CA1103477A - 1-aryl-1,4-dihydro-4-oxo-pyridazines - Google Patents

Abstract

U>.S. SN 776,394 Filed March 10, 1977 ?N76-39-US
?EL:mml 1-ARYL-1,4-DIHYDRO-4-OXO-PYRIDAZINES
Abstract of the Disclosure Compounds of the formula

Description

~ 3~ 7 The Disclosure This invention relates to novel compounds whicn show activity as plant growth regulators, particularly as chernical hybridization agents, to growth regulant compo-sitions which comprise these compounds~ and ko methods ofregulating the growth of plants~ particularly by inducing selective male sterility, with these compounds and compo-sitions.
The cereal grains, such as corn, wheat~ rice, rye~
barley, millets, sorghum, and teff are among the major food crops throughout the world. This importance has led ` to extensive research to improve both the productivity and food value of these crops. One of the most important approaches taken to improve the qualiky and yield of the cereal grains has been ~ybrid-isation. While hybridization has been an effeckive technique for some crops, most notably corn~ there have been a number of problems with present kechniques. For example, corn hybridization requires time-consuming hand detasseling or inerficient mechanical ~ 20 detasseling, possibly injuring the corn plant. Corn, barley, ;~ and wheat hybridization by means of cytoplasmic male sterile varieties can only be done with a limited genetic base, requiring a maintainer line and a restorer line. Further-more, cytoplasmic male sterile techniques with barley and wheat necessitate a highly sophisticated approach to deal with the genetic complexities of these crops, and great success has not yet been achieved in developing a suitable approach. Since the induction of selective male sterility by chemical means would obviate many of the problems con-fronting the present hybridization techniques, new compounds-' C ~

34~7~
`.' which selectively produce the desired sterility would beextremely desirable in dependably and ecorlomically supplyin~
i the male sterile plants needed for hybridization.
A new class of compounds has now been found which can be used to induce selective male sterility in cereal . grains. The compounds o~ the invention are 4-pyridazones - having the formula :~ ' O

~; ~ ~ R1 (I) ~, . L2 ,`` ~
wherein Rl is a carboxy group (-COOH), or an agronomically-acceptable salt or ester thereof, or a carkaIkoxy group COOR, wherein R is a alkyl group, preferably having up t o 1 2 c arb on atoms, most preferably . . , up to 4 c~arbon atoms ?:

R is a phenyl group or a phenyl group ~
substituted with up to three substituents selected from alkyl groups, aryl groups, alkoxy groups, phenoxy groups, halogen atoms, nitro groups, per-haloalkyl groups, alkoxyalkyl groups, alkoxyalkoxy groups, amino groups, alkylamino groups, dialkyl-amino groups, cyano groups, carbalkoxy groups, carbamoyl groups, alkyl or dialkyl carbamoyl groups~
sulfo groups, sulfonamido groups, alkylczrbonyl or carboxyalkyl groups, alkanoyloxy groups, haloalkyl groups, alkanoylamido ~roups, alkylthio groups, alkylsulfinyl groups, and alkylsulfonyl groups;

, :` :
.R3 i~ an alkyl group, pre~erahly having up to 4 carbon atoms, and R is a hy~rogen atom, an alkyl group, preferably having up to 4 carbon atoms, or a halogen atom, preferably a bromine or a chlorine atom.

The present invention, in one aspect, provides a growth regulant composition which comprises from about 0.05~ to about 98% by weight of a compound of the formula:

O

I R4 ~ R
, 11 11 . R /N

wherein Rl is a carboxy group, or an agronomically-acceptable salt or ester thereoi, or a carb(Cl-C12) alkoxy group;
R2 is an unsubstituted phenyl group or a phenyl group substituted with up to t~ree substituents selected 1¦
from alkyl groups, aryl groups, alkoxy groups, phenoxy groups, halogen atoms/ nitro groups, per-.halcalkyl groups, alkoxyalkyl groups, alkoxyalkoxy groups, amino groups, alkylamino groups, dialkyl-amino groups, cyano groups, carbalkoxy groups, i - carbamoyl groups, alkyl or dialkyl carbamoyl groups, sulfo groups, sulfonamidO groups, alkylcarbonyl or carboxyalkyl groups, alkanoyloxy groups, haloalkyl groups, alkanoylamido groups, alkyl~hio groups, '.~
alkylsulfinyl groups, and alkylsulfonyl groups; ¦ .

-3a-~~ ~

-`" 13L~ 39~
: .
~ --R3 is a (Cl-C4)alkyl group: and R is a (Cl-C~ alkyl group~ or a halogen atom; or mixtures of such compoundsi and the balanae being an agronomically-acceptable carrier.

In a preferred embodiment of the invention, Rl is ;~ a carboxy group or a salt thereof~ R3 is a methyl group, .~ R ~s a hydrogen atom or a halogen atom, and R is.a substi-tuted phenyl group.
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When Rl is a salt of a carboxy group, an alkali metal, alkaline earth metal, or transition metal can provide the cation. The cation can also be an ammonium or substi-tuted ammonium group. Representative metal salt cations include alkali metal cations9 which are preferred, such as sodlum, potassium,lithium~ or the like, alkaline earth metal cations, such as calcium, magnesium, barium, strontium, vr the like, or heavy metal cations, such as zinc, manganese, cupric, cuprous, ferric, ferrous, titanium~ aluminum, or -~ 10 the like. Among the ammonium salts are those in which the ammonium cation has the formula NZ Z Z3Z , wherein each of Z , Z , Z3, and Z is individually a hydrogen atom, a hydroxy group, a (Cl-C4)alkoxy group, a (Cl-C20)alkyl group, a (C3-C8)alkenyl group, a (C3-C8)alkynyl group, a (C2-C8)-hydroxy alkyl group, a (C2-Cg)alkoxyalkyl group, a (C2-C6)-aminoalkyl group, a (C2-C6)haloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenylalkyl group, having up to 4 carbon atoms in~the alkyl moiety, an amino or alkyl-substituted amino group, or any ~- 20 two of zl, z2, z3, or Z4 can be taken together to form with the nitrogen atom a 5- or 6-member heterocyclic ring, optionally having up to one additional hetero oxygen~ nitro-gen, or sulfur atom in the ring, and preferably saturated, such as a piperidineS morpholine, pyrrolidine, or piperazine ring, or the like, or any three of z , z2, z3, or Z4 can be taken together to form with the nitrogen atom a 5- or 6-member aromatic heterocyclic ring, such asa pyrrole or pyridine ring. When the ammonium group contains a substi-tuted alkyl, substituted phenyl, or substituted phenylalkyl group, the substituents will generally be selected from ~.~,'J

~3~77 halogen atom~, (Cl-Cg)alkyl groups, tCl-c4)alkoxy groups, hydroxy groups, nitro groups, trifluoromethyl groups, cyano groups, amino groups~ (Cl-C4)alkylthio groups3 and the like.
Such substituted phenyl groups preferably have up to two - 5 such substltuents.. Representative ammonium cations include ammonium, dimethylammonium ':

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2-ethylhexylammonium, bis(2-hydroxyethyl)ammonium, tris(2-hydroxyethyl~ammonium, dicyclohexyl.ammonium, t-octylammonium, 2-hydroxyethylammonium, morpholinium, piperidinium, 2-phen-eth~lammoni.um, 2-methylbenzylammonium, _-hexylammonium, triethyl.ammonium, trimethylammonium, tri(n-butyl)ammonium~
- . methoxyethylammonium, diisopropylammonlum, pyridinium, diallylammonium, pyrazolium, propargylammonium, dimethyl-hydrazinium, hydroxyammonium, methoxyammonium, dodecylammon-ium, octadecylammoniuml 4-dichlorophenylammonium, 4-nitro-benzylammonium, benz-yltrimethylammonium, 2-hydroxyethyl-; dimethyloctadecylammonium, 2-hydroxyethyldiethyloctylammonium, . decyltrimethylammonium, hexyltriethylammonium, 4-methyl-benzyltrimethylammonium, and the like.
Repres~entative embodiments of R2 include phenyl : 15 groups substituted with alkyl groups, preferably having : up to 4 carbon atoms, aryl groups, preferably phenyl or ` substituted phenyl groups, alkoxy groups, preferably having . up to 4 carbon atoms, phenoxy or substituted phenoxy groups~ ¦
~ halogen atoms~ such as-fluorine, chlorine, bromine, and iodine atoms, nitro groups, perhaloalkyl groups, such as ~ I;
trifluoromethyl groups, alkoxyalkyl groups, pre~erably .
having up to 6 carbon atoms, alkoxyalkoxy groups,:preferably having up to 6 carbon atoms, amino groups, alkyl or dialkyl ¦ :

amino groups, preferably having up to 4 carbon atoms in each ) . 25 alkyl substituent, cyano groups, carbalkoxy groups, prefer- :
ably having up to 4 carbon atoms in the alkoxy moiety, carbamoyl groups, alkyl or dialkyl carbamoyl groups, prefer-ably having up to 4 carbon atoms in each alkyl substituent, sulfo groups, sulfonamide groups, alkylcarbonyl or carboxy-alkyl groups, preferably having up to 4 carbon atoms in the

3~7 `
alkyl moiety, alkanoyloxy groupsa preferably ~laving up to . 4 earbon atoms, haloalkyl groups, alkanoylamido groups, preferably having up to 4 earbon atoms, alkylthio groups, preferably having up to 4 carbon atoms. alkylsulfinyl groups, preferably having up to 4 earbon atoms, alkylsulfonyl groups~
. preferably having up to 4 carbon atoms, and the like. Pre~-erably, the substituted phenyl group will have up to three of the above substituents and the substituents will have a total of up to six carbon atoms. The most preferred sub-. 10 stituents on the phenyl group are 1 or 2 halogen atoms, a (Cl-C4)alkyl, preferably methyl, group, a (Cl-C4~alkoxy, preferably methoxy group, or a tri~luoromethyl group.

, .~ . Typical compounds within the scope of this ~ invention include:

:: 15 1-phenyl-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic r~ aeid 1-(4-ehlorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic aeid 1-(4-fluorophenyl)-1,4-dihydro-4-oxo-6-methy:lpyridazine-3-: 20 earboxylic acid 1-(4-bromophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylie aeid . , 1-(4-iodophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3_ .carboxylic acid ::~ 25 1-(3-fluorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-earboxylie acid 1-(3-chlorophenyl) 1,4 dihydro-4-oxo-6-methylpyridazine-3-carboxylicacid 1-(3-bromophe~yl)-1,4-dihydro-4-oxo-6-methylpyridazine-3_ earboxylic acid 1-~3,4-dichlorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic acid 1-(2-fluorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-earboxylic aeid 35 1-(2-chlorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-earboxylic acid ,,~ ~, .

~r~3~

1-(4-tri:fluorornetilylphe~yl.)~1,4-dihydro-LI-oxo-6-methyl-pyridazine-3-carboxy]ic acid 1-(3-trifluoromethylphenyl)-1,4-dihydro-4-oxo-6~methyl-pyridazine-3-carboxylic acid 5 1-phenyl-1,4-dihydro-4-oxo-6-ethylpyridazine-3-carboxylic acid 1-(4-chlorophenyl)-1,4-dlhydro-4-oxo-6-ethylpyridazine-3-carboxylic acid `~ 1-(4~fluorophenyl)-1,4-dihydro-4-oxo-6-ethylpyridazine-3-. 10 carboxylic acid 1-(3,4-dichlorophenyl)-1~4-dihydro-4-oxo-6-ethylpyridazine-3-carboxylic acid I-phenyl-1,4-dihydro-4-oxo-6-propylpyridazine-3-carboxylic acid 1-phenyl-1,4-dihydro-4-oxo-5,6-dimethylpyridazine-3-carboxylic acid 1-(4-chlorophenyl)-1~4-dihydro-4-oxo-5,6-dimethylpyridazine-3-carboxylic acid l-phenyl-1,4-dihydro-4-oxo-5-ethyl-6-methylpyridazine-3-. 20 carboxylic acid l-phenyl-1,4-dihydro-4-oxo-5,6-diethylpyridazine-3-carboxylic acid 1-(4-methylphenyl)-1,4-dihydro-4-oxo-6-methylpyridaæine-3-carboxylic acid 1-(2-chloro-4-methyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic acid 1-(2,4,6-trichlorophenyl)-1,4-dihydro-4-oxo-6-methylpyri-daæine-3-carboxylic acid 1-~3-ethoxyphenyl)-1,4-dihydro-4-oxo-6-ethylpyridazine-3-carboxylic acid 1-(4-methylthiophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic acid 1-(3-cyanophenyl)-5-bromo-1,4 dihydro-4-oxo-6-ethylpyrida-zine-3-carboxylic acid 1-phenyl-5-bromo-1,4-dihydro-4-oxo~6-methylpyridazine-3-carboxylic acid 1-(3-chlorophenyl)-5-chloro-1,4-dihydro-4-oxo-6-methylpyri-~
dazine-3-carboxylic acid 1-(4-chlorophenyl)-5-bromo-1,4-dihydro-4-oxo-6-ethylpyrida-zine-3-carboxylic acid, and the like, 3~
..
:, and the salts and esters of the above acids. .
The compounds of the invention can be prepared -;` by severa]. convenient preparative routes. In the first method, a 4-hydroxy-2-pyrone of the formula OH

; 5 :. O
' .

wherein R6 is a hydrogen~atom.or an alkyl group and R3 iæ
defined above, or a salt of a pyrone of Formula II, prepared :
. by treating the pyrone with an equivalent of.a suitable ; :
aqueous base such as: potassium or sodium hydroxide, acetate, or carbonate, is reacted at about -lO to about 50C in a polar solvent, such::as water, methanol, ethanol, glyme, .
dimethylformamide, or the like, with a diazonium sal-t, such as diazonium chlorideS prepared by conventional diazotiza- :
tion technique from an amine Or the formula R2 ~ NH2 (III) wherei.n x2 is as defined above. The product hydrazone, which has the formula O
NNH-R
~ (IV) RYr ~ O O

wherein R2, R3, and~R~ are as defined above, is then treated with either an aqueous acid, such as hydrochloric acid, trifluoroacetic acid, sulfuric acid, methanesulforic acid, nitric aeid, or the like, or an aqueous base~ such as sodium .
-8-- .

~3qL~7~

carbonate, sodium hydroxide, or the like, at a temperature of about 20 to about 150C, preferably about 40 to about 100C, to yield, by a rearrangement, a pyridazine of the formula O
R6 J~ ~ ~C02H
~ 1 ~ (V) ~ ~ N
R3 l2 wherein R2, R3, and R are as defined above.
Esters of the pyridazine of Formula V are pre- ¦
pared by esterification with a suitable alcohol, preferably a (Cl-C4)alkanol. One convenient technique is a Fischer esterification, using anhydrous hydrochloric acid or sul-furic acid as a catalyst and the alcohol as the solvent.
This esterificatlon is generally carried out at about 35 to about 150C, optionally using an inert cosolvent such ~as methylene chloride, ethylene chloricle, diethyl ether, toluene, xylene, or the like. Salts of the pyridazines of Formula V and th;eir~5-halo analogues can be prepared by ~ ~
conventlonal techniques, such as by neutralization with an ~ -ap~proprlate inorean~c or or~anic~ b~se, in a soluent- such as water or methanol.
~The compounds of the invention in which R4 is a halogen atom can be prepared by reacting the corresponding pyridazines in which R4 is a hydrogen atom with one equi~
valent of a halogenatin~ agent such as bromine, chlorine, sulfuryl brornide, sulfuryl chloride~ or the like in a suitable inert solvent such as hexane, benzene, ethylene dichloride, methanol, or the like, at a temperature of about ~3gL~7~

O to 50C., pref'erably at room ternperature.
The follo~ing examples will further illustrate the compounds of the invention and their preparation, but are not intended to limit the invention in any way. All temperatures are in degrees Ce1sius and parts and percen-- tages are by welght, un~ess otherwise indicated. Specific illustrative preparations of the compounds of Examples .. I
lO, 12, l~l, and 16 are provided. Table I lists typical compounds of the invention and their melting points and ~ lO elemental analyses.

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TABLE I
.
l-Aryl-1,4-dihydro-4-oxo-pyridazines . O
R4 \ ~ ~ C02H

N ~N
CH3 ¦ -X : , ~.
.
Example 4 No R X m.p.(C3 %C %H %N %Hal Calc. 5~ 0~ 3.65 11.29 7.65 1 H 3-F 213-5 Found 58.o7 3.60 11.33 7.68 2 H 4-CH , 202-3 ~ 56.22 3.63 10.09~12.77 C13 . 55.92 3.84 10.90 13.36 ~-. .
3 H 4-I ~ 241-2 40.47 2,55 7.87 35.64 ~-41.20 2.46 8.05 35.67 .

4 H 4-Br 243 46.62 2.93 9.06 25.85 47.45 3.14 9.26~2~.64 H 4-CF 234-5 52.35 3.04 9.40 19.11 3 51.99 2.97 ~9.13 18.94 6 H 4-No2 244-5 52.37 3.30 15.27 52.76 3.33 15.69 -~
.
7 H 4_CH3 162-3 63.92 4.95 11.47 ~3.66 4~89 11.52 .
8 H 2,3-ben- 218-20 61.06 3.52 8.90 11.27 zo-4-C1 61;.07 3.42 8.86~11.00 9 H 4-oCH 169-70 59.94 4.64 10.77 -----3 60.14 4.62 10~.82 ~
H 4-F I85-7 58.06 3.65 11.29 7.65 58.73 3.64 11.74 7~.47 11 H 3s4- 220-2 48.18 2.69 9.37 23.71 diCl 48.03 2.73 9.21 23.96 12 H 4-C1 229-30 54.45 3.43 10.59 13.39 54.l~9 3.44 10.44 13.59 .
-~ TABLE I (Cont'd) Example ll No. R Y` ' m.p.(C) %C %H %N %Hal 13 H 3-C1 192-3 Calc.
Found : 14 H H 173 . !
Br 4-CH3 241 48.31 3.43 8.67 24.73 `'` 49.37 3.59 9.25 23.65 ' ' 16 Br 4-~ 219-20 44.o6 2.46 ~.57 24.43*
'' 10 44.50 2.52 9.00 24.26 ' 17 ~'Br'4-~r >25 37.1ll 2. o8 7 . 22 41.19 ' 36.78 ].98 7.35 l~o.83 ' '' 18 Br H 22~ 46.62 2.93 ~, o6 25.85 46.68 2.88 .9.25 25.62 19 Cl 4-Br 255-9 41.95 2.35 8.16 23.26~
41.65 2.31 7.74 23.17 -~% Br; % F: calc. 5.81; found 5.83 ' **% Br; % F: calc.10.37; found 9.91 I Example 10 ~ ¦

Preparation of i-(4-fluorophenyl)-1,4-dihydro-4-oxo-6- l' methylpyridazine-3-carboxylic acid~ _ 4-Hydroxy-6-methyl-2-pyrone (7.88 g)~is suspended in 25Q ml water, and 6.63 g of anhydrous sodium carbonate is added to the suspension to~effect solution of the pyrone.

In-a separate flask~, 7.22 g of 4-fluoro aniline ,: : ~: ., is mixed with 25 ml concentrated hy~drochloric acld and 31 ml water. The resulti~n~ solution is maintained at about

5 ko 10 and a solution of 4.75 g of sodium nitrate in 16 ml of water is added. The resulting solution of 4-fluoro-phenyldiazonium chloride is added dropwise to the stirred pyrone solution, while maintaining the temperature at about 5 to 10, and the pH at about 8 to 9 by adding small amounts ' of aqueous sodium hydroxide.
The resulting hydrazone is refluxed for about 2 ~l4~3~7 ; hours with 500 ml of concentrated hydrochloric acid.
Coating and filtration yields 10.2 g of 1-(4-~luorophenyl)-1,4-dihydro-ll-oxo-6-methylpyridazine-3-carboxylic acid which is recrystallized from chloroform/ether (mp-185-7).
Example 12 Preparation of 1-(4~chlorophenyl)-1.4-dihydro-4-oxo-6-methylpyridazine-carboxylic acid and its sodium salt p-Chloroaniline (12.75 g) is dissolved in 40 ml of concentrated hydrochloric acid and cooled to 0. A
solution of 7.6 ~ sodium nitrite temperature between 0 and ., .
5. The diazotized aniline is added under ice cooling to a previously prepared solution of 12.6 g 4-hydroxy-6-methyl-2-pyrone and 55 g sodium carbonate in 500 ml of water.
The resultant slurry is heated at reflux over-night. When complete ~reaction is not observed, the pH is adjusted to 12 and refluxing is continued. The dark solution is neutrallzed to pH 6-7 with acetic acid and treated with activated charcoal. The filtrate is acidified to pH 2 with concentrated hydrochloric acid under ice :: :
cooling to precipitate product. The acid is recrystallized from acetone/hexane yielding 10.5 g (39%) 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic acid (mp-229 230QC~.
The acid (5.0~g) is converted to the sodium salt by treatment with 0.76 g sodium hydroxide in 200 ml of anhydrous methanol. The solvent is removed and the solid is washed with ether and dried in vacuo at 90C. Analysis calculated for Cl2H8ClN20Na l/2 H20: C, 48.752 H, 3.07;
N, 9.48; Cl, 11.99; Na, 7.78. Found: C, 48.11; H, 2.80;
N, 9 24; Cl, 12.37; Na, 7.62.

~13-l~V3~

Example 14 Preparation of l-Phenyl 1,4-dihydro-4-oxo-~-methylpyridazine-3-carboxvlic acid __ In 375 ml of water is suspended 11.8 g of 4-hydroxy-

6-methyl-2-pyrone, and ~.95 g of anhydrous sodium carbonate . is added to e~fect solution of the pyrone.
-~ In a separate flask, 9.08 g of aniline is mixed ; with 37.5 ml of concentrated hydrochloric acid and 47 ml of water. ~he resulting solution i~s maintained at about 5 to 10 and a solution of 7.13 g of sodium nitrite in 24 ml water is added. The resulting solution of phenyldiazonium chloride is drop-added to the stirred pyrone solution, while~
malntaining a temperature of about 5 to 10. The pH is maintained at about 8 to 9 by the addition of smaIl amounts of sodium hydrox1de solution.
After the addition is complete, the resulting hydrazone (18 g) is isolated by filtration and resuspended in 500 ml of concentrated hydrochloric acid. The mixture is refluxed for 2 1/2 hours, and then cooled. The l-phenyl-1,4:-dihydro-4-oxo-6-methy~lpyridazine-3-carboxylic ac1d precipitates out as brownish crystals which are recrystallized from water. Yield - 7.0 g; mp-173~
~ j .
Prèparation of 1-(4-fluorophenyl)-5-bromo-1,4-dihydro-4-oxo-meth~lpyridazine-3-carboxylic acid _ 1-(4-Fluorophenyl)-1,4-dihydro-4-oxo-6-methyl-pyridazine-3-carboxylic (1.5 g) is suspended in 100 ml of dry methanol~ and 0.242 g of sodium hydroxide is added. To the solution is added dropwise 1~038 g of bromine dissolved in 50 ml of methanol. The solvent is removed leaving a white solid, which is taken up in dilute base and ~3~ 7 "
the solution acidified with hydrochloric acid. The resulting precipi~ate i5 filt-ered and recrystallized from chloroform/ether to yield 1.4 g of 1-(4-fluorophenyl)-5-bromo-1,4-dihydro-4-oxo-5-methylpyridazine-3-carboxylic acid. (mp-219-20).
I The compounds of the invention are particularly useful as chemical hybridization agents in cereal crops~
such as wheat, barley, corn, ri~ce, sorghum, millets, oats, rye and the like. When used as chemical hybridization ~: 10 agents, the compounds effe~ctively induce a high degree of selective male sterility, that is without also inducing sig-nificant female sterility, in the treated plants and without causing signi~icant growth inhibition of the treated plants. As used herein, the term male sterility includes both actual male sterility, as evidenced by a lack of male flower parts or by sterile pollen, and functional male sterility, in which the male flower parts are unable to cause pollination. The compounds of the invention also cause other plant growth regulatory responses, such as for example, control of flowering, control of fruiting and - inhibition of seed formation in non-cereal species, and - other related growth regulatory respon3es.
., ~
- When used as plant growth regulators, the com-pounds of the invention are applied in any amount which ~ 25 will be surficlent to effect the desired plant response I without causing any undesirable or phytotoxic response. For example, when the compounds of the invention are used as chemical hybridization agents, they are generally applied to the crops to be treated at a rate of about 1/32 to about 20 pounds per acre and preferably about 1/8 to about 10 3~!7~
, :

.' .:
~ pounds per acre. The rate of application will vary depending -- on the crop being treated, the compound being used for treat-ment, and related factorss To obtain hybrid seed, the following procedure is generally employed. The two parents to be crossed are planted in alternate strips. ~he female p~arent is treated with a compound o~ the invention. The male-sterile female parent thus produced will be pollinated by pollen from the other, male-fertile, male parent, and the seed produced by the female parent will be hybrid seed which can then be harvested by oonventional means.
~ A preferred method of applying a compound of the - invention as a chemical hybridization agent is by foliar application. When this method is employed, selective male sterility is most effectively;induced when the compRund is applied between flower initiation and meiosis. The com-. . .
pounds of the inventions may also be applied~as a seed treatment by soaking~the seed in a liquid formulatlon con-taining the~ activè compound or by coating the seed with the : ` : : :
~ 20 compound~ In seed treatment applications, the compounds .~ , of the invention will generally be applied at a rate of about 1/4 to 10 pounds per hundred weight of seed. The compounds of the invention are also effective when ap~plied to the soil or to the water surface in rice crops.~
The compounds of the invention can be used as plant growth regulators elther individually or in mixtures.
For example, they can be used in combination with ot~her plant growth regulators, such as auxins, gibberellins, ethylene-releasing agents such as ethephon, pyridones, cytokinins, maleic hydrazide, succinic acid 2,2-dimethyl-J 3~!7~7 hydrazide, cho:line and its salts, (2-chloroethyl)trirnethyl-amrrloniuM chlor~de, triiodobenzoic acid~ tributyl-2,4-dichlorobenzylphosphonium chloride, polymeric N-vinyl-2-oxazolidinones, tri(dimethylaminoethyl)phosphate and its salts, and N-diMethylaMino-1,2,3,6-tetrahy~rophthalamic acid and its salts, an~ the like,~ and~ under some conditions may be used advantageously with other agricultural chemicals such as herbicides, f`ungicides, insecticides, and plant bactericides.
A compound of the invention can be applied to the growth medlum or to plants to be treated either by i.tself or, as is genera]ly done~ as a component in a growth regulant composition or formulation which also comprises an agronomica]ly acceptable carrier. By "agronomically acceptable carrier" lS meant any substance which can be used to dissolve, disperse, or dif~use a compound in the composition without impairing the effectiveness of the compound and~which by itself has no si~nificant detrimental effect on the soil, equipment, crops, or agronomic environ-ment. Mixtures of the compounds~of the invention may alsobe used in any of~these formulations. The compositions of the invention can be either solid or liquld formulations or solutions. For example, the compounds can be formulated as wettable powders, emulsifiable concentrates, dusts, granular formulations, aerosols, or flowable emulsion concentrates.
In such formulations, the compounds are extend~ed with a liquid ox solid carrier and, when desired suitable surfac-tants are incorporated.
It is usually desirable, particularly in foliar applications, to include adjuvants, such as wetting agents, :

spreadi.ng agents, dispersing agents, stickers, adhesives, : and the 'like, in accordance with agricu].tural practi.ces4 . . .
i~ Examples of ad~uvants which are commonly used in the art ~ can be found in the John W. McCutcheon, Inc. publication "Detergents and Emu].sifiers Annual."
The compounds of the invention can be dissolved in any appropriate solvent. Examples of solvents which are usefu1 in the practice of this invention include water3 alcohols, ketones, aromàtic hydrocarbons, halogenated I0`: hyd'r'o-carbo:ns,. dim2thyl.formamide, dIoxane, dimet~yl sulfoxide, ' and the like. Mixtures of these solvents can also be used.
The concentration of the solution can vary from about 2%
to about 98% by weight with a preferred range being about 20% to about 75%.
For the preparation of emulsifiabIe concentrates 5 the compound can be dissolved in organic solvents, such as : benzene, toluene, xylene, methylated naphthalene, corn oil, `. pine oil, o-dichlorobenzene, isophorone, cyclohexanone, ~ methyl oleate, and the like, or in mixtures of these sol '~ 20 vents, together with an emulsifying agent or surfactant ' which permits dispersion in water. Suitable emulsifiers include, ~or example, the ethylene oxide deri~atives of alkylphe'nols or long-chain alcohols, mercaptans, carboxylic acids, and reactive amines and partially esterified poly-25 hydric alcohols. Solvent-soluble sulfates or sulfonates~
such as the alkaline earth salts or amine salts of alkyl-benzenesulfonates and the fatty alcohol sodium sulfates, having surface-active properties can be used as emulsifiers either alone or in conjunction with an ethylene oxide 30 reaction product. Flowable emulsion concentrates are.

f formulated similarly to the emulsifiable concentrates and include, in addition to the above components~ water and a stabilizing agent such as a water-soluble cellulose deriva-tive or a water-soluble salt of a polyacrylic acid. The ConCentratlOn of the active ingredient in emulsifiable concentrates is usually about 10% to 60~ by weight and in flowable emulsion concentrates is usually about 10% to 60% by weight and in flowable emulsion concentrates this can be as high as about 75%.
Wettable powders suitable for spraying, can be prepared by admixing the compound with a finely divided solid, such as clays, inorganic silicates and carbonates~
and silicas and incorporating wetting agents, sticking agents, and/or dispersing agents in such mixtures. The concentration of active ingredients in such formulations is usually in the range of about 20% to 98% by we-ight, preferably about 40% to 75%. A dispersing agent may generally const~tute about 0.5% to about 3% by weight of the composition, and a wetting a~ent may eeneraIly constitute from about 0.1% to about ~% weight of the composition.
Dusts can be prepared by mixing the compounds of the invention with flnely divided inert solids which may be organic or inorganic in nature. Materials useful for this purpose include, for example, botanical flours, silicas, silicates, carbonates and clays~ One convenient method of preparing a dust is to dilute a wettable powder with a finely divided carrler. Dust concentrates containing about 20% to 80% of the active inGredient are commonly made and are subsequently diluted to about 1% to 10% by weight use concentration.

_ Granular formulations can be prepareri by irnpre~,~
nat-ing a solid such as granular fuller's earth, vermiculite, ground ccrn cobs, seed hulls, including bran or other graln hulls, or slmilar material. A solution of one or more of the compounds in a volatile organic solvent can be sprayed or mixed with the granular solid and the solvent then removed by evaporation. The granular material can have any suitable slze, with a preferable size range of 16 to 60 me~sh. The active~ compound will usually comprise about 2 to 10~ 157 by weight of t~he granular~formulation.
Salts o~ the compounds of the inventlon can be formulated and applied as aqueous solutions. The salts will typ1cally comprise about 0.05 to about 50% by weight, ; preferably about 0.1% to about 10%, of the solution. These compositions can also be further diluted with water i~ desired prior to actual applicatlon. In some applications, the activity of these compositions can be enhanced by incor-porating into the compositions an adjuvant such as~glycerin, methylethylcellulose, hydroxyethylcellulose, polyoxyethylene-^~ 20 sorbitan monooleate, polypropylene glycol, polyacrylic acid, ~ polyethylene sodium malate, polyethylene oxide, or the like.
. : :
The adjuvant will generalIy comprise about 0.1 to about 5%by weight, preferably about 0.5 to about 2%, of the composi-tion. Such compositions can also optionally include an agronomically-acceptable surfactant.
The compounds of the invention can be applied as sprays by methods commonly employed, such as conventional hydraulic sprays, aerial sprays, and dusts. For low-volume applicationæ a solution of the compound is usually used.
The dilution and volume of application will usually depend -20~

~ ~3~t~

upon such factors as the type of equlpment employed, the method of application, the area to be treated and the type and stage of development of the crop being treatedO
The following example- will further illustrate the growth regulatory activity of the compounds of the inven~ion but is not intended to limit the invention in any way.
Ex~mple 20 Chemical Hybridization Activity The following procedures are used~to evaluate the activity of the compounds of the invention for inducing male sterility in cerea]s.
An awned variety (Fielder) and an awnless variety (Mayo-64) of spring wheat are planted at the rate of 6 to 8 seeds per 6" pot containing a sterile medium of 3 parts soil and 1 part humus. The plants are grown under short-day ; (9 hour) conditions for the first 4 weeks to obtain good vegetative growth before flower initiation. The plants are ~- then moved to long-day (16 hour) conditions which are - 2Q provided by high intensity lights in the greenhouseO The plants are fertilized at 2,4, and 8 weeks after planting with a water soluble fertilizer (16-25-16) at the rate of 1 tsp/gal of water, and are frequently splrayed with an appropriate insecticide, such as Isotox~, for aphid control and dusted with sulfur for powdery mildew control.
Test compounds are foliarly applied to the awned ~emale plants when these plants reach the flag leaf emergence state (stage 8 on Feekes' scale). All compounds are applied in a carrier volume of 50 gal/A containing a surfactant~
such as Triton~ X-100, at the rate of 2 oz/50 gal.

1. Trademark for an insecticide containing lindane 2. Trademark of Rohm and Haas Company for octylphenoxy ' a~ polyethoxy ethanol; it is a nonionic surfactant ._ .. ..

.` ` `
3~'7 After spike emergence but before anthesis~ 4 to 6 spikes per pot are bagged to prevent outcrossing. At the first signs of flower opening~ two spikes per pot are cross : pollinated~ using the approach method, with the awnless male . . ~
parent. As soon as the seeds became plainly visible, spike length is ~easured and seeds per spikelet counted in both bagged and crossed spikes. Male sterility can:then be calculated as percent inhibition of seed set in bagged spikes of treated plants, and female fertility in crossed spikes can be ca~culated as percent of control seed set.

After maturity the seed on crossed spikes are planted for determination of percent hybridization.
~ Percent sterilityg percent fertility, and percent : spike length inhibition are calculated from the following formulaS: ' a) % Steril~ty = Sc - t X 100 S = seeds/spikelet in bagged spikes of control plants St - seeds/spikelet in bagged spikes of treated plants b) % Fertility = Ft X 100 c F~ = seeds/splkelets in approach crossed spikes o~ treated plants F = seeds/spikelet in unbagged spikes of control plants 3~
:: ' . ' :
c) % Spike inhibition = Hc _ Ht X 100 c Hc = Spike length of control plants Ht = Spike length of treated plants ¦~

- ~able III summari~es typical results obtained in .: 5 the evaluat1on of compounds of the invention. A~dash indi-cate:s that no determinat:ion of value was made.
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, TABLE III
.~; Gametocidal Activity O

R4 -- J~c ~2 CH3 jN
.,,, , I .
I

.
X
~: 4 % Sterility (at lbs/A) : X R R 8 4 2 1 1~2 1i4 `: 3~ H H___ 100 ~ 72 ~ 7 ; 5 : 74 83 ; 3F H Na --- 100 100 100 100 81 4-CH3~3-Cl H H16 9 10 14 : 10 ---4-CH3,3~Cl H Na0 14 2 13 ~6 ---4~I H ~ H ~ 100 -100 100 ~99~
4-I ~ : N2100 ~100 ~100100~ 100 ~ 97 :~ : 82 4-Br H H --- 100 100 100 100 ---4-Br H Na100 100 100 100100+ 98 :86 :: 73 3 H H___ 100 97 100 96 ~
4-CF3 H NalQ0 100 100 100 97+ 99 : 15 4-N02 H H 9 18 --~
4-N2 H Na9 16 8 16 8 ---4-CH3 H H73 41 -- --- --- _ _ 4-CH H Na100 98~ 92+ 38 12 ---3 100 1~0 4-Cl H H33 15 --- - _ ___ ___ (naphthyl) 4-Cl H Na 0 5 4 l~ 9 ___ (naphthyl) 4-oCH3 H H100 94 --- --- __ ___ 3~Lr,~

:: TABLE III (cont'd) , ~
_ % Sterility (at lbs/A) _ X _ R4 R 8 4 2 1 1/2 1/4 4-oCH H Na100 100 99 83 43 ---4-~' H H 100 -~ -4-F H Na 100 100 100 100 95 66 3,4-diCl H H 100 ~-- --- -- --- ---3,4-diCl H Na 100 98 92 16 --- ~~~
4-Cl H H 100 100 96 --- ___ ___ .~ 4-Cl H Na 100 100100+ 100+ 100+ 100 -: 45 34 90 72 3-Cl H Na 86 --- - - --- --- ---3-Cl H Na 100 100 74 64+ 94 __ H H Na 100 100 100 100 97+ 40 : 90 97 Br H --- 6 2 10 7 ---4-CH3 Br Na 9 3 ~~~ 8 7 ---4-F Br H -- --- --- --- --- ---4-F Br Na 100 100 100 100+ 84+ 15 :73 ; 4-Br Br H --- --- --- 82 48~ 32 Z5 4-Br Br Na --~
-: H Br H --- --- --- --- __ __ H Br Na --- --- --- 100 88 18 4-Br CI Na ~- 100 100 92 55 _ _ 4-C1 H CH3 ++ --- ++ --- 100 4-C1 H C2H5 100 --~ 100 - - 100 --_ + multiple results that multiple separate tests were ~arried out * 35 at 1/8 lb/A
.. ** 0 at 1/8 lb/A
*** 96 at 1/8 lb/A

~3`fl~7~7 *** 99 at 1/~ lb/A
f+ spike emergence inhibited at 2 and 8 lb/A
It is to be understood that changes and variations can be made without departing from the spirit and scope of the invention as defined by the appended clai~s.

~ . .

.

Claims (16)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A method of inducing male sterility in a cereal grain plant which comprises treating the plant prior to meiosis with an amount effective to produce male sterility in the plant of a compound of the formula (I) wherein R1 is a carboxy group, or an agronomically-acceptable salt or ester thereof, or a carb(C1-C12)alkoxy group;
R2 is an unsubstituted phenyl group or a phenyl group substituted with up to three substituents selected from alkyl groups, aryl groups, alkoxy groups, phenoxy groups, halogen atoms, nitro groups, per-haloalkyl groups, alkoxyalkyl groups, alkoxyalkoxy groups, amino groups, alkylamino groups, dialkyl-amino groups, cyano groups, carbalkoxy groups, carbamoyl groups, alkyl or dialkyl carbamoyl groups, sulfo groups, sulfonamido groups, alkylcarbonyl or carboxyalkyl groups, alkanoyloxy groups, haloalkyl groups, alkanoylamido groups, alkylthio groups, alkylsulfinyl groups, and alkylsulfonyl groups;
R3 is a (C1-C4)alkyl group; and R4 is a hydrogen atom, a (C1-C4)alkyl group, or a halogen atom.

2. The method of claim 1 wherein R1 is a carboxy group or an agronomically-acceptable salt thereof.

3. The method of claim 2 wherein R2 is an unsub-stituted phenyl group or a phenyl group substituted with one or two halogen atoms, a methyl group, a methoxy group, or a trifluoromethyl group.

4. The method of claim 3 wherein R4 is a hydrogen atom.

5. The method of claim 4 wherein R3 is a methyl group.

6. The method of claim 5 wherein R2 is a halo-phenyl group.

7. The method of claim 6 wherein R2 is a 4-halo-phenyl group.

8. The method of claim 6 wherein R2 is a 3-halo-phenyl group.

9. The method of claim 5 wherein R2 is a tri-fluoromethylphenyl group.

10. The method of claim 3 wherein R3 is a methyl group and R4 is a halogen atom.

11. The method of claim 10 wherein R2 is a halo-phenyl group and R4 is a bromine atom.

12. The method of claim 2 wherein the cereal grain is wheat.

13. The method of claim 2 wherein the cereal grain is barley.

14. The method of claim 2 wherein the cereal grain is corn.

15. A growth regulant composition which comprises from about 0.05% to about 98% by weight of a compound of the formula:

wherein R1 is a carboxy group, or an agronomically-acceptable salt or ester thereof, or a carb(C1-C12) alkoxy group;
R2 is an unsubstituted phenyl group or a phenyl group substituted with up to three substituents selected from alkyl groups, aryl groups, alkoxy groups, phenoxy groups, halogen atoms, nitro groups, per-haloalkyl groups, alkoxyalkyl groups, alkoxyalkoxy groups, amino groups, alkylamino groups, dialkyl-amino groups, cyano groups, carbalkoxy groups, carbamoyl groups, alkyl or dialkyl carbamoyl groups, sulfo groups, sulfonamido groups, alkylcarbonyl or carboxyalkyl groups, alkanoyloxy groups, haloalkyl groups, alkanoylamido groups, alkylthio groups, alkylsulfinyl groups, and alkylsulfonyl groups;
R3 is a (C1-C4)alkyl group; and R4 is a (C1-C4) alkyl group, or a halogen atom; or mixtures of such compounds; and the balance being an agronomically-acceptable carrier.

16. The composition of claim 15 wherein R1 is a carboxy group or an agronomically acceptable salt thereof, R2 is an unsubstituted phenyl group or a phenyl group sub-stituted with one or two halogen atoms, a methyl group, a methoxy group, or a trifluoromethyl group, R3 is a methyl group, and R4 is a halogen atom.