U.S. patent application number 10/639560 was filed with the patent office on 2004-02-19 for pesticidal activity of functionalized alkenes.
Invention is credited to Linderman, Russell J., Roe, R. Michael, Thompson, Deborah M., Vanderherehen, Matthew.
Application Number | 20040034097 10/639560 |
Document ID | / |
Family ID | 25367870 |
Filed Date | 2004-02-19 |
United States Patent
Application |
20040034097 |
Kind Code |
A1 |
Linderman, Russell J. ; et
al. |
February 19, 2004 |
Pesticidal activity of functionalized alkenes
Abstract
The present invention provides non-peptide organic compounds
that have a structure analogous to or reminiscent of the TMOF
structure and have pesticidal activity. Thus the present invention
concerns pesticidal compounds that inhibit digestion in pests by
terminating or otherwise blocking synthesis of digestive enzymes by
activating a TMOF receptor (collectively referred to herein as
"pesticidal compounds"). The pesticidal compounds and other
compounds of the present invention are usefully employed in the
control of pests, particularly insect pests Such as mosquitoes,
which ingest blood.
Inventors: |
Linderman, Russell J.;
(Green Oaks, IL) ; Roe, R. Michael; (Apex, NC)
; Thompson, Deborah M.; (Raleigh, NC) ;
Vanderherehen, Matthew; (Raleigh, NC) |
Correspondence
Address: |
Kenneth D. Sibley
Myers Bigel Sibley & Sajovec
Post Office Box 37428
Raleigh
NC
27627
US
|
Family ID: |
25367870 |
Appl. No.: |
10/639560 |
Filed: |
August 13, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10639560 |
Aug 13, 2003 |
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09876502 |
Jun 7, 2001 |
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6660770 |
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09876502 |
Jun 7, 2001 |
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09457509 |
Dec 8, 1999 |
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6521664 |
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Current U.S.
Class: |
514/532 ;
514/570; 514/617 |
Current CPC
Class: |
C07C 69/618 20130101;
A01N 37/38 20130101; C07C 57/42 20130101; A01N 37/18 20130101; Y10S
424/10 20130101; Y10S 514/875 20130101; C07C 57/60 20130101; C07C
2601/14 20170501; G01N 33/5082 20130101; Y10S 514/919 20130101;
C07C 69/608 20130101; A01N 37/10 20130101; Y10S 514/951 20130101;
C07C 403/20 20130101; C07C 57/26 20130101; C07C 59/64 20130101 |
Class at
Publication: |
514/532 ;
514/570; 514/617 |
International
Class: |
A01N 037/10; A01N
037/18 |
Claims
That which is claimed is:
1. A method for controlling a pest, comprising administering to
said pest a pesticidally effective amount of a pesticidal compound
of formula I: 14wherein: X is selected from the group consisting of
--CHCH--, --CH.sub.2CH.sub.2--, and --CC--; Z is selected from the
group consisting of --OH, --NH.sub.2 and --OR.sub.6 wherein R.sub.6
is loweralkyl; m.gtoreq.0 and n.gtoreq.1 and together total an
integer from 1 to 12; the ring bearing substituents R.sub.1,
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 is a phenyl ring or a
cyclohexyl ring; and R.sub.1, R.sub.2, R.sub.3, R.sub.4, and
R.sub.5 are each independently selected from the group consisting
of --H, --OH, halo, loweralkyl, loweralkoxy and phenyl; subject to
the proviso that: when the ring is a phenyl ring, a pair of R.sub.1
and R.sub.2, R.sub.2 and R.sub.3, or R.sub.3 and R.sub.4 on the
phenyl ring may together represent
--CR.sub.7.dbd.CR.sub.8--CR.sub.9.dbd.- CR.sub.10--, to form with
the phenyl ring illustrated above a naphthyl ring system, wherein
R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are each independently
selected from the group consisting of --H, --OH, halo, loweralkyl,
and loweralkoxy.
2. A method according to claim 1, wherein X is
--CH.sub.2CH.sub.2--.
3. A method according to claim 1, wherein X is --CHCH--.
4. A method according to claim 1, wherein X is --CC--.
5. A method according to claim 1, wherein R.sub.1 is selected from
the group consisting of hydroxy, bromo, fluoro, methyl, methoxy,
propoxy, and ethoxy;
6. A method according to claim 1, wherein R.sub.1 is selected from
the group consisting of bromo and propoxy.
7. A method according to claim 1, wherein Z is OH.
8. A method according to claim 1, wherein Z is NH.sub.2.
9. A method according to claim 1, wherein m is 2 to 12.
10. A method according to claim 1, wherein m is 3 to 10.
11. A method according to claim 1, wherein m is 4 to 8.
12. A method according to claim 1, wherein m is 4 to 6.
13. A method according to claim 1, wherein n is 2 to 12.
14. A method according to claim 1, wherein n is 3 to 10.
15. A method according to claim 1, wherein n is 4 to 8.
16. A method according to claim 1, wherein n is 4 to 6.
17. A method according to claim 1, wherein R.sub.2 is H.
18. A method according to claim 1, wherein R.sub.3 is H.
19. A method according to claim 1, wherein R.sub.5 is H.
20. A method according to claim 1, wherein R.sub.2 and R.sub.3 are
both H.
21. A method according to claim 1, wherein R.sub.2 and R.sub.5 are
both H.
22. A method according to claim 1, wherein R.sub.3 and R.sub.5 are
both H.
23. A method according to claim 1, wherein R.sub.2, R.sub.3 and
R.sub.5 are all H.
24. A method according to claim 1, wherein R.sub.1 is a
halogen.
25. A method according to claim 1, wherein R.sub.3 is a
halogen.
26. A method according to claim 1, wherein R.sub.1 is an
alkoxy.
27. A method according to claim 1, wherein R.sub.3 is an
alkoxy.
28. A method according to claim 1, wherein R.sub.1 and R.sub.3 are
both a halogen.
29. A method according to claim 1, wherein R.sub.1 and R.sub.3 are
both an alkoxy.
30. A method according to claim 1, wherein said pest is an insect
pest.
31. A method according to claim 1, wherein said pest is an insect
selected from the group consisting of coleopterans, lepidopterans,
and dipterans.
32. A method according to claim 1, wherein said pest is a
blood-sucking insect.
33. A method according to claim 1, wherein said pest is an insect
of the suborder Nematocera.
34. A method according to claim 1, wherein said pest is an insect
of the family Colicidae.
35. A method according to claim 1, wherein said pest is an insect
of a subfamily selected from the group consisting of Culicinae,
Corethrinae, Ceratopogonidae and Simuliidae.
36. A method according to claim 1, wherein said pest is an insect
of a genus selected from the group consisting of Culex, Theobaldia,
Aedes, Anopheles, Aedes, Forciponiya, Culicoides and Helea.
37. A method according to claim 1, wherein said pest is an insect
species selected from the group consisting of: Aedes aegypti, Culex
quinquefasciatus, Anopheles albimanus, Anopheles quadrimaculatus,
Lutzomyia anthrophora, Culicoides variipennis, Stomoxys calcitrans,
Musca domestica, Ctenocephalides feliz, and Heliothis
virescens.
38. A method according to claim 1, wherein said pest is selected
from the group consisting of flies, fleas, ticks, and lice.
39. A method according to claim 1, wherein said pest is a
mosquito.
40. A method according to claim 1, wherein said pest is selected
from the group consisting of beetles, caterpillars, and mites.
41. A method according to claim 1, wherein said pest is selected
from the group consisting of ants and cockroaches.
42. A method according to claim 1, wherein said compound of Formula
I is selected from the group consisting of: E-7-phenylhept-4-enoic
acid; E-7-(4-methoxyphenyl)hept-4-enoic acid; methyl
E-7-phenylhept-4-enoate; E-7-phenylhept-4-enoic acid amide;
Z-7-phenylhept-4-enoic acid; E-7-(2,4-difluorophenyl)hept-4-enoic
acid; E-10-phenyldec-6-enoic acid; E-1-(4-methoxyphenyl)dec-4-enoic
acid; E-7-(4-hydroxyphenyl)hept-4-enoic acid;
E-7-(2,4-dibromophenyl)hept-4-enoic acid;
E-7-(4-methylphenyl)hept-- 4-enoic acid;
E-7-(2,4-diethylphenyl)hept-4-enoic acid;
E-7-(2-ethoxyphenyl)hept-4-enoic acid;
E-7-(2,4,-dipropoxyphenyl)hept-4-e- noic acid:
E-10-(2,4-difluorophenyl)dec-4-enoic acid;
E-7-(2,4-difluorophenyl)hept-4-enoic acid amide;
E-7-(4-methoxyphenyl)hep- t-4-enoic acid amide;
E-10-phenyldec-6-enoic acid amide;
E-7-(2,4-difluorophenyl)dec-6-enoic acid amide;
E-7-(4-methoxyphenyl)dec-- 6-enoic acid amide;
Z-7-phenylhept-4-enoic acid amide; Methyl
E-7-(2,4-difluorophenyl)hept-4-enoate; Methyl
E-7-(4-methoxyphenyl)hept-4- -enoate; Methyl
E-10-phenyldec-6-enoate; Methyl E-7-(2,4-difluorophenyl)de-
c-6-enoate; Methyl E-7-(4-methoxyphenyl)dec-6-enoate; Methyl
Z-7-phenylhept-4-enoate; Ethyl
E-7-(2,4-difluorophenyl)hept-4-enoate; Ethyl
E-7-(4-methoxyphenyl)hept-4-enoate; Ethyl E-10-phenyldec-6-enoate;
Propyl E-7-(2,4-difluorophenyl)dec-6-enoate; Propyl
E-7-(4-methoxyphenyl)dec-6-enoate; Propyl Z-7-phenylhept-4-enoate;
Ethyl E-7-phenylhept-4-enoate; Propyl E-7-phenylhept-4-enoate;
Butyl E-7-phenylhept4-enoate; Ethyl E-10-phenyldec-6-enoate; Propyl
E-10-phenyldec-6-enoate; and Butyl E-10-phenyldec-6-enoate.
43. A method of initiating a TMOF receptor-mediated biological
response, comprising contacting to a TMOF receptor in vivo or in
vitro for a time and in an amount sufficient to initiate a TMOF
receptor-mediated biological response a compound of Formula I:
15wherein: X is selected from the group consisting of --CHCH--,
--CH.sub.2CH.sub.2--, and --CC--; Z is selected from the group
consisting of --OH, --NH.sub.2 and --OR.sub.6 wherein R.sub.6 is
loweralkyl; m.gtoreq.0 and n.ltoreq.1 and together total an integer
from 1 to 12; the ring bearing substituents R.sub.1, R.sub.2,
R.sub.3, R.sub.4 and R.sub.5 is a phenyl ring or a cyclohexyl ring;
and R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are each
independently selected from the group consisting of --H, --OH,
halo, loweralkyl, loweralkoxy and phenyl; subject to the proviso
that: when the ring is a phenyl ring, a pair of R.sub.1 and
R.sub.2, R.sub.2 and R.sub.3, or R.sub.3 and R.sub.4 on the phenyl
ring may together represent
--CR.sub.7.dbd.CR.sub.8--CR.sub.9.dbd.CR.sub.10--, to form with the
phenyl ring illustrated above a naphthyl ring system, wherein
R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are each independently
selected from the group consisting of --H, --OH, halo, loweralkyl,
and loweralkoxy.
44. A method according to claim 43, wherein said biological
response is inhibition of biosynthesis of a digestive enzyme.
45. A method according to claim 43, wherein said digestive enzyme
is trypsin.
46. A method according to claim 43, wherein said contacting step is
carried out in vivo in an insect pest.
47. A method according to claim 43, wherein X is
--CH.sub.2CH.sub.2--.
48. A method according to claim 43, wherein X is --CHCH--.
49. A method according to claim 43, wherein X is --CC--.
50. A pest control composition comprising a pesticidal carrier and
a pesticidal compound of Formula I: 16wherein: X is selected from
the group consisting of --CHCH--, --CH.sub.2CH.sub.2--, and --CC--;
Z is selected from the group consisting of --OH, --NH.sub.2 and
--OR.sub.6 wherein R.sub.6 is loweralkyl; m.gtoreq.0 and n.gtoreq.1
and together total an integer from 1 to 12; the ring bearing
substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 is a
phenyl ring or a cyclohexyl ring; and R.sub.1, R.sub.2, R.sub.3,
R.sub.4, and R.sub.5 are each independently selected from the group
consisting of --H, --OH, halo, loweralkyl, loweralkoxy and phenyl;
subject to the proviso that: when the ring is a phenyl ring, a pair
of R.sub.1 and R.sub.2, R.sub.2 and R.sub.3, or R.sub.3 and R.sub.4
on the phenyl ring may together represent
--CR.sub.7.dbd.CR.sub.8--CR.sub.9.dbd.CR.sub.10--, to form with the
phenyl ring illustrated above a naphthyl ring system, wherein
R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are each independently
selected from the group consisting of --H, --OH, halo, loweralkyl,
and loweralkoxy.
51. A composition according to claim 50, wherein said composition
is a liquid composition.
52. A composition according to claim 50, wherein said pesticidal
carrier is included in said composition in an amount from 0.1% to
99.9999% by weight.
53. A composition according to claim 50, wherein said pesticidal
carrier comprises an aqueous solution.
54. A composition according to claim 50, wherein said pesticidal
carrier comprises an organic solvent.
55. A composition according to claim 50, wherein said pesticidal
carrier comprises an emulsion.
56. A composition according to claim 50, wherein said composition
is a solid composition.
57. A composition according to claim 50, wherein said composition
is a bait granule.
58. A composition according to claim 50, wherein said compound of
Formula I is selected from the group consisting of:
E-7-phenylhept-4-enoic acid; E-7-(4-methoxyphenyl)hept-4-enoic
acid; methyl E-7-phenylhept-4-enoate; E-7-phenylhept-4-enoic acid
amide Z-7-phenylhept-4-enoic acid;
E-7-(2,4-difluorophenyl)hept-4-enoic acid; E-10-phenyldec-6-enoic
acid; E-1-(4-methoxyphenyl)dec-4-enoic acid;
E-7-(4-hydroxyphenyl)hept-4-enoic acid;
E-7-(2,4-dibromophenyl)hept-4-enoic acid;
E-7-(4-methylphenyl)hept-- 4-enoic acid; E-7-(2,4-di
ethylphenyl)hept-4-enoic acid; E-7-(2-ethoxyphenyl)hept-4-enoic
acid; E-7-(2,4,-dipropoxyphenyl)hept-4-e- noic acid:
E-10-(2,4-difluorophenyl)dec-4-enoic acid;
E-7-(2,4-difluorophenyl)hept-4-enoic acid amide;
E-7-(4-methoxyphenyl)hep- t-4-enoic acid amide;
E-10-phenyldec-6-enoic acid amide;
E-7-(2,4-difluorophenyl)dec-6-enoic acid amide;
E-7-(4-methoxyphenyl)dec-- 6-enoic acid amide;
Z-7-phenylhept-4-enoic acid amide; Methyl
E-7-(2,4-difluorophenyl)hept-4-enoate; Methyl
E-7-(4-methoxyphenyl)hept-4- -enoate; Methyl
E-10-phenyldec-6-enoate; Methyl E-7-(2,4-difluorophenyl)de-
c-6-enoate; Methyl E-7-(4-methoxyphenyl)dec-6-enoate; Methyl
Z-7-phenylhept-4-enoate; Ethyl
E-7-(2,4-difluorophenyl)hept-4-enoate; Ethyl
E-7-(4-methoxyphenyl)hept-4-enoate; Ethyl E-10-phenyldec-6-enoate;
Propyl E-7-(2,4-difluorophenyl)dec-6-enoate; Propyl
E-7-(4-methoxyphenyl)dec-6-enoate; Propyl Z-7-phenylhept-4-enoate;
Ethyl E-7-phenylhept-4-enoate; Propyl E-7-phenylhept-4-enoate;
Butyl E-7-phenylhept 4-enoate; Ethyl E-10-phenyldec-6-enoate;
Propyl E-10-phenyldec-6-enoate; and Butyl
E-10-phenyldec-6-enoate.
59. A method of identifying a non-peptide TMOF agonist from a
peptide TMOF agonist, said method comprising the steps of: modeling
in a computer a model peptide TMOF agonist selected from the group
consisting of TMOF and peptide TMOF analogs; determining in said
computer spatial orientations for at least one key feature of said
model peptide compound; generating in said computer a putative
non-peptide TMOF agonist structure, said structure including (i)
said at least one key feature and (ii) spatial orientations for
said at least one key feature corresponding to said spatial
orientations for said at least one key feature of said model
peptide compound; then synthesizing said putative non-peptide TMOF
agonist; and then screening said putative non-peptide TMOF agonist
to determine the presence of TMOF activity therein.
60. A method according to claim 59, wherein said modeling step is
carried out with simulated annealing.
61. A method according to claim 59, wherein said screening step is
carried out in vivo on insects.
62. A method according to claim 59, wherein said at least one key
feature of said non-peptide TMOF agonist structure comprises (i) a
phenyl ring, and (ii) a carboxylate functional group.
63. A method of controlling a pest, comprising administering to
said pest a pesticidally effective pesticidal amount of a
non-peptide TMOF analog.
64. A method according to claim 63, wherein said non-peptide TMOF
analog is an organic compound that has TMOF activity.
65. A method according to claim 64, wherein said organic compound
that has TMOF activity includes (i) a phenyl group, and (ii) a
carboxylate group.
66. A method according to claim 64, wherein said organic compound
has the stricture P--R--C, where P is a phenyl group, R is an
alkane, alkene, or alkyne, and C is a carboxylate group.
67. A method according to claim 1, wherein said method is an insect
repellant method, and said administering step is carried out by
applying said compound of formula I to a subject or substrate from
which said insect is to be repelled in an amount sufficient to
repel said insect.
68. A method according to claim 1, wherein the ring is a cyclohexyl
ring.
69. A method according to claim 1, wherein m is 0.
70. A method according to claim 1, wherein at least one of R.sub.1,
R.sub.2, R.sub.3, R.sub.4 or R.sub.5 is phenyl.
71. A method according to claim 43, wherein the ring is a
cyclohexyl ring.
72. A method according to claim 43, wherein m is 0.
74. A method according to claim 43, wherein at least one of
R.sub.1, R.sub.2, R.sub.3, R.sub.4 or R.sub.5 is phenyl.
75. A composition according to claim 50, wherein said composition
is a topical repellant composition.
76. A composition according to claim 50, wherein the ring is a
cyclohexyl ring.
77. A composition according to claim 50, wherein m is 0.
78. A composition according to claim 50, wherein at least one of
R.sub.1, R.sub.2, R.sub.3, R.sub.4 or R.sub.5 is phenyl.
79. A compound of the formula: 17wherein: X is selected from the
group consisting of --CHCH--, --CH.sub.2CH.sub.2--, and --CC--; Z
is selected from the group consisting of --OH, --NH.sub.2 and
--OR.sub.6 wherein R.sub.6 is loweralkyl; m.gtoreq.0 and n.gtoreq.1
and together total an integer from 1 to 12; the ring bearing
substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 is a
phenyl ring or a cyclohexyl ring; and R.sub.1, R.sub.2, R.sub.3,
R.sub.4, and R.sub.5 are each independently selected from the group
consisting of --H, --OH, halo, loweralkyl, loweralkoxy and phenyl;
subject to the proviso that: when the ring is a phenyl ring, a pair
of R.sub.1 and R.sub.2, R.sub.2 and R.sub.3, or R.sub.3 and R.sub.4
on the phenyl ring may together represent
--CR.sub.7.dbd.CR.sub.8--CR.sub.9.dbd.CR.sub.10--, to form with the
phenyl ring illustrated above a naphthyl ring system, wherein
R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are each independently
selected from the group consisting of --H, --OH, halo, loweralkyl,
and loweralkoxy.
80. A compound according to claim 79, subject to the further
proviso that when: the ring bearing substituents R.sub.1, R.sub.2,
R.sub.3, R.sub.4 and R.sub.5 is a phenyl ring, each of R.sub.1,
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 is --H, and n and m are each
2, Z is not --OH or --OR.sub.6.
81. A compound according to claim 80, which when contacted to a
TMOF receptor in vivo or in vitro effects a TMOF receptor-mediated
biological response.
82. A compound according to claim 80, which when contacted to a
TMOF receptor in vivo or in vitro effects inhibition of
biosynthesis of a digestive enzyme.
83. A compound according to claim 80, which when contacted to a
TMOF receptor in vivo or in vitro effects inhibition of trypsin
biosynthesis.
84. A compound selected from the group consisting of:
E-7-(4-methoxyphenyl)hept-4-enoic acid; E-7-phenylhept-4-enoic acid
amide; E-7-(2,4-difluorophenyl)hept-4-enoic acid;
E-10-phenyldec-6-enoic acid; E-1-(4-methoxyphenyl)dec-4-enoic acid;
E-7-(4-hydroxyphenyl)hept-4-- enoic acid;
E-7-(2,4-dibromophenyl)hept-4-enoic acid;
E-7-(4-methylphenyl)hept-4-enoic acid;
E-7-(2,4-diethylphenyl)hept-4-enoi- c acid;
E-7-(2-ethoxyphenyl)hept-4-enoic acid; E-7-(2,4,-dipropoxyphenyl)h-
ept-4-enoic acid: E-10-(2,4-difluorophenyl)dec-4-enoic acid;
E-7-(2,4-difluorophenyl)hept-4-enoic acid amide;
E-7-(4-methoxyphenyl)hep- t-4-enoic acid amide;
E-10-phenyldec-6-enoic acid amide;
E-7-(2,4-difluorophenyl)dec-6-enoic acid amide;
E-7-(4-methoxyphenyl)dec-- 6-enoic acid amide;
Z-7-phenylhept-4-enoic acid amide; Methyl
E-7-(2,4-difluorophenyl)hept-4-enoate; Methyl
E-7-(4-methoxyphenyl)hept-4- -enoate; Methyl
E-10-phenyldec-6-enoate; Methyl E-7-(2,4-di
fluorophenyl)dec-6-enoate; Methyl
E-7-(4-methoxyphenyl)dec-6-enoate; Ethyl
E-7-(2,4-difluorophenyl)hept-4-enoate; Ethyl
E-7-(4-methoxyphenyl)hept-4-enoate; Ethyl E-10-phenyldec-6-enoate;
Propyl E-7-(2,4-difluorophenyl)dec-6-enoate; Propyl
E-7-(4-methoxyphenyl)dec-6-e- noate; Ethyl E-10-phenyldec-6-enoate;
Propyl E-10-phenyldec-6-enoate; and Butyl
E-10-phenyldec-6-enoate.
85. A compound according to claim 79, wherein: X is --CHCH-- or
--CC--; Z is NH.sub.2; n is from 2 to 12; and R.sub.1, R.sub.2,
R.sub.3, R.sub.4 and R.sub.5 are not all --H.
86. A compound according to claim 79, wherein: X is --CC--; Z is
NH.sub.2; and R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are
not all --H.
87. A compound according to claim 79, wherein at least one of
R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 is not --H.
88. A compound according to claim 79, wherein the ring bearing
substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 is a
cyclohexyl ring.
89. A compound according to claim 79, wherein at least one of
R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 is selected from the
group consisting of --OH and loweralkoxy.
90. A compound according to claim 79, wherein at least one of
R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 is --OH.
91. A compound according to claim 79, wherein at least one of
R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 is loweralkoxy.
92. A compound selected from the group consisting of:
E-7-(4-Hydroxyphenyl)hept-4-enoic acid; E-7-(4-M
ethoxyphenyl)hept-4-enoi- c acid; Ethyl
E-7-(cyclohexyl)hept-4-enoate; Ethyl E-7-((4-phenyl)phenyl)h-
ept-4-enoate; E-7-(cyclohexyl)hept-4-enoic acid; and
E-7-((4-phenyl)phenyl)hept-4-enoic acid.
93. A compound according to claim 79, wherein the ring bearing
substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 is a
cyclohexyl ring and Z is --OH or --OR.sub.6.
94. A compound according to claim 79, wherein the ring bearing
substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 is a
cyclohexyl ring and Z is --OH.
95. A compound according to claim 79, wherein the ring bearing
substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 is a
cyclohexyl ring and Z is --OR.sub.6.
96. A compound according to claim 79, wherein at least one of
R.sub.1, R.sub.2, R.sub.3, R.sub.4 or R.sub.5 is phenyl.
97. A compound according to claim 79, wherein m is 0.
98. A compound according to claim 79, disposed in insect-repelling
relationship to a locus containing or susceptible to infestation by
insects that are repelled by said compound.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 09/876,502 filed Jun. 7, 2001, which is a
continuation-in-part of commonly owned, copending application Ser.
No. 09/457,509, filed Dec. 8, 1999, the disclosures of which are
incorporated by reference herein in their entirety.
FIELD OF THE INVENTION
[0002] The present invention concerns functionalized alkenes, along
with alkane and alkyne analogs thereof, that have pesticidal
activity, along with methods of use thereof.
BACKGROUND OF THE INVENTION
[0003] Many blood-ingesting pests are known to feed on humans and
animals, and many pests are vectors for pathogenic microorganisms
that threaten human and animal health, including commercially
important livestock, pets and other animals. Various species of
mosquitoes, for example, transmit diseases caused by viruses, and
many are vectors for disease-causing nematodes and protozoa.
Mosquitoes of the genus Anopheles transmit Plasmodium, the
protozoan which causes malaria, a devastating disease which results
in approximately I million deaths annually. The mosquito species
Aedes aegypti transmits an arbovirus that causes yellow fever in
humans. Other arboviruses transmitted by Aedes species include the
causative agents of dengue fever, eastern and western encephalitis,
Venezuelan equine encephalitis, St. Louis encephalitis,
chikungunya, oroponehe and bunyarnidera. The genus Culex, which
includes the common house mosquito C. pipiens, is implicated in the
transmission of various forms of encephalitis and filarial worms.
The common house mosquito also transmits Wuchereria banuffi and
Brugia malayi, which cause various forms of lymphatic filariasis,
including elephantiasis. Trypanasomas cruzi, the causative agent of
Chagas' disease, is transmitted by various species of
blood-ingesting Triatominae bugs. The tsetse fly (Glossina spp.)
transmits African trypanosomal diseases of humans and cattle. Many
other diseases are transmitted by various blood-ingesting pest
species. The order Diptera contains a large number of
blood-ingesting and disease-bearing insects, including, for
example, mosquitoes, black flies, no-see-ums (punkies), horse
flies, deer flies and tsetse flies.
[0004] Various pesticides have been employed in efforts to control
or eradicate populations of disease-bearing pests, such as
disease-bearing blood-ingesting pests. For example, DDT, a
chlorinated hydrocarbon, has been used in attempts to eradicate
malaria-bearing mosquitoes throughout the world. Other examples of
chlorinated hydrocarbons are BHC, lindane, chlorobenzilate,
methoxychlor, and the cyclodienes (e.g., aldrin, dieldrin,
chlordane, heptachlor, and endrin). The long-term stability of many
of these pesticides and their tendency to bioaccumulate render them
particularly dangerous to many non-pest organisms.
[0005] Another common class of pesticides is the organophosphates,
which is perhaps the largest and most versatile class of
pesticides. Organophosphates include, for example, parathion,
Malathion, diazinon, naled, methyl parathion, and dichlorvos.
Organophosphates are generally much more toxic than the chlorinated
hydrocarbons. Their pesticidal effect results from their ability to
inhibit the enzyme cholinesterase, an essential enzyme in the
functioning of the insect nervous system. However, they also have
toxic effects on many animals, including humans.
[0006] The carbamates, a relatively new group of pesticides,
include such compounds as carbamyl, methomyl, and carbofuran. These
compounds are rapidly detoxified and eliminated from animal
tissues. Their toxicity is thought to involve a mechanism similar
to the mechanism of the organophosphates; consequently, they
exhibit similar shortcomings, including animal toxicity.
[0007] A major problem in pest control results from the capability
of many species to develop pesticide resistance. Resistance results
from the selection of naturally-occurring mutants possessing
biochemical, physiological or behavioristic factors that enable the
pests to tolerate the pesticide. Species of Anopheles mosquitoes,
for example, have been known to develop resistance to DDT and
dieldrin. DDT substitutes, such as Malathion.TM., propoxur and
fenitrothion are available; however, the cost of these substitutes
is much greater than the cost of DDT.
[0008] There is clearly a longstanding need in the art for
pesticidal compounds that are pest-specific, that reduce or
eliminate direct and/or indirect threats to human health posed by
presently available pesticides, that are environmentally compatible
in the sense that they are biodegradable, are not toxic to non-pest
organisms, and have reduced or no tendency to bioaccummulate.
[0009] Many pests, including for example blood-imbibing pests, must
consume and digest a proteinaceous meal to acquire sufficient
essential amino acids for growth, development and the production of
mature eggs. Adult pests, such as adult mosquitoes, need these
essential amino acids for the production of vitellogenins by the
fat body. These vitellogenins are precursors to yolk proteins which
are critical components of oogenesis. Many pests, such as house
flies and mosquitoes, produce oostatic hormones that inhibit egg
development by inhibiting digestion of the protein meal and thereby
limiting the availability of the essential amino acids necessary
for egg development.
[0010] Serine esterases such as trypsin and trypsin-like enzymes
(collectively referred to herein as "TTLE") are important
components of the digestion of proteins by insects. In the
mosquito, Aedes aegypti, an early trypsin that is found in the
midgut of newly emerged females is replaced, following the blood
meal, by a late trypsin. A female mosquito typically weighs about 2
mg and produces 4 to 6 ug of trypsin within several hours after
ingesting a blood meal. Continuous boisynthesis at this rate would
exhaust the available metabolic energy of a female mosquito; as a
result, the mosquito would be unable to produce mature eggs, or
even to find an oviposition site. To conserve metabolic energy, the
mosquito regulates TTLE biosynthesis with a peptide hormone named
Trypsin Modulating Oostatic Factor (TMOF). Mosquitoes produce TMOF
in the follicular epithelium of the ovary 12-35 hours after a blood
meal; TMOF is then released into the hemolymph where it binds to a
specific receptor on the midgut epithelial cells, signaling the
termination of TTLE biosynthesis. This regulatory mechanism is not
unique for mosquitoes; flesh flies, fleas, sand flies, house flies,
dog flies and other insect pests which need protein as part of
their diet have similar regulatory mechanisms.
[0011] In 1985, Borovsky purified an oostatic hormone 7,000-fold
and disclosed that injection of a hormone preparation into the body
cavity of blood imbibed mosquitoes caused inhibition of egg
development and sterility (Borovsky, D. [1985] Arch. Insect
Biochem. Physiol. 2:333-349). Following these observations,
Borovsky (Borovsky, D. [1988] Arch. Ins. Biochem. Physiol.
7:187-210) reported that injection or passage of a peptide hormone
preparation into mosquitoes inhibited the TTLE biosynthesis in the
epithelial cells of the gut. This inhibition caused inefficient
digestion of the blood meal and a reduction in the availability of
essential amino acids translocated by the hemolymph, resulting in
arrested egg development in the treated insect. Borovsky observed
that this inhibition of egg development does not occur when the
oostatic hormone peptides are inside the lumen of the gut or other
parts of the digestive system (Borovsky, D. [1988], supra).
[0012] Following the 1985 report, the isolated hormone, (a ten
amino acid peptide) and two TMOF analogues were disclosed in U.S.
Pat. Nos. 5,011,909 and 5,130,253, and in a 1990 publication
(Borovsky et al. [1990] FASEB J. 4:3015-3020). Additionally, U.S.
Pat. No. 5,358,934 discloses truncated forms of the full length
TMOF which have prolines removed from the carboxy terminus,
including the peptides YDPAP, YDPAPP, YDPAPPP, and YDPAPPPP.
[0013] D. Borovsky and R. Linderman, U.S. patent application Ser.
No. 09/295,996, filed Apr. 21, 1999, discloses additional novel
peptides and the use thereof to control insect pests.
[0014] TMOF analogs that have been identified to date are primarily
peptide analogs. In order to provide a greater diversity of new
pesticidal compounds, it would be desirable to possess compounds
that are TMOF analogues, yet are not peptides.
SUMMARY OF THE INVENTION
[0015] The present invention is based on the discovery of
non-peptide organic compounds that have a structure analogous to or
reminiscent of the TMOF structure and have pesticidal activity.
Thus the present invention concerns pesticidal compounds that
inhibit digestion in pests by terminating or otherwise blocking
synthesis of digestive enzymes by activating a TMOF receptor
(collectively referred to herein as "pesticidal compounds"). The
pesticidal compounds and other compounds of the present invention
are usefully employed in the control of pests, particularly insect
pests such as mosquitoes, which ingest blood.
[0016] Thus, a first aspect of the present invention is a method of
controlling a pest such as an insect pest, comprising administering
to said pest a pesticidally effective amount of a non-peptide TMOF
analog (that is, an organic compound that has TMOF activity). This
definition is specifically intended to exclude the peptide TMOF
agonists or analogs disclosed in inter alia U.S. Pat. Nos.
5,011,909; 5,130,253; and 5,358,934, the disclosures of which are
incorporated by reference herein in their entirety.
[0017] Particular pesticidal compounds/non-peptide TMOF analogs of
the present invention have the formula I below: 1
[0018] wherein:
[0019] X is selected from the group consisting of --CHCH--,
--CH.sub.2CH.sub.2--, and --CC--;
[0020] Z is selected from the group consisting of --OH, --NH.sub.2
and --OR.sub.6 wherein R.sub.6 is loweralkyl;
[0021] m.gtoreq.0 and n.gtoreq.1 and together total an integer from
1, 2, 3 or 4 to 6, 8, 10 or 12;
[0022] the ring bearing substituents R.sub.1, R.sub.2, R.sub.3,
R.sub.4 and R.sub.5 is a phenyl ring or a cyclohexyl ring;
[0023] R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are each
independently selected from the group consisting of --H, --OH,
halo, loweralkyl, loweralkoxy and phenyl; subject to the proviso
that:
[0024] when the ring is a phenyl ring, a pair of R.sub.1 and
R.sub.2, R.sub.2 and R.sub.3, or R.sub.3 and R.sub.4 on the phenyl
ring may together represent
--CR.sub.7.dbd.CR.sub.8--CR.sub.9.dbd.CR.sub.10--, to form with the
phenyl ring illustrated above a naphthyl ring system, wherein
R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are each independently
selected from the group consisting of --H, --OH, halo, loweralkyl,
and loweralkoxy.
[0025] A second aspect of the present invention is a method of
initiating a TMOF receptor-mediated biological response. The method
comprises contacting to a TMOF receptor in vivo or in vitro for a
time and in an amount sufficient to initiate a TMOF
receptor-mediated biological response a compound of Formula I as
described herein. The biological response may be any suitable
biological response mediated by the TMOF receptor, including but
not limited to inhibition of biosynthesis of a digestive enzyme
such as trypsin.
[0026] As noted above, the pesticidal compounds of the present
invention have advantageous biological activity against pests. The
novel compounds of the invention are particularly active against
blood-sucking insects, particularly against species of mosquitoes
such as Aedes aegypti that are common vectors of arthropod-borne
viral diseases, such as arboviruses. Other biting pests such as
flies, fleas, ticks, and lice can also be controlled using
compounds and methods of the subject invention. These pests utilize
TTLE as their primary blood-digesting enzymes.
[0027] The subject compounds can also be used to control pests of
agricultural crops, for example by applying the compounds to the
agricultural crops. These pests include, for example, coleopterans
(beetles), lepidopterans (caterpillars), and mites. The compounds
of the subject invention can also be used to control household
pests including, but not limited to, ants and cockroaches.
[0028] Another aspect of the subject invention pertains to a method
for controlling pests, particularly insect pests, comprising
administering to said pest a pesticidally effective amount of a
pesticidal compound of the subject invention.
[0029] The subject invention provides pest control compositions
comprising pesticidal compounds and a suitable pesticidal carrier.
The pest control compositions are formulated for application to the
target pests or their situs.
[0030] The methods and materials of the subject invention provide a
novel approach to controlling insects and insect-transmitted
diseases. The compounds of the subject invention have advantageous
activity and increased resistance to proteolysis over previously
disclosed compounds.
[0031] While the present invention is in part explained with
reference to TMOF activity, it will be appreciated that this
statement of underlying activity is provided for explanation, and
that applicants do not intend to be bound by any particular theory
of the invention. For example, the compounds of the invention may
also be used as pest or insect repellants, and the compounds of the
invention may control pests or insects by mechanisms in addition
to, or different from, TMOF activity.
[0032] The present invention is explained in greater detail
below.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0033] As used herein, the term "pesticidally effective" is used to
indicate an amount or concentration of a pesticidal compound which
is sufficient to reduce the number of pests in a geographical locus
as compared to a corresponding geographical locus in the absence of
the amount or concentration of the pesticidal compound.
[0034] The term "pesticidal" is not intended to refer only to the
ability to kill pests, Such as insect pests, but also includes the
ability to interfere with a pest's life cycle in any way that
results in an overall reduction in the pest population. For
example, the term "pesticidal" includes inhibition of a pest from
progressing from one form to a more mature form, e.g., transition
between various larval instars or transition from larva to pupa or
pupa to adult. Further, the term "pesticidal" is intended to
encompass anti-pest activity during all phases of a pest's life
cycle; thus, for example, the term includes larvacidal, ovicidal,
and adulticidal activity.
[0035] The term "loweralkyl" as used herein means C.sub.1 to
C.sub.4 alkyl, preferably methyl, ethyl or propyl.
[0036] The term "loweralkoxy" as used herein means C.sub.1 to
C.sub.4 alkoxy, preferably methoxy, ethoxy, or propoxy.
[0037] The term "halo" as used herein means halogen, preferably
fluoro, chloro, bromo or iodo, most preferably fluoro.
[0038] 1. Pesticidal Compounds.
[0039] Compounds useful in the present invention have the general
formula I below: 2
[0040] wherein:
[0041] X is selected from the group consisting of --CHCH--,
--CH.sub.2CH.sub.2--, and --CC--;
[0042] Z is selected from the group consisting of --OH, --NH.sub.2
and --OR.sub.6 wherein R.sub.6 is loweralkyl;
[0043] m.gtoreq.0 and n.gtoreq.1 and together total an integer from
1 to 12; and
[0044] R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are each
independently selected from the group consisting of --H, --OH,
halo, loweralkyl, loweralkoxy and phenyl; subject to the proviso
that:
[0045] a pair of R.sub.1 and R.sub.2, R.sub.2 and R.sub.3, R3 and
R.sub.4, or R.sub.4 and R.sub.5 on the phenyl ring may together
represent --CR.sub.7.dbd.CR.sub.8--CR.sub.9.dbd.CR.sub.10--, to
form with the phenyl ring illustrated above a naphthyl ring system,
wherein R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are each
independently selected from the group consisting of --H, --OH,
halo, loweralkyl, and loweralkoxy.
[0046] In one preferred group of compounds of formula I above, n
and m are each at least 1 and together total an integer from 2, 3
or 4 to 6, 8, 10 or 12.
[0047] In another preferred group of compounds of formula I above,
the ring is a phenyl ring.
[0048] In another preferred group of compounds of formula I above,
the ring is a cyclohexyl ring.
[0049] In another preferred group of compounds of formula I above,
m is 0.
[0050] In another preferred group of compounds of formula I above,
at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4 or R.sub.5 is
phenyl.
[0051] Another preferred group of compounds of formula I above have
the general formula II as given below: 3
[0052] wherein Z, n, m, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and
R.sub.5 are as described above. In compounds of formula II, the
phenyl ring and the carbonyl carbon may be either cis (Z) or trans
(E) with respect to one another. The trans configuration is
preferred.
[0053] Specific examples of compounds as described above
include:
[0054] E-7-phenylhept-4-enoic acid, which has the structure: 4
[0055] E-7-(4-methoxyphenyl)hept-4-enoic acid, which has the
structure: 5
[0056] Methyl E-7-phenylhept-4-enoate, which has the structure:
6
[0057] E-7-phenylhept-4-enoic acid amide, which has the structure:
7
[0058] Z-7-phenylhept-4-enoic acid, which has the structure: 8
[0059] E-7-(2,4-difluorophenyl)hept-4-enoic acid, which has the
structure: 9
[0060] E-10-phenyldec-6-enoic acid, which has the structure: 10
[0061] and E-10-(4-methoxyphenyl)dec-4-enoic acid, which has the
structure: 11
[0062] Additional examples of acids of the present invention
include:
[0063] E-7-(4-hydroxyphenyl)hept-4-enoic acid;
[0064] E-7-(2,4-dibromophenyl)hept-4-enoic acid;
[0065] E-7-(4-methylphenyl)hept-4-enoic acid;
[0066] E-7-(2,4-diethylphenyl)hept-4-enoic acid;
[0067] E-7-(2-ethoxyphenyl)hept-4-enoic acid;
[0068] E-7-(2,4,-dipropoxyphenyl)hept-4-enoic acid: and
[0069] E-10-(2,4-difluorophenyl)dec-4-enoic acid.
[0070] Additional examples of amides of the present invention
include:
[0071] E-7-(2,4-difluorophenyl)hept-4-enoic acid amide;
[0072] E-7-(4-methoxyphenyl)hept-4-enoic acid amide;
[0073] E-10-phenyldec-6-enoic acid amide;
[0074] E-7-(2,4-difluorophenyl)dec-6-enoic acid amide;
[0075] E-7-(4-methoxyphenyl)dec-6-enoic acid amide; and
[0076] Z-7-phenylhept-4-enoic acid amide.
[0077] Additional examples of esters of the present invention
include:
[0078] Methyl E-7-(2,4-difluorophenyl)hept-4-enoate;
[0079] Methyl E-7-(4-methoxyphenyl)hept-4-enoate;
[0080] Methyl E-10-phenyldec-6-enoate;
[0081] Methyl E-7-(2,4-difluorophenyl)dec-6-enoate;
[0082] Methyl E-7-(4-methoxyphenyl)dec-6-enoate;
[0083] Methyl Z-7-phenylhept-4-enoate;
[0084] Ethyl E-7-(2,4-difluorophenyl)hept-4-enoate;
[0085] Ethyl E-7-(4-methoxyphenyl)hept-4-enoate;
[0086] Ethyl E-10-phenyldec-6-enoate;
[0087] Propyl E-7-(2,4-difluorophenyl)dec-6-enoate;
[0088] Propyl E-7-(4-methoxyphenyl)dec-6-enoate;
[0089] Propyl Z-7-phenylhept-4-enoate;
[0090] Ethyl E-7-phenylhept-4-enoate;
[0091] Propyl E-7-phenylhept-4-enoate;
[0092] Butyl E-7-phenylhept 4-enoate;
[0093] Ethyl E-10-phenyldec-6-enoate;
[0094] Propyl E-10-phenyldec-6-enoate; and
[0095] Butyl E-10-phenyldec-6-enoate.
[0096] Additional examples of compounds of the invention include
the following: 12
[0097] Still additional examples of compounds of the invention are
as follows: 13
[0098] In all of the specific alkene active compounds named or
illustrated above, the double bond can be replaced with a single
bond to produce an analogous series of active compounds that are
alkanes.
[0099] In all of the specific alkene active compounds named or
illustrated above, the double bond can be replaced with a triple
bond to produce an analogous series of active compounds that are
alkynes.
[0100] In all of the specific alkene, alkane and alkyne compounds
named or illustrated above, the phenyl ring can be replaced with a
naphthyl ring to produce an analogous series of active compounds
based upon a naphthyl ring system.
[0101] Compounds of the present invention can be made by the
techniques described in the Examples below, or variations thereof
that will be apparent to those skilled in the art.
[0102] Compounds of the present invention can be made by the
technique described in M. Ansell and J. Ducker, Reduced cyclic
Compounds. Part XI. The Cyclisation of .omega.-Arylalkanoic Acids.
J. Chem. Soc. 206-212 (1961) or variations thereof that will be
apparent to those skilled in the art.
[0103] A further aspect of the subject invention are addition
salts, complexes, or prodrugs such as esters of the compounds
described herein, especially the nontoxic pharmaceutically or
agriculturally acceptable acid addition salts. The acid addition
salts can be prepared using standard procedures in a suitable
solvent from the parent compound and an excess of an acid, such as
hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic,
succinic, ethanedisulfonic or methanesulfonic acids. Esterification
to form derivatives such as the methyl or ethyl esters, can also be
performed using standard procedures. Tartarate salts can be
prepared in accordance with standard procedures.
[0104] Also, derivation of the pesticidal compounds with long chain
hydrocarbons will facilitate passage through the cuticle into the
pest body cavity. Therefore, in a further embodiment, the subject
invention provides compositions comprising the pesticidal compounds
bound to lipids or other carriers.
[0105] 2. Methods and Formulations for Control of Pests.
[0106] The subject invention concerns novel pest control compounds
and methods for using such compounds. Specifically exemplified are
novel pesticidal compounds, compositions comprising said pesticidal
compounds and the use of such pesticidal compounds and compositions
in controlling pests, particularly insect pests such as
mosquitoes
[0107] Preferably, the subject compounds have an LD.sub.50 against
mosquito larvae of less than 3.0 .mu.mole/ml. More preferably, the
compounds have an LD.sub.50 of less than 2.0 .mu.mole/ml, and, most
preferably, the compounds have an LD.sub.50 of less than 1.0
.mu.mole/ml. As used herein, "LD.sub.50" refers to a lethal dose of
a peptide able to cause 50% mortality of larvae maintained on a
diet of 1 mg/ml autoclaved yeast supplemented with the pesticidal
polypeptide.
[0108] Control of pests using the pest control compounds of the
subject invention can be accomplished by a variety of methods known
to those skilled in the art. The plant pests that can be controlled
by the compounds of the subject invention include pests belonging
to the orders Coleoptera, Lepidopterans, Hemiptera and
Thysanoptera. These pests all belong to the phylum Arthropod. Other
pests that can be controlled according to the subject invention
include members of the orders Diptera, Siphonaptera, Hymenoptera
and Phthiraptera. Other pests that can be controlled by the
compounds of the subject invention include those in the family
Arachnida, such as ticks, mites and spiders.
[0109] The use of the compounds of the subject invention to control
pests can be accomplished readily by those skilled in the art
having the benefit of the instant disclosure. For example, the
compounds may be encapsulated, incorporated in a granular form,
solubilized in water or other appropriate solvent, powdered, and
included into any appropriate formulation for direct application to
the pest or to a pest inhabited locus.
[0110] Formulated bait granules containing an attractant and the
pesticidal compounds of the present invention can be applied to a
pest-inhabited locus, such as to the soil. Formulated product can
also be applied as a seed-coating or root treatment or total plant
treatment at later stages of the crop cycle. Plant and soil
treatments may be employed as wettable powders, granules or dusts,
by mixing with various inert materials, such as inorganic minerals
(phyllosilicates, carbonates, sulfates, phosphates, and the like)
or botanical materials (powdered corncobs, rice hulls, walnut
shells, and the like). The formulations may include
spreader-sticker adjuvants, stabilizing agents, other pesticidal
additives, or surfactants.
[0111] Liquid formulations may be aqueous-based or non-aqueous
(i.e., organic solvents), or combinations thereof, and may be
employed as foams, gels, suspensions, emulsions, microemulsions or
emulsifiable concentrates or the like. The ingredients may include
rheological agents, surfactants, emulsifiers, dispersants or
polymers.
[0112] As would be appreciated by a person skilled in the art, the
pesticidal concentration will vary widely depending upon the nature
of the particular formulation, particularly whether it is a
concentrate or to be used directly. The pesticidal compound will be
present in the composition by at least about 0.0001% by weight and
may be 99 or 100% by weight of the total composition. The
pesticidal carrier may be from 0.1% to 99.9999% by weight of the
total composition. The dry formulations will have from about
0.0001-95% by weight of the pesticide while the liquid formulations
will generally be from about 0.0001-60% by weight of the solids in
the liquid phase. These formulations will be administered at about
50 mg (liquid or dry) to 1 kg or more per hectare.
[0113] The formulations can be applied to the pest or the
environment of the pest, e.g., soil and foliage, by spraying,
dusting, sprinkling or the like.
[0114] The pest control compounds may also be provided in tablets,
pellets, briquettes, bricks, blocks and the like which are
formulated to float, maintain a specified depth or sink as desired.
In one embodiment the formulations, according to the present
invention, are formulated to float on the surface of an aqueous
medium; in another embodiment they are formulated to maintain a
depth of 0 to 2 feet in an aqueous medium; in yet another
embodiment the formulations are formulated to sink in an aqueous
environment.
[0115] The term "control" is intended to include control by
repelling insects, as discussed in greater detail below.
[0116] 3. Repellant Methods and Compositions.
[0117] In insect repellant methods, the insect is administered the
active agent by applying the active agent to a subject or substrate
in an amount sufficient to repel insects.
[0118] Subjects to be treated with compounds of the present
invention include both human and animal subjects (e.g., dogs, cats,
horses, cattle). Subjects may be directly or indirectly treated,
such as by applying the active compound to the skin of the subject,
or by applying the active compound to an article worn by or
otherwise protecting the subject.
[0119] Substrates to be treated with compounds of the present
invention include, but are not limited to, floors, plants,
containers, walls, pools or open bodies of water, etc.
[0120] Insects that may be repelled by the methods of the present
invention include ticks, fleas, cockroaches, and biting flies,
typically of the order diptera, and further including mosquitoes,
horse flies, deer flies, black flies, gnats, no-see ums, chiggers,
etc.
[0121] The term "mosquito" as used herein concerns any type of
mosquito (e.g., Anopheles, Aedes, and Culex), including but not
limited to Tiger mosquitoes, Aedes aboriginis, Aedes Aegypti,
Aedes, albopictus, Aedes cantator, Aedes sierrensis, Aedes
sollicitans, Aedes squamiger, Aedes sticticus, Aedes vexans,
Anopheles quadrimaculatus, Culex pipiens, and Culex
quinquefaxciatus.
[0122] The term "tick" as used herein includes any type of tick,
including but not limited to, deer ticks, the American dog tick
(Dermacentor variabilis), Ornithodoros parkeri, O. moubata, and
Dermacentor andersoni.
[0123] The term "cockroach" as used herein refers to any type of
cockroach, including but not limited to the American cockroach
(Periplaneta americana), German cockroach (Blattella germanica),
oriental cockroach (Blatta orientalis), wood cockroach (Parcoblatta
pennsylvanica), brownbanded cockroach (Supella lonigipalpa), and
smokybrown cockroach (Periplaneta fuliginosa).
[0124] Other insect that can be treated by the repellant methods of
the present invention include, but are not limited to: lice (Order
Phthiraptera), such as head and body lice of humans, Pediculus
humanus capitis and P. H. humanus; Fleas (Order Siphonaptera), such
as cat and dog fleas, Ctenocephalides sp. human fleas,
Echidnophaga, Pulex sp. Bees, wasps and ants (Order Hymenoptera)
mites such as Sarcoptes scabei (human itch mite) the North American
chigger or red bug, Trombicula sp. nematodes such as human
parasitic nematodes, Silverfish (Order Thysanura), such as Lepisma
saccharina, firebrat, Thermobia domestica; Termites (Order
Isoptera) such as Reticulitermes flavipes, Incisitermes minor,
Marginitermes hubbardi, and Cryptotermes brevis; Earwigs (Order
Dermaptera); Psocids (Order Psocoptera) such as booklice; Beetles
(Order Coleoptera), particularly wood eating beetles; Centipedes
such as Lithobius, Geophilus, Scutigera and millipides such as
Julus terrestris; Scorpions such as Centruroides sculpturatus and
Mastigoproctus gianteus; etc.
[0125] Liquid repellant formulations may be aqueous-based or
non-aqueous (i.e., organic solvents), or combinations thereof, and
may be employed as foams, gels, suspensions, emulsions,
microemulsions or emulsifiable concentrates or the like. The
ingredients may include rheological agents, surfactants,
emulsifiers, dispersants or polymers.
[0126] In one embodiment, a floor wax composition may include
repellant compounds as described herein, in an amount effective to
repel cockroaches that might otherwise feed upon the composition
once applied to floors, or to simply repel cockroaches from floor
surfaces to which they are applied.
[0127] As will be appreciated by a person skilled in the art, the
repellant concentration will vary widely depending upon the nature
of the particular formulation, particularly whether it is a
concentrate or to be used directly. The repellant compound will be
present in the composition in a concentration of at least about
0.0001% by weight and may be 10, 50, 99 or 100% by weight of the
total composition. The repellant carrier may be from 0.1% to
99.9999% by weight of the total composition. The dry formulations
will have from about 0.0001-95% by weight of the pesticide while
the liquid formulations will generally have from about 0.0001-60%
by weight of the solids in the liquid phase.
[0128] The formulations may be applied to the subject's skin, or
may be applied to garments, belts, collars, or other articles worn
by the subject from whom insects are to be repelled. The
formulation may be applied to netting or screening that protects a
subject, particularly a sleeping subject. The formulations may be
applied to non-animal substrates from which insects are to be
repelled, such as plants. Application to subjects or substrates may
be carried out by spraying, dusting, sprinkling or the like.
[0129] The compounds according to the present invention may be
employed alone or in mixtures with one another and/or with such
solid and/or liquid dispersible carrier vehicles as described
herein or as otherwise known in the art, and/or with other known
compatible active agents, including, for example, insecticides,
acaricides, rodenticides, fungicides, bactericides, nematocides,
herbicides, fertilizers, growth-regulating agents, etc., if
desired, in the form of particular dosage preparations for specific
application made therefrom, such as solutions, emulsions,
suspensions, powders, pastes, and granules as described herein or
as otherwise known in the art which are thus ready for use.
[0130] The repellant compounds may be administered with other
insect control chemicals, for example, the compositions of the
invention may employ various chemicals that affect insect behavior,
such as insecticides, attractants and/or repellents, or as
otherwise known in the art. The repellant compounds may also be
administered with chemosterilants.
[0131] The repellant compounds are suitably applied by any method
known in the art including, for example, spraying, pouring,
dipping, in the form of concentrated liquids, solutions,
suspensions, sprays, powders, pellets, briquettes, bricks and the
like, formulated to deliver a repellant effective concentration of
the repellant compound. The repellant formulations may be applied
in a repellant effective amount to an area of pest infestation or
an area susceptible to infestation, a body of water or container, a
barn, a carpet, pet bedding, an animal, clothing, skin, and the
like.
[0132] 4. Computational Chemistry Methods.
[0133] Methods of identifying a non-peptide TMOF agonist from a
peptide TMOF agonist are a further aspect of the present invention.
Such methods typically comprise the steps of:
[0134] modeling in a computer (preferably with simulated annealing)
a model peptide TMOF agonist selected from the group consisting of
TMOF and peptide TMOF analogs;
[0135] determining in said computer spatial orientations for at
least one key feature of said model peptide compound;
[0136] generating in said computer a putative non-peptide TMOF
agonist structure, said structure including (i) said at least one
key feature and (ii) spatial orientations for said at least one key
feature corresponding to said spatial orientations for said at
least one key feature of said model peptide compound; then
[0137] synthesizing said putative non-peptide TMOF agonist; and
then
[0138] screening said putative non-peptide TMOF agonist to
determine the presence of TMOF activity therein.
[0139] Peptide TMOF agonists or analogs that may be used as a basis
for modeling of the instant invention include but are not limited
to those disclosed in, inter alia, U.S. Pat. Nos. 5,011,909;
5,130,253; and 5,358,934, the disclosures of which are incorporated
by reference herein in their entirety.
[0140] TMOF and other TMOF peptide agonists (preferably tripeptide
fragments of TMOF) may be modeled by the INSIGHT.TM. software
(available through the North Carolina Super Computing Center for
academic use) using a simulated annealing protocol as described by
Lovas and Murphy (S. Lovas and R. Murphy, Molecular Modeling of
Neuropeptides, in Neuropeptide Protocols, pp. 209-217 (Irvine, G.
B.; Williams, C. H., Eds. Humana Press, N.J. 1997)) and Damewood
(J. Damewood, Rev. Computational Chem. 9, 1-79 (1996). Peptide
Mimetic Design with the Aid of Computational Chemistry). Composite
structural data was then used to determine approximate spatial
orientations for what were deemed to be key structural features,
particularly as a phenyl ring and a carboxylate functional group.
These data indicated a greater degree of flexibility in the
N-terminus than in the C-terminus of the peptide structures.
Non-peptide analogs were then subjected to energy minimization by
molecular mechanics and distances between functional groups
compared to the data obtained in the data set of the TMOF
fragments. These data indicated a starting point for analog
synthesis as exemplified by E-7-phenylhept-4-enoic acid. Actual
compounds having structures corresponding to structures generated
by the computational techniques are then synthesized in accordance
with known techniques, and screened for activity in a bioassay such
as described below. Thus, compounds produced by the method that
have TMOF agonist activity and can be used in the methods described
herein generally have the structure P--R--C, where P is a phenyl
group, R is an alkane, alkene, or alkyne, and C is a carboxylate
group, all of which may be substituted or unsubstituted.
[0141] The following examples are illustrative of the practice of
the present invention and should not be construed as limiting. All
percentages are by weight and all solvent mixture proportions are
by volume unless otherwise noted.
EXAMPLE 1
Preparation of E-7-Phenylhept-4-enoic Acid
[0142] E-7-Phenylhept-4-enoic acid was prepared from commercially
available dihydrocinnamaldehyde in five steps.
Dihydrocinnamaldehyde was combined with the lithium salt of ethyl
diethoxyphosphonioacetate in tetrahydrofuran at room temperature.
The resulting unsaturated ester, ethyl 5-phenylpent-2-enoate, was
purified by chromatography. The unsaturated ester was then reduced
to the allylic alcohol, E-5-phenylpent-2-en-1-ol, by reaction with
excess diisobutylaluminum hydride in tetrahydrofuran at -78.degree.
C. The purified alcohol was then converted to the bromide,
E-1-bromo-5-phenylpent-2-ene, by reaction with triphenylphosphine
and carbon tetrabromide in methylene chloride at 0.degree. C. The
purified bromide was then used to alkylate the sodium salt of
diethyl malonate to provide the diester, methyl
E-1-carbomethoxy-5-phenylhept-4-enoate. The diester was purified by
chromatography and then subjected to saponification using
methanolic sodium hydroxide. The diacid was purified by acid/base
extraction and then used directly in the next step of the reaction
sequence. Decarboxylation was effected by heating the neat diacid
at 170.degree. C. (under Ar) for 30 minutes. The product,
E-7-phenylhept-4-enoic acid, was obtained in greater than 95%
purity. Any residual diacid was removed by dissolving the acid in
hexane and filtering. All compounds in the reaction sequence were
fully characterized by spectral analysis (infrared and nuclear
magnetic spectroscopy) and new compounds were analyzed by
combustion analysis.
EXAMPLE 2
7-Phenylheptanoic Acid
[0143] 7-Phenylheptanoic acid was prepared from
E-7-phenylhept-4-enoic acid by hydrogenation at 40 psi using 5%
palladium on carbon as the catalyst. Quantitative conversion of the
alkene to the alkane was observed by thin layer chromatographic
analysis. The product acid was purified by chromatography on silica
gel and fully characterized by spectroscopic methods (infrared and
nuclear magnetic resonance) and combustion analysis.
EXAMPLE 3
E-7-(4-Methoxyphenyl)hept-4-enoic Acid
[0144] E-7-(4-Methoxyphenyl)hept-4-enoic acid was prepared in the
same fashion as E-7-phenylhept-4-enoic acid by substituting
3-(4-methoxyphenyl) propional for dihydrocinnamaldehyde as the
starting material in the synthetic sequence.
3-(4-methoxyphenyl)propional was combined with the lithium salt of
ethyl diethoxyphosphonioacetate in tetrahydrofuran at room
temperature. The resulting unsaturated ester, ethyl
5-(4-methoxyphenyl)pent-2-enoate, was purified by chromatography.
The unsaturated ester was then reduced with excess
diisobutylaluminum hydride in tetrahydrofuran at -78.degree. C. The
purified alcohol was then converted to the bromide,
E-1-bromo-5-(4-methoxyphenyl)pent-2-ene, by reaction with
triphenylphosphine and carbon tetrabromide in methylene chloride at
0.degree. C. The purified bromide was then used to alkylate the
sodium salt of diethyl malonate to provide the diester, methyl
E-1-carbomethoxy-5-(4-methoxyphenyl)hept-4-enoate. The diester was
purified by chromatography and then subjected to saponification
using methanolic sodium hydroxide. The diacid was purified by
acid/base extraction and then used directly in the next step of the
reaction sequence. Heating the neat diacid at 170.degree. C. (under
Ar) for 30 minutes effected decarboxylation. The product,
E-7-(4-methoxyphenyl)hept-- 4-enoic acid, was obtained in greater
than 95% purity. Any residual diacid was removed by dissolving the
acid in hexane and filtering. All compounds in the reaction
sequence were fully characterized by spectral analysis and new
compounds were analyzed by combustion analysis.
EXAMPLE 4
E-7-(4-hydroxyphenyl)hept-4-enoic Acid
[0145] E-7-(4-hydroxyphenyl)hept-4-enoic acid was prepared from
E-7-(4-methoxyphenyl)hept-4-enoic acid by removal of the methyl
ether with boron tribromide. Boron tribromide was added to a
solution of E-7-(4-methoxyphenyl)hept-4-enoic acid in methylene
chloride at -78.degree. C. and stirred for four hours. The product,
E-7-(4-hydroxyphenyl)hept-4-enoic acid, was obtained by aqueous
work-up of the reaction mixture followed by chromatography on
silica gel, and was fully characterized by spectroscopic methods
(infrared and nuclear magnetic resonance) and combustion
analysis.
EXAMPLE 5
Bioassay of Compounds
[0146] Mosquito larval mortality was followed for three days in
microtiter plates containing 160 .mu.L sterile water, 1-4 .mu.L of
the test compound dissolved in dimethylsulfoxide, and 10 .mu.L of
2% Brewer's yeast. Controls were run under the same conditions
without the test compounds. Larval mortality in the controls was 3%
for 1-3 .mu.L dimethylsulfoxide, and up to 20% for 4 .mu.L
dimethylsulfoxide. Data for various compounds of the invention as
an LD.sub.50 are given in Table 1 below.
1TABLE 1 Bioassay of Active compounds. Compound Activity
(LD.sub.50) 7-Phenylheptanoic acid 0.19 .+-. 0.02 mM
E-7-(4-Hydroxyphenyl)hept-4-enoic acid 0.59 .+-. 0.03 mM
E-7-Phenylhept-4-enoic acid <0.08 mM
E-7-(4-Methoxyphenyl)hept-4-enoic acid 1.28 mM
EXAMPLE 6
Ethyl E-7-(Cyclohexyl)hept-4-enoate (IBI218)
[0147] Ethyl E-7-(cyclohexyl)hept-4-enoate was prepared in two
steps from the known compound 3-cyclohexylpropanal. A
tetrahydrofuran solution of 3-cyclohexylpropanal was treated with
vinyl magnesium bromide (as a solution in tetrahydrofuran) at
0.degree. C. The resulting allyl alcohol derivative,
5-cyclohexyl-3-hydroxypent-1-ene, was purified by chromatography.
The allylic alcohol was then dissolved in triethyl orthoacetate and
heated to 140.degree. C. to effect a Claisen rearrangement. The
product, ethyl E-7-(cyclohexyl)hept-4-enoate, was obtained in
>95% purity after chromatography. The product was fully
characterized by spectral analysis(infrared and nuclear magnetic
spectroscopy) and combustion analysis.
EXAMPLE 7
Ethyl E-7-((4-phenyl)phenyl)hept-4-enoate (IBI 221)
[0148] Ethyl E-7-((4-phenyl)phenyl)hept-4-enoate was prepared in
two steps from the known compound 3-((4-phenyl)phenyl)-propanal. A
tetrahydrofuran solution of 3-((4-phenyl)phenyl)propanal was
treated with vinyl magnesium bromide (as a solution in
tetrahydrofuran) at 0.degree. C. The resulting allyl alcohol
derivative, 5-((4-phenyl)phenyl)-3-hydroxypent-1-ene, was purified
by chromatography. The allylic alcohol was then dissolved in
triethyl orthoacetate and heated to 140 C. to effect a Claisen
rearrangement. The product, ethyl
E-7-((4-phenyl)phenyl)hept-4-enoate, was obtained in >95% purity
after chromatography. The product was fully characterized by
spectral analysis(infrared and nuclear magnetic spectroscopy) and
combustion analysis.
EXAMPLE 8
E-7-(Cyclohexyl)hept-4-enoic Acid (IBI172)
[0149] Ethyl E-7-(cyclohexyl)hept-4-enoate was saponified in
methanolic sodium hydroxide at room temperature. The resulting
acid, E-7-(cyclohexyl)hept-4-enoic acid, was obtained in >95%
purity after chromatography. The product was fully characterized by
spectral analysis (infrared and nuclear magnetic spectroscopy) and
combustion analysis.
EXAMPLE 9
E-7-((4-phenyl)phenyl)hept-4-enoic Acid (IBI165)
[0150] Ethyl E-7-((4-phenyl)phenyl)hept-4-enoate was saponified in
methanolic sodium hydroxide at room temperature. The resulting
acid, E-7-((4-phenyl)phenyl)hept-4-enoic acid, was obtained in
>95% purity after chromatography. The product was fully
characterized by spectral analysis infrared and nuclear magnetic
spectroscopy) and combustion analysis.
EXAMPLE 10
Repellent Assay for Ticks
[0151] A repellent assay for ticks is carried out as follows:
[0152] (1) Prepare 15 mg/ml test solution of test compound in 100%
acetone in individual 500 uL bullet tubes. Prepare control solution
(1 uL olive oil plus 100 uL 100 acetone).
[0153] (2) prepare half circle test papers (radious=2.25 cm) from
Whatman filter paper (#2 qualitative).
[0154] (3) Saturate test papers with 60 uL of 100% acetone,
control, or test solution. Test papers are in individual sterile
petri dishes during this process.
[0155] (4) Allow test papers to air dry at room temperature for one
hour.
[0156] (5) Select and place ten ticks into separate sterile glass
petri dishes.
[0157] Allow ticks to acclimate to covered dishes for one hour.
[0158] (6) Transfer one test paper treated with a test solution and
one test paper treated with the control solution to each of
separate sterile petri dish bottoms. On control included two test
papers treated with acetone. A second control included two test
papers treated with the control solution.
[0159] (7) Place ten ticks in between the two test papers. Place
the test arenas in a dark room at room temperature.
[0160] (8) Record the location of ticks 15 minutes, 1 hour and 2
hours after being placed in the test arenas.
[0161] Results with a variety of different active compounds are
given in the Table 2 below.
2TABLE 2 Ornithodoros parkeri repellent assay. 15 minutes 1 hour 2
hours Time # ticks on # ticks on # ticks on # ticks on # ticks on #
ticks on Compound compound acetone compound acetone compound
acetone 152 8 1 9 1 9 156 1 7 1 8 1 9 172 2 8 10 10 218 10 10 10
219 10 2 8 220 2 7 6 4 2 8 221 5 5 4 4 2 8 olive oil 8 2 6 4 5 5
acetone 3 2 5 5 4 6
[0162] The examples and embodiments described herein are for
illustrative purposes only and that various modifications or
changes in light thereof will be suggested to persons skilled in
the art and are to be included within the spirit and purview of
this application and the scope of the appended claims.
* * * * *