Note: Descriptions are shown in the official language in which they were submitted.
BACKGROUND AND SUMMARY OF THE INVENTION
The present invention is directed to compounds for
use in controlling insects. More particularly, the present
invention is directed to chromene compounds which have
been found to be effective in inhibiting the effects of
juvenile hormone in insects.
Of the various chemical compounds which have been
employed in the prior art as insecticides for controlling
insects, many of such prior art compounds have also been
found to be harmful to humans and other animal l~fe. In
addition, many species of insect pests have developed a
resistance and even immunity to available insecticides.
Alternative prior art methods for controlling in-
sects have included the use of hormones, which interfere
with the development of insects. Although such hormones
have the advantage of apparently being harmless to other
- : . : :, ., ,, ~.:,, .;, . -: . . - . :
`~`` 1~8~i322
animals, their use is generally limited to application ;~
relatively late in the insect life cycle, after the
insect has already produced its undesirable pest effect.
The endocrine systems of insects secrete a
certain hormone known as juvenile hormone which functions
to control the biological activities of metamorphosis,
reproduction, diapause and sex attractant production.
.-.
In particular, juvenile hormone functions initially to
maintain the young developing insect in an immature con-
dition until is has developed to the point where it is
ready to molt to the adult form. When maturation of the ~; -
insect begins, the body ceases to secrete juveni~e hormone
until after the insect has passed into the adult form ~ ~-
at which time secretion of juvenile hormone recommences
;,., !,
in order to promote the development of the sex ogans. `
The forms in which juvenile hormone are known to `~
occur in nature are discussed in the following publica-
tions: Trautmann et al., Z. Naturforsch, 29C 161-168
(1974); Judy et al., Proc. Nat. Acad. Sci. USA, 70,
1509-1513 (1973); Roller et al., Angew. Chem. Int. Ed.
., 6, 179-180 (1967); Meyer et al., Proc. Nat. Acad.
Sci. USA, 60, 853-860 (1968); Judy et al., Life Sci., 13,
1511-1516 (1973); Jennings et al., Life Sci., 16,
1033-1040 (1975); and Judy et al., Life Sci., 16, 1059- ~ ~
1066 (1975). ~ ~ `
In accordance with the present invention, it has
been discovered that the lipid extract of the common
bedding plant, Ageratum, contains two active compounds:
(1) 6, 7-dimethoxy-2,2-dimethyl-3-chromene; and (2) 7-
methoxy-2, 2-dimethyl-3-chromene; each of which is ef- ;
fective to inhibit the effects of juvenile hormone in
:
.
1~8~;322
insects. The first compound has been described by A.
R. Alertsen in the article "Ageratochromene, a ~Ieterocyclic
Compound from the Essential Oils of some Ageratum Species"
in Acta Chem. Scand. 9 (1955) No. 10 p. 1725-1726.
Additional work in this area has been published by R. Huls
in the article "Syntheses De Chromenes Substitues" in
Bull. Soc. Chim. Belg., 67 (1958), pp. 22-32.
By the present invention, chromene compounds are
provided which have been found to effectively inhibit
the effects of juvenile hormone, both during early --
development of the insect and after reaching adulthood
when the sex organs are undergoing development. By so
inhibiting the effects of juvenile hormone, the maturing
- insect which has been treated with the present compounds
is caused to die within a short time of such treatment.
In addition, the ability of a treated insect to reproduce
is prevented. The compounds of the present invention have
also been found to interrupt embryogenesis in insect eggs, - ~`~
to induce diapause in insects and to prevent sex pheromone
secretion in insects. The present compounds may be applied
by suitable means including topically, orally or in a
vapor state as a fumigant.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS ~-
In accordance with the principles of the present
invention, compounds suitable for use as anti-juvenile
hormones have the following general structure:
'.,:
~
108632Z
:~:
wherein: :~
R and Rl are H or an alkyl, straight or branched chain,
of 1 to 4 carbon atoms;
R2 is hydrogen;
R3 is hydrogen or alkoxy of 1 to 6 carbon atoms; or -
R4 is alkoxy of 1 to 6 carbon atoms R3 and R4 are joined
with a -OCH2O- group and R5 is hydrogen. -
The present invention also relates to a process
for the manufacture of compounds of the above formula,
which process comprises reacting a compound of the general
Formula I:
R :~
4 ~ w .
3 ~
2 :~ -
wherein W is OH, and R2, R3, R4 and R5 are substituents
given in Figure I, with a compound of the general formulae
II: .
R R ~ ~
,.~ I I ,,~.. ..
Rl-C=CH-V or Rl-f-CH=CH2
OH
wherein,
: V is -COOH, -CH2OH, -CH2Br or -C-N ~-
R and Rl are as given in connection with Figure I;
:: in the presence of a Friedel-Crafts catalyst such as formic :
: acid, AlC13, ZnC12, polyphosphoric acid, Sn C14 or other
similar catalyst well known in the art. A suitable solvent
which is compatible with the Friedel-Crafts catalyst may `~
be employed as necessary. Such a solvent may be, for ex- ::
- 4 -
. ~
" , , ,..... ~ . . . .
~08632Z
ample, ether, nitrobenzene or carbon disulfide. The
reaction produces a chromanone of the general Formula
III:
: R5 R
R4 ~ R
R2 0
wherein the substituents are those given with -
regard to Figure I. The addition of he.at, by means such :
as conducting the reaction on a steam bath for one to
several hours, may be employed although such heating is
, not always necessary for obtaining the chromanone pro-
I duct.
1 The compounds of Formula III are reduced with a
reducing agent which may be any of those well known to ~:
one skilled in the art, such as lithium aluminum hydride -~
~; or sodium borohydride, in a suitable solvent such as
tetrahydrofuran or ether, to give a chromanol of the
general Formula IV: ~:
5 R ~;
4 ~ 1
R3 :~
wherein the substituents are those given in con- -
nection with Figure I. If, following reduction the reaction
mixture containing the compounds of Formula IV are treated
with a dilute acid such as hydrochloric, toluenesulfonic
: 30 or other similar acid well known to those skilled in the
art, dehydration of the hydroxyl group occurs giving the
chromenes directly corresponding to the compounds given in
1086322
connection with Figure I. When the chromanols are isolate
directly, subsequent treatment with a catalytic amount of
acid such as toluenesulfonic in refluxing benzene causes
dehydration to the chromene.
In the case of the reaction of compounds of general
Formula I with unsaturated aldehydes of Formula II in
the presence of Friedel-Crafts catalysts, the desired
chromenes are produced directly.
The following specific examples further illustrate
the preparation of compounds within the scope of the
general structures shown above.
Example 1
Synthesis of 6, 7-dimethoxy-2, 2-dimethyl-3-chromene
The amount of 10 g of 3, 4-dimethoxyphenol and 7.8
g of 3, 3-dimethyl acrylic acid were combined in a 125 ml
erlenmeyer flask and dissolved with the addition of 40 ml -
anhydrous ethyl ether. The ether was removed in vacuo
and while the contents of the flask remained liquid, 50
gm of polyphosphoric acid was added. The flask and con-
tents were placed on a steam bath and heated with stirring
for 1 hour. At the end of 1 hour, 75 ml of water was added -
and the contents stirred into sol-~tion for 5 minutes. The -
- solution was allowed to cool and a substantial sticky
precipitate formed. The aqueous layer was decanted and
extracted with 100 ml of ether. The ether extract was -
washed successively with 150 ml of water, 100 ml of 5~ ;~
sodium carbonate and 100 ml of saturated NaCl solution.
The ether extract was dried over anhydrous sodium sulfate.
The sticky residue formed on cooling was dissolved in 300
ml of chloroform and washed successively with 150 ml of
water, two 150 ml portions of 5% sodium carbonate solution
- 6 -
108632Z
and 150 ml of saturated NaCl solution. The chloroform
solution was dried over anhydrous sodium sulfate. The
ethereal and chloroform extracts were combined and the
solvents removed in vacuo leaving 16.17 gm of offwhite
crystalline chromanone.
The chromanone was dissolved in 400 ml of dry
ethyl ether and 2.5 gm of lithium aluminum hydride was
added in portions. The reaction was refluxed for 2 hours
and then allowed to come to room temperature. The excess
lithium aluminum hydride was destroyed by dropwise addition
of water and 150 ml of 4N HCl was added slowly to the
reaction mixture. Stirring was continued for 15 minutes.
The reaction mixture was extracted with ether and washed
successively with 100 ml of water, 100 ml 5% sodium
carbonate solution and 100 ml saturated NaCl solution.
The ethereal extract was dried over anhydrous sodium
sulfate. Removal of the ether in vacuo gave 15.6 g of
crude chromene.
Distillation at 4 mm gave 10 gm of pure 6, 7- ~ ~
dimethoxy-2, 2-dimethyl-3-chromene BP 142-144C. The ~ ~`
residue remaining after distillation was chromatographed
over Florisil, trade name of a magnesium silicate adsorbent, ~-
and eluted with increasing concentrations of ether in
petroleum ether to yield 2.2 g of additional pure chromene.
The combined yield was 12.2 gm or a total yield of 79%
of the theoretical. Purity was determined to be greater
than 99% by thin-layer and gas-liquid chromatography.
The structure was verified by infra-red and nuclear
magnetic resonace spectroscopy.
An alternate synthesis involves the reaction of
an appropriate phenol with 3-methyl-2-butene-1-ol or
: .. , . . . .. ... .. . . . . ~
1()86322
3-methyl-1-bromo-2-butene or 3-methyl-1-butene-3-ol in the
presence of a catalyst such as formic, 85% polyphosphoric
acid, acetic acid or ZnC12 to produce the corresponding
chromane. The chromane is treated with a dehydrogenating
agent such as chloranil or DDQ (2, 3-dichloro-5, 6-dicyano-
1, 4-benzoquinone) in a suitable solvent such as benzene
or xylene to introduce the double bond and give the corres-
ponding chromene.
Example 2
Synthesis of 6, 7-methylenedioxy-2, 2-dimethyl
chromene. 5.1 gm of 3-methyl-1-bromo-2-butene was com-
bined with 4 gm of 3, 4-methylenedioxyphenol and dissolved
in 50 ml pentane and 50 ml benzene. 2 gm of
anhydrous Zn~12 was added and the reaction mix-
ture refluxed for 1 hour and cooled. The
mixture was extracted with ether and washed
successively with 100 ml of water, 100 ml 5% sodium car-
bonate and 100 ml of saturated salt solution. After drying `~ ;
the extract over anhydrous sodium sulfate, the solvent was
removed in vacuo leaving 7.4 g of crude chromane. The ;
crude material was fractionated on a column of Florisil
and eluted with increasing concentrations of ether in
petroleum ether to yield 4.5 g of pure chromane.
One gram of the chromane was dissolved in 75 ml of
benzene and 1.2 g of DDQ added. The reaction mixture was
refluxed for 4 hours, then cooled and filtered. Removal of -
the solvent from the filtrate gave 1.35 g of crude product.
Chromatography over Florisil gave 0.95 gm of pure 6, 7-
methylenedioxy-2, 2-dimethyl chromene. Structure and
purity were determined by thin-layer and gas-liquid chroma-
tography and NMR spectroscopy.
1~6322
Example 3
A complimentary synthesis similar to the above
involves reaction of an appropriate phenol with an allylic
alcohol in the presence of formic acid to yield the
chromane in high yield. This, followed by dehydrogenation ~ - 3
with chloronil or DDQ, gives the desired chromene.
Thus were combined 2 g of 3, 4-dimethoxy phenol
and 1.9 g of 3-methyl-1-pentene-3-ol in 10 ml formic acid
with stirring at room temperature for 18 hours. Formic
acid was removed in vacuo. The residue dissolved in ether
was washed successively with 100 ml of water, 100 ml 5%
sodium carbonate and 100 ml saturated salt solution. The
ether solution was dried over anhydrous sodium sulfate
and gave 3.5 gm of crude product on removal of the ether
in vacuo. Chromatography over Florisil gave 2.5 g of pure -~
chromane. The amount of 0.88 gm of the pure chromane was ~-
dissolved in 100 ml benzene and refluxed for 1 hour with
0.95 g DDQ. After cooling, filtration and removal of the
.:
solvent, the filtrate gave 1.1 g crude product which on
chromatography over Florisil gave 0.55 g of pure 6, 7-
, .
dimethoxy-2-methyl-2-ethyl chromene. Purity and structure
were determined by thin-layer and gas-liquid chromatography
and by MNR spectroscopy.
Example 4
The synthesis of chromenes which are unsubstituted
in the 2-position was accomplished by reaction of the
approriate phenol with acrylonitrile under basic catalysis
to give the phenoxy-propionitrile which was converted to
the corresponding phenoxy-propionate by treatment with
acid. Ring closure to the chromanone was effected by
, treatment with polyphosphoric acid and the chromene
: _ g _
' ~86322
obtained by reduction of the chromanone with any of
several reagents such as lithium aluminum hydride or
sodium borohydride followed by treatment with acid to
promote dehydration to the chromene.
Thus 5 gm of 3, 4-dimethoxyphenol, 6.88 g acrylo-
nitrile and 0.5 ml of Triton B, trade name of N-Benzyl-
trimethylammonium hydroxide, (40% soln.), were combined
and refluxed for 18 hours. After cooling the reaction
mixture was extracted with chloroform and washed with 5~
sodium hydroxide, and with saturated salt solution. The
organic layer after drying over anhydrous sodium sulfate
gave 4.4 gm of 3, 4-dimethoxy phenoxy propionitrile on
removal of the solvent. The amount of 2.2 g of the -
nitrile was combined with 40 ml of water and 80 ml of con-
centrated hydrochloric acid and refluxed for 2 hours. -
The reaction mixture on cooling was extracted with ether -;
and washed with water and 5% sodium hydroxide. The basic
wash was acidified with 6 N hydrochloric acid and ex- ~;
i tracted twice with ether. The ethereal extract was
washed twice with water and with saturated salt solution. -
Drying over anhydrous sodium sulfate and removal of the
solvent in vacuo gave 1.25 g of the crude 3, 5-dimethoxy
phenoxy propionic acid. The crude product was combined -`
with 5 gm of polyphosphoric acid and heated at 75-85C i
. , ,
for 1 hour. The reaction mixture was extracted with
ether and washed with 10% sodium carbonate solution and
saturated salt solution. Drying over anhydrous sodium
carbonate and removal of the solvent gave 0.35 gm of ;
pure 6, 7-dimethoxy chromanone. The chromanone was dis-
solved in 50 ml dry ether and refluxed 1 hour with an
excess of lithium aluminum hydride. On cooling, the re-
action was stopped by addition of 10 ml of water and then ~
.-. :
- 1 0
36:}ZZ
stirred for 15 minutes with 10 ml of 2N hydrochloric
acid. The reaction mixture was extracted with ether
and washed with water and saturated salt solution to
give on drying and removal of the solvent 0.31 gm of
pure 6, 7-dimethoxy chromene.
Example 5
The following Table I provides a flow chart show-
ing the isolation of the two natural products from
Ageratum, including the column fractionation and thin-
layer chromatography.
. ~
,'~' .
?i;
-- 11 -- ,
10~632Z
U~ _
~, ,,
CO
:
o ~ ~ C~
~ ,
~ ~ e . o\ ~ .
,~ ,
. ~ o ~ ~ -
:- ~ji o ~~1 : h ~ ~! o ~
O ~ ) ~ o ~ 11 :
f~ ~ _ . . ~
E~ ~~ ~ ~ ~ .
. O . ~ 1:~1 ~ I E~ _
E3
O ~ a) ~ . oP
~-1 O oo 3 ~
~ ~ J~ ~ ~ ~ O ~ -- ;'
N _ ~ 0 3 o ~ I ~ .
D ~ p ,0 0 ~ ~ Iy ~ ~a ~ ~, O~) ,
O r~ ~ ~ Ll~ u~ O o t. u~
.a ~la ~ ,, ~ o IY . ~ ~ ~,) 7~
~ ~ ~ _ \ / ~
0~ ~ li:l ~ 1 P;
o Q, ~ ~ .
,¢ .~ 5~ o .~ ~ ~ ~ ~ m .
. ~ ~ ~ m ~ .~
o ~ ~ o O
~ s~ ~ a) ~ ~ m ,~ -
~ ~ ~ ~ .~ .~ .~
dP t` ~ ` O
L~ e ~~
~ O C,) ~ ~
.~
O 11 N 11 N
e~ C~ 3 o ~ o U~
.~ O ~o
:~ O ~ U \
~ ~ o~ ~ Z~ Z~ ~ ,
'' ~ ~ -~
O O ~
.~ \ O O
~ ~ 0~ 0
-- 12 --
'
J 0~6:}Z2
Induction of Precocious Development
In accordance with the present invention, the
chromenes and substituted chromenes were synthesized and found
to cause precocious maturation when applied to an immature
insect. The juvenile hormone (JH) is a natural insect hormone
which acts to keep the developing insect immature until it is
ready to molt to the adult form. When maturation of the
insect begins, the insect ceases to produce JH and the insect
matures to the adult form. The compounds of the present
invention have been found to stop the action of JH and cause
the immature insect to begin the maturation process. For some
insects the induced lack of JH causes such rapid maturation
that the immature insect dies shortly prior to, or during
the molting process. In other insects the lack of JH
causes them to molt into miniature adults which completely
avoids the tremendous feeding potential of the immature
stages and results in tiny adults which are sterile, very
fragile and which die soon after molting. The anti-juvenile
hormone action can be overcome by the application of exogenous
juvenile hormone, which indicates that the anti-juvenile
hormone compounds act by interfering with the synthesis of
J juvenile hormones.
.. . .
~ r
.~
: ~ :
- 13 -
10863Z2
Induction of Precociuos Maturation
in the Milkweed Bug ~y Lipid Extract
of Ageratum
:
Crude Lipid Extract of
AgeratumlJConcentration Precocious
~g/cm2 Adults %~
'
-:
100
7 80 ~ ~
4 27.8 ~-
2 0 ` ~-~
Control 0 ~ ~ -
Ether-acetone (1-1) extract of macrerated
plant tissue.
Twenty 2nd instar nymphs were continuously
exposed to the extract residue spread over
a 9 cm petri dish containing milkweed seeds
and water. Insects molted to apparently
. .- .
normal 3rd and 4th instar nymphs and then - '
molted precociously to adult insects.
;'` '~ ~',:
.. .. ~': ~
~,i. . . .
:~. .
.. .
..
. . .
''''
. .
- 14 -
: '
1~6322
Induction of Precocious Maturation
in the Milkweed Bug by Pure Ageratochromene
Ageratochromene~ Precocious
~g/cm Adults %~
0.7 90 -~
0.4 15 --
control 0.0
~,
~/Pure synthetic ageratochromene (6, 7-dimethoxy-
-~ 2, 2-dimethyl-3-chromene). Twenty 2nd instar
nymphs were confined in a 9 cm petri dish with
the synthetic anti-JH compound prepared in ac-
cordance with the present invention.
~/Insects molted to 3rd and 4th instars and then
molted into precocious adults.
., -.
:', ,'
Sterilization
~- In the normal adult insect, JH (or gonadotropic ,
, hormone) is produced again after molting to the adult form and
~ is then necessary for the development of the insect ovaries.
c Treatment of adult insects with the compounds of the present
invention as desecribed hereinafter was found to prevent or
~ stop the action of JH and the insect ovaries fail to develop. `~
;! If the insect ovaries were developed at the time of treatment,
they rapidly regressed to the undeveloped state. In either
event reproduction was prevented.
'; ;:
- - 15 -
~0863ZZ
Sterilization of Insects with
Anti-Juyenile Hormone
. .
Concentrations of synthetic ,~
Ageratochromene necessary
to prevent ovary development Insect
~ .
7.0 ~g/cm2 ~ Adult Milkweed Bug
(Oncopeltus fasciatus)
7.0 ~g/cm2 ~ Cotton Stainer
(Dsydercus intermedius)
1.5 ~g/cm ~ Apple Maggot
(Rhagoletis pomonella)
1000 ppm spray ~ Mexican Bean Beetle
J (Epilachna varivestis)
Eight newly emerged adults confined to treated 9 cm petri
, dish for 48 hours. Ovaries examined for development after ;
., .
6 days. -
- ~ Ten newly emerged adults confined to treated 9 cm petri
dish for 72 hours. Ovaries examined for development after
13 days.
-^~ 20 ~ Forty-five newly emerged apple maggot females were con-
f fined to a 9 cm petri dish containing a residue of the
, test compound for 30 hours. After treatment flies were
held in oviposition cages and examined for ovarian devel-
opment when control insects began oviposition.
Ten newly emerged Mexican Bean Beetle females were sprayed
while feeding on a bean plant with emulsified agerato-
- - 16 -
~08632Z
chromene. Ovaries were dissected out and examined for
development when controls began oviposition.
Ovicidal Activity
The control of embryogenesis in the insect egg by
juvenile hormone is poorly understood. However, molting is
known to occur in certain insect eggs and juvenile hormones
have been extracted from insect eggs, implying a presumptive ~
role of JH during embryogenesis. The compounds of the ~ -
present invention were found to demonstrate ovicidal
activity by contact and by fumigation, presumably by inter-
fering with JH production by the insect embryo.
Ovicidal Activity of Anti-Juvenile Hormone
Compound by Contact Spray on
Mexican Bean Beetle Eggs
i ~
Concentration of Synthetic % % Dead
Ageratochromene in Spray~ Hatch Nymphs
100 ppm 2.7 100
~i10 ppm 18.4 76.7
Control 80.0 0.0 -
,,"~ ' ~
~`~ 20 ~ Four day old eggs on bean leaves were sprayed with
~¦ Ageratochromene in emulsion formulation. ~ -
r i ,
- 17 -
1(~86322
Ovicidal Activity of Anti-Juvenile
Hormone Compound by Fumigation
~,
Concentration (mg) Synthetic
Ageratochromene Necessary to
Prevent Egg Hatch or Survival
of 1st Instar Insects ~ Insect
0.5 mg Milkweed Bug
0.2 mg Mexican Bean Beetle
" ~
~J Newly laid eggs were confined in watch glasses exposed
to vapors of compound placed on lid of watch glass. A
small percentage of nymphs or larvae sometimes emerged ~
, from the eggs but died within a few hours. ~ -
,,., . :
,l Diapause Induction
Many insects enter a state known as diapause in
;~ order to survive inclement climatic conditions such as
~, winter, hot dry summers, etc. During diapause insects do `
not feed, mate or reproduce. Diapause occurs in many in-
sects when the production of JH ceases. The compounds of ~ -
the present invention were found to stop the action of JH
when applied topically and to cause the insect to go into
diapause. Insects in diapause stop feeding, thus are unable
to cause crop damage and if diapause is prolonged, the in-
sects become weak and die. The induction of diapause with
these anti-JH chemicals thus becomes a very unique method
of insect control.
,,'~
- 18 -
108G:}ZZ
Induction of Diapause in
Adult Colorado Potato Beetles
Synthetic
Ageratochromene Insects Entering
Topical (~g) ~ Diapause ~-
'
500 40
250 38
: 100 75
Control 0
~:
.~ .,''
~ Insects were treated topically on the abdomen with the
;:, antijuvenile hormone in 1 ~1 of acetone and placed upon :
potato plants growing in soil.
2 After 21 days insects remaining on the potato plants
were judged non-diapausing. Insects which had entered
-, the soil and become quiescent were screened from the soil ~-
~ ~ .
.~ and judged to be diapausing. ~ ~
~ ~ : -
'~ .' ;.-
.,~ , ,,
. ~. ,.
,
":
.' , .
-- 19 --
10863;Z2
Induction of Precocious Maturation and Sterilization of
Milkweed Bug by ~nti-Juvenile Hormone Compounds
Compound Concentration~ ~g/cm2 .
~ ~, o ~ll
4.0
~0~
'7; -~ ~
~ 0~ 0 ~/ r
1 . 5
~' ~ ~ 4.0 ;:
- ...................................................................... . ..
\~ 0~ f 1 ~ 5
5~: ~ ~ O
,, ' :
, .
0.7
, /~ O ,. ,.:
'.~
- Twenty 2nd instar nymphs were confined to 9 cm petri ~:
dishes containing the residue of the anti-juvenile hormone
compound and all became precocious adults. Precocious :
adults were examined after 5 days for ovarian development
and all were determined to be sterile. :~ ;
:
- 20 -
.. . - ,.
.. . . . .
