MCLOUGHLIN JIM I
OTAL ANITA E
PHILLION DENNIS P
SHAH AJIT S
PARLOW JOHN J
| WO1990007493A1 | 1990-07-12 |
| EP0463488A1 | 1992-01-02 |
| 1. | Compounds of Formula I: wherein Ct and C2 are carbon atoms which are part of an aromatic ring and are selected from the group consisting of phenyl, thienyl, pyrimidinyl, pyridyl, and pyrazolyl, with the provisos that when the ring is pyrazolyl, pyridyl, or pyrimidinyl, then Z is limited to O or S and that the N of pyrazolyl is substituted by a lower aliphatic group or aryl; W is alkoxyimino, alkoxymethylene or alkylthiomethylene; Rt is independently selected from the group consisting of halogen, cyano, CrC4 alkyl, C C4 alkoxy, wherein the alkyl or alkoxy are optionally substituted by halogen, and p is 0, 1, or 2; Z is CH2, CH(OH), CO, O, S, NR2 wherein R2 is hydrogen or a lower aliphatic group, CH2CH2, CH=CH, , CH2O, CH2S, CH2S(O), OCH2, SCH2, S(O)CH2, CH2ON=C(R3) or CH=NB wherein B is OCO, N=CR3, or OCR3R4 wherein R3 and R^ are independently hydrogen or C C4 alkyl optionally substituted by halogen; A is an aromatic moiety having 1. |
| 2. | aromatic rings connected linearly from Z to Ii wherein the aromatic rings are optionally connected to each other and to Ii in a linear manner with oxygen, nitrogen, or sulfur; wherein each aromatic ring is optionally independently substituted by R10 groups; q is 0 or 1 ; wherein K, L, M, and Q are independently C or N with the proviso that not more than one or two of K, L, M or Q can be N at once and when K, L, M and Q are carbon each is optionally substituted by R5; n is 1 or 2; and each R5 and R10 group is independently selected from the group consisting of (a) halogen, (b) lower aliphatic group optionally substituted by halogen or CrC4 alkoxy, (c) C C4 alkoxy optionally substituted by halogen, (d) CN, (e) (Yι)qιC(=X)(Y2)q2Rg, where ; X is O or S, qj and q2 are 0 or 1, Y[ and Y2 are independently selected from the group consisting of O, S, and NR8; each R8 is independently selected from the group consisting of hydrogen and a lower aliphatic group optionally substituted by halogen or a C C4 alkoxy group, wherein R8 cannot be hydrogen if both q] and q2 are 1 and Y2 is O or S; (f) S(O)RQ where r is 0, 1, or 2, wherein R9 is a lower aliphatic group optionally substituted by halogen or a C C alkoxy group or Rg is an aryl group optionally substituted by halogen, a CrC alkoxy group, or a C, C alkyl group, (g) Si(Rς,)3, (h) C(=NOCH3)CH3, or (i) aryl, aryloxy, arylthio, and arylamino optionally substituted by halogen, C C alkoxy, or a lower aliphatic group optionally substituted by halogen or C,C4 alkoxy, u is an integer from 0 to 4 R,s is halogen, hydroxy, CpC4 alkoxy, or a lower aliphatic group, optionally substituted with CrC4 alkoxy or halogen; s is 0, 1 , or 2; and 56 Ris: a) C — Y — R, e) f) N — N g) wherein X is S or O; Y is a bond, oxygen, sulfur, or nitrogen carrying a hydrogen, a C C4 alkyl group or a C C4 alkoxy group; each R7 is independently selected from the group consisting of hydrogen, and a lower aliphatic group optionally substituted by halogen, hydroxy, or a CrC4 alkoxy group; and XjisCHorN; 57 or an agronomically acceptable salt thereof. |
| 3. | 2 The compound of claim 1 wherein W is alkoxyimino. |
| 4. | The compound of claim 2 wherein R is a> X H . I C — Y — R7 wherein X and Y are oxygen atoms and R7 is methyl. |
| 5. | The compound of claim 2 wherein Cj and C2 form a phenyl group. |
| 6. | The compound of claim 4 wherein Z is CH2ON=C(R3). |
| 7. | The compound of claim 5 wherein q = 1, A is phenyl, and R3 is methyl. |
| 8. | The compound of claim 6 wherein K, L, M, and Q are carbon atoms and n = 1. 8. |
| 9. | The compound of claim 6 wherein K, L, M, and Q are carbon atoms and n = 2. |
| 10. | The compound of claim 4 wherein Z is CH2O. |
| 11. | The compound of claim 9 wherein q = 0. |
| 12. | The compound of claim 10 wherein K, L, M, and Q are carbon atoms and n = 1. |
| 13. | The compound of claim 10 wherein K, L, M, and Q are carbon atoms and n = 2. 13. |
| 14. | The compound of claim 9 wherein q = 1 and A is phenyl. |
| 15. | The compound of claim 13 wherein K, L, M, and Q are carbon atoms and n = 1. |
| 16. | The compound of claim 13 wherein K, L, M, and Q are carbon atoms and n = 2. |
| 17. | The compound of claim 9 wherein q = 1 and A is phenoxy. |
| 18. | The compound of claim 17 wherein K, , M, and Q are carbon atoms and n = 1. 18. |
| 19. | The compound of claim 17 wherein K, L, M, and Q are carbon atoms and n = 2. |
| 20. | The compound of claim 4 wherein Z is CH=NB. |
| 21. | The compound of claim 19 wherein q = 1, A is phenyl, and B is OCR3R4 wherein R3 is hydrogen and Rj is methyl. |
| 22. | The compound of claim 20 wherein K, L, M, and Q are carbon atoms and n = 1. 22. |
| 23. | The compound of claim 3 wherein Cj and C2 form a thienyl group. |
| 24. | The compound of claim 22 wherein Z is CH2ON=C(R3). |
| 25. | The compound of claim 23 wherein q = 1, A is phenyl, and R3 is methyl. |
| 26. | The compound of claim 24 wherein K, L, M, and Q are carbon atoms and n = 1. |
| 27. | The compound of claim 24 wherein K, L, M, and Q are carbon atoms and n = 2. |
| 28. | The compound of claim 22 wherein Z is CH2O. |
| 29. | The compound of claim 27 wherein q = 1 and A is phenyl. |
| 30. | The compound of claim 28 wherein K, L, M, and Q are carbon atoms and n = 1. |
| 31. | The compound of claim 2 wherein R is a> X , II I C — Y — R 7 wherein X is an oxygen atom, Y is an NH group, and R7 is methyl. |
| 32. | The compound of claim 30wherein C, and C2 form a phenyl group. |
| 33. | The compound of claim 31 wherein Z is CH2ON=C(R3). |
| 34. | The compound of claim 32 wherein q = 1, A is phenyl, and R3 is methyl. |
| 35. | The compound of claim 33 wherein K, L, M, and Q are carbon atoms and n = 1. |
| 36. | The compound of claim 33 wherein K, L, M, and Q are carbon atoms and n = 2. |
| 37. | The compound of claim 31 wherein Z is CH O. |
| 38. | The compound of claim 36 wherein q = 1 and A is phenyl. |
| 39. | The compound of claim 37 wherein K, L, M, and Q are carbon atoms and n = 1. 39. |
| 40. | The compound of claim 37 wherein K, L, M, and Q are carbon atoms and n = 2. |
| 41. | The compound of claim 31 wherein Z is CH=NB. |
| 42. | The compound of claim 40 wherein q = 1, A is phenyl, and B is OCR3R4 wherein R3 is hydrogen and R, is methyl. |
| 43. | The compound of claim 41 wherein K, L, M, and Q are carbon atoms and n = 1. |
| 44. | 43 The compound of claim 41 wherein K, L, M, and Q are carbon atoms and n = 2. |
| 45. | The compound of claim 30 wherein C( and C2 form a thienyl group. |
| 46. | The compound of claim 44 wherein Z is CH2ON=C(R3). |
| 47. | The compound of claim 45 wherein q = 1, A is phenyl, and R3 is methyl. |
| 48. | The compound of claim 46 wherein K, L, M, and Q are carbon atoms and n = 1. 48. |
| 49. | The compound of claim 46 wherein K, L, M, and Q are carbon atoms and n = 2. |
| 50. | The compound of claim 44 wherein Z is CH2O. |
| 51. | The compound of claim 49 wherein q = 1 and A is phenyl. |
| 52. | The compound of claim 50 wherein K, L, M, and Q are carbon atoms and n = 1. |
| 53. | The compound of claim 2 wherein R is wherein X, is a carbon atom. |
| 54. | The compound of claim 52 wherein C, and C2 form a phenyl group. |
| 55. | The compound of claim 53 wherein Z is CH2O. |
| 56. | The compound of claim 54 wherein q = 1 and A is phenyl. |
| 57. | The compound of claim 54 wherein K, L, M, and Q are carbon atoms and n = 1. |
| 58. | The compound of claim 2 wherein R is wherein X] is a nitrogen atom. |
| 59. | The compound of claim 57 wherein C| and C2 form a phenyl group. |
| 60. | The compound of claim 58 wherein Z is CH2O. |
| 61. | The compound of claim 59 wherein q = 1 and A is phenyl. |
| 62. | The compound of claim 60 wherein K, L, M, and Q are carbon atoms and n = 1. |
| 63. | The compound of claim 2 wherein R is a» X , II + C — Y — R7 wherein X is an oxygen atom, Y is an NH group, and R7 is a lower aliphatic group optionally substituted with OH. |
| 64. | The compound of claim 62 wherein Ci and C2 form a phenyl group. |
| 65. | The compound of claim 63 wherein Z is CH O. |
| 66. | The compound of claim 64 wherein q = 1 and A is phenyl. |
| 67. | The compound of claim 65 wherein K, L, M, and Q are carbon atoms and n = 1. |
| 68. | The compound of claim 1 wherein W is alkoxymethylene. |
| 69. | The compound of claim 67 wherein R is 60 a) χ , II + C Y— R7 I wherein X and Y are oxygen atoms and R7 is methyl. |
| 70. | The compound of claim 68 wherein Cj and C2 form a phenyl group. |
| 71. | The compound of claim 69 wherein Z is CH2O. |
| 72. | The compound of claim 70 wherein q = 1 and A is phenyl. |
| 73. | The compound of claim 71 wherein K, L, M, and Q are carbon atoms and n = 1. |
| 74. | The compound of claim 71 wherein K, L, M, and Q are carbon atoms and n = 2. |
| 75. | The compound of claim 69 wherein Z is O. |
| 76. | The compound of claim 74 wherein q = 1 and A is pyrimidinyloxyphenyl. |
| 77. | The compound of claim 75 wherein K, L, M, and Q are carbon atoms and n = 1. |
| 78. | The compound of claim 75 wherein K, L, M, and Q are carbon atoms and n = 2. |
| 79. | The composition for use as a fungicide comprising a fungicidally effective amount of a compound of Formula I of claim 1 together with an agronomically acceptable carrier. |
| 80. | A method of using the compound of claim 1 as a fungicidal agent comprising treatment with an effective amount of a compound of claim 1. |
| 81. | A method of synthesizing a compound of Formula I of claim 1 wherein W is alkoxyimino, R is , II + C — Y — R7 I wherein X and Y are oxygen atoms and R7 is methyl; Ci and C2 form a phenyl group or a thienyl group, p = 0, Z is CH2O or CH2ON=C(R3) wherein R3 is methyl; q is 0 or 1, A is aryloxy or a phenyl group optionally substituted with an R10 group, K, L, M, and Q are carbon atoms, s is 0 or 1 , and Re is a lower aliphatic group; comprising the steps of: (a) reacting methyl2(bromomethyl)phenyl2(methoxyimino)acetate or methyl3 bromomethyl2thienyl2(methoxyimino)acetate with a nucleophile chosen from the group consisting of (i) an oxime and a base in a solvent, (ii) a substituted phenol and a basic salt in a solvent; or (iii) an alcohol and a base in a solvent; and (b) processing the reaction mixture of (a) to obtain the Formula I compound. |
| 82. | A method of synthesizing a compound of Formula I of claim 1 wherein W is alkoxymethylene, R is a> X , II I C — Y — R7 I wherein X and Y are oxygen atoms and R7 is methyl; C, and C2 form a phenyl group, p = 0, Z is CH2O, q is 1, A is phenyl, K, L, M, and Q are carbon atoms, and s is 0; comprising the steps of: (a) reacting methyl 2[2(iodomethyl)phenyl]3methoxypropenoate with a substituted phenol and a basic salt in a solvent; (b) processing the reaction mixture of (a) to obtain the Formula I compound. |
| 83. | A method of synthesizing a compound of Formula I of claim 1 wherein W is alkoxyimino, R is a» X , II + C — Y — R7 I wherein X and Y are oxygen atoms and R7 is methyl; Cj and C2 form a phenyl group, p = 0, Z is CH=NB wherein B is OCR3R,, R3 is hydrogen and R4 is methyl; q is 1 , A is a phenyl group, K, L, M, and Q are carbon atoms, and s is 0; comprising the steps of: (a) reacting methyl 2[(hydroxyimino)methyl]α(methoxyimino)phenylacetate with a base in a solvent, then with a benzylic bromide; and (b) processing the reaction mixture of (a) to obtain the Formula I compound. |
| 84. | A method of synthesizing a compound of Formula I of claim 1 wherein W is alkoxymethylene, R is a> X , II + I C — Y — R7 ' wherein X and Y are oxygen atoms and R7 is methyl; C] and C2 form a phenyl group, p = 0, Z is O; q is 1, A is heteroaryloxyaryl, K, , M, and Q are carbon atoms, and s is 0; 62 comprising the steps of: (a) reacting methyl 2[2(6chloropyrimidine4yloxy)phenyl]3methoxypropenoate with a substituted phenol and a basic salt in a solvent containing a catalyst; and (b) processing the reaction mixture of (a) to obtain the Formula I compound. |
| 85. | A method of synthesizing a compound of Formula I of claim 1 wherein W is alkoxyimino, R is a) χ _ι ,_ c II — Y — R wherein X is an oxygen atom, Y is an NH group, and R7 is methyl or CH2CH(OH)CH3; Ci and C2 form a phenyl group or a thienyl group, p = 0, Z is CH2O, CH2ON=C(R3) wherein R3 is methyl, or CH=NB wherein B is OCR3R4, R3 is hydrogen and R4 is methyl; q is 1, A is phenyl optionally substituted with an R10 group, K, L, M, and Q are carbon atoms, s is 0 or 1, and R^ is a lower aliphatic group; comprising the steps of: (a) reacting methyl esters having the structure of Formula 1 wherein R is CO2CH3 with aqueous methylamine or lamino2propanol; and (b) processing the reaction mixture of (a) to obtain the Formula I compound. |
| 86. | A method of synthesizing a compound of Formula I of claim 1 wherein W is alkoxyimino, R is wherein Xj is carbon or nitrogen; Cx and C2 form a phenyl group, p = 0, Z is CH2O; q is 1 , A is phenyl, K, L, M, and Q are carbon atoms, and s is 0; comprising the steps of: (a) reacting Nmethoxy 2[4(lindanyl)phenoxymethyl] benzenecarboximidoyl chloride with an azoles and a base in a solvent; and (b) processing the reaction mixture of (a) to obtain the Formula I compound. |
The present invention relates to novel oxime ethers and their use as fungicides, particularly in the agricultural field.
Various arylalkoxyiminoacetic acid derivatives having utility are known as fungicidal agents. For example, a compound ofthe formula:
CONHCH 3
N
/
O
is described in EP 398692. Further a compound ofthe formula:
N
/
O
is described in WO92/13830 and EP 463488. Furthermore, a compound of the formula:
- 2 is described in EP 499823. Also, a compound ofthe formula:
U 2
u Y r Y UsCHj u 4 is described in EP 515901. Further, US Patent No. 4,829,085 discloses other compounds in this class. Other references of interest are WO 95/04728, EP 0633252A1 and WO 94/22844.
However, none of the disclosed compounds in the above references provide any teaching to the present invention.
The present invention comprises compounds of Formula I:
wherein Ci and C 2 are carbon atoms which are part of an aromatic ring and are selected from the group consisting of phenyl, thienyl, pyrimidinyl, pyridyl, and pyrazolyl, with the provisos that when the ring is pyrazolyl, pyridyl, or pyrimidinyl, then Z is limited to O or S and that the N of pyrazolyl is substituted by a lower aliphatic group or aryl; W is alkoxyimino, alkoxymethylene or alkylthiomethylene; Rj is independently selected from the group consisting of halogen, cyano, C C 4 alkyl,
C,-C 4 alkoxy, wherein the alkyl or alkoxy are optionally substituted by halogen, and p is 0, 1, or 2;
Z is -CH 2 -, -CH(OH)-, -CO-, -O-, -S-, NR 2 wherein R 2 is hydrogen or a lower aliphatic group, -CH 2 CH 2 -, -CH=CH-,
, -CH 2 O-, -CH 2 S-, -CH 2 S(O)-, -OCH 2 -, -SCH 2 -, -S(O)CH 2 -, - CH 2 ON=C(R 3 )- or -CH-NB wherein B is -O-CO-, -N=CR 3 , or -0-CR 3 R 4 - wherein R 3 and R 4 are independently hydrogen or C r C 4 alkyl optionally substituted by halogen;
A is an aromatic moiety having 1-2 aromatic rings connected linearly from Z to I] wherein the aromatic rings are optionally connected to each other and to Ij in a linear manner with oxygen, nitrogen, or sulfur; q is 0 or 1. Each aromatic ring is optionally independently substituted by R 10 groups as defmed below. For example, A in Formula I may be expressed as phenyl rings with O, S, or N connecting atoms as follows:
wherein Bj and B 2 are O, S or N, the N which is optionally substituted with H or C r
C 4 alkyl; R 10 is defined below, and t is an integer from 0 to 1 ;
Examples of A are aryl, heteroaryl, aryloxy, heteroaryloxy, arylaryl, heteroarylheteroaryl, arylheteroaryl, heteroarylaryl, arylaryloxy, aryloxyaryl, aryloxy aryloxy, heteroary lheteroary loxy , heteroaryloxy heteroaryl, heteroaryloxy heteroarylox , arylheteroaryloxy, aryloxyheteroaryl, aryloxyheteroaryloxy, heteroarylaryloxy, hetero- aryloxyaryl, heteroaryloxyaryloxy; other combinations which include sulfur and nitrogen as connecting atoms are also contemplated. Specific examples of A for the aryl ring systems include benzene and naphthalene, and the heteroaryl ring systems include quinoline, isoquinoline, cinnoline, phthalazine, 1 ,3-benzodiazine, 1 ,4-benzodiazine, 1,2,4-benzotriazine, benzothiophene, benzoftiran, indole, benzimidazole, benzoxazole, benzothiazole, 1,2-benz- isoxazole, 2,1-benzisoxazole, 1 ,2-benzisothiazole, 2,1-benzisothiazole, pyridine, pyrimidine, pyrimidinyloxyphenyl, pyridazine, pyrazine, 1,3,5-triazine, pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, 1 ,2,4-triazole, 1 ,2,4-oxadiazole, 1,2,4-thiadiazole, and tetrazole. Substituent A is preferably a phenyl group.
I, is:
wherein
K, L, M, and Q are independently C or N with the proviso that not more than one or two of K, L, M or Q can be N at once and when K, L, M and Q are carbon each is optionally substituted by R 5 ; n is 1 or 2; and each R 5 and R 10 group is independently selected from the group consisting of (a) halogen, (b) lower aliphatic group optionally substituted by halogen or C r C 4 alkoxy, (c) C r C 4 alkoxy optionally substituted by halogen, (d) -CN, (e) -(Yι) q| C(=X)(Y 2 ) q R 8 , where ; X is
O or S, q j and q 2 are 0 or 1, Y, and Y 2 are independently selected from the group consisting of O, S, and -NR 8 ; each R 8 is independently selected from the group consisting of hydrogen and a lower aliphatic group optionally substituted by halogen or a C C 4 alkoxy group, wherein R 8 cannot be hydrogen if both q, and o 2 are 1 and Y 2 is O or S; (f) -S(O) r R 9 where r is 0, 1, or 2, wherein R > is a lower aliphatic group optionally substituted by halogen or a C,-C 4 alkoxy group or Rc, is an aryl group optionally substituted by halogen, a C r C 4 alkoxy group, or a C r C 4 alkyl group, (g) -S^Ro^ j , (h) -C(=NOCH 3 )CH 3 , or (i) aryl, aryloxy, arylthio, and arylamino optionally substituted by halogen, C,-C 4 alkoxy, or a lower aliphatic group optionally substituted by halogen or C r C 4 alkoxy, u is an integer from 0 to 4;
R $ is halogen, hydroxy, C,-C 4 alkoxy, or a lower aliphatic group, optionally substituted with C,-C alkoxy or halogen; s is 0, 1, or 2; and R is: a) χ
, II
-h C — Y — R 7
d) N — O
N=
e)
wherein X is S or O;
Y is a bond, oxygen, sulfur, or nitrogen carrying a hydrogen, a C C alkyl group or a Cj-C 4 alkoxy group; each R 7 is independently selected from the group consisting of hydrogen and a lower aliphatic group optionally substituted by halogen, hydroxy, or a C C 4 alkoxy group; and X, is CH or N; or an agronomically acceptable salt thereof.
The present invention is also a process for the preparation of a compound of Formula I.
The present invention is also a composition for use as a fungicide comprising a fungicidally effective amount of a compound of Formula I together with an agronomically acceptable carrier.
The present invention is also a method using the compound of Formula I as a fungicidal agent comprising treatment with a fungicidally effective amount ofthe compound.
Throughout this application, examples of halogen groups are fluorine, chlorine, bromine and iodine, in particular fluorine and chlorine; examples of the C r C alkyl groups are methyl, ethyl, isopropyl, n-propyl, butyl, tert-butyl, sec-butyl, especially methyl and ethyl, and examples of C Q alkoxy groups are methoxy, ethoxy, propoxy, 2-propoxy, 2-propen- oxy, 2-propynoxy, butoxy, 2-butoxy, tert-butoxy, 2-butenoxy, 3-butenoxy, 2-butynoxy, 3- butynoxy, l-methyl-2-propenoxy, and l-methyl-2-propynoxy.
A "lower aliphatic group" is defined as an aliphatic group of 1-6 carbons which may be a straight or branched chain with any number of double and triple bonds. Examples of lower aliphatic groups are methyl, ethyl, ethenyl, ethynyl, 1 -propyl, 1-methylethyl, 1- propenyl, prop-l-en-2-yl, 2-propenyl, 1 -propynyl, 2-propynyl, 1 -butyl, 2-butyI, 2-methyl-2- propyl, 2-methylpropyl, 1-butenyl, l-buten-2-yl, 1 -buten-3-yl, 3-butenyl, 2-butenyl, 2-buten- 2-yl, 2-methyl-2-propenyl, 2-methyl-l -propenyl, 1-butynyl, 2-butynyl, 3-butynyl, 3-butyn-2- yl, 1,3-butadienyl, l ,3-butadien-2-yl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3- methylbutyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1 -pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, l-penten-2-yl, 2-penten-2-yl, l-methyl-2-butenyl, 1-methyl- 3-butenyl, l-ethyl-2-propenyl, 1 -ethyl- 1 -propenyl, 2-ethyl-l -propenyl, 2-methyl-2-butenyl, 2- methyl-3-butenyl, 3-methyl-l-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl- 2-propenyl, 1-isopropyvinyl, 1,2-dimethyl-l -propenyl, 1 ,2-dimethyl-2-propenyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, l-methyl-2-butynyl, l-methyl-3-butynyl, l-ethyl-2- propynyl, 2-methyl-3-butynyl, 3-methyl-l-butynyl, 1,1 -dimethy 1-2-propynyl, 1 ,3-pentadienyl, 1 ,4-pentadienyl, 2,4-pentadienyl, l,3-pentadien-2-yl, l,4-pentadien-2-yl, 1 -methyl- 1,3- butadienyl, l,4-pentadien-3-yl, l,3-pentadien-3-yl, 2-methyl-l, 3-butadienyl, 3-methyl-l,3- butadienyl, 3-methyl-l,3-butadien-2-yl, 1 -hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 3-methyl- pentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1 ,2-dimethy Ibutyl, 1,3-dimethylbutyl, 1- (isopropyl)propyl, 1 -ethyl- 1 -methylpropyl, 2,2-dimethylbutyl, 2,3 -dimethy Ibutyl, 3,3- dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,
4-hexenyl, 5-hexenyl, 1 -butylethenyl, 1 -methyl- 1 -pentenyl, l-methyl-2 -pentenyl, l-methyl-3- pentenyl, l-methyl-4-pentenyl, l-propyl-2 -propenyl, 1 -propyl- 1 -propenyl, 1 -ethyl- 1-butenyl, l-ethyl-2-butenyl, l-ethyl-3-butenyl, 2-methylpentenyl, 2-propyl-2 -propenyl, 2-methyl-2- pentenyl, 2-methyl-3-pentenyl, 2-methyl-4-pentenyl, 3-methylpentenyl, 3-methyl-2-pentenyl, 3-ethyl-3-butenyl, 3-methyl-3-pentenyl, 3 -methyl -4-pentenyl, 4-methylpentenyl, 4-methyl-2- pentenyl, 4-methyl-3-pentenyl, 4-methyl-4-pentenyl, l ,l-dimethyl-2-butenyl, 1 ,1 -dimethy 1-3- butenyl, 1 -(sec-butyl)vinyl, 1 ,2-dimethylbutenyl, l-methyl-2-ethyl-2-propenyl, 1 ,2-dimethyl- 2-butenyl, l ,2-dimethyl-3-butenyl, l-(iso-butyl)vinyl, 1 ,3-dimethylbutenyl, 1 ,3-dimethyl-2- butenyl, l ,3-dimethyl-3-butenyl, l-ethyl-2-methyl-2-propenyl, 1 -ethyl-2-methylpropenyl, 1- (iso-propyl)propenyl, 1 -(iso-propyl)-2-propenyl, 1 -ethyl- l-methyl-2-propenyl, 2,2-dimethyl- 3-butenyl, 2,3-dimethylbutenyl, 2-(iso-propyl)-2-propenyl, 2,3-dimethyl-2-butenyl, 2,3- dimethyl-3-butenyl, 3,3-dimethylbutenyl, l,l,2-trimethyl-2-propenyl, l-(tert-butyl)vinyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, l-methyl-2 -pentynyl, l-methyl-3- pentynyl, 1 -methyl-4-pentynyl, 1-propy 1-2 -propynyl, 1 -ethyl-2-butynyl, 1 -ethyl-3-butynyl, 2- methyl- 3 -pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1 ,1 - dimethyl-2-butynyl, l ,l-dimethyl-3-butynyl, l,2-dimethyl-3-butynyl, 1 -(iso-propyl)-2- propynyl, 1 -ethyl- l-methyl-2 -propynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethylbutynyl, 1,3- hexadienyl, 1 ,4-hexadienyl, 1 ,5-hexadienyl, 2,4-hexadienyl, 2,5-hexadienyl, 3,5-hexadienyl, 1 -methyl- 1 ,3-pentadienyl, 1 -methyl- 1 ,4-pentadienyl, l-methyl-2,4-pentadienyl, 1 ,4-hexadien- 3-yl, l,5-hexadien-3-yl, 2,4-hexadien-3-yl, 2,5-hexadien-3-yl, 1 -ethyl- 1 ,3-butadienyl, 1,3- hexadien-3-yl, 2-methyl-l, 3-pentadienyl, 2-methyl-l , 4-pentadienyl, 2-(l-propenyl)-2- propenyl, 2-(2-propenyl)-2 -propenyl, 2-methyl-2,4-pentadienyl, 3-methyl-l,3-pentadienyl, 3- ethyl-l ,3-butadienyl, 3-methyl-l,4-pentadienyl, 3-methyl-2,4-pentadienyl, 2-(l ,3-butadien-2- yl)ethyl, 4-methyl-l,3-pentadienyl, 4-methyl- 1 ,4-pentadienyl, 4-methyl-2,4-pentadienyl, 3- ethyl-1.3-butadien-2-yl, 3-methyl-l,3-pentadien-2-yl, 3-methyl-l,4-pentadien-2-yl, 1,2- dimethyl-l,3-butadienyl, l-(l ,3-butadien-2-yl)ethyl, 4-methyl- l,3-pentadien-2-yl, 4-methyl- l,4-pentadien-2-yl, l,3-dimethyl-l,3-butadienyl, 2-methyl-l, 4-butadien-3-yl, 2-methyl-2,4- pentadien-3-yl, 3-methyl-l,4-pentadien-3-yl, 2,3-dimethyl-l,3-butadienyl, and 2-(iso- propenyl)propenyl. Examples of alkoxyimino, alkoxymethylene or alkylthiomethylene groups for the W substituent in Formula I are C C 4 alkoxyimino moieties such as methoxyimino, ethoxyimino,
n-propoxyimino, isopropoxyimino, n-butoxyimino, sec-butoxyimino and tert-butoxyimino, preferably methoxyimino; C,-C 4 alkoxymethylene moieties such as methoxymethylene, ethoxymethylene, n-propoxymethylene, iso-propoxymethylene, n-butoxymethylene, sec- butoxy ethylene and tert-butoxymethylene, preferably methoxymethylene; and C,-C 4 alkylthiomethylene moieties such as methylthiomethylene, ethylthiomethylene, n- propylthiomethylene, isopropylthiomethylene, n-butylthiomethylene, sec-butylthiomethylene and tert-butylthiomethylene, preferably methylthiomethylene. The preferred group is a C r C alkoxyimino group.
Generally, the compounds of the present invention can be prepared, for example, by methods which are themselves known or are analogous to those described in the chemical literature. In each case the starting materials are also known, commercially available or can be prepared by methods analogous to those described in the literature. Some of the specific methods contemplated are (a) react methyl-2-(bromomethyl)phenyl-2-(methoxyimino)acetate or methyl-3-bromomethyl-2-thienyl-2-(methoxyimino)acetate with one of the following nucleophiles (i) an oxime with a base such as sodium hydride in a solvent such as DMF, (ii) a substituted phenol with a basic salt such as potassium tert-butoxide in a solvent such as THF, or with a basic salt such as potassium carbonate in a solvent such as DMF; or (iii) an alcohol with a base such as tert-butoxide in a solvent such as THF; (b) react methyl 2- [(hydroxyimino)methyl]-α-(methoxyimino)phenylacetate with a base such as sodium hydride in a solvent such as DMF, then with a benzylic bromide; (c) react methyl 2-[2- (iodomethyl)phenyl]-3-methoxypropenoate with substituted phenols and a basic salt such as potassium carbonate in a solvent such as DMF; (d) react methyl 2-[2-(6-chloropyrimidine-4- yloxy)phenyl]-3-methoxypropenoate with substituted phenols and a basic salt such as potassium carbonate in a solvent such as DMF containing a catalyst such as copper (I) chloride; (e) react the methyl esters of Formula I (R=CO 2 CH 3 ) with aqueous methylamine or l-amino-2-propanol to afford amides of Formula I (R=CONHR 7 ); (f) react N-methoxy 2-[4- (l-indanyl)phenoxymethyl] benzenecarboximidoyl chloride with azoles and a base such as sodium hydride in a solvent such as DMF; to produce the compounds of Formula I. Other bases and solvents which would produce the compounds of Formula I are also contemplated. In addition, compounds of the Formula I, in which Z is -CH=NB wherein B is -O-
CR3R4- and -N=CR 3 -, can be synthesized by the procedures described as in U.S. 5,407,902
and 5,254,717 and the like. Similarly, specific compounds of Formula I in which Z is -
CH 2 ON=C(R 3 )-, can readily be prepared by methods described in AU-A-44918/93. The compounds of the Formula I in which Z is -CH 2 O- can be synthesized by the procedures as described in U.S. 5,395,854 and the like. The compounds of Formula I for the remainder of the definitions of Z can be synthesized by the procedures analogous to those described in U.S.
5,371,222 or U.S. 5,371,223.
Preparation of compound of the Formula I may result in E/Z isomer or mixtures thereof. If the isomers are required to be separated, this may be accomplished by conventional means. Compounds with the E configuration are particularly preferred. The compounds of Formula I are suitable as fungicides and for controlling pests such as insects, nematodes and acarids.
The compounds of Formula I have excellent activity against a wide spectrum of fungi which are pathogenic on plants, especially from the classes of Ascomycetes, Oomycetes and
Basidiomycetes. Compounds of this invention may have systemic activity and can be employed as leaf and soil fungicides. Compounds of this invention may also be particularly important for controlling a large number of fungi on various crops such as cereals, including wheat, barley and rice; coffee; sugarcane; grapevines; fruit and ornamental plants and vegetables such as cucumbers, beans and pumpkins; and on the seeds of these plants.
The compounds of the present invention are particularly suitable for controlling plant diseases exemplified by the following:
Peronospora species on fruits and vegetables
Hemileia vastratrix on coffee
Erysiphe graminis on cereals
Erysiphe species on vegetables, fruits, and ornamentals Sphaerotheca species on vegetables
Monilinia species on fruits, vegetables, and ornamentals
Uncinula necator on grapes
Puccinia species on cereals
Rhizoctonia species on cereals, turf, and rice Ustilago species on cereals
Tilletia species on cereals
Pyrenophora species on cereals Mycosphaerella species on cereals and bananas Gaemannomyces on cereals Venturia inaequalis on apples Ustilago species on cereals
Leptosphaeria nodorum on cereals Botrytis cinerea on fruits and vegetables
Pseudocercosperella herpotrichoides on cereals
Pyricularia oryzae on rice Phytophthora species on fruits, vegetables, tobacco, and ornamentals
Verticillium species on fruits, vegetables, and ornamentals
Plasmopora viticola on grapes
Fusarium species on cereals, fruits, and vegetables
Microdochium nivale on cereals Alternaria species on fruits and vegetables
Pythium species on fruits, vegetables and turf.
The compounds are applied by treating the fungi or the plants, seeds, materials or soil to be protected from fungal attack with a fungicidal amount of the active ingredients. The application is carried out before or after infection of the materials, plants or seeds by the fungi. The compounds of Formula I are also suitable for controlling pests from the classes of insects, acarids and nematodes. They can be employed as pesticides in crop protection and in the hygiene, store protection and veterinary sectors.
The compounds of the present invention may be used as is without adding any other components, but generally, they are formulated into emulsifiable concentrates, wettable powders, suspension formulations, granules, dusts, and the like by mixing with a solid or liquid carrier, a surface active agent and other adjuvants for formulation. The compounds of the present invention may also be microencapsulated or otherwise formulated for delayed release of activity.
The content of a compound of the present invention contained as an active ingredient in these formulations is 0.1 to 99.9%, preferably 0.2 to 80% by weight, and more preferably 2 to 50% by weight. The concentration of the active compound in the spray solutions as they
are applied to growing plants will be much less, from about 1 to about 1000, preferably from about 10 ppm up to about 1000 ppm.
The exact amount of active ingredient per hectare to be employed in the treatment or prevention of disease is dependent upon various factors, including the plant species and stage of development of plants and disease, the amount of rainfall, and the specific adjuvants employed. In foliar applications a dosage from about 1 to about 2000 g/ha, preferably from about 20 to about 250 g/ha, is usually employed. In soil applications a dosage from about 1 to about 2000 g/ha, preferably from about 50 to about 500 g/ha is usually employed. Lower or higher rates may be required in some instances. When the active ingredient is used for treating seed, rates of .0005 to 100 g per Kg of seed, preferably from .01 to 50 g per Kg of seed is employed. One skilled in the art can readily determine from this specification, including the following examples, the optimum rate to be applied in any particular case.
The solid carriers include, for example, fine powders or granules of kaolin clay, attapulgite clay, bentonite, acid clay, pyrophyllite, talc, diatomaceous earth, calcite, corn starch powder, walnut shell powder, urea, ammonium sulfate, synthetic hydrated silicon dioxide, and the like. The liquid carrier includes, for example, aromatic hydrocarbons such as xylene, methylnaphthalene and the like, alcohols such as isopropanol, ethylene glycol, cellosolve and the like, ketones such as acetone, cyclohexanone, isophorone and the like, vegetable oils such as soybean oil, cottonseed oil and the like, dimethyl sulfoxide, acetonitrile, water, and the like.
The surface active agents used for emulsification, dispersion, wetting, etc., include, for example, anionic surface active agents, such as salts of alkyl sulfate, alkyl or aryl sulfonates, dialkylsulfo-succinates, salts of polyoxyethylene alkyl aryl ether phosphoric acid esters, or naphthalenesulfonic acid/formalin condensates, etc., and nonionic surface active agents, such as polyoxyethylene alkyl ether, polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acid esters, or polyoxyethylene sorbitan fatty acid esters, etc. Other adjuvants for formulation include, for example, xanthan gum, lignosulfonates, alginates, polyvinyl alcohol, gum arabic, and CMC (carboxymethyl cellulose).
Penetrating agents, to increase systemic activity may also be added to the compounds of the present invention. When used in plant protection, a compound according to the invention or mixtures thereof, as such or in their formulations, can also be used in the form of
mixture with other active ingredients, for example, herbicides, bactericides, acaricides, nematocides, insecticides, growth regulators, other fungicides and compounds identified as synergists, and may furthermore be mixed and applied together with fertilizers. The mixtures are advantageous, for example to broaden the spectrum of action or to prevent the build-up of resistance. In some cases, synergistic effects are observed, which means that the activity of the mixture is greater than the total ofthe activities ofthe individual components.
Examples of fungicides which may be combined with the novel compounds are: 2- aminobutane; 2-anilino-4-methyl-6-cyclopropylpyrimidine; 2' ,6'-dibromo-2-methyl-
4 'trifluoromethoxy-4' -trifluoromethyl- 1 ,3-thiazol-5-carboxanilide; 2,6-dichloro-N-(4- trifluoromethylbenzyl)benzamide; (E)-2-methoxyimino-N-methyl-2-(2-phenoxyphenyl)- acetamide; 8-hydroxyquinoline sulphate; methyl (E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4- y loxy ]phenyl]-3-methoxyacry late; methyl (E)-methoximino { alpha(o-tolyloxy )-o-tolyl]acetate; 2-phenylphenol (OPP), aldimorph, ampropylfos, anilazine, azaconazole, benalaxyl, benodanil, benomyl, binapacryl, biphenyl, bitertanol, blasticidin-S, bromuconazole, bupirimate, buthiobate, calcium polysulphide, captafol, captan, carbendazim, carboxin, quinomethionate, chloroneb, chloropicrin, chlorothalonil, chlozolinate, cufraneb, cymoxanil, cyproconazole, cyprodinil, cyprofuram, dichlorophen, diclobutrazole, diclofluanid, diclomezin, dicloran, diethofencarb, difenoconazole, dimethirimol, dimethomorph, diniconazole, dinocap, diphenylamine, dipyrithion, ditalimfos, dithianon, dodine, drazoxolon, edifenphos, epoxyconazole, ethirimol, etridiazole, fenarimol, fenbuconazole, fenfuram, fenitropan, fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, fluoromide, fluquinconazole, flusilazole, flusulfamide, flutolanil, flutriafol, folpet, foxetyl-aluminium, fthalide, fuberidazole, furalaxyl, furmecyclox, guazatine, hexachlorobenzene, hexaconazole, hymexazole, imazalil, imibenconazole, iminoctadine, iprobenfor (IBP), iprodione, isoprothiolane, kasugamycin, copper preparations, such as: copper hydroxide, copper naphthenate, copper oxychloride, copper sulphate, copper oxide, oxine copper and Bordeaux mixture, mancopper, mancozeb, maneb, mepanipyhrim, mepronil, metalaxyl, metconazole, methasulfocarb, methfuroxam, metiram, metsulfovax, myclobutanil, nickel dimethyldithiocarbamate, nitrothal-isopropyl, nuarimol, ofurace, oxadixyl, oxamocarb, oxycarboxin, perfurazoate, penconazole, pencycuron, phosdiphen, pimaricin, piperalin, polyoxin, probenazole, prochloraz, procymidone, propamocvarb, propiconazole, propineb,
pyrazophos, pyrifenox, pyrimethanil, pyroquilon, quintozen (PCNB), sulphur and sulphur preparations, tebuconazole, tecloftalam, tecnazen, tetraconazole, thibendazole, thicyofen, thifluzimide, thiophanate-methyl, thiram, tolclophos-methyl, tolylfluanid, triadimefon, triadimenol, triazoxide, trichlamide, tricyclazole, tridemorph, triflumizole, triforine, triticonazole, validamycin A, vinclozolin, zineb, ziram and the compounds described as the invention in EP 0538231, U.S. application Serial Number 08/356,770, U.S. patent 5,223,526, PCT US95/11219, PCT US95/11439, PCT US95/1 1436, PCT US95/11301, and PCT US95/1 1438.
Additionally, the present invention compounds may also be combined with compounds which enhance the natural resistance of plants such as are described in U.S. Patent No. 5,384,321 or WO 95/15684.
Examples of bactericides which may be combined with the novel compounds of the present invention are: Bronopol, dichlorophen, nitrapyrin, nickel dimethyldithiocarbamate, kasugamycin, octhilinon, furanecarboxylic acid, oxytetracyclin, probenazole, streptomycin, tecloftalam, copper sulphate and other copper preparations.
Examples of insecticides, acaricides and nematicides which may be combined with the novel compounds of the present invention are: Abamectin, AC 303 630, acephate, acrinathrin, alanycarb, aldicarb, alphamethrin, amitraz, avermectin, AZ 60541, azadirachtin, azinphos A, azinphos M, azocyclotin, Bacillus thuringiensis, bendiocarb, benfuracarb, bensultap, betasyluthrin, bifenthrin, BPMC, brofenprox, bromophos A, bufencarb, buprofezin, butocarboxin, butylpyridaben, cadusafox, carbaryl, carbofuran, carbophenothion, carbosulphan, cartap, CGA 157 419, CGA 184699, chloethocarb, chlorethoxyfos, chlorfenvinphos, chlorfluazuron, chlormephos, chlorpyrifos, chlorpyrifos M, cis-resmethrin, clocythrin, clofentezine, cyanophos, cycloprothrin, cyfluthrin, cyhalothrin, cyhexatin, cypermethrin, cyromazine, deltamethrin, demeton M, demeton S, demeton-S-methyl, diafenthiuron, diazinon, dichlofenthion, dichlorvos, dicliphos, dicrotophos, diethione, diflubenzuron, dimethoate, dimethylvinphos, dioxathion, disulphoton, edifenphos, emamectin, esfenvalerate, ethiofencarb, ethione, ethofenprox, ethoprophos, etofenprox, etrimphos, fenamiphos, fenazaquin, fenbutatin oxide, fenitrothion, fenobucarb, fenothiocarb, fenoxycarb, fenpropathrin, fenpyrad, fenpyroximate, fenthion, fenvalerate, fipronil, fluazinam, flucycloxuron, flucythrinate, flufenoxuron, flufenprox, fluvalinate, fonophos, formothion, tSIBSTTTUTE SHEET (RULE 26)
fosthiazate, fubfenprox, furathiocarb, HCH, heptenophos, hexaflumuron, hexythiazox, imidacloprid, iprobenfos, isazophos, isofenphos, isoprocarb, isoxathione, ivemectin, lambda- cyhalothrin, lufenuron, malathion, mecarbam, meavinphos, mesulphenphos, metaldehyde, methacrifos, methamidophos, methidathion, methiocarb, methomyl, metolcarb, milbemectin, monocrotophos, moxidectin, naled, NC 184, NI 25, nitenpyram, omethoate, oxamyl, oxydemethon M, oxydeprofos, parathion A, parathion M, permethrin, phenthoate, phorate, phosalone, phosmet, phospham; don, phoxim, pirimicarb, propaphos, propoxur, prothiofos, prothoate, pymetrozin, pyrachlophos, pyradaphenthion, pyresmethrin, pyrethrum, pyridaben, pyrimidifen, pyriproxifen, quinalphos, RH 5992, salithion, sebufos, silafluofen, sulphotep, sulprofos, tebufenozid, tebufenpyrad, tebupirimphos, teflub enzuron, tefluthrin, temephos, terbam, terbufos, tetrachlorvinphos, thiafenox, thiodicarb, thiofanox, thiometon, thionazin, thuringiensin, tralomethrin, triarathen, triazophos, triazuron, trichlorfon, triflumuron, trimethacarb, vamidathio, XMC, xylylcarb, zetamethrin.
PREPARATION EXAMPLES The following examples are illustrative of the present invention and are not meant to be limiting thereto. Abbreviations have the meanings shown: ha hectare Kg kilogram g gram
RT room temperature RH relative humidity HPLC chromatography on silica (Waters 500 A, preparative liquid chromatograph)
DMF dimethylformamide mL milliliter
DMSO dimethylsulfoxide m v material per volume v/v volume per volume ave average
EXAMPLES OF USE
Typical biological data indicating the excellent fungicidal activity ofthe compounds of the invention obtained using the bioevaluation in vitro assay method of Example 1 and the bioevaluation in vivo assay methods of Examples 2-6. EXAMPLE 1
Microdochium nivale Spore Germination Inhibition Water agar with 1.5% agar (m/v) is heated on a hot plate to melting and dispensed into 50 mL erlenmeyer flasks with 10 mL. of agar per flask. One flask is required for each treatment in the treatment list. These are then autoclaved to sterilization. When the molten agar is cool enough to begin pouring, approximately 55°C , the test compounds in solvent are dispensed into the agar to achieve the desired final concentration described in the Table. The agar to solvent ratio is 1000:1 v/v. After adding the material and solvent the agar is gently agitated, and poured into a petri plate.
Commercial and internal standards included in each test are incorporated in the same manner as the experimental compounds.
After the agar has cooled and solidified the plates are ready for inoculation. A conidial suspension of the fungus, Microdochium nivale, is prepared with roughly 20,000 spores/mL of sterile distilled water. Three drops of this suspension are dispensed onto each plate equidistantly in a triangular pattern. The plates are then incubated at 21°C for 20 hours. At that time the germ tubes should be sufficiently long enough to measure using an ocular lens scale on a microscope. Several germ tubes in each inoculum drop are measured to determine the average amount of growth. This procedure is then repeated for the other two drops. The average of the three inoculum drops is then used in the following equation to determine the effectiveness of each treatment. Inhibition = 100-[(ave. treatment length/ave. control length) x 100]
EXAMPLE 2 Barley Powdery Mildew Protectant Methods The following describes the procedures and methods used in the barley powdery mildew foliar assay. A) Pathogen/Inoculum Production
The barley powdery mildew fungus, Erysiphe graminis f. sp. hordei, is maintained continuously on barley seedlings in an isolated, environmentally controlled growth chamber.
B) Host Propagation
Barley seedlings, cv. Perry, are grown to the second leaf stage in a growth chamber set at 21 °C , 80 % RH with a 12 hour photoperiod.
C) Test Compound Preparation
1 ) Experimental compounds:
The compounds were applied at 20 and 5 ppm. Formulation is generally in 20% acetone, 79.95% water, and 0.05% Tween® 20. Three pots (with 3 plants/pot) are utilized per treatment rate. The application volume is 2 mL per treatment. Formulated materials/products are brought up to the appropriate treatment volume with water containing .05% Tween® 20, v/v.
2) Controls and standards:
The commercial standard used is Alto® (active ingredient cyproconazole) at the rate 5 of 20 and 5 ppm. A set of control plants, treated with the formulation blank and inoculated, are also included.
D) Compound Application
Compound is sprayed onto the leaves ofthe plants (pots positioned on a rotating table) using a DeVilbiss Model 152 hand sprayer. Coverage of the first leaf is essential. After the 0 plants have thoroughly dried they are returned to the growth room and randomized.
E) Inoculation Incubation
Twenty four hours later the treated plants are removed to a "mildew chamber" and inoculated by gently brushing their leaves with the leaves of a previously infected plant with actively sporulating mildew pustules. The mildew incubation chamber settings are identical 5 to that ofthe host propagation chamber (see above).
F) Evaluation
The test is assessed 6-7 days after inoculation. Treatments are evaluated by visually estimating the percentage of the leaf area infected on the first leaf. Three ratings are made on each pot (replicate). Phytotoxicity and growth effects are also noted and recorded at this o time.
G) Data Handling
Treatment means are calculated and percent disease control is determined by the formula:
% Control = (control mean - treatment mean) x 100/ control mean The inoculated control treatment mean is used for this calculation. EXAMPLE 3
Barley Powdery Mildew Curative Methods This method is conducted as in Example 2 above with the following exception: Plants are inoculated as described and then 24 hours later the incubation period is temporarily interrupted for chemical treatment. EXAMPLE 4
Wheat Glume Blotch Foliar Assay Methods A) Pathogen Inoculum Production
The wheat glume blotch fungus, Leptosphaeria nodorum, is maintained in the pycnidial state on yeast malt agar (YMA) at 20°C, 12 hour photoperiod. Test inoculum is prepared by flooding seven day old culture plates with deionized water amended with Tween® 20 (0.1% v/v) and gently scraping the pycnidia to release the extruding masses of conidia. The resulting spore suspension is filtered through two layers of cheese cloth and adjusted to 4 x 10^ spores/mL utilizing the Tween® 20 solution. B) Host Propagation
Winter wheat plants, cv. Caldwell, are grown in 5.7 cm^ pots, three per pot, and maintained in a growth chamber set at 20°C, 80 % RH with a 12 hour photoperiod. C) Test Compound Preparation
1) Experimental compounds: Compounds are most commonly applied at the dose rate of 20 ppm. Formulation is generally in 20% acetone, 79.95% water, and 0.05% Tween® 20. Three pots (with 3 plants/pot) are utilized per treatment rate. Application volume is 3 mL /treatment. Formulated commercial products are diluted to the appropriate treatment volume with water containing 0.05% Tween® 20, v/v. 2) Controls and standards:
The commercial standard used is Horizon® (active ingredient tebuconazole) at the rate of 20 ppm. A set of control plants, treated with a formulation blank and inoculated, are also included.
D) Compound Application Seedlings are sprayed at the two-leaf stage (GS 12) using a DeVilbiss Model
152 hand operated sprayer set at 15-20 psi. Coverage of the first leaf is essential. The plants are allowed to dry, returned to the growth room, and randomized.
E) Inoculation/Incubation
Twenty four hours after compound application and prior to inoculation, the test plants are preconditioned for at least one hour in a dark growth chamber set at 20°C and 100% RH. After the preconditioning period is over, the prepared conidial suspension is applied to run-off using a DiVilbiss hand operated sprayer. The plants are then returned to the preconditioning chamber and incubated at the same settings for 96 hours. Light is supplied to the plants during the last twelve hours of incubation. At the end of the 96 hour period, the plants are returned to the environmental conditions under which they were grown.
F) Test Evaluation
Eight to ten days after removal from the high humidity chamber, or twelve to fourteen days after inoculation, treatments are evaluated by visually estimating the percentage of the leaf area (on the first leaf) covered with lesions. Three ratings are made on each pot which constitutes a replicate.
G) Data Handling
As per "Barley Powdery Mildew Assay Methods" in Example 2.
EXAMPLE 5 Wheat Leaf Rust Protectant Methods The methods for conducting this assay are the same as those described for Example 2 with the following exceptions:
Wheat variety "Caldwell" is seeded into 5.7 cm pots containing a commercial potting soil and grown in a growth chamber with 21°C ambient temperature and a 12 hour light cycle. At application time the plants should have one fully formed leaf, and there should be at least three plants per pot.
Then one day following compound application, the plants are inoculated with the pathogen, Puccinia recondita. To inoculate a test, urediospores are dislodged from previously infected inoculum plants onto the foliage of the test plants, and the plants are placed in a mist tent for 24 hours at 20°C in the dark. The test can then be returned to the previous growing conditions until foliar symptoms are evident and the plants can be assessed.
EXAMPLE 6 Vine Downy Mildew Protectant Methods The procedures and methods used in the foliar vine downy mildew disease assay are as follows: A) Pathogen/Inoculum Production
The vine downy mildew fungus is an obligate parasite and must be maintained on a living host. Vine seedlings are infected each week with a spore suspension of P. viticola in order to provide spores for assay.
B) Host Propagation Grape seedlings, variety "Carignane", Vitus vinifera, are grown from seed. The seedlings are maintained under a shade cloth in an environmentally controlled greenhouse. Plants are ready for assay when they have two to three fully expanded leaves.
C) Test Compound Preparation
1) Experimental compounds: The compounds were applied at 20 and 5 ppm. Formulation is generally in 20% acetone, 79.95% water, and 0.05% Tween® 20. Three pots (with one plant/pot) are utilized per treatment rate. The application volume is 2 mL per treatment . Formulated materials/products are brought up to the appropriate treatment volume with water containing .05% Tween 20, v/v. 2) Controls and standards:
The commercial standard used is Ridomil® (active ingredient metalaxyl) at the rate of 20 and 5 ppm. A set of control plants, treated with the formulation blank and inoculated, are also included.
D) Compound Application Compound is sprayed onto the upper and lower surfaces ofthe second and third leaf of each plant. The plants are returned to the growth room after they have dried, and randomized.
E) Inoculation/Incubation
Treated vines are inoculated 24 hours after chemical applications. A 20,000/mL spore suspension is applied to the lower surface of the leaves. Inoculated plants are placed in a dark dew chamber set at 20°C for 24 hours. Following the initial incubation, the plants are moved to a growth chamber set at 21°C , 85% RH with a 12 hour photoperiod.
F) Evaluation
The test is assessed 6-7 days after inoculation. Prior to disease assessment, the treated plants are placed in a dew chamber overnight to allow spores to develop on the underside of the leaves. Infection level is then evaluated by visually estimating the percentage of the leaf underside covered with spores. Phytotoxicity and growth effects are also noted and recorded at this time.
G) Data Handling
Treatment means are calculated and percent disease control is determined by the formula: "(control mean - treatment mean) times 100/ control mean". The inoculated control treatment mean is used for this calculation.
SYNTHESIS OF INTERMEDIATES 1-Indanol, 2-indanol, β-Tetralol, and 4-(l-indanyl)phenol were purchased from commercial sources. 2-(4-Bromophenyl)-2-methyl-l,3-dioxolane, methyl 2-(bromo- methyl)benzoate, methyl-2-(bromomethyl)phenyl-2-(methoxyimino)acetate, methyl-3- bromomethyl-2-thienyl-2-(methoxyimino)acetate, 4-(l-tetralinyl)phenol, methyl 2-[2- (chloromethyl)phenyl]-3-methoxypropenoate, methyl 2-[(hydroxyimino)methyl]-α-
(methoxyimino)phenylacetate, and methyl 2-[2-(6-chloropyrimidine-4-yloxy)phenyl]-3- methoxypropenoate were prepared according to published literature procedures. The compounds of intermediates a-aa showed satisfactory spectral data. Examples 7-16 illustrate the synthesis of those intermediates for which methods for synthesis are not available in the literature.
EXAMPLE 7 Method A: Synthesis of Intermediates a-d A solution of n-butyllithium in hexanes (1 equiv) was added dropwise to a dry- ice/acetone cooled solution of 2-(4-bromophenyl)-2 -methyl- 1,3-dioxo lane (1 equiv) in THF. The resulting solution was stirred at -78°C for lh, then a solution of a ketone (1 equiv) in THF
was added to this cold solution of aryl lithium. The reaction was allowed to warm to room temperature, quenched with saturated aqueous ammonium chloride, and extracted with ether. The organic solution was dried over magnesium sulfate and the product purified by chromatography over silica gel eluted with ethyl acetate/hexane mixtures. The product of the above reaction was mixed with excess aqueous 2N HCI, and enough acetone added to effect solution. A catalytic amount of para-toluene sulfonic acid was added and the solution was refluxed for Id to hydrolyze the ketal and dehydrate the benzylic carbinol. The reaction was concentrated to remove most of the acetone, then was extracted with ether. The organic extract was washed with brine, dried over magnesium sulfate, and the product purified by chromatography over silica gel eluted with ethyl acetate/hexane mixtures.
A solution of the above olefin in ethanol or ethyl acetate was hydrogenated over a catalytic amount of 5-10% Pd/C in a Parr hydrogenation apparatus. Selective reduction of the olefin over the ketone could be achieved with short reaction times. Overnight hydrogenation saturated the olefin and reduced the ketone to the alcohol. The reaction was filtered through celite, concentrated and purified by chromatography over silica gel eluted with ethyl acetate/hexane mixtures. Intermediates a-d were prepared as intermediates using Method A. Intermediate a, 4-(l-indanyl)acetophenone
Intermediate b, l-(l-hydroxyethyl)-4-(5-methoxy-l-indanyl)benzene
Intermediate c, l-(l-hydroxyethyl)-4-(l-tetralinyl)benzene
Intermediate d, 4-(5-methoxy-l-tetralinyl)acetophenone
- 22
EXAMPLE 8
Method B: Synthesis of Intermediates e and f
Manganese dioxide (5 equiv) was added to a benzene solution of a benzylic alcohol from method A. The mixture was refluxed for lh, then was filtered through celite and concentrated to afford the crude ketone.
Intermediates e-f were prepared as intermediates using Method B.
Intermediate e, 4-(5-methoxy-l-indanyl)acetophenone
Intermediate f, 4-(l-tetralinyl)acetophenone
EXAMPLE 9
Method C: Synthesis of Intermediates g-j A mixture of the acetopheone (1.0 equiv) from method A or B, hydroxylamine hydrochloride (1.25 equiv), and sodium acetate (1.25 equiv) was refluxed in methanol overnight to form the oxime. The resulting reaction mixture was concentrated to remove most of the methanol, then the residue was partitioned between ethyl acetate and water. The organic portion was washed with brine, dried over magnesium sulfate, and, if necessary, purified by chromatography over silica gel with ethyl acetate/hexane mixtures. Intermediates g-j were prepared as intermediates using Method C.
Intermediate g, 4-(l-indanyl)acetophenone oxime
Intermediate h, 4-(5-methoxy-l-indanyl)acetophenone oxime
Intermediate i, 4-(l-tetralinyl)acetophenone oxime
Intermediate j, 4-(5-methoxy-l-tetralinyl)acetophenone oxime
EXAMPLE 10
Method D: Synthesis of Intermediates k-o A solution of a substituted indanone (1.0 equiv) in THF was added dropwise to an ice water cooled 0.5M solution of 4-anisyl magnesium bromide (1.0 equiv) in THF. The reaction was allowed to stir at room temperature overnight, then was quenched with aqueous ammonium chloride and partitioned between ether and water. The organic phase was dried over magnesium sulfate and concentrated to afford the crude carbinol. The carbinol was dissolved in acetone and dehydration effected by adding aqueous 5%
HCI to the cloud point. This was refluxed for lh, then was stripped under vacuum and purified by chromatography over silica gel with ethyl acetate/hexane mixtures.
A solution ofthe olefin in ethyl acetate was hydrogenated over catalytic 5% Pd/C in a Parr apparatus. The reaction was then filtered through celite, concentrated, and purified by
chromatography over silica gel eluted with ethyl acetate/hexane mixtures or recrystallization from hexanes.
A IM solution of boron tribromide (1.2 equiv) in methylene chloride was added dropwise to an ice water cooled solution of this reduced O-methyl phenol (1.0 equiv) in methylene chloride. The cooling bath was removed and the resulting reaction was stirred overnight at room temperature. The reaction was quenched by pouring over ice and separating the layers. The methylene chloride phase was dried over magnesium sulfate, concentrated, and the product purified by reverse phase chromatography or recrystallization from hexanes.
Intermediates k-o were prepared as intermediates using method D.
Intermediate k, 4-(5-chloro-l-indanyl)phenol
Intermediate 1, 4-(5-fluoro-l-indanyl)phenol
Intermediate m, 4-(2-methyl-l-indanyl)phenol
Intermediate n, 4-(3-methyl-l-indanyl)phenol
Intermediate o, 4-(4-methyl-l-indanyl)phenol
EXAMPLE 11
Synthesis of Intermediate p
An 0.5M solution of 4-anisyl magnesium bromide in THF (66.7 mL, 33.3 mmol) was added dropwise to an ice-water cooled solution of benzyl acetone (5.0 mL, 33.3 mmol) in
THF. The resulting reaction was allowed to warm to room temperature, and after lh was partitioned between aqueous ammonium chloride and ether. The organic phase was dried over magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with 1:5 ethyl acetate/hexanes to afford 6.2 g of 4-(l-hydroxy-4-phenyl-2-butyl) anisole as a clear oil.
A mixture of 4-(l-hydroxy-4-phenyl-2-butyl) anisole (5.92 g, 23.1 mmol) in excess polyphosphoric acid was stirred at room temperature for 2h, then poured into ice-water and extracted with ether. The organic phase was dried over magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with 5% ethyl acetate in hexanes to afford 2.12 g of 4-(l -methyl- 1 -indanyl) anisole as a yellow oil.
A IM solution of boron tribromide (10.0 mL, 10.0 mmol) was added dropwise to an ice-water cooled solution of 4-(l -methyl- 1 -indanyl) anisole (2.1 g, 8.8 mmol) in methylene chloride. The cooling bath was removed and the resulting reaction was stirred at room temperature overnight. The reaction was quenched by pouring over ice and separating the layers, then the methylene chloride phase was washed with brine, dried over magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with 15% ethyl acetate in hexanes to afford 1.73 g of 4-(l -methyl- 1 -indanyl) phenol as a light green oil. Intermediate p, 4-(l -methyl- l-indanyl)phenol
EXAMPLE 12
Synthesis of Intermediate q
3 -Pheny 1-1 -propyl magnesium bromide was prepared from the reaction of 3 -phenyl- 1- bromopropane (8.0 mL, 52.6 mmol) and magnesium turnings (1.40 g, 57.6 mmol) in THF. This solution was added dropwise to an ice-water cooled solution of 3-methyl-para- anisaldehyde (7.70 mL, 52.6 mmol) in THF. The resulting reaction was allowed to warm to room temperature, and after lh was partitioned between aqueous ammonium chloride and ether. The organic phase was dried over magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with 15% ethyl acetate in hexanes to afford 8.35 g of 2- methyl-4-(l-hydroxy-4-phenyl-l -butyl) anisole as a clear oil.
A IM solution of titanium tetrachloride in toluene (74.1 mL, 74.1 mmol) was added dropwise to a solution of 2-methyl-4-(l-hydroxy-4-pheny 1-1 -butyl) anisole (5.0 g, 18.5 mmol) in methylene chloride. The mixture was stirred at room temperature for 3h, then the reaction was quenched by pouring into excess aqueous saturated sodium bicarbonate. After stirring for 5 min the mixture was extracted with ether, and the organic phase was dried over magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with hexanes to afford 2.46 g of 2-methyl-4-(l-tetralinyl) anisole as a clear oil.
A IM solution of boron tribromide (10.7 mL, 10.7 mmol) was added dropwise to an ice-water cooled solution of of 2-methyl-4-(l-tetralinyl) anisole (2.46 g, 9.7 mmol) in methylene chloride. The cooling bath was removed and the resulting reaction was stirred at room temperature overnight. The reaction was quenched by pouring over ice and separating the layers, then the methylene chloride phase was washed with brine, dried over magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with 15% ethyl acetate in hexanes of 2-methyl-4-(l-tetralinyl) phenol as an oil. Intermediate q, 2-methyl-4-(l-tetralinyl)phenol
EXAMPLE 13
Method E: Synthesis of Intermediates r-w l,l '-(Azodicarbonyl)dipiperidine (1.0 equiv) was added to an ice-water cooled solution of a secondary alcohol (1.0 equiv), 3- or 4-hydroxyphenyl benzoate (1.0 equiv), and
triphenylphosphine (1.0 equiv) in THF. After 10 min the reaction was allowed to warm to room temperature and stir overnight. Hexanes were added and the slurry was filtered to remove the solid by-products which had precipitated. The filtrate was then concentrated and purified by chromatography over silica gel eluted with ethyl acetate/hexane mixtures to give the 3- or 4-alkoxyphenyl benzoate.
Aqueous 5% sodium hydroxide (0.7 volumes) was added to an 0.2M solution of the 3- or 4-alkoxyphenyl benzoate in 1,4-dioxane (1 volume). The resulting mixture was stirred overnight at room temperature, then was partitioned between ether and water. The organic phase was washed with water and dried over magnesium sulfate, then was concentrated and purified by crystallization from ether/hexanes or by chromatography over silica gel eluted with ethyl acetate/hexane mixtures to give the 3- or 4-alkoxyphenol.
Intermediates r-w were prepared as intermediates using method E. Intermediate r, 4-(l-indanoxy)phenol
Intermediate s, 4-(2-indanoxy)phenol
Intermediate t, 4-(2-tetraIinoxy)phenol
Intermediate u, 3-(l-indanoxy)phenol
Intermediate v, 3-(2-indanoxy)phenol
Intermediate w, 3-(2-tetralinoxy)phenol
EXAMPLE 14 Synthesis of Intermediate x
Sodium borohydride (321 mg, 8.4 mmol) was added in portions to an ice-water cooled solution of 4-(l-indanyl)acetophenone (intermediate a, 1.00 g, 4.2 mmol) in methanol. After 3 hours the reaction was quenched by the careful addition of excess aqueous 3% HCI, then was concentrated under vacuum to remove the methanol. The residue was diluted with ether and washed with water followed with brine, then was dried over magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with 1 :4 ethyl acetate/hexanes to afford 600 mg (61%) of l-(l-hydroxyethyl)-4-(l-indanyl)benzene as a colorless oil.
Intermediate x, l-(l-hydroxyethyl)-4-(l-indanyl)benzene
EXAMPLE 15
Method F: Synthesis of Intermediates y and z Pyridine (2 equiv) was added dropwise to an ice-water cooled solution of phosphorus tribromide (3 equiv) in benzene. To this solution was added a solution of intermediate x or b (3 equiv) and pyridine (1 equiv) in benzene. The resulting reaction mixture was allowed to warm and stir at room temperature overnight, then was quenched by pouring into icy water and extracting with ether. The organic phase was washed with brine and dried over magnesium sulfate, then was concentrated and purified by chromatography over silica gel
eluted with ethyl acetate/hexane mixtures. Intermediates y and z were prepared intermediates using method F.
Intermediate y, l-(l-bromoethyl)-4-(l-indanyl)benzene
Intermediate z, l-(l-bromoethyl)-4-(5-methoxy-l-indanyl)benzene
EXAMPLE 16
Synthesis of Intermediate aa
A mixture of methyl 2-(bromomethyl)benzoate (10.00 g, 43.7 mmol), 4-(l- indanyl)phenol (1 1.47 g, 54.5 mmol), and potassium carbonate (13.27 g, 96.0 mmol) in DMF was heated at 60°C for 4h, then was allowed to stir at room temperature for 3d. The resulting reaction mixture was partitioned between ether and water, then the organic phase was dried over magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with 4% ethyl acetate in hexanes to afford 14.8 g of methyl 2-[4-(l- indanyl)phenoxymethyl]benzoate as a colorless oil.
Excess aqueous 5% sodium hydroxide was added to a solution of methyl 2-[4-(l- indanyl)phenoxymethyl]benzoate (14.7 g, 41.0 mmol) in dioxane. Reverse-phase HPLC showed complete reaction after stirring the reaction at room temperature overnight. Most of the dioxane was removed under vacuum and the residue was partitioned between ether and water. The organic phase was filtered and concentrated to a colorless oil which was crystallized by the addition of ether and hexanes. The solid was collected and washed with hexanes to afford 12.7 g of sodium 2-[4-(l-indanyl)phenoxymethyl]benzoate as a white solid.
Oxalyl chloride (6.22 mL, 72.5 mmol) was added dropwise to a solution of of sodium
2-[4-(l-indanyl)phenoxymethyl]benzoate (12.56 g, 36.5 mmol) and catalytic DMF (2 drops) in methylene chloride. The resulting reaction was allowed to stir overnight at room
temperature, then was concentrated under vacuum to afford 2-[4-(l- indanyl)phenoxymethyl]benzoyl chloride as a viscous yellow-orange oil.
A solution of 2-[4-(l-indanyl)phenoxymethyl]benzoyl chloride (12.56 g, 34.6 mmol) in methylene chloride (100 mL) was added to a mixture of methoxylamine hydrochloride (4.34 g, 52.0 mmol) in aqueous 5% sodium hydroxide (50-100 mL). The organic phase was separated and washed with aqueous 5% HCI, then was dried over magnesium sulfate and concentrated to a solid. The solid was slurried in hexanes and collected to afford 6.84 g, of N- methoxy 2-[4-(l-indanyl)phenoxymethyl]benzamide as a white solid.
Carbon tetrachloride (2.54 mL, 25.6 mmol) was added dropwise to a solution of (N- methoxy 2-[4-(l-indanyl)phenoxymethyl]benzamide (6.54 g, 17.5 mmol) and triphenylphosphine (6.89 g, 26.3 mmol) in acetonitrile (100 mL). The resulting reaction mixture was refluxed for lh, then was allowed to stir overnight at room temperature to give a black solution. This was concentrated, the solids were filtered off, and the filtrate was diluted with 5% ethyl acetate in hexanes. The additional solids which formed were filtered off, and the filtrate was concentrated to afford 6.8 g of a red oil which was purified by chromatography over silica gel eluted with 6% ethyl acetate/hexanes to afford 5.8 g of of N-methoxy 2-[4-(l- indanyl)phenoxymethyl]benzenecarboximidoyl chloride as a yellow oil.
Intermediate aa, N-methoxy-2-[4-( 1 -indanyl)phenoxymethyl]benzenecarboximidoyl chloride
SYNTHESIS OF COMPOUNDS
Examples 17-54 illustrate the synthesis of compounds from the intermediates.
EXAMPLE 17
Method G : Synthesis of Samples 1-7 A 60% oil dispersion of sodium hydride (1.1 equiv) was added to a solution of the oxime (1.0 equiv) from method C in DMF. The mixture was stirred at room temperature for 5 min, then methyl -(E)-2-(bromomethylphenyl)-2-methoxyiminoacetate (1.0 equiv) was added
and the mixture was heated at 40°C for 9h. The resulting mixture was diluted with ether and washed with water, then was dried over magnesium sulfate and purified by reverse phase chromatography.
Sample 1, Methyl 2-[[[[l-[4-(l-indanyl)phenyl]ethylidenyl]amino]oxy]methyl]-Î ±- methoxyimino phenylacetate
Intermediate g was reacted according to method G to give the Sample 1 as an oil. *H NMR (CDC1 3 ) δ 7.6-7.5 (m, 3H), 7.4 (m, 2H), 7.3 (m, IH), 7.2-7.1 (m, 5H), 6.9 (m, IH), 5.1 (s, 2H), 4.4 (t, J = 8Hz, IH), 4.1 (s, 3H), 3.8 (s, 3H), 3.1-2.9 (m, 2H), 2.6 (m, IH), 2.2 (s, 3H), 2.1-2.0 (m, IH).
Sample 2, Methyl 2-[[[[l-[4-(5-methoxy-l-indanyl)phenyl]ethylidenyl]amino]oxy ]- methyl]-α-methoxyimino phenylacetate
Intermediate h was reacted according to method G to give 100 mg (33%) of sample 2 as a colorless oil. 'H NMR (CDC1 3 ) δ 7.6-7.5 (m, 3H), 7.4 (m, 2H), 7.2 (m, 3H), 6.9-6.8 (m, 2H), 6.7 (m, IH), 5.1 (s, 2H), 4.3 (t, J = 8Hz, IH), 4.1 (s, 3H), 3.8 (m, 6H), 3.1-2.9 (m, 2H), 2.6 (m, IH), 2.2 (s, 3H), 2.1-2.0 (m, IH).
Sample 3, Methyl 2-[[[[l-[4-(l-tetralinyl)phenyl]ethylidenyl]amino]oxy]methyI ]-α- methoxyimino phenylacetate
Intermediate i was reacted according to method G to give 90 mg (34%) of sample 3 as a colorless oil. Η NMR (CDC1 3 ) δ 7.5 (m, 3H), 7.4 (m, 2H), 7.2-7.0 (m, 6H), 6.8 (m, IH), r
5.1 (s, 2H), 4.1 (t, J = 8Hz, IH), 4.0 (s, 3H), 3.8 (s, H), 3.0-2.8 (m, 2H). 2.2-2.1 (m, 4H), 1.9- 1.7 (m, 3H).
Sample 4, Methyl 2-[[[[l-[4-(5-methoxy-l-tetralinyl)phenyl]ethylidenyl]amino] oxy]- methyl]-α-methoxyimino phenylacetate
Intermediate j was reacted according to method G to give 120 mg (35%) of sample 4 as a colorless oil. IH NMR (d 6 -acetone) δ 7.6-7.5 (m, 3H), 7.4 (m, 2H), 7.2 (m, IH), 7.1 (m, 2H), 7.0 (m, IH), 6.8 (m, IH), 6.4 (m, IH), 5.1 (s, 2H), 4.2 (t, J = 8Hz, IH), 4.0 (s, 3H), 3.9 (s, 3H), 3.8 (s, 3H), 2.8-2.7 (m, 2H), 2.2 (s, 3H), 2.1 (m, IH), 1.9-1.7 (m, 3H).
Sample 5, 2-[l-(methoxycarbonyl) methoxyiminomethyl]-3-[[[[l-[4-(l- indanyl)phenyl]ethylidenyl]amino]oxy]methyl] thiophene
Intermediate g was reacted according to method G to give 100 mg (34%) of sample 5 as a colorless oil. »H NMR (CDC1 3 ) δ 7.6 (m, 2H), 7.5 (m, IH), 7.3 (m, IH), 7.2-7.1 (m, 5H), 6.9 (m, IH), 5.1 (s, 2H), 4.3 (t, J = 8Hz, IH), 4.1 (s, 3H), 3.8 (s, 3H), 3.1-2.9 (m, 2H), 2.6-2.5 (m, IH), 2.2 (s, 3H), 2.1-2.0 (m, IH).
Sample 6, 2-[l-(methoxycarbonyl)methoxyiminomethyl]-3-[[[[l-[4-(l- tetralinyl)phenyl]ethylidenyl]amino]oxy]methyl] thiophene
isomer 1
Intermediate i was reacted according to method G to give 110 mg (36%) of sample 6 as a colorless oil. Η NMR (CDC1 3 ) δ 7.6-7.4 (m, 3H), 7.2-7.0 (m, 6H), 6.8 (m, IH), 5.1 (s, 2H), 4.1 (m, 4H), 3.8 (s, 3H), 3.0-2.8 (m, 2H), 2.2-2.1 (m, 4H), 1.9-1.7 (m, 3H).
Sample 7, 2-[l-(methoxycarbonyl)methoxyiminomethyl]-3-[[[[l-[4-(l- tetralinyl)phenyl]ethylidenyl]amino]oxy]methyl] thiophene
isomer 2
Intermediate i was reacted according to method G to give 110 mg (36%) of sample 7 as a colorless oil. ! H NMR (CDC1 3 ) δ 7.6 (m, 2H), 7.3 (m, IH), 7.2-7.0 (m, 6H), 6.8 (m, IH), 5.3 (s, 2H), 4.1 (t, J = 8Hz, IH), 4.0 (s, 3H), 3.9 (s, 3H), 3.0-2.8 (m, 2H), 2.3 (s, 3H), 2.2 (m, IH), 1.9-1.7 (m, 3H).
EXAMPLE 18 Method H: Synthesis of Samples 8-16 A IM solution of potassium tert-butoxide in THF (1.1 equiv) was added dropwise to a solution of either a substituted phenol (1.2 equiv) or alcohol (1.2 equiv) in THF. To this solution of potassium phenoxide or alkoxide was added a solution of methyl 2-bromomethyl phenyl-2-(methoxyimino)acetate (1.0 equiv) in THF. The resulting mixture was stirred at room temperature for Id, then was partitioned between ether and water. The organic phase was dried over magnesium sulfate, concentrated, and purified by normal-phase or reverse- phase chromatography.
Sample 8, Methyl 2-[4-(5-chloro-l-indanyl)phenoxymethyl]-α-methoxyimino phenylacetate
Intermediate k was reacted according to method H to give sample 8 as an oil. l H NMR (CDC1 3 ) δ 7.6 (m, IH), 7.5-7.4 (m, 2H), 7.3-7.2 (m, 2H), 7.1-7.0 ( , 3H), 6.9-6.8 (m, 3H), 5.0 (s, 2H), 4.2 (t, J = 8Hz, IH), 4.0 (s, 3H), 3.8 (s, 3H), 3.1-2.8 (m, 2H), 2.6-2.5 (m, IH), 2.1-2.0 (m, IH).
Sample 9, Methyl 2-[4-(5-fluoro-l-indanyl)phenoxymethyl]-α-methoxyimino phenyl¬ acetate
Intermediate 1 was reacted according to method H to give sample 9 as an oil. 'H NMR (CDClj) δ 7.5 (m, IH), 7.4 (m, 2H), 7.2 (m, IH), 7.1-7.0 (m, 2H), 6.9 (m, IH), 6.8 (m, 4H), 4.9 (s, 2H), 4.2 (t, J = 8Hz, IH), 4.0 (s, 3H), 3.8 (s, 3H), 3.0-2.8 (m, 2H), 2.6-2.5 (m, IH), 2.0 (m, IH).
Sample 10, Methyl 2-[4-(2-methyl-l -indanyl )phenoxymethyl]-oc-methoxyimino phenylacetate
Intermediate m was reacted according to method H to give sample 10 as an oil. *H NMR (CDCLJ δ 7.6 (m, IH), 7.5-7.4 (m, 2H), 7.3-7.1 (m, 5H), 6.9 (m, 2H), 6.8 (m, 2H), 4.9 (s, 2H), 4.3 (d, J = 8Hz, IH), 4.0 (s, 3H), 3.8 (s, 3H), 3.1-3.0 (m, IH), 2.9-2.6 (m, 2H), 0.7 (d, J = 7Hz, 3H).
Sample 11, Methyl 2-[4-(3-methyl-l-indanyl)phenoxymethyl]-α-methoxyimino phenylacetate
Intermediate n was reacted according to method H to give 107 mg of sample 1 1 as a white solid, mp 93.5°-97.5°C. IH NMR (CDC1 3 ) δ 7.6 (m, IH), 7.5-7.3 (m, 2H), 7.2 (m, 3H), 7.1 (m, 3H), 6.8 (m, 3H), 4.9 (s, 2H), 4.2 (t, J = 8Hz, IH), 4.0 (s, 3H), 3.8 (s, 3H), 3.2 (m, IH), 2.7-2.6 (m, IH), 1.6-1.5 (m, IH), 1.4 (d, J = 7Hz, 3H).
Sample 12, Methyl 2-[4-(4-methyl-l-indanyl)phenoxymethyl]-α-methoxyimino phenylacetate
Intermediate o was reacted according to method H to give sample 12 as a solid, 108°- 109.5°C. IH NMR (CDC1 3 ) δ 7.5 ( , IH), 7.4 (m, 2H), 7.2 (m, IH), 7.1-7.0 (m, 4H), 6.8 (m, 3H), 4.9 (s, 2H), 4.3 (t, J = 8Hz, IH), 4.0 (s, 3H), 3.8 (s, 3H), 3.0-2.8 (m, 2H), 2.5 (m, IH), 2.3 (s, 3H), 2.0 (m, IH). Sample 13, Methyl 2-[4-(l -methyl- l-indanyl)phenoxymethyl]-α-methoxyimino phenylacetate
- 36 - Intermediate p was reacted according to method H to give sample 13 as an oil. J H NMR of a mixture of isomers (CDC1 3 ) δ 7.5 (m, IH), 7.4 (m, 2H), 7.3-7.0 (m, 7H), 6.8 (m, 2H), 4.9 (m, 2H), 4.0 (m, 3H), 3.8 (m, 3H), 2.9-1.8 (m, 4H), 1.6 (m, 3H).
Sample 14, Methyl 2-(l-indanoxymethyl)-α-methoxyimino phenylacetate
1-Indanol was reacted according to method H to give 55mg (15%) of sample 14 as a white solid. >H NMR (CDC1 3 ) δ 7.50-7.48 (m, IH), 7.43-7.32 (m, 3H), 7.25-7.14 (m, 4H), 4.91 (dd, J = 6.5 Hz, 4.0 Hz, IH), 4.49 (dd, J = 14.7 Hz, 12.0 Hz, 2H), 4.00 (s, 3H), 3.77 (s, 3H), 3.14-3.04 (m, IH), 2.84-2.72 (m, IH), 2.34-2.23 (m, IH), 2.14-2.04 (m, IH). Sample 15, Methyl 2-(2-indanoxymethyl)-α-methoxyimino phenylacetate
2-Indanol was reacted according to method H to give 58 mg (14%) of sample 15 as a yellow oil. »H NMR of a mixture of isomers (CDC1 3 ) δ 7.47-7.29 (m) and 7.22-7.12 (m, 8H combined), 5.69-5.60 (m) and 4.37-4.30 (m, IH combined), 4.45 (s) and 4.29 (s, 2H combined), 4.03 (s) and 4.00 (s, 3H combined), 3.81 (s) and 3.21 (s, 3H combined), 3.42-3.34
(m) and 3.17-2.94 (m, 4H combined).
Sample 16, Methyl 2-(2-tetralinoxymethyl)-α-methoxyimino phenylacetate
β-Tetralol was reacted according to method H to give 57 mg (15%) of sample 16 as a red oil. »H NMR of a mixture of isomers (CDC1 3 ) δ 7.48-7.27 (m) and 7.17-7.02 (m, 8H combined), 5.38-5.31 (m) and 3.80-3.70 (m, IH combined), 4.51 (dd, J = 12.2 Hz, 2.5 Hz) and
SUBÎTITUTE SHEET (RULE 26)
4.27 (s, 2H combined), 4.03 (s) and 4.02 (s, 3H combined), 3.83 (s) and 3.22 (s, 3H combined), 3.19-2.88 (m, 2H), 2.83-2.70 (m, 2H), 2.14-1.75 (m, 2H).
EXAMPLE 19 Method I: Synthesis of Samples 17-26 A mixture of a 4-substituted phenol (1.0-1.5 equiv), methyl 2-bromomethyl phenyl-2-
(methoxyimino)acetate (1.0 equiv) or methyl 3-bromomethyl-2-thienyl-2- (methoxyimino)acetate (1.0 equiv)), and potassium carbonate (2.0-2.2 equiv) in DMF was heated overnight at 60°C. The resulting mixture was cooled and partitioned between ether and water. The organic phase was dried over magnesium sulfate, concentrated, and purified by either recrystallization for ether/hexane mixtures or chromatography over silica gel eluted with ethyl acetate/hexane mixtures.
Sample 17, Methyl 2-[4-(l-indanyl)phenoxymethyl]-α-methoxyimino phenylacetate
4-(l-Indanyl)phenol was reacted according to method I to give 1.71 g (58%) of sample 17 as a white solid, mp 86°-87°C. »H NMR (CDC1 3 ) δ 6.8-7.58 (m, 12H), 4.92 (s, 2H), 4.26 (t, IH), 4.01 (s, 3H), 3.82 (s, 3H), 3.01 (m, 2H), 2.53 (m, IH), 2.0 (m, IH).
Sample 18, Methyl 2-[4-(l-tetalinyl)phenoxymethyl]-α-methoxyimino phenylacetate
4-(l-Tetralinyl)phenol was reacted according to method I to give 90 mg (54%) of sample 18 as a white solid, mp 83°-85°C. J H NMR (CDC1 3 ) δ 7.5 (m, IH), 7.4 (m, 2H), 7.2 (m, IH), 7.1-6.9 (m, 5H), 6.8 (m, 3H), 4.9 (s, 2H), 4.1-4.0 (m, 4H), 3.8 (s, 3H), 2.9-2.8 (m, 2H), 2.2 (m, IH), 1.9-1.7 (m, 3H).
Sample 19, Methyl 2-[4-(l-tetralinyl)-2-methyl phenoxymethyl]-α-methoxyimino
38
Intermediate q was reacted according to method I to give 80 mg (29%) of sample 19 as a white solid, mp 112 0 -114.5°C. Η NMR (CDC1 3 ) δ 7.6 (m, IH), 7.5-7.3 (m, 2H), 7.2 (m, IH), 7.1-7.0 (m, 3H), 6.9-6.8 (m, 3H), 6.7 (m, IH), 4.9 (s, 2H), 4.0 (m, 4H), 3.8 (s, 3H), 3.0- 2.8 (m, 2H), 2.2 (s, 3H), 2.1 (m, IH), 1.9-1.7 (m, 3H).
Sample 20, Methyl 3-[4-(l-indanyl)phenoxymethyl]thienyl-2-(α-methoxyimino acetate)
4-(l-Indanyl)phenol was reacted according to method I to give 200 mg (58%) of sample 20 as a yellow oil. l NMR (CDC1 3 ) δ 7.5 (m, IH), 7.3 (m, IH), 7.2-7.0 (m, 5H), 6.9 (m, IH), 6.8 (m, 2H), 4.9 (s, 2H), 4.3 (t, J = Hz, IH), 4.1 (s, 3H), 3.8 (s, 3H), 3.1-2.9 (m, 2H), 2.6-2.5 (m, IH), 2.0 (m, IH).
Sample 21, Methyl 2-[4-(l-indanoxy)phenoxymethyl]-α-methoxyimino phenylacetate
Intermediate r was reacted according to method to give 54 mg (51%) of compound 21 as a white solid. Η NMR (CDC1 3 ) δ 7.56-7.53 (d, IH), 7.47-7.37 (m, 3H), 7.30-7.19 (m, 4H), 6.92-6.82 (symmetrical m, 4H), 5.67-5.64 (dd, J = 6.7 Hz, 4.3 Hz, IH), 4.91 (s, 2H), 4.03 (s, 3H), 3.84 (s, 3H), 3.18-3.08 (m, IH), 2.95-2.85 (m, IH), 2.56-2.45 (m, IH), 2.25-2.14 (m, IH). Sample 22, Methyl 2-[4-(2-indanoxy)phenoxymethyl]-α-methoxyimino phenylacetate
39
Intermediate s was reacted according to method I to give 60 mg (40%) of compound 22 as a white solid. Η NMR (CDC1 3 ) δ 7.55-7.52 (m, IH), 7.46-7.36 (m, 2H), 7.26-7.16 (m, 5H), 6.81 (s, 4H), 5.08 (d of t, J = 6.2 Hz, 3.1 Hz, IH), 4.90 (s, 2H), 4.02 (s, 3H), 3.83 (s, 3H), 3.32 (dd, J = 16.7 Hz, 6.2 Hz, 2H), 3.15 (dd, J = 16.7 Hz, 3.1 Hz, 2H).
Sample 23, Methyl 2-[4-(2-tetralinoxy)phenoxymethyl]-α-methoxyimino phenylacetate
Intermediate t was reacted according to method I to give 96 mg (21%) of sample 23 as an oil. ! H NMR (CDC1 3 ) δ 7.55-7.54 (m, IH), 7.46-7.37 (m, 2H), 7.22-7.20 (m,
IH), 7.15-7.07 (m, 4H), 6.88-6.81 (m, 4H), 4.91 (s, 2H), 4.63-4.57 (m, IH), 4.03 (s, 3H), 3.84
(s, 3H), 3.20-3.14 (m, IH), 3.05-2.94 (m, 2H), 2.88-2.80 (m, IH), 2.19-2.12 (m, IH), 2.06-
1.96 (m, IH).
Sample 24, Methyl 2-[3-(l-indanoxy)phenoxymethyl]-α-methoxyimino phenylacetate
Intermediate u was reacted according to method I to give 149 mg (56%) of sample 24 as an oil. *H NMR (CDC1 3 ) δ 7.55-7.14 (m, 9H), 6.63-6.50 (m, 3H), 5.72 (m, IH), 4.92 (s, 2H), 4.01 (s, 3H), 3.81 (s, 3H), 3.17-3.09 (m, IH), 2.94-2.87 (m, IH), 2.57-2.48 (m, IH), 2.22-2.14 (m, IH).
Sample 25, Methyl 2-[3-(2-indanoxy)phenoxymethyl]-α-methoxyimino phenylacetate
- 40 -
Intermediate v was reacted according to method I to give 200 mg (50%) of sample 25 as an oil. »H NMR (CDC1 3 ) δ 7.57-7.54 (d, IH), 7.47-7.36 (m, 2H), 7.27-7.15 (m, 6H), 6.58- 6.38 (m, 3H), 5.16-5.1 1 (m, IH), 4.94 (s, 2H), 4.02 (s, 3H), 3.83 (s, 3H), 3.41-3.31 (m, 2H), 3.22-3.14 (m, 2H).
Sample 26, Methyl 2-[3-(2-tetralinoxy)phenoxymethyl]-α-methoxyimino phenylacetate
Intermediate w was reacted according to method I to give of sample 26 as an oil. *H NMR (CDC1 3 ) δ 7.55-7.53 (m, IH), 7.45-7.37 (m, 2H), 7.21-7.07 (m, 6H), 6.56-6.49 (m, 3H), 4.92 (s, 2H), 4.72-4.65 (m, IH), 4.01 (s, 3H), 3.81 (s, 3H), 3.21-3.16 (m, IH), 3.03-2.94 (m, 2H), 2.89-2.80 (m, IH), 2.20-2.14 (m, IH), 2.06-1.97 (m, IH).
EXAMPLE 20 Method J: Synthesis of Samples 27 and 28 A solution of methyl 2-[2-(chloromethyl)phenyl]-3-methoxypropenoate (1.0 equiv) and sodium iodide (1.5 equiv) in acetone was stirred at room temperature and monitored to completion by GC. The resulting mixture was filtered, concentrated under vacuum, then diluted with chloroform and filtered again to remove the remaining sodium salts. The filtrate was concentrated and purified by chromatography over silica gel eluted with ethyl acetate/hexane mixtures to afford methyl 2-[2-(iodomethyl)phenyl]-3-methoxypropenoate as a yellow solid.
A mixture of methyl 2-[2-(iodomethyl)phenyl]-3-methoxypropenoate (1.2 equiv), a 4- substituted phenol (1.0 equiv), and potassium carbonate (2.3 equiv) in DMF was heated and stirred at 70°C for 15h. The resulting reaction was cooled to room temperature and
- 41 - partitioned between ether and water, then the organic phase was washed with brine, then was dried over magesium sulfate and concentrated to an oil. This oil was dissolved in methylene chloride and reacted with the hydroxide form of an amberlite resin for 8h to remove the remaining 4-substituted phenol. The resin was filtered off and the methylene chloride solution was concentrated to afford product.
Sample 27, Methyl 2-[2-[4-(l-indanyl)phenoxymethyl]phenyl]-3-methoxypropenoate
4-(l-Indanyl)phenol was reacted according to method J to give 103 mg (75%) of sample 27 as a yellow oil. ] H NMR (CDC1 3 ) δ 7.63 (s, IH), 7.62-6.79 (m, 12H), 4.99 (s, 2H), 4.32 (t, J = 11.2 Hz, IH), 3.85 (s, 3H), 3.74 (s, 3H), 3.07-2.94 (m, 2H), 2.65-2.54 (m, IH), 2.1 1-1.98 (m, IH).
Sample 28, Methyl 2-[2-[4-(l-tetralinyl)phenoxymethyl]phenyl]-3-methoxy- propenoate
4-(l-Tetralinyl)phenol was reacted according to method J to give 113 mg (80%) of sample 28 as a pale yellow oil. »H NMR (CDC1 3 ) δ 7.56 (m, IH), 7.34-6.73 (m, 12H), 4.93 (s, 2H), 4.04 (t, J = 6Hz, IH), 3.80 (s, 3H), 3.68 (s, 3H), 2.88-2.83 (m, 2H), 2.11 (m, IH), 1.86-1.74 (m, 3H).
EXAMPLE 21 Method K: Synthesis of Samples 29 and 30
A 60% oil dispersion of sodium hydride (1.1 equiv) was added to a solution of methyl 2-[(hydroxyimino)methyl]-α-(methoxyimino) phenylacetate in DMF. The mixture was stirred at room temperature for 5 min, then the bromide (1.0 equiv) from method F was added and the reaction stirred at 40°C for 9h. This was partitioned between ether and water, then the
organic phase was dried over magnesium sulfate, concentrated, and purified on a silica gel prep plate eluted with a mixture of ethyl acetate/hexanes.
Sample 29, Methyl 2-[[[[l-[4-(l-indanyl)phenyl]ethyl]oxy]imino]methyl]-α- (methoxyimino) phenylacetate
Intermediate y was reacted according to method K to give 100 mg (26%) of sample 29 as a colorless oil. »H NMR (CDC1 3 ) δ 8.0 (s, IH), 7.6 (m, IH), 7.4 (m, 2H), 7.3-7.2 (m, 3H), 7.2-7.1 (m, 5H), 6.9 (m, IH), 5.3 (q, J = 7Hz, IH), 4.3 (t, J = 8Hz, IH), 4.0 (s, 3H), 3.8 (s, 3H), 3.1-2.9 (m, 2H), 2.6-2.5 (m, IH), 2.1-2.0 (m, IH), 1.6 (d, J = 7Hz, 3H).
Sample 30, Methyl 2-[[[[l-[4-(5-methoxy-l-indanyl)phenyl]ethyl]oxy]imino]methy l]- α-(methoxyimino) phenylacetate
Intermediate z was reacted according to method K to give 300 mg (29%) of sample 30 as an oil. *H NMR of a mixture of isomers (CDC1 3 ) δ 8.0 (s, IH), 7.6 (m, IH), 7.4 (m, 2H), 7.3 (m, 2H), 7.2 (m, 3H), 6.8 (m, 2H), 6.7 (m, IH), 5.3 (m, IH), 4.3 (t, J = 8Hz, IH), 4.0 (m, 3H), 3.8 (m, 3H), 3.7 (m, 3H), 3.0-2.8 (m, 2H), 2.6-2.5 (m, IH), 2.0 (m, IH), 1.6 (m, 3H).
EXAMPLE 22
Method L: Synthesis of Samples 31 and 32
A mixture of a 4-substituted phenol (1.25 equiv), (E)-methyl 2-[2-(6- chloropyrimidine-4-yloxy)phenyl]-3-methoxypropenoate (1.00 equiv), potassium carbonate
(1.50 equiv), and catalytic copper(I) chloride in DMF was heated overnight at 95°-100°C.
The resulting mixture was cooled and partitioned between ether and water. The organic phase was washed with aqueous 2N sodium hydroxide followed with brine, then was dried over
magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with ethyl acetate/hexane mixtures.
Sample 31 , Methyl 2-[2-[6-[4-(l-indanyl)phenoxy]pyrimidin-4-yloxy]phenyl]-3- methoxypropenoate
4-(l-Indanyl)phenol was reacted according to method L to give 160 mg (51%) of sample 31 as a white solid; ] H NMR (CDC1 3 ) δ 8.4 (s, IH), 7.5 (s, IH), 7.4-7.1 (m, 9H), 7.1- 6.9 (m, 3H), 6.2 (s, IH), 4.4 (t, J = 8Hz, IH), 3.7 (s, 3H), 3.6 (s, 3H), 3.1-2.9 (m, 2H), 2.6 (m, IH), 2.1-2.0 (m, IH). Sample 32, Methyl 2-[2-[6-[4-(l-tetralinyl)phenoxy]pyrimidin-4-yloxy]phenyl]-3 - methoxypropenoate
4-(l-Tetralinyl)phenol was reacted according to method L to give 132 mg (42%) of sample 32 as a white solid. *H NMR (CDC1 3 ) δ 8.4 (s, IH), 7.5 (s, IH), 7.4-7.3 (m, 3H), 7.2- 7.1 (m, 5H), 7.1-7.0 (m, 3H), 6.9 (m, IH), 6.2 (s, IH), 4.2 (t, J = 7Hz, IH), 3.7 (s, 3H), 3.6 (s, 3H), 3.0-2.8 (m, 2H), 2.2 (m, IH), 1.9-1.7 (m, 3H).
EXAMPLE 23 Method M: Synthesis of Samples 33-51 Excess aqueous 40% methylamine (1 mL, 200 equiv) was added to a solution of an ortho-substituted methyl α-(methoxyimino) phenylacetate (20-30 mg) in THF. After stirring at 40°C overnight, the volatile components were removed under vacuum and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate and purified on a silica gel prep plate with a 3:7 ethyl acetate/hexane solution.
Sample 33, N-Methyl-2-[[[[l-[4-(l-indanyl)phenyl]ethylidenyl]amino]oxy] methyl]-α- methoxyimino benzeneacetamide
The compound of sample 1 was reacted according to method M to give sample 33 as an oil. ] H NMR (CDC1 3 ) δ 7.6-7.5 (m, 3H), 7.4 (m, 2H), 7.3 (m, IH), 7.2-7.1 (m, 5H), 6.9 (m, IH), 6.7 (m, IH), 5.1 (s, 2H), 4.4 (t, J = 8Hz, IH), 4.0 (s, 3H), 3.1-2.8 (m, 5H), 2.6 (m, IH), 2.2 (s, 3H), 2.1-2.0 (rp, IH).
Sample 34, N-Methyl-2-[[[[ 1 -[4-(5-methoxy- 1 -indany l)phenyl]ethylidenyl]- amino]oxy]methyl]-α-methoxyimino benzeneacetamide
The compound of sample 2 was reacted according to method M to give 20 mg (67%) of sample 34 as a white solid. J H NMR (CDC1 3 ) δ 7.6-7.5 (m, 3H), 7.4 (m, 2H), 7.2 (m, 3H), 6.8 (m, 2H), 6.7-6.6 (m, 2H), 5.1 (s, 2H), 4.3 (t, J = 8Hz, IH), 3.9 (s, 3H), 3.8 (s, 3H), 3.1-2.8 (m, 5H), 2.6 (m, IH), 2.2 (s, 3H), 2.1-2.0 (m, IH).
Sample 35, N-Methyl-2-[[[[l-[4-(l-tetralinyl)phenyl]ethylidenyl]amino]o xy]methyl]- α-methoxyimino benzeneacetamide
The compound of sample 3 was reacted according to method M to give 27 mg (77%) of sample 35 as a colorless oil. Η NMR (CDC1 3 ) δ 7.5 (m, 3H), 7.4 (m, 2H), 7.2-7.0 (m, 6H),
6.8 (m, IH), 6.7 (m, IH), 5.1 (s, 2H), 4.1 (t, J = 8Hz, IH), 3.9 (s, 3H), 3.0-2.8 (m, 5H), 2.2-2.1 (m, 4H), 1.9-1.7 (m, 3H).
Sample 36, N-Methyl-2-[[[[ 1 -[4-(5-methoxy- 1 -tetralinyl)phenyl]ethylidenyl]amino]- oxy]methyl]-α-methoxyimino benzeneacetamide
The compound of sample 4 was reacted according to method M to give 25 mg (83%) of sample 36 as a colorless oil. 'H NMR (d 6 -acetone) δ 7.6 (m, 2H), 7.5 (m, IH), 7.4-7.3 (m,
2H), 7.2 (m, IH), 7.1 (m, 2H), 7.0 (m, IH), 6.8 (m, IH), 6.4 (m, IH), 5.1 (s, 2H), 4.1 (t, J =
8Hz, IH), 3.9 (s, 3H), 3.8 (s, 3H), 2.8 (d, J = 5Hz, 3H), 2.7 ( , 2H), 2.2 (s, 3H), 2.1 (m, IH), 1.9-1.7 (m, 3H).
Sample 37, N-Methyl-3-[[[[ 1 -[4-( 1 -indanyl)phenyl]ethylidenyl]amino]oxy]methyl]-α- methoxyimino-2-thiopheneacetamide
The compound of sample 5 was reacted according to method M to give 20 mg (80%) of sample 37 as a solid. 'H NMR (CDC1 3 ) δ 7.6 (m, 2H), 7.5 (m, IH), 7.3 (m, IH), 7.2-7.1 (m, 5H), 6.9 (m, IH), 6.7 (m, IH), 5.1 (s, 2H), 4.3 (t, J = 8Hz, IH), 4.0 (s, 3H), 3.1-2.8 (m, 5H), 2.6 (m, IH), 2.2 (s, 3H), 2.1-2.0 (m, IH).
Sample 38, N-Methyl-3-[[[[ 1 -[4-( 1 -tetralinyl)phenyl]ethylidenyl]amino]oxy]methyl]- α-methoxyimino-2-thiopheneacetamide
isomer 1
The compound of sample 6 was reacted according to method M to give 15 mg (75%) of sample 38 as a colorless oil. J H NMR (CDC13) δ 7.6-7.4 (m, 3H), 7.2-7.0 (m, 6H), 6.8 (m, IH), 6.7 (m, IH), 5.1 (s, 2H), 4.1 (t, J = 8Hz, IH), 4.0 (s, 3H), 3.0-2.8 (m, 5H), 2.2-2.1 (m, 4H), 1.9-1.7 (m, 3H).
Sample 39, N-Methyl-3-[[[[l -[4-(l-tetralinyl)phenyl]ethylidenyl]amino]oxy]methyl]- -methoxyimino-2-thiopheneacetamide
isomer 2
The compound of sample 7 was reacted according to method M to give 15 mg (75%) of sample 39 as a colorless oil. J H NMR (CDC13) δ 7.5 (m, 2H), 7.3 (m, IH), 7.2-7.0 (m, 6H), 6.8 (m, IH), 6.4 (m, IH), 5.3 (s, 2H), 4.1 (t, J - 8Hz, IH), 4.0 (s, 3H), 3.0-2.8 (m, 5H), 2.2 (s, 3H), 2.1 (m, IH), 1.9-1.7 (m, 3H).
Sample 40, N-Methyl-2-[4-(5-chloro-l -indanyl)phenoxymethyl]-α-methoxyimino benzeneacetamide
The compound of sample 8 was reacted according to method M to give 25 mg (83%) of sample 40 as a white solid. ! H NMR (CDC1 3 ) δ 7.6 ( , IH), 7.5-7.4 (m, 2H), 7.3-7.2 (m, 2H), 7.1-7.0 (m, 3H), 6.9-6.8 (m, 3H), 6.7 (m, IH), 4.9 (s, 2H), 4.2 (t, J = 8Hz, IH), 4.0 (s, 3H), 3.1-2.8 (m, 5H), 2.6-2.5 (m, IH), 2.1-2.0 (m, IH).
Sample 41, N-Methyl-2-[4-(5-fluoro -l-indanyl)phenoxymethyl]-α-methoxyimino benzeneacetamide
The compound of sample 9 was reacted according to method M to give 20 mg (80%) of sample 41 as a colorless oil. i H NMR (CDC1 3 ) δ 7.5 (m, IH), 7.4 (m, 2H), 7.2 (m, IH), 7.0 (m, 2H), 6.9 (m, IH), 6.8 (m, 4H), 6.7 (m, IH), 4.9 (s, 2H), 4.2 (t, J = 8Hz, IH), 4.0 (s, 3H), 3.0-2.8 (m, 5H), 2.6-2.5 (m, IH), 2.0 (m, IH).
Sample 42, N-Methyl-2-[4-(2-methyl -l-indanyl)phenoxymethyl]-α-methoxyimino- benzeneacetamide
The compound of sample 10 was reacted according to method M to give 15 mg (75%) of sample 42 as a white solid. J H NMR (CDC1 3 ) δ 7.6 (m, IH), 7.5-7.4 (m, 2H), 7.3-7.1 (m, 5H), 6.9 (m, 2H), 6.8 (m, 2H), 6.7 (m, IH), 4.9 (s, 2H), 4.3 (d, J = 8Hz, IH), 4.0 (s, 3H), 3.1 - 3.0 (m, IH), 2.9 (d, J = 5Hz, 3H), 2.8-2.6 (m, 2H), 0.7 (d, J = 7Hz, 3H).
Sample 43, N-Methyl-2-[4-(3-methyl- 1 -indanyl)phenoxymethyl]-α-methoxyimino benzeneacetamide
The compound of sample 1 1 was reacted according to method M to give 25 mg (83%) of sample 43 as a white solid. J H NMR (CDC1 3 ) δ 7.57-7.55 (m, IH), 7.45-7.40 (m, 2H), 7.28-7.23 (m, 3H), 7.16-7.13 (m, 3H), 6.90-6.86 (m, 3H), 6.72-6.71 (m, IH), 4.97 (s, 2H),
4.23-4.16 (m, IH), 3.96 (s, 3H), 3.26-3.14 (m, IH), 2.91 (d, J = 5Hz, 3H), 2.71 (d of t, J = 6.0 Hz, 12.1 Hz, 1 H), 1.61 (q, J = 1 1.9 Hz, 1 H), 1.40 (d, J = 7Hz, 3H).
Sample 44, N-Methyl-2-[4-(4-methyl-l-indanyl)phenoxymethyl]- -methoxyimino benzeneacetamide
The compound of sample 12 was reacted according to method M to give 25 mg (83%) of sample 44 as a white solid, mp 136°-138.5°C. ] H NMR (CDC1 3 ) δ 7.5 (m, IH), 7.4 (m, 2H). 7.2 (m, IH), 7.1-7.0 (m, 4H), 6.9-6.8 (m, 3H), 6.7 (m, IH), 4.9 (s, 2H), 4.3 (t, J = 8Hz, IH), 4.0 (s, 3H), 3.1-2.8 (m, 5H), 2.6 (m, IH), 2.3 (s, 3H), 2.1-2.0 (m, IH).
Sample 45, N-Methyl-2-[4-( 1 -methyl- 1 -indanyl)phenoxymethyl]-α-methoxyimino benzeneacetamide
The compound of sample 13 was reacted according to method M to give sample 45 as an oil. 'H NMR as a mixture of isomers (CDC1 3 ) δ 7.5 (m, IH), 7.4 (m, 2H), 7.3-7.0 (m, 7H), 6.8 (m, 2H), 6.7 (m, IH), 4.9 (m, 2H), 3.9 (m, 3H), 3.0-1.8 (m, 7H), 1.6 (m, 3H).
Sample 46, N-Methyl-2-[4-( 1 -indanyl)phenoxymethyl]-α-methoxyiminobenzene- acetamide
The compound of sample 17 was reacted according to method M to give 268 mg (67%) of sample 46 as a white solid, mp 96°-98°C. Η NMR (CDC1 3 ) δ 6.8-7.52 (m, 12H), 6.65 (s, IH), 4.92 (s, 2H), 4.3 (t, IH), 3.92 (s, 3H), 3.8-3.1 (m, 5H), 2.52 (m, IH), 2.00 (m, IH). Sample 47, N-Methyl-2-[4-(l-tetralinyl)phenoxymethyl]-α-methoxyiminobe nzene- acetamide
The compound of sample 18 was reacted according to method M to give 22 mg (88%) of sample 47 as a white solid, mp 118-120°C. 'H NMR (CDC1 3 ) δ 7.5 (m, IH), 7.4 (m, 2H), 7.2 (m, IH), 7.1-6.9 (m, 5H), 6.8 (m, 3H), 6.7 (m, IH), 4.9 (s, 2H), 4.0 (t, J = 7Hz, IH), 3.9 (s, 3H), 2.9-2.7 (m. 5H), 2.2 (m, IH), 1.9-1.7 (m, 3H).
Sample 48, N-Methyl-2-[2-methyl-4-( 1 -tetralinyI)phenoxymethyl]-α-methoxyimino benzeneacetamide
The compound of sample 19 was reacted according to method M to give sample 48.
•H NMR (CDC1 3 ) δ 7.6 (m, IH), 7.5-7.3 (m, 2H), 7.2 (m, IH), 7.1-7.0 (m, 3H), 6.9-6.8 (m, 3H), 6.7 (m, 2H), 4.9 (s, 2H), 4.0 (t, J = 7Hz, IH), 3.9 (s, 3H), 3.0-2.8 (m. 5H), 2.2 (s, 3H), 2.1 (m, IH), 1.9-1.7 (m, 3H).
Sample 49, N-Methyl-3-[4-( 1 -indanyl)phenoxymethyl]-α-methoxyimino-2-thiophene- acetamide
The compound of sample 20 was reacted according to method M to give 20 mg (80%) of sample 49 as a colorless oil. ^H NMR (CDC1 3 ) δ 7.5 (m, IH), 7.3 (m, IH), 7.2-7.0 (m, 5H), 6.9 (m, IH), 6.8 (m, 2H), 6.7 (m, IH), 5.0 (s, 2H), 4.3 (t, J = 8Hz, IH), 4.0 (s, 3H), 3.1-2.8 (m, 5H), 2.6-2.5 (m, IH), 2.0 (m, IH).
Sample 50, N-MethyI-2-[[[[l-[4-(l-indanyl)phenyl]ethyl]oxy]imino]methyl ]-α- methoxyiminobenzeneacetamide
The compound of sample 29 was reacted according to method M to give 23 mg (77%) of sample 50 as a colorless oil. »H NMR (CDC1 3 ) δ 8.0 (s, IH), 1.1 (m, IH), 7.4 (m, 2H), 7.3- 7.2 (m, 3H), 7.2-7.1 (m, 5H), 7.0 (m, IH), 6.6 (m, IH), 5.3 (q, J = 7Hz, IH), 4.3 (t, J = 8Hz, IH), 3.8 (s, 3H), 3.1-2.8 (m, 5H), 2.6-2.5 (m, IH), 2.1-2.0 (m, IH), 1.6 (d, J = 7Hz, 3H).
Sample 51, N-Methyl-2-[[[[l-[4-(5-methoxy-l-indanyl)phenyl]ethyl]oxy]im ino]- methyl]- -methoxyimino benzeneacetamide
The compound of sample 30 was reacted according to method M to give sample 51. »H NMR of a mixture of isomers (CDC1 3 ) δ 8.0 (s, IH), 7.7 (m, IH), 7.4 (m, 2H), 7.3 (m, 2H), 7.2 (m, 3H), 6.8 (m, 2H), 6.7 (m, IH), 6.6 (m, IH), 5.3-5.2 (m, IH), 4.3 (t, J = 8Hz, IH), 3.9 (m, 3H), 3.8 (m, 3H), 3.1-2.8 (m, 5H), 2.6-2.5 (m, IH), 2.1-2.0 (m, IH), 1.6 (m, 3H).
EXAMPLE 24
Method N: Synthesis of Samples 52 and 53 A 60% oil dispersion of sodium hydride (2.0 equiv) was added to a solution of an azole (2.0 eq) in DMF, the mixture was stirred at room temperature for 10 min. N-methoxy 2- [4-(l-indanyl)phenoxymethyl] benzenecarboximidoyl chloride (intermediate aa, 1.0 equiv) was then added and the mixture was heated at 120°C for 2h. The reaction was partitioned between ether and water. The organic phase was washed twice with 5% HCI, dried over magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with ethyl acetate/hexane mixtures. Sample 52, N-[methoxyimino[2-[4-(l-indanyl)phenoxymethyl]phenyl]methyl] imidazole
Imidazole was reacted according to method N to give 610 mg (48%) of sample 52 as a pale yellow oil. »H NMR (CDC1 3 ) δ 8.12 (s, IH), 7.66-7.63 (m, IH), 7.56 (t, J = 9Hz, IH), 7.46-7.07 (m, 9H), 6.96-6.92 (m, IH), 6.77-6.72 (m, 2H), 5.02 (s, 2H), 4.29 (t, J = 9Hz, IH), 3.98 (s, 3H), 3.10-2.90 (m, 2H), 2.61-2.51 (m, IH), 2.09-1.96 (m, IH).
Sample 53, 1 -[methoxy imino[2-[4-( 1 -indanyl)phenoxymethyl]phenyl]methyl]- 1 ,2,4- triazole
1,2,4-Triazole was reacted according to method N to give 850 mg (67%) of sample 53 as a yellow oil. ] H NMR (CDC1 3 ) δ 9.12 (s, IH), 7.97 (s, IH), 7.60-7.50 (m, 2H), 7.46 (m,
2H), 7.31-7.28 ( , IH), 7.22-7.11 (m, 2H), 7.07 (d, J = 8Hz, 2H), 6.94 (d, J = 8Hz, IH), 6.74
(d, J = 8Hz, 2H), 4.93 (s, 2H), 4.28 (t, J = 8Hz, IH), 4.07 (s, 3H), 3.10-2.90 (m, 2H), 2.60-
2.50 (m, IH), 2.08-1.95 (m, IH).
- 52 - EXAMPLE 25
Synthesis of Sample 54
A solution of methyl 2-[4-(l-indanyl)phenoxymethyl]-α-methoxyimino phenylacetate
(sample 17, 80 mg) in excess 1 -amino-2 -propanol was heated at 120°C for 12h. The resulting mixture was diluted with ethyl acetate and washed with water to remove most of the excess 1 - amino-2-propanol. The ethyl acetate solution was then dried over magnesium sulfate, concentrated, and purified by reverse-phase chromatography to give 80 mg (88%) of sample
54 as an oil. >H NMR (CDC1 3 ) δ 7.5 (m, IH), 7.4 (m, 2H), 7.3-7.0 (m, 7H), 6.8 (m, 2H), 4.9
(s, 2H), 4.3 (t, J = 8Hz, IH), 3.9 (s, 3H), 3.9 (m, IH), 3.5 (m, IH), 3.2 (m, IH), 3.1-2.9 (m, 2H), 2.5 (m, IH), 2.1-2.0 (m, IH), 1.2 (d, J = 6Hz, 3H).
Sample 54, N-(2-hydroxypropyl)-2-[4-(l-indanyl)phenoxymethyl]-α-methox yimino benzeneacetamide
EXAMPLE 26 Activity Table - Samples 1-54 and Standards
Samples 1-54 and commercial standards for the given disease were tested for their activity using the protocols described in Examples 1-6. The data appear in the Table below wherein "*" means that the stated value is is mean of more than one test and "-" indicates that no data is available.
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