45(m, lH).

By proceeding in a similar manner the following compounds were prepared: ethyl 5-cyclopropyl-4-[2-(2-methylthiobenzyl)benzoyl] isoxazole- 3-carboxylate (Compound 82), NMR 1.06-1.27(m,4H), 1.21(t,3H), 2.12(m,lH), 2.43(s,3H), 4.16(q,2H), 4.34(s,2H), 7.05-7.46(m,8H); ethyl 5 -cyclopropyl-4-[4-fluoro-2-(2- phenylethyl)benzoyl3isoxazole-3 -carboxylate (Compound 83), m.p. 50-

54°C; ethyl 5-cyclopropyl-4-[2-(2-isopropylthiobenzyl)benzoyl3 isoxazole-3-carboxylate (Compound 283), NMR 1.09-1.35(m,4H), 1.22 (t,3H), l.29(d,6H) 2.15(m,lH), 3.34(sep,lH) 4.18(q,2H), 4.46(s,2H), 7.04-7.5(m,8H); ethyl 5-cyclopropyl-4-[2-{2,4-bis(methylthio)benzyl}benzoyl] isoxazole-3 -carboxylate (Compound 215), NMR 1.08-1.3(m,4H), 1.2

(t,3H), 2.13(m,lH), 2.43(s,3H) 2.48(s,3H) 4.14(q,2H), 4.28(s,2H), 6.96(d,2H) 7.11-7.58(m,5H); ethyl 5-cyclopropyl-4-[2-(2-methylthio-3-fluorobenzyl)benzoyl] isoxazole-3-carboxylate (Compound 284), NMR 1.08-1.3(m,4H), 1.2 (t,3H), 2.15(m, lH), 2.34(s,3H) 2 4.16(q,2H), 4.53(s,2H), 6.9-

7.5(m,7H); ethyl 5-cyclopropyl-4-[2-(2-trifluoromethylbenzyl)benzoyl] isoxazole-3 -carboxylate (Compound 285), NMR l. l-1.35(m,4H), 1.2 (t,3H), 2.25(m, lH), 4.14(q,2H), 4.44(s,2H), 7.05-7.7(m,8H); and ethyl 5-cyclopropyl-4-[2-(2-methylbenzyl)benzoyl] isoxazole-3- carboxylate (Compound 286), NMR 1.08-1.3(m,4H), 1.17(t,3H), 2.15(m, lH), 2.23(s,3H) 4.12(q,2H), 4.25(s,2H), 6.99-7.45(m,8H).

Example 5

Hydroxylamine hydrochloride (l.Og) was added to a stined mixture of 1 -[2-benzyl-3-methyl-4-(methylthio)phenyl]-3-cyclopropyl-2- ethoxymethylenepropan- 1,3 -dione (4.68g) and sodium acetate (0.9g) in ethanol. The mixture was stined overnight, diluted with water and extracted (ether). The extract was evaporated to dryness and purified by chromatography eluting with ethyl acetate/hexane to give 5-[2-benzyl-3- methyl-4-(methylthio)phenyl]-4-cyclopropylcarbonyl isoxazole

(Compound 84, 0.19g) as a yellow gum, NMR 0.8-0.9(m,2H), 1.05(m,2H), 1.7-2. l(m,lH), 2.28(s,3H), 2.5(s,3H), 4.01(s,2H), 6.88(dd,2H), 7.1-7.2(m,5H), 8.6(s,lH).

The following compounds were prepared in a similar manner: 5-[2-{2-chloro-4-(methylthio)benzyl}phenyl]-4- cyclopropylcarbonyl isoxazole (Compound 287), NMR 0.76(m,2H) l.l(m,2H) 1.8(m,lH) 2.41(s,3H) 4.03(s,2H) 6.87(d,lH) 6.97(d,lH) 7.12-7.48(5H) 8.64(s,lH);

5-[2- {4-fluoro-2-(methylthio)benzyl} phenyl]-4- cyclopropylcarbonyl isoxazole (Compound 288), NMR 0.75(m,2H) l. l(m,2H) 1.72(m,lH) 2.42(s,3H) 3.96(s,2H) 6.8-6.9(3H) 7.3-7.5(4H) 8.65(s,lH);

5-[2-{2-methyl-3-(methylthio)benzyl}phenyl3-4- cyclopropylcarbonyl isoxazole (Compound 289), NMR 0.86(m,2H) 1.16(m,2H) 1 82(m, IH) 2. l(s,3H) 2.42(s,3H) 4.0(s,2H) 6.77(1H) 7.0-

7.15(3H) 7.3-7.45(3H) 8.65(s,lH); and

5-[2-benzyl-4-trifluoromethylphenyl]-4-cyclopropylcarbonyl isoxazole (Compound 291), NMR 0.75-0.84(m,2H) 1.04-1.12(m,2H) 1.65(m,lH) 4.07(s,2H) 6.9-7.75(8H,m) 8.62(s,lH).

Example 6 A mixture of 4-(2-benzylbenzoyl)-5-cyclopropylisoxazole (5.0g) and triethylamine (1.8g) was stined in dichloromethane for 1.25 hours, then washed with hydrochloric acid (2M). The organic phase was dried (magnesium sulphate) and evaporated to dryness. The residue was dissolved in ether, washed with water, dried (magnesium sulphate) and evaporated. The residue was triturated with hexane to give l-(2- benzylphenyl)-2-cyano-3-cyclopropylpropan-l,3-dione as an orange solid (Compound 85, 0.24g), m.p. 76-77.5°C.

The following compounds were prepared in a similar manner: 1 -[2-benzyl-4-(ethylthio)phenyl]-2-cyano-3 -cyclopropylpropan- 1 ,3-dione as an orange gum (Compound 86), NMR 1.2(m,2H),

1.3(m,5H), 2.3(m,lH), 2.9(q,2H), 4.1(s,2H), 7.2(m,7H), 7.4(d,lH), 17.4(br,lH); l-[2-benzy 4-(methylthio)phenyl]-2-cyano-3-cyclopropylpropan- 1,3-dione as an orange gum (Compound 87), NMR 1.2(m,2H), 1.3(m,2H), 2.3(m,lH), 2.5(s,3H), 4.1(s,2H), 7.2(m,7H), 7.5(d,lH),

17.5(br, lH); l-[2-(2-methylthiobenzyl)phenyl]-2-cyano-3-cyclopropylpropan - 1,3-dione (Compound 292), NMR 1.18-1.35(m,4H), 2.35(m, lH), 2.39(s,3H), 4.22(s,2H), 6.98-7.53(m,8H); 1 -[2-(2-methylsulphinylbenzyl)phenyl]-2-cyano-3- cyclopropylpropan-l,3-dione (Compound 293), NMR 1.25-1.4(m,4H), 2.32(m,lH), 2.35(s,3H), 4.25(s,2H), 7.13-7.55(m,7H) 8.01(d, lH);

1 -[2-(2-methylsulphonylbenzyl)phenyl] -2-cyano-3 - cyclopropylpropan- 1,3 -dione (Compound 294), NMR 1.24-1.38(m,4H), 2.34(m,lH), 2.77(s,3H), 4.64(s,2H), 7.19-7.63(m,7H) 8.07(d,lH); l-[2-(2-methylbenzyl)phenyl]-2-cyano-3-cyclopropylpropan-l,3 - dione (Compound 295), NMR 1.2-1.36(m,4H), 2.17(s,3H), 2.32(m,lH) 4.13(s,2H), 7.0-7.5(m,8H); and l-[4-fluoro-2-(2-methylbenzyl)phenyl]-2-cyano-3- cyclopropylpropan-l,3-dione (Compound 296), NMR 1.2-1.36(m,4H),

2.16(s,3H), 2.32(m,lH) 4.11(s,2H), 6.85-7.52(m,7H).

Example 7 l-Fluoro-2,4,6-trimethylpyridinium triflate(2.0g) was added to a stined solution of 5-cyclopropyl-4-[(2- methylthiobenzyl)benzoyl]isoxazole(1.0g) in dichloromethane and acetonitrile at room temparatue. The reaction mixture was refluxed for 3 hours, cooled, extracted (dichloromethane), washed (water), dried (magnesium sulfate) and evaporated. The residue purified by chromatography on silica gel eluting with ethyl acetate/hexane to give 5- cyclopropyl-4-[2-(2-fluoromethylthiobenzyl)benzoyl3isoxazole (Compound 297) as a gum, NMR 1.15-1.35(4H), 2.57(lH,m),

4.31(2H,s) 5.59(2H,d,J=52.6Hz) 7.05-7.26(3H) 7.26-7.43(3H) 7.56(lH)8.18(lH,s).

The following compound was prepared in a similar manner: ethyl 5-cyclopropyl-4-[2-(2-fluoromethylthiobenzyl)benzoyl]- isoxazole-3-carboxylate (Compound 298), NMR 1.13-1.34(4H,m)

1.19(3H,t) 2.24(lH,m) 4.13(2H,s) 5.26(2H,d) 7.11-7.58(7H) 8.1(lH,d). Example 8

A mixture of 4-(3-fluoro-2-methylbenzoyl)-5-cyclopropyl isoxazole (0.74g), N-bromosuccinimide (0.80g) and benzoylperoxide (0 02g) in carbon tetrachloride was inadated with a 300W bulb lamp for

4 hours, then filtered and evaporated. To a stined solution of this crude bromide, 2-methylthiobenzeneboronic acid (0.50g) and tetrakis(triphenylphosphine)palladium(0) (0.1 Og) in toluene, was added 5ml of a 2M aqueous solution of Na 2 CO3- The vigorously stined mixture was warmed to 100 °C for 3 hours, cooled and extracted (ethyl acetate ).The organic phase was dried (anhydrous magnesium sulfate), evaporated and purified by chromatography on silica gel eluting with ethyl acetate/hexane to give 4-[3-fluoro-2-(2-methylthiobenzyl)benzoyl]- 5-cyclopropylisoxazole (0.13g) (Compound 299), NMR 1.14-1.30(4H), 2.40(s,3H), 2.55(m,lH), 4.20(s,2H), 6.85(d,lH), 6.97(1H), 7.08-

7.42(5H), 8.15(s,lH).

The following compounds were prepared in a similar manner: ethyl 5 -cyclopropyl-4-[3 -chloro-2-(2- methylthiobenzyl)benzoyl]isoxazole-3-carboxylate (Compound 300) NMR 1.10-1.30(7H) 2.25(m,lH) 2.50(s,3H) 4.10(q,2H) 4.30(s,2H)

6.63(d,lH) 7.00(1H) 7.13-7.50(4H) 7.58(1H); and

ethyl 5-cyclopropyl-4-[3,4-dichloro-2-(2- methylthiobenzyl)benzoyl] isoxazole-3-carboxylate (Compound 153) NMR 1.10-1.30(7H), 2.25(m,lH),2.50(s,3H), 4.14(q,2H), 4.34(s,2H), 6.60(d,lH)7.00(lH) 7.15-7.25(2H) 7.30(d,lH)7.79(d,lH). Example 9

Sodium hydride (0.02g) was added to a stirred solution of ethyl 5- cyclopropyl-4-[2-(2-methylthiobenzyl)benzoyl3isoxazole-3-car boxylate (l.Og) in methanol at room temperature. The reaction mixture was stined for lhour, hydrochloric acid (2M) added and then evaporated. The residue was extracted with ether, dried (anhydrous magnesium sulphate), evaporated and the residue purified by chromatography on silica gel to give methyl 5-cyclopropyl-4-[2-(2- methylthiobenzyl)benzoyl3isoxazole-3-carboxylate (0.78g) (Compound 301), NMR 1.08-1.32(m,4H), 2.15(m,lH), 2.43(s,3H), 3.67(s,3H), 4.34(s,2H), 7.2(m,8H).

The following compound was prepared in a similar manner: isopropyl 5-cyclopropyl-4-[2-(2-methylthiobenzyl)benzoyl]- isoxazole-3 -carboxylate (Compound 302), NMR 1.01-1.3(m,4H), 1.2(d,6H), 2.05(m,lH), 2.43(s,3H), 4.34(s,2H), 5.08(sep,lH), 7.01- 7.49(m,8H).

Example 10

A mixture of 3-cyclopropyl-l-{2-[(2,2-difluorobenzodioxol-4- yl)methyl]phenyl}propan-l,3-dione (1.4lg) and N,N- dimethylfoπnamide-dimethylacetal (1.05ml) in toluene was heated at 90°C for 18 hours. The mixture was then evaporated to give 3- cyclopropyl-l-(2-[(2,2-difluorobenzodioxol-4-yl)methyl]pheny l}-2- dimethylaminomethylenepropan-l,3-dione. A solution of this in ethanol was stirred with hydroxylamine hydrochloride (0.33g) for 30 minutes. Water and ether were added and the organic phase washed (water and brine), dried (sodium sulphate) and evaporated. Purification by chromatography on silica gel eluting with ethyl acetate/hexane (1:4) gave 4-cyclopropylcarbonyl-5- { 2-[2,2-(difluorobenzodioxol-4- yl)methyl]ρhenyl}isoxazole (Compound 303), NMR 0.64 - 0.73 (2H, m), 1.00 - 1.07 (2H, m), 1.59 - 1.67 (IH, m), 3.98 (2H, s), 6.53 - 6.59 (IH, m), 6.80 - 6.84 (2H, m), 7.27 - 7.41 (3H, m), 7.43 - 7.50 (IH, m), 8.59

(IH, s).

Example 11

Using the procedure described in Example 4 above there was obtained from 3-cyclopropyl-l-[2-(2-methylbenzyl)phenyl]propan-l,3- dione: ethyl 5-[2-(2-methylthiobenzyl)phenyl]-4-cyclopropylcarbonyl isoxazole-3 -carboxylate (Compound 290), NMR 0.74-0.8 l(m,2H), 1.1 1- 1.18(m,2H), 1.42(3H,t), 1.8(m,lH), 2.35(s,3H), 2.42(s,3H), 4.12(s,2H), 4.47(2H,q), 6.9-7.5(m,8H).

Reference Example 1

A mixture of l-[2-benzyl-4-(methylthio)phenyl]-3- cyclopropylpropan-l,3-dione (9.66g) and N,N-dimethylformamide- dimethylacetal (5.93 ml) in toluene was heated at 80°C for 18 hours. The mixture was then evaporated to give l-[2-benzyl-4- (methylthio)phenyl3-3-cyclopropyl-2-N,N-dimethylaminomethyle ne- propan-l,3-dione as a brown gum (11 33g). This was used directly in the next stage.

Similarly prepared from the appropriate starting materials were compounds of formula (II) above in which L represents NMe 2 :

(a) NMR 0 60 - 0.69 (2H, m), 0.87 - 0 94 (2H, m), 1 72 - 1.83 (IH, m), 2.74 (3H, bs), 3.1 (3H, bs), 4 28 (2H, s), 6.89 - 7 44 (8H, m).

Reference Example 2

A mixture of l-(2-benzyl-4-ethylthio-3-methylphenyl)-3- cyclopropylpropan-l,3-dione(4.4g) and triethylorthoformate (4g) in acetic anhydride (50 ml) was heated at reflux temperature for 4 hours. The excess reagent and solvent were evaporated under reduced pressure, to give l-(2-benzyl-4-ethylthio-3-methylphenyl)-3-cyclopropyl-2- ethoxymethylenepropan- 1,3 -dione (4.9g) as a yellow oil, which was used directly in the next stage. Similarly prepared from the appropriate starting materials were compounds of formula (II) in which L represents OEt:

Reference Example 3

A suspension of magnesium turnings (0.82g) in methanol was stined whilst a solution of t-butyl 3-cyclopropyl-3-oxopropionate (6.33g) in methanol was added. The mixture was heated at 60°C for 0.75 hour, cooled and evaporated. Toluene was added and the mixture re- evaporated. The residue was redissolved in toluene and a solution of 2- benzyl-4-(ethylthio)benzoyl chloride (9.19g) added. The mixture was stined at ambient temperature for 2 days, then hydrochloric acid (2M) added and the stirring continued for another 1 hour. The organic phase was washed with hydrochloric acid (2 M) then with water and dried (magnesium sulphate). 4-Toluene-sulphonic acid (0.5g) was added and the mixture stined at reflux for 2 hours, cooled and washed in turn with saturated sodium bicarbonate solution and water, and dried (magnesium sulphate). Evaporation to dryness gave l-[2-benzyl-4-(ethylthio)phenyl]- 3-cyclopropylpropan-l,3-dione (10.18g) as a brown oil, NMR 0.9(m,2H), l.l(m,2H), 1.3(t,3H), 1.7(m,lH), 2.9(q,2H), 4.2(s,2H), 5.8(s,lH), 7.2(m,7H), 7.4(d,lH).

By proceeding in a similar manner the following compounds of formula (VI) above may be prepared:

(a)NMR0.9(m,2H), l.l(m,2H), 1.6(m,lH), 2.4(s,3H), 4.2(s,2H), 5.8(s,lH), 7.1(m,7H), 7.4(d,lH), 16.1(br,lH).

(b) NMR 0.97(m,2H), 1.18(m,2H), 1.7(m,lH), 4.23(s,2H), 5.82(s,2H), 7.1-7.5(m,9H).

(c) NMR 0.95(m,2H), l.l(m,2H), 1.65(m,lH), 2.4(s,3H), 2.46(s,3H) 4.29(s,2H), 6.91(m,2H), 7.03-7.16(m,2H), 7.22(m,2H), 7.48(d,lH).

(d)NMR0.8(m,2H), 1.0(m,2H), 1.3(t,3H), 1.5 (m,lH), 2.1(s,3H), 2.3(s,2H), 2.9(q,2H), 4.2(s,2H), 5.7(s,2H), 6.95-7.3(m,7H).

(e)NMR0.8(m,2H), 1.0(m,2H), 1.5(m,lH), 2.0(s,3H), 4.2(s,2H), 5.7(s,2H), 6.9-7.4(m,7H).

(f)NMR0.9(m,2H), 1.15(m,2H), 1.6(m,lH), 2.2(s,3H), 2.4(s,lH), 2.5(s,3H), 4.3(s,2H), 5.8(s,2H), 7.0-7.45(m,7H).

(g)NMR0.85(m,2H), l.l(m,2H), 1.6(m,lH), 2.05(s,3H), 4.6(s,2H), 5.7(s,lH), 7.0-7.25(m,5H), 7.35(d,lH), 7.45(d,lH), 15.8(br,lH).

(h) NMR 0.9(m, lH), l. l(m,2H), l ' .65(m, lH), 2.1(s,3H), 2.35(s,3H), 4.2(s,2H), 5.8(s,2H), 6.85-7.45(m,7H).

(I) NMR 0.9(m,2H), 1.08(m,2H), 1.6(m,lH), 4.1(s,2H), 5.75(s,2H), 6.7-6.9(m,2H), 6.95(d,2H), 7.15(d,2H), 7.4(dd,lH). (j) NMR 0.9(m,2H), l.l(m,2H), 1.6(m, lH), 4.12(s,2H),

5.75(s,2H), 6.25-7.18(m,6H), 6.4(dd,lH).

(k) NMR 0.95(m,2H), 1.16(m,2H), 1.66(m,lH), 2.45(s,3H), 4.2(s,2H), 5.85(s,2H), 7.0-7.2(m,6H), 7.42(d,lH).

(1) NMR 0.88(m,2H), 1.08(m,2H), 1.6(m,lH), 2.4(s,3H), 4.1(s,2H), 5.75(s,2H), 6.92-7.2(m,6H), 7.35(d,lH).

(m) NMR 0.9(m,2H), l. l(m,2H), 1.6(m,lH), 4.25(s,2H), 5.8(s,2H), 6.85-6.9(m,lH), 7.0(m,lH), 7.1(m,2H), 7.3(m,lH), 7.4(dd,lH).

(n) NMR 0.87(m,2H), 1.06(m,2H), 1.6(m,lH), 2.32(s,3H), 4.28(s,2H), 5.28(s,2H), 6.82-7. l(m,5H), 7.3(m,lH), 7.4(d,lH).

(o) NMR 0.9(m,2H), l. l(m,2H), 1.57(m,lH), 2.2(s,3H), 2.52(s,3H), 4.5(s,2H), 5.61(s,2H), 6.47(d, lH), 6.95(t,lH), 7.1- 7.3(m,2H), 7.44(q,2H).

(p) NMR 0.83-0.90 (m, 2H), 1.00-1.08 (m, 2H), 1.47-1.57 (m, IH), 2.34(s, 3H), 4.30 (s, 2H), 5.65 (s, IH), 6.95-7.28 (m, 8H).

(q) NMR 0.92-0.99 (m, 2H), 1.09-1.18 (m, 2H), 1.62 (d, 3H), 2.31- 2.38 (m, IH), 2.35 (s, 3H), 5.04 (q, 2H), 5.78 (s, IH), 7.07-7.43 (m, 8H).

(r) 0.93 - 1.02 (2H, m), 1.13 - 1.21 (2H, m), 1.64 - 1.74 (IH, m), 4.28 (2H, s), 5.88 (IH, s), 6.76 - 7.51 (7H, m).

(s) NMR 0.85-0.95(m,2H) 1.07-1.14(m,2H) 1.64(m,lH) 2.29(s,3H) 2.44(s,3H) 4.27(s,2H) 5.84(s,lH) 6.87-6.93(2H) 7.04- 7.12(2H) 7.22-7.27(2H) 7.55(d,lH)

(t) NMR 0.90-0.97(2H) 1.12-1.18(2H) 1.68(m,lH) 2.42(s,3H) 4.27(2H) 5.86(1H) 6.92(1H) 7.05-7.38(5H) 7.52(d,lH)

(u) NMR 0.95-1.05(m,2H) 1.13-1.18(m,2H) 1.70(m,lH) 2.47(s,3H) 4.27(2H) 5.86(1H) 6.90-7.45(6H) 7.54(d,lH)

(v) NMR 0.95-1.12(m,2H) 1.15-1.21(ra,2H) 1.72(m,lH) 2.47(s,3H) 4.29(2H) 5.88(s,lH) 6.94(s,lH) 7.04-7.40(5H) 7.50(d,lH) (w) NMR 0.95- 1.02(m,2H) 1.15-1.22(m,2H) 1.72(m,lH)

2.22(s,3H) 2.47(s,3H) 4.25(2H) 5.89(s,lH) 6.83(1H) 7.1-7.35(4H) 7.50(d,lH)

(x) NMR 0.95-1 00(m,2H) 1 15(m,2H) 1 70(m,lH) 2 44(s,3H) 4 20(2H) 5 86(1H) 6 85-7 5(7H) Reference Example 4

A methanol solution of methyl 4-bromo-2-(2-methylsulphonyl-2- phenylethyl)benzoate (3.0g) and lithium hydroxide monohydrate (4 6 ml of a 2M solution in water) was stined at room temperature for 20 hours, then at 60°C for 3 hours. The solution was washed with ethyl acetate and the aqueous phase acidified with hydrochloric acid (10 M) and then extracted (ethyl acetate). The extract was washed (brine), dried (magnesium sulphate) and evaporated to give 4-bromo-2-(2- methylsulphonyl-2-phenylethyl)benzoic acid (2.7g), m.p. 160 3-160 5°C Reference Example 5 n-Butylithium (20 ml o ' f a 2 5 M solution in hexanes) was added to a solution of benzylmethylsulphone (8.5g) in tetrahydrofuran at 0°C A solution of methyl 4-bromo-2-bromomethylbenzoate (15.3g) in tetrahydrofuran was then added below -70°C The mixture was allowed to warm to -40°C then re-cooled to -70°C, and saturated ammonium chloride added. After warming to room temperature the mixture was partitioned between ethyl acetate and brine, and the organic phase washed (brine), dried (magnesium sulphate) and evaporated The residue was purified by chromatography eluting with ethyl acetate/hexane, followed by re-crystallisation from ethyl acetate/hexane to give methyl 4- bromo-2-(2-methylsulphonyl-2-phenylethyl)benzoate (7 4g), m p. 101 5- 102°C Reference Example 6

A mixture of 2-[4-chloro-3-methylthio-2-(2- methylthiobenzyl)phenyl3-4,4-dimethyl-l,3-oxazoline (6 6g) and concentrated hydrochloric acid was heated under reflux for 17 hours, cooled and poured onto ice/water The mixture was extracted (ether) and the organic phase itself extracted with sodium hydroxide solution.

The basic extract was acidified to pHl with concentrated hydrochlonc acid, extracted with ether, and the extract dried (magnesium sulphate) and evaporated to give 4-chloro-3-methylthio-2-(2- methylthiobenzyl)benzoic acid (2.4g), m.p. 125-130°C The following compounds were prepared by proceeding in a similar manner.

2-Benzyl-3-(methylthio)benzoic acid, m p.l55-157°C

2-[l-Methyl-2-(methylthio)benzyl]benzoic acid, NMR 1.68 (d, 3H), 2.31 (s, 3H), 5.50 (q, IH), 7.10 (d, IH), 7.18-7.29 (m, 4H), 7.32- 7.41 ( , 2H), 8.01 (d, IH).

4-Fluoro-2-[2-(methyl)benzyl]benzoic acid, NMR 2.22 (3H, s), 4.46 (2H, s), 6.63 (IH, dd), 6.91-7.03 (2H, m), 7.11 - 7.23 (3H, m),

8.15 (IH, dd).

Reference Example 7

A solution of 2-methylthiobenzylmagnesium bromide was prepared from 2-methylthiobenzyl bromide (1 .5g) and magnesium (1.9g) in dry ether, and added via a cannula to a solution of 2-(4-chloro-2-fluoro-3- methylthiophenyl)-4,4-dimethyl-l,3-oxazoline (9.0g) in dry ether. The reaction mixture was heated under reflux overnight, cooled, and poured onto a mixture of ice and hydrochloric acid (2 M). The mixture was basified with sodium hydroxide solution (5 M) and extracted (ether). The organic phase was dried (anhydrous magnesium sulphate) and evaporated to give 2-[4-chloro-3-methylthio-2-(2- methylthiobenzyl)phenyl]-4,4-dimethyl- 1,3 -oxazoline (6.6g), NMR 1.12(s,6H), 2.2(s,3H), 2.52(s,3H), 3.83(s,2H), 4.8(s,2H), 6.39(d,lH), 6.94(m, lH), 7.1-7.22(m,2H), 7.45(d,lH), 7.63(d,lH). By proceeding in a similar manner the following compound was prepared from 2-phenylethylmagnesium bromide:

2-[4-fluoro-2-(2-phenylethyl)phenyl]-4,4-dimethyl-l,3-oxa zoline, NMR 1.37(s,6H), 2.83(dd,2H), 3.26(dd,2H), 4.02(s,2H), 6.9(m,2H), 7.15-7.3(m,5H), 7.76(m,lH). By proceeding in a similar manner the following compounds were also prepared.

2-[2-Benzyl-3-(methylthio)phenyl]-4,4-dimethyl-l,3-oxazol ine, NMR 1.28 (s, 6H), 2.4 (s, 3H), 3.97( s, 2H), 4.58 (s, 2H), 7.05-7.38 (m, 7H), 7.57 (d, IH). 4,4-Dimethyl-2-[2-(2-methylthiobenzyl)phenyl]- 1 ,3 -oxazoline,

NMR 1.45 (s, 6H), 2.50 (s, 3H), 4.18 (s, 2H), 4.79 (s, 2H), 7.11-7.21 (m, 3H), 7.25-7.31 (m, 2H), 7.38-7.40 (m, IH), 7.43-7.52 (m, IH), 7.94-8.05 (m, IH).

4,4-Dimethyl-2-(4-fluoro-2-[2-(methyl)benzyl]phenyl}-l,3- oxazoline, NMR 1.29 (6H, s), 2.22 (3H, s), 4.46 (2H, s), 6.63 (IH, dd),

6.91 - 7.03 (2H, m), 7.11 - 7.23 (3H, m), 8.15 (IH, dd). Reference Example 8

n-Butyl lithium (11.8ml of a 2.5M hexane solution) was added to a stined solution of 4,4-dimethyl-2-{2-[2-(methylthio)benzyι]phenyl }-l,3- oxazoline (6.1g) in tetrahydrofuran, below -60°C. After 2.5 hours, methyl iodide (3. lg) was added below-60°C and the mixture was warmed to room temperature over 2.5 hours, then cooled to 0°C and hydrochloric acid (2M) added. The mixture was extracted (ethyl acetate) and the organic phase dried (anhydrous magnesium sulphate), evaporated and purified by chromatography, eluting with ethyl acetate / hexane (1 :5) to give 4,4-dimethyl-2-(2-[l-methyl-2-(methylthio)benzyl} phenyl }-l,3- oxazoline (5.8g), NMR 1.36 (s, 6H) 1.65 (d, 3H), 2.41 (s, 3H), 4.29 (d,

IH), 4.48 (d, IH), 5.21 (q, IH), 6.99 (d, IH), 7.08-7.24 (m, 3H), 7.34- 7.40 (m, 2H), 7.51-7.59 (m, IH), 7.99 (d, IH). Reference Example 9

A mixture of methyl 2-[2-(bromomethyl)benzyl]-4-fluorobenzoate (lg), sodium thiomethoxide (0.26g) and tetra- n butylammonium iodide

(0.022g) in methanol was stined at 0°C for two hours. The mixture was poured onto water and extracted with ether. The organic phase was dried (magnesium sulphate), evaporated and purified by chromatography, eluting with dichloromethane-hexane to give methyl 4-fluoro-2-[2- (methylthiomethyl)benzyl]benzoate,(0.48g), NMR 2.03 (3H, s), 3.67

(2H, s), 3.87 (3H, s), 4.54 (2H, s), 6.70 (IH, dd), 6.92 - 7.02 (2H, m), 7.17 - 7.31 (3H, m), 8.00 (IH, dd). Reference Example 10

A mixture of methyl 4-fluoro-2-[2-(methyl)benzyl]benzoate (12.55g), N-bromosuccinimide (12.08g) and dichloromethane was inadiated with a 150W tungsten light for five hours at reflux temperature. The suspension was filtered and the filtrate washed with water, dried (magnesium sulphate) and evaporated. The residue was purified by chromatography, eluting with ethyl acetate-hexane to give methyl 2-[2-(bromomethyl)benzyl]-4-fluorobenzoate (2.77g), m.p. 63 -

64.2°C

Reference Example 11

A solution of 4-fluoro-2-[2-(methyl)benzyl]benzoyl chloride in toluene was treated with methanol. After stirring for 17 hours the solvents were evaporated to give methyl 4-fluoro-2-[2-

(methyl)benzyl]benzoate (12.55g), NMR 2.22 (3H, s), 3.86 (3H, s), 4.40 (2H, s), 6.62 (IH, dd), 6.91 - 7.0 (2H, m), 7.10 - 7.22 (3H, m), 8.02 (IH, dd).

Reference Example 12

A solution of 4-fluoro-2-[2-(methyl)benzyl]benzoic acid (12g) in dichloromethane was treated with oxalyl chloride (5.12ml) and a few drops of N,N-dimethylforraamide and the mixture was stined for 90 minutes. The solvents were evaporated to give 4-fluoro-2-[2-

(methyl)benzyl]benzoyl chloride used directly in the next stage. Reference Example 13 A mixture of methyl 4-fluoro-2-[2- (methoxymethyl)benzyl)]benzoate (lg) and sodium thiomethoxide (0.32g) in N,N-dimethylformamide was stined at room temperature for four hours. The mixture was poured onto ice-water and the solid filtered, dissolved in ether, dried (magnesium sulphate) and evaporated to give methyl 2-[2-(methoxymethyl)benzyl]-4-(methyIthio)benzoate (0.99g), NMR 2.31 (3H, s), 3.30 (3H, s), 3.73 (3H, s), 4.37 (2H, s), 4.39 (2H, s), 6.78 (IH, d), 6.82 - 6.87 (IH, m), 7.03 (IH, dd), 7.10 - 7.19 (2H, m),

7.29 - 7.34 (IH, m), 7.83 (IH, d). Reference Example 14

Sodium (0.106g) was dissolved in methanol and a suspension of methyl 2-(2-bromomethylbenzyl)-4-fluorobenzoate (1.4g) in methanol and tetra- n butylammonium iodide (0.03 g) were added. The mixture was heated at reflux for two hours, poured onto ice-water and the ether extract dried (magnesium sulphate) and evaporated to give methyl 2-[2- (methoxymethylbenzyl)]-4-fluorobenzoate (l.Olg), NMR 3.35 (3H, s), 3.84 (3H, s), 4.41 (2H, s), 4.46 (2H, s), 6.68 (IH, dd), 6.94 - 7.01 (2H, m), 7.20 - 7.28 (2H, m), 7.38 - 7.43 (IH, m), 8.00 (IH, dd).

Reference Example 15

A mixture of methyl 3-methylbenzoate(4.5g) and N- bromosuccinimide(6.4g) , benzoylperoxide (0.2g) in carbon tetrachloride was irradiated with a 300W bulb lamp for 4 hours. The reaction mixture was filtered and the filtrate evaporated. To a stined solution of this crude bromide, 2-methylthiobenzeneboronic acid (5.0g) and tetrakis triphenylphosphine palladium(O) (1.0g) in toluene was added 30ml of a 2M aqueous solution of Na 2 CO3. The vigorously stined mixture was warmed to 100 °C for 4hours, cooled, extracted (ethyl acetate), dried (anhydrous magnesium sulfate) and evaporated . Purification by chromatography eluting with ethyl acetate/hexane gave methyl 3-(2- methylthio)benzylbenzoate (4.54g), NMR 2.43(s,3H), 3.90(s,3H), 4.13(s,2H) ,7.05-7.40(6H), 7.85-7.93(m,2H).

Reference Example 16

A solution of methyl 2-(2-methylthiobenzyl)benzoate (2.85g) and methyl 1-methylcyclopropyl ketone(2.0g) in tetrahydrofuran was added dropwise to a suspension of sodium hydride(60% dispersion in mineral oil, 0.70g) in tetrahydrofuran at 60 °C. The mixture was refluxed for 2 hours, cooled and ether and IN HCl added. The organic layer was washed with water, dried (magnesium salfate) and evaporated. The residue was purified by chromatography eluting with ethyl acetate/hexane to give l-[(2-methylthiobenzyl)phenyl]-3-(l- methylcyclopropyl)propan- 1,3-dione (1.8g), NMR 0.75(2H,m)

1.20(3H,s) 1.28(2H,m) 2.25(3H,s) 4.27(2H,s) 5.82(lH,s) 6.90(lH,d) 7.15-7.18(2H) 7.20-7.40(4H) 7.56(lH,d).

By proceeding in a similar manner the following compound was prepared: l-t-butyl-3-[(2-methylthiobenzyl)phenyl]propan-l,3-dione(1.8 g),

NMR, 1.12(9H,s) 2.45(3H,s) 4.27(2H,s) 5.86(lH,s) 6.90(lH,d) 7.03- 7.40(6H) 7.55(lH,d).

Reference Example 17

A solution of 2-methylthio-phenylmagnesium bromide was prepared from 2-bromothioanisole (5g) and magnesium (0.65g) in dry ether, and added via a cannula to a solution of phthalic anhydride (4g) in dry tetrahydrofuran. The reaction mixture was heated under reflux for 3 hours, cooled, and poured onto ice and hydrochloric acid (2 M) and extracted (ethyl acetate). The organic phase was dried (anhydrous magnesium sulphate) and evaporated to give 2-(2- methylthiobenzoyl)benzoic acid (5g) as a white solid .

Reference Example 18

A suspension of 2-(2-methylthiobenzoyl)benzoic acid (5g), zinc powder (12g) and copper sulphate (0. lg) in 25% ammonia solution was heated under reflux for 5hours. The filtered solution was acidified with hydrochloric acid, extracted (ethyl acetate), dried (anhydrous magnesium sulphate) and evaporated to give 2-(2-methylthiobenzyl)benzoic acid (3.8g), NMR, 2.45(3H,s) 4.28(lH,bs) 4.52(2H,s) 6.9-7.80(7H) 8.02(lH,d). Reference Example 19 n-Butyl lithium (45ml of a 1.6N solution in n-hexane) was added to a solution of 4,4-dimethyl-2-phenyl-l,3-oxazoline (14g) in

tetrahydrofuran below -60 °C and the mixture allowed to warm to -20 °C then recooled to -70 °C. A solution of 2-methylthio-4- trifluoromethoxybenzoyl chloride (17g) in tetrahydrofuran was then added whilst stirring below -65 °C. After 2hours the mixture was warmed to room temperature, water and ethyl acetate added, and the organic layer washed(water and brine), dried(magnesium salfate) and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate/n-hexane to give 4,4-dimethyl-2[2-(2- methylthio-4-trifluoromethoxybenzoyl)phenyl]-l,3-oxazoline, NMR, 1.02(6H,s) 2.48(3H,s) 3.63(2H,s) 6.82(1H) 7.12(1H) 7.24(1H) 7.48-

7.60(3H) 7.86(1H).

Reference Example 20

A solution of methyl 4 " -fluoro-2-[2-(methylthiomethyl)- benzyl]benzoate (0.48g) and cyclopropyl methyl ketone (0.2 lg) in dry tetrahydrofuran was added over 15 minutes to sodium hydride (0.138g of

60%) stirred at reflux in tetrahydrofuran under nitrogen. After 2.5 hours the mixture was cooled and ether and sodium bicarbonate solution added. The organic phase was dried and evaporated to give 1- cyclopropyl-3 - { 4-fluoro-2- [2-(methylthiomethyl)benzyl]phenyl } - 1 , 3 - propandione NMR 0.93-1.03 (2H, m), 1.12 - 1.22 (2H, m), 1.66 - 1.76

(IH, m), 2.01 (3H, s), 3.62 (2H, s), 4.38 (2H, s), 5.88 (IH, s), 6.73 (IH, dd), 6.91 - 7.06 (2H, m), 7.15 - 7.30 (3H, m), 7.51 (IH, dd), 11.7 (IH, bs).

By proceeding in a similar manner was prepared l-cyclopropyl-3- {2-[2-(methoxymethyl)benzyl]-4-(methylthio)phenyl}-l,3-propa ndione

NMR 0.92 - 1.00 (2H, m), 1.12 - 1.17 (2H, m), 1.64 - 1.71 (IH, m), 2.41 (3H, s), 3.39 (3H, s), 4.31 (2H, s), 4.43 (2H, s), 5.88 (IH, s), 6.91 (IH, d), 6.99 - 7.02 (IH, m), 7.14 (IH, d), 7.21 - 7.27 (2H, m), 7.37 - 7.41 (IH, m), 7.49 (IH, d), 16.08 (IH, bs).

According to a feature of the present invention, there is provided a method for controlling the growth of weeds (i.e. undesired vegetation) at a locus which comprises applying to the locus a herbicidally effective amount of at least one isoxazole or 2-cyano- 1,3 -dione derivative of formula (I) or an agriculturally acceptable salt thereof. For this purpose, the isoxazole or 2-cyano-l,3-dione derivatives are normally used in the form of herbicidal compositions (i.e. in association with compatible

diluents or carriers and/or surface active agents suitable for use in herbicidal compositions), for example as hereinafter described.

The compounds of formula (I) show herbicidal activity against dicotyledonous (i.e. broad-leafed) and monocotyledonous (i.e. grass) weeds by pre- and/or post-emergence application.

By the term "pre-emergence application" is meant application to the soil in which the weed seeds or seedlings are present before emergence of the weeds above the surface of the soil. By the term "post- emergence application" is meant application to the aerial or exposed portions of the weeds which have emerged above the surface of the soil.

For example, the compounds of formula (I) may be used to control the growth of: broad-leafed weeds, for example, Abutilon theophrasti. Amaranthus retroflexus. Bidens pilosa. Chenopodium album. Galium aparine. Ipomoea spp. e.g. Ipomoea purpurea. Sesbania exaltata. Sinapis arvensis. Solanum nigrum and Xanthium strumarium. and grass weeds, for example Alopecurus mvosuroides. Avena fatua. Digitaria sanguinalis. Echinochloa crus-ga li. Sorghum bicolor. Eleusine indica and Setaria spp. e.g. Setaria faberii or Setaria viridis. and sedges, for example, Cvperus esculentus.

The amounts of compounds of formula (I) appUed vary with the nature of the weeds, the compositions used, the time of application, the climatic and edaphic conditions and (when used to control the growth of weeds in crop-growing areas) the nature of the CΓODS. When applied to a crop-growing area, the rate of application should be sufficient to control the growth of weeds without causing substantial permanent damage to the crop. In general, taking these factors into account, application rates between 0.01kg and 5kg of active material per hectare give good results. However, it is to be understood that higher or lower application rates may be used, depending upon the particular problem of weed control encountered.

The compounds of formula (I) may be used to control selectively the growth of weeds, for example to control the growth of those species hereinbefore mentioned, by pre- or post-emergence application in a directional or non-directional fashion, e.g. by directional or non- directional spraying, to a locus of weed infestation which is an area used, or to be used, for growing crops, for example cereals, e.g. wheat, barley, oats, maize and rice, soya beans, field and dwarf beans, peas, lucerne,

cotton, peanuts, flax, onions, carrots, cabbage, oilseed rape, sunflower, sugar beet, and permanent or sown grassland before or after sowing of the crop or before or after emergence of the crop. For the selective control of weeds at a locus of weed infestation which is an area used, or to be used, for growing of crops, e.g. the crops hereinbefore mentioned, application rates between 0.01kg and 4.0kg, and preferably between 0.01kg and 2.0kg, of active material per hectare are particularly suitable.

The compounds of formula (I) may also be used to control the growth of weeds, especially those indicated above, by pre- or post- emergence application in established orchards and other tree-growing areas, for example forests, woods and parks, and plantations, e.g. sugar cane, oil palm and rubber plantations. For this purpose they may be applied in a directional or non- directional fashion (e.g. by directional or non-directional spraying) to the weeds or to the soil in which they are expected to appear, before or after planting of the trees or plantations at application rates between 0.25kg and 5.0kg, and preferably between 0.5kg and 4.0kg of active material per hectare.

The compounds of formula (I) may also be used to control the growth of weeds, especially those indicated above, at loci which are not crop-growing areas but in which the control of weeds is nevertheless desirable.

Examples of such non-crop-growing areas include airfields, industrial sites, railways, roadside verges, the verges of rivers, irrigation and other waterways, scrublands and fallow or uncultivated land, in particular where it is desired to control the growth of weeds in order to reduce fire risks. When used for such purposes in which a total herbicidal effect is frequently desired, the active compounds are normally applied at dosage rates higher than those used in crop-growing areas as hereinbefore described. The precise dosage will depend upon the nature of the vegetation treated and the effect sought.

Pre- or post-emergence application, and preferably pre-emergence application, in a directional or non-directional fashion (e.g. by directional or non-directional spraying) at application rates between 1.0kg and 20.0kg, and preferably between 5.0 and 10.0kg, of active material per hectare are particularly suitable for this purpose.

When used to control the growth of weeds by pre-emergence application, the compounds of formula (I) may be incoφorated into the soil in which the weeds are expected to emerge. It will be appreciated

that when the compounds of formula (I) are used to control the growth of weeds by post-emergence application, i.e. by application to the aerial or exposed portions of emerged weeds, the compounds of formula (I) will also normally come into contact with the soil and may also then exercise a pre-emergence control on later-germinating weeds in the soil.

Where especially prolonged weed control is required, the application of the compounds of formula (I) may be repeated if required.

According to a further feature of the present invention, there are provided compositions suitable for herbicidal use comprising one or more of the isoxazole or 2-cyano- 1 ,3 -dione derivatives of formula (I), in association with, and preferably homogeneously dispersed in, one or more compatible agriculturally- acceptable diluents or carriers and/or surface active agents [i.e. diluents or carriers and/or surface active agents of the type generally accepted in the art as being suitable for use in herbicidal compositions and which are compatible with compounds of formula (I)]. The term "homogeneously dispersed" is used to include compositions in which the compounds of formula (I) are dissolved in other components. The term "herbicidal compositions" is used in a broad sense to include not only compositions which are ready for use as herbicides but also concentrates which must be diluted before use.

Preferably, the compositions contain from 0.05 to 90% by weight of one or more compounds of formula (I).

The herbicidal compositions may contain both a diluent or carrier and surface-active (e.g. wetting, dispersing, or emulsifying) agent. Surface-active agents which may be present in herbicidal compositions of the present invention may be of the ionic or non-ionic types, for example sulphoricinoleates, quaternary ammonium derivatives, products based on condensates of ethylene oxide with alkyl and polyaryl phenols, e.g. nonyl- or octyl-phenols, or carboxylic acid esters of anhydrosorbitols which have been rendered soluble by etherification of the free hydroxy groups by condensation with ethylene oxide, alkali and alkaline earth metal salts of sulphuric acid esters and sulphonic acids such as dinonyl- and dioctyl-sodium sulphonosuccinates and alkali and alkaline earth metal salts of high molecular weight sulphonic acid derivatives such as sodium and calcium lignosulphonates and sodium and calcium alkylbenzene sulphonates.

Suitably, the herbicidal compositions according to the present invention may comprise up to 10% by weight, e.g. from 0.05% to 10%

by weight, of surface-active agent but, if desired, herbicidal compositions according to the present invention may comprise higher proportions of surface-active agent, for example up to 15% by weight in liquid emulsifiable suspension concentrates and up to 25% by weight in liquid water soluble concentrates.

Examples of suitable solid diluents or carriers are aluminium silicate, talc, calcined magnesia, kieselguhr, tricalcium phosphate, powdered cork, absorbent carbon black and clays such as kaolin and bentonite. The solid compositions (which may take the form of dusts, granules or wettable powders) are preferably prepared by grinding the compounds of formula (I) with solid diluents or by impregnating the solid diluents or carriers with solutions of the compounds of formula (I) in volatile solvents, evaporating the solvents and, if necessary, grinding the products so as to obtain powders. Granular formulations may be prepared by absorbing the compounds of formula (I) (dissolved in suitable solvents, which may, if desired, be volatile) onto the solid diluents or carriers in granular form and, if desired, evaporating the solvents, or by granulating compositions in powder form obtained as described above. Solid herbicidal compositions, particularly wettable powders and granules, may contain wetting or dispersing agents (for example of the types described above), which may also, when solid, serve as diluents or carriers.

Liquid compositions according to the invention may take the form of aqueous, organic or aqueous-organic solutions, suspensions and emulsions which may incorporate a surface-active agent. Suitable Uquid diluents for incorporation in the liquid compositions include water, glycols, tetrahydrofurfuryl alcohol, acetophenone, cyclohexanone, isophorone, toluene, xylene, mineral, animal and vegetable oils and light aromatic and naphthenic fractions of petroleum (and mixtures of these diluents). Surface-active agents, which may be present in the Uquid compositions, may be ionic or non-ionic (for example of the types described above) and may, when liquid, also serve as diluents or carriers. Powders, dispersible granules and liquid compositions in the form of concentrates may be diluted with water or other suitable diluents, for example mineral or vegetable oils, particularly in the case of liquid concentrates in which the diluent or carrier is an oil, to give compositions ready for use.

When desired, liquid compositions of the compound of formula (I) may be used in the form of self-emulsifying concentrates containing the active substances dissolved in the emulsifying agents or in solvents containing emulsifying agents compatible with the active substances, the simple addition of water to such concentrates producing compositions ready for use.

Liquid concentrates in which the diluent or carrier is an oil may be used without further dilution using the electrostatic spray technique. Herbicidal compositions according to the present invention may also contain, if desired, conventional adjuvants such as adhesives, protective colloids, thickeners, penetrating agents, stabilisers, sequestering agents, anti-caking agents, colouring agents and conosion inhibitors. These adjuvants may also serve as carriers or diluents. Unless otherwise specified, the following percentages are by weight. Prefened herbicidal compositions according to the present invention are: aqueous suspension concentrates which comprise from 10 to 70% of one or more compounds of formula (I), from 2 to 10% of surface- active agent, from 0.1 to 5% of thickener and from 15 to 87.9% of water; wettable powders which comprise from 10 to 90% of one or more compounds of formula (I), from 2 to 10% of surface-active agent and from 8 to 88% of solid diluent or carrier; water dispersible granules which comprise from 1 to 75%, e.g. 50 to 75%, of one or more compounds of formula (I), from 2 to 10% of surface-active agent and from 1 to 20%, e.g. 5-15%, of water soluble binder;

Uquid emulsifiable suspension concentrates which comprise from 10 to 70% of one or more compounds of formula (I), from 5 to 15% of surface-active agent, from 0.1 to 5% of thickener and from 10 to 84.9% of organic solvent; granules which comprise from 1 to 90%o, e.g. 2 to 10% of one or more compounds of formula (I), from 0.5 to 7%, e.g. 0.5 to 2%, of surface-active agent and from 3 to 98.5%, e.g. 88 to 97.5%, of granular carrier; and emulsifiable concentrates which comprise 0.05 to 90%, and preferably from 1 to 60% of one or more compounds of formula (I), from 0.01 to 10%, and preferably from 1 to 10%, of surface-active agent

and from 9.99 to 99.94%, and preferably from 39 to 98.99%, of organic solvent.

Herbicidal compositions according to the present invention may also comprise the compounds of formula (I) in association with, and preferably homogeneously dispersed in, one or more other pesticidally active compounds and, if desired, one or more compatible pesticidally acceptable diluents or carriers, surface-active agents and conventional adjuvants as hereinbefore described. Examples of other pesticidally active compounds which may be included in, or used in conjunction with, the herbicidal compositions of the present invention include herbicides, for example to increase the range of weed species controlled for example alachlor [2-chloro-2,6'-diethyl-N-(methoxy-methyl)-acetanilide], atrazine [2-chloro-4-ethylammo-6-isopropylamino-l,3,5-triazine], bromoxynil [3,5-dibromo-4-hydroxybenzonitrile], chlortoluron [N , -(3-chloro-4- methylphenyl)-N,N-dimethylurea], cyanazine [2-chloro-4-( 1 -cyano- 1 - methylethylamino)-6-ethylamino-l,3,5-triazine], 2,4-D [2,4- dichlorophenoxy-acetic acid], dicamba [3,6-dichloro-2-methoxybenzoic acid], difenzoquat [1,2- dimethyl-3,5-diphenyl-pyrazolium salts3, flampropmethyl [methyl N-2-(N- benzoyl-3-chloro-4-fluoroanilino)- propionate3, fluometuron [N'-(3-trifluoro- methylphenyι)-N,N- dimethylurea], isoproturon [N'-(4-isopropylphenyl)-N,N-dimethylurea] , insecticides, e.g. synthetic pyrethroids, e.g. permethrin and cypermethrin, and fungicides, e.g. carbamates, e.g. methyl N-(l-butyl-carbamoyl- benzimidazol-2-yl)carbamate, and triazoles e.g. l-(4-chloro-phenoxy)- 3,3- dimethyl-l-(l,2,4-triazol-l-yl)-butan-2-one.

Pesticidally active compounds and other biologically active materials which may be included in, or used in conjunction with, the herbicidal compositions of the present invention, for example those hereinbefore mentioned, and which are acids, may, if desired, be utilized in the form of conventional derivatives, for example alkaU metal and amine salts and esters.

According to a further feature of the present invention there is provided an article of manufacture comprising at least one of the isoxazole or 2-cyano- 1,3 -dione derivatives of formula (I) or, as is prefened, a herbicidal composition as hereinbefore described, and preferably a herbicidal concentrate which must be diluted before use, comprising at least one of the isoxazole or 2-cyano- 1,3 -dione derivatives of formula (I) within a container for the aforesaid derivative or

derivatives of formula (I), or a said herbicidal composition, and instructions physically associated with the aforesaid container setting out the manner in which the aforesaid derivative or derivatives of formula (I) or herbicidal composition contained therein is to be used to control the growth of weeds. The containers will normally be of the types conventionally used for the storage of chemical substances which are solid at normal ambient temperatures and herbicidal compositions particularly in the form of concentrates, for example cans and drums of metal, which may be internally lacquered, and plastics materials, bottles or glass and plastics materials and, when the contents of the container is a solid, for example granular, herbicidal compositions, boxes, for example of cardboard, plastics materials and metal, or sacks. The containers will normally be of sufficient capacity to contain amounts of the isoxazole or 2-cyano-l,3-dione derivative or herbicidal compositions sufficient to treat at least one acre of ground to control the growth of weeds therein but will not exceed a size which is convenient for conventional methods of handling. The instructions will be physically associated with the container, for example by being printed directly thereon or on a label or tag affixed thereto. The directions will normaUy indicate that the contents of the container, after dilution if necessary, are to be appUed to control the growth of weeds at rates of application between 0.01kg and 20kg of active material per hectare in the manner and for the purposes hereinbefore described.

The following Examples illustrate herbicidal compositions according to the present invention:

Example Cl:

An emulsifiable concentrate is formed from: Active ingredient (Compound 1) 20% w/v

N-Methylpynolidone (NMP) 25% w/v Calcium dodecylbenzenesulphonate 70%

(CaDDBS) (Arylan CA) 4% w/v

Nonylphenol ethylene oxide propylene oxide condensate (NPEOPO)(Synperonic NPE 1800) 6% w/v Aromatic solvent (Solvesso) to 100 volumes by stirring NMP, active ingredient (Compound 1), CaDDBS,

NPEOPO and Aromatic solvent until a clear solution is formed, and adjusting to volume with Aromatic solvent.

Example C2

A wettable powder is formed from: Active ingredient (Compound 1 ) 50% w/w

Sodium dodecylbenzenesulphonate (Arylan SX85) 3% w/w

Sodium methyl oleoyl taurate (Arkopon T) 5% w/w

Sodium polycarboxylate (Sopropon T36) 1% w/w Microfine silicon dioxide (Tixosil 38) 3% w/w China clay 38% w/w by blending the above ingredients together and grinding the mixture in an air jet mill.

Example C3

A suspension concentrate is formed from:

Active ingredient (Compound 1) 50% w/v

Antifreeze (Propylene glycol) 5% w/v

Ethoxylated tristyrylphenol phosphate

(Soprophor FL) 0.5% w/v

Nonyl phenol 9 mole ethoxylate

(Ethylan BCP) 0.5% w/v

Sodium polycarboxylate (Sopropon T36) 0.2% w/v

Attaclay (Attagel) 1.5% w/v

Antifoam (Rhodorsil AF426R) 0.003% w/v

Water to 100 volumes by stirring the above ingredients together and milling in a bead i

Example C4

A water dispersible granule is formed from:

Active ingredient (Compound 1) 50% w/w

Sodium dodecylbenzenesulphonate

(Arylan SX 85) 3% w/w

Sodium methyl oleoyl taurate (Arkopon T) 5% w/w

Sodium polycarboxylate (Sopropon T36) 1% w/w

Binder (Sodium lignosulphonate) 8% w/w

China clay 30% w/w

Microfine silicon dioxide (Tixosil 38) 3% w/w

by blending the above ingredients together, grinding the mixture in an air jet mill and granulating by addition of water in a suitable granulation plant (e.g. Fluid bed drier) and drying. Optionally the active ingredient may be ground either on its own or admixed with some or all of the other ingredients.

The compounds of the invention have been used in herbicidal applications according to the following procedures.

METHOD OF USE OF HERBICIDAL COMPOUNDS:

TEST METHOD A a) General

Appropriate quantities of the compounds used to treat the plants were dissolved in acetone to give solutions equivalent to application rates of up to 4000g test compound per hectare (g/ha). These solutions were apphed from a standard laboratory herbicide sprayer deUvering the equivalent of 290 litres of spray fluid per hectare. b) Weed control : Pre-emergence

The seeds were sown in 70 mm square, 75 mm deep plastic pots in non-sterile soil . The quantities of seed per pot were as follows: -

Weed species Approx number of seeds/pot

1) Broad-leafed weeds

Abutilon theophrasti 10

Amaranthus retroflexus 20 Galium aparine 10

Ipomoea purpurea 10

Sinapis arvensis 15

Xanthium strumarium 2

2) Grass weeds Alopecurus myosuroides 15

Avena fatua 10

Echinochloa crus-galli 15

Setaria viridis 20

3) Sedges Cyperus esculentus 3

Crop

1) Broad-leafed

Cotton Soya 2) Grass

Maize 2

Rice 6

Wheat 6

The compounds of the invention were applied to the soil surface, containing the seeds, as described in (a). A single pot of each crop and each weed was allocated to each treatment, with unsprayed controls and controls sprayed with acetone alone.

After treatment the pots were placed on capillary matting kept in a glass house, and watered overhead. Visual assessment of crop damage was made 20-24 days after spraying. The results were expressed as the percentage reduction in growth or damage to the crop or weeds, in comparison with the plants in the control pots. c) Weed control : Post-emergence

The weeds and crops were sown directly into John Innes potting compost in 75 mm deep, 70 mm square pots except for Amaranthus which was pricked out at the seedling stage and transfened to the pots one week before spraying. The plants were then grown in the greenhouse until ready for spraying with the compounds used to treat the plants. The number of plants per pot were as follows :- 1 ) Broad leafed weeds

Weed species Number of plants per pot Growth stage

Abutilon theophrasti 3 1-2 leaves

Amaranthus retroflexus 4 1-2 leaves

Galium aparine 3 1 st whorl

Ipomoea purpurea 3 1-2 leaves

Sinapis arvensis 4 2 leaves

Xanthium strumarium 1 2-3 leaves

2) Grass weeds

Weed species Number of plants per pot Growth stage

Alopecurus myosuroides 8-12 1-2 leaves

Avena fatua 12-18 1-2 leaves

Echinochloa crus-galli 4 2-3 leaves

Setaria viridis 15-25 1-2 leaves.

3) Sedges

Weed species Number of plants per pot Growth stage

Cyperus esculentus 3 3 leaves.

1) Broad leafed

Crops Number of plants per pot Growth stage

Cotton 2 1 leaf

Soya 2 2 leaves.

2) Grass

Crops Number of plants per pot Growth stage

Maize 2 2-3 leaves

Rice 4 2-3 leaves

Wheat 5 2-3 leaves.

The compounds used to treat the plants were applied to the plants as described in (a). A single pot of each crop and weed species was allocated to each treatment, with unsprayed controls and controls sprayed with acetone alone.

After treatment the pots were placed on capillary matting in a glass house, and watered overhead once after 24 hours and then by controUed sub-irrigation. Visual assessment of crop damage and weed control was made 20-24 days after spraying. The results were expressed as the percentage reduction in growth or damage to the crop or weeds, in comparison with the plants in the control pots.

TEST METHOD B

Paddv post-emergence application in greenhouse

Paddy field soil was filled in 170 cm 2 plastic pots, a suitable amount of water and chemical fertilisers were added thereto and kneaded to convert it to a state of a paddy.

Paddy rice plants (variety; Koshihikari), that had been grown in advance in a greenhouse to a stage of two leaves, were transplanted to each pot (two seedlings per pot). Then in each pot there were sown predetermined amounts of seeds ofEchinochloa orvzicola. Monochoria vaginalis. Lindernia procumbens and Scirpus juncoides respectively, and water was added to a depth of 3 cm.

After having grown the plants in a greenhouse untU Echinochloa oryzicola reached a stage of 1.5 leaves, solutions were prepared in 100% acetone using compounds described in the Examples so that they

contained active ingredients in an amount equivalent to 75, 300 and 1200 g/ha. The solutions were applied by dropping with a pipette.

After 21 days from the application with the chemicals, herbicidal effects on each weed and phytotoxicity on paddy rice plants were visually assessed, and the results expressed as the percentage reduction in growth or damage to the crop or weeds in comparison with the plants in the control pots.

When applied pre- or post-emergence in Test Method A at lOOOg/ha compounds 1, 2, 4, 6, 7, 10, 17-19, 21, 22, 24-32, 36, 38-54, 57-64, 71-76, 78, 81, 84, 86-97, 106-108, 120-122, 136, 141, 146, 165,

167, 212-215, 217, 221-225, 227, 231, 233, 242-245, 250-261, 270, 271, 284, 285, 288, 289, 292-294 and 298-300 gave at least 80% reduction in growth of one or more of the weed species.

When applied pre-emergence in Test Method A at lOOOg/ha compounds 20, 33, 79, 80, 83 and 263 gave at least 80% reduction in growth of one or more of the weed species.

When applied post-emergence in Test Method A at lOOOg ha compounds 3, 35, 37, 77, 85, 153, 218, 219, 230, 232, 234, 239, 262, 297 and 303 gave at least 80% reduction in growth of one or more of the weed species.

At levels of application toxic to the weeds these compounds were selective in at least one of the crop species.

When appUed at 1200g/ha or less, in Test Method B, compounds 3-30, 32, 33, 35, 37, 43-53, 70-72, 74-78, 80-83, 85, 88, 89, 91-99, 103, 106-108, 117, 120-122, 136, 141, 146, 153, 165-168, 170, 172-174,

212-299 and 301-303 of the invention gave at least 80% reduction in growth of one or more of the weed species Usted above.