Method of altering the alkaloid composition in poppy plants

52 Pages·2013·3.03 MB·English

US008377851B2
(12) United States Patent (10) Patent N0.: US 8,377,851 B2
Cotterill (45) Date of Patent: Feb. 19, 2013
(54) METHOD OF ALTERING THE ALKALOID Trinexapac Data Sheet, Compendium of Pesticide Common
COMPOSITION IN POPPY PLANTS Names,Datasheet [online]. Alanwood., 2011 [retrieved on May 20,
201 1]. Retrieved from the Internet: <URL:http://www.alanwood.net/
pesticides/indexicniframe.html> p. l.*
(75) Inventor: Paul Cotterill, Latrobe (AU)
Brown et al., Phytochemistry, 47(5), pp. 679-687 (1998).
Facchini et al., Plant Physiology, American Society of Plant Physi
(73) Assignee: GlaxoSmithKline Australia Pty. Ltd.,
ologists, vol. 112, pp. 1669-1677 (1996).
Boronia, Victoria (AU) Facchini et al., Phytochemistry, 49(2), pp. 481-490 (1998).
Huang, et al, “Distribution of morphinan and
( * ) Notice: Subject to any disclaimer, the term of this benzo[c}phenanthridine alkaloid gene transcript in Papaver
patent is extended or adjusted under 35 somniferum, ” Phytochemistry(2000)53 :5 55 -564.
Facchini, et al, “Uncoupled defense gene expression and antimicro
U.S.C. 154(b) by 955 days.
bial alkaloid accumulation in elicited opium poppy cell cultures,”
Plant Physiology (1996)1 l 1 :687-697.
(21) Appl. No.: 11/568,651 Millgate, et al., “Morphine-pathway block in topl poppies,”
Nature(2004)431:413-414.
(22) PCT Filed: May 6, 2005 Opposition by Tasmanian Alkaloids Pty Ltd. Against European
Patent Ep-B-l 755 373 granted in the name of Glaxosmithkline
(86) PCT No.: PCT/AU2005/000651 Australia PTY Ltd. (2 pages) Mar. 1, 2011; printed Jan. 18, 2011.
Geoff Johnson Dean Curriculum Vitae, March 1, 2011 ; printed Jan.
§ 371 (0X1)’ 18, 201 1.
(2), (4) Date: Aug. 28, 2008 Geoff Dean Email: SFS Strikes Again (Email Press Release) dated
May 5, 2004.
(87) PCT Pub. No.: WO2005/107436 Geoffrey Johnson Dean Declaration signed Dec. 15, 2010.
A.J. Fist: The Tasmanian Poppy Industry: A Case Study of the Appli
PCT Pub. Date: Nov. 17, 2005 cation of Science and Technology; The Regional Institute 2001; pp.
1-8.
(65) Prior Publication Data Heidrun, Halbwirth et al., Induction of Antimicrobial
3-Deoxy?avonoids in Pome Fruit Trees Controls Fire Blight Z
US 2009/0075822 A1 Mar. 19, 2009 Naturforsch [C] 58 (11-12):765-70, 2003.
Bruce Ross Mounster, Resume Mar. 1, 2011; printed Jan. 18, 2011.
Related US. Application Data Bruce Ross Mounster Declaration signed on Dec. 21, 2010.
Bruce Mounster: Short Poppy Shock Bonus; Tasmanian Country,
(60) Provisional application No. 60/569,385, ?led on Jun. Friday May 7, 2004.
4, 2004. Qian Y.L. et al., In?uence of Trinexapac-Ethyl on Diamond
Zoysiagrass in a Shade Environment; Crop Sci, 39: 202-208 (1999).
(30) Foreign Application Priority Data Rademacher, Wilhelm: Growth Retardants: Effects on Gibberellin
Biosynthesis and Other Metabolic Pathways; Annu. Rev. Plant.
Physiol. Plant Mol Biol. 2000; vol. 51 pp. 501-531.
Jun. 4, 2004 (AU) .............................. .. 2004202517
Rademacher, W.: On the Mode of Action of Acylcylcohexane
diones i A New Type of Plant Growth Retardant with Possible
(51) Int. Cl.
Relationships to DaminoZide; Acta Horticulturae 329, 1993 Plant
A01N 43/40 (2006.01)
Growth Regulators, pp. 31-34. Raj ala a. et al .; Timing Applications of
A01N 3 7/08 (2006.01) Growth Regulators to Alter Spring Cereal Development at High
C07D 489/00 (2006.01) Latitudes; Agricultural and Food Science in Finland, vol. 11 (2002)
(52) US. Cl. ...... .. 504/260; 504/313; 504/320; 504/334; 233-244.
546/44 Table of Contents from Annual Review of Plant Physiology and Plant
Molecular Biology, vol. 51, 2000.
(58) Field of Classi?cation Search ................ .. 504/101,
Vegetables and Allied Crop Industries Annual Report 1984-1985,
504/260, 313, 320, 334; 546/44
vol. 3, part 1, pp. 19-21.
See application ?le for complete search history.
* cited by examiner
(56) References Cited
Primary Examiner * Johann Richter
U.S. PATENT DOCUMENTS
Assistant Examiner * Andriae M Holt
4,560,403 A 12/1985 Motojimaet al.
(74) Attorney, Agent, or Firm * Nora L. Stein; Theodore R.
4,693,745 A 9/1987 Brunner
4,909,835 A 3/1990 Tobler Furman
6,083,882 A 7/2000 Evans et a1.
(57) ABSTRACT
FOREIGN PATENT DOCUMENTS
The method of altering the alkaloid composition of a poppy
AU B-8369/91 3/1992
plant comprising the step of applying an effective amount of
AU 646074 B2 * 2/1994
acylcyclohexanedione compound or agriculturally accept
OTHER PUBLICATIONS able salt thereof to said poppy plant or locus thereof. Further,
the present invention also provides the method of altering the
Forbes, JJ, Poppies-Growth Regulators, 1984-85, Vegetables and
alkaloid composition of a poppy plant comprising the step of
Allied Crop Industries Annual Report, Department of Agriculture
applying an effective amount of methyl jasmonate or agricul
Tasmania, vol. 3, Part 1, pages Title page and 19-21.*
turally acceptable salt thereof to said poppy plant or locus
Rademacher, W., On the Mode of Action of
Acylcylcohexanediones-A New Type of Plant Growth Retardant thereof.
with Possible Relationships to DaminoZide, 1993, Acta
Horticulturae, Plant Growth Regulators, vol. 329, pp. 31-34.* 8 Claims, 1 Drawing Sheet
US. Patent Feb. 19, 2013 US 8,377,851 B2
Proposed Metabolic Pathways of Trinexapac-othyi (66A 163935) In Plants
0
0 OH
66151163935 (parent)
0
/\ o / 0
OH
OH
o O
CGA 312753 mono~elhylester Ho 0
\ _* CGA 179500 sugar oodugale
O OH
CGA 179500
0 0
OH HO
HO \
O OH
00A 29;: O CGA 351210
3
HO \
O O OH
HO 0
CGA 313458 sugar conluqab
O / \
O
Ho OH Conjugates
OH Esters, GWQOSideg
CGA 275537 0
lricarbally?c add 0
0 .
HO / OH "ll-‘22L? cum: acid cyciu
OH I
cmluoatel can. mm 0
Esters aconlllc acid Bound residuea
US 8,377,851 B2
1 2
METHOD OF ALTERING THE ALKALOID As can be seen, from the above table the yield of thebaine
COMPOSITION IN POPPY PLANTS and oripavine is confounded With that of other alkaloids.
Thus, the supply of thebaine and oripavine is to a great degree
This application is a §37l national phase entry of Intema limited to some fraction of the demand for morphine.
tional Application No. PCT/AU2005/00065l, ?led May 6, As seen from Table I oripavine is not recoverable from
2005 Which claims priority to Us. provisional U.S. Ser. No. Papaver somiferum in any practical yield. Since oripavine has
60/569,385 ?led Jun. 4, 2004 and international patent appli traditionally not been demanded in the same quantities as
cation AU2004/2025l7 ?led Jun. 4, 2004. thebaine, there has been no real shortage of this material.
HoWever Papaver somniferum is noW being increasingly cul
FIELD OF THE INVENTION tivated for the production of oripavine for the pharmaceutical
market.
The present invention relates to the ?eld of improved pro Traditionally, trinexapac-ethyl, an acylcyclohexanedione
duction of alkaloids from poppy plants. More particularly, the compound has been used as a plant groWth regulator, Which
present invention relates to the application of certain com reduces stem groWth by inhibition of internode elongation. It
pounds, including cyclohexanedione compounds, to poppy is absorbed by the foliage With translocation to the groWing
plants and/or loci in order to alter alkaloid composition. shoot. Used commonly on highly maintained turfgrasses, it
has had a role in evaluating groWth suppression patterns and
BACKGROUND OF THE INVENTION suppression of seedhead formation. Further uses of trinex
apac-ethyl include the prevention of lodging in cereals, on
20
The opium or oil poppy, Papaver somniferum, is an erect Winter oilseed rape and as a maturation promoter in sugar
annual plant Which is cropped in order to produce alkaloids
cane. Prohexadione-calcium is the calcium salt of another
such as morphine, thebaine, oripavine, codeine, pseudomor
acylcyclohexanedione compound and is a plant groWth regu
phine and the like. Alkaloids are extracted from the poppy lator and retardant and, like trinexapac-ethyl, has also been
capsules of Papaver somniferum by tWo commercial meth
25 used as an anti-lodging agent in small grain cereals. It could
ods. In one method, the immature capsule is cut and the latex also be used as a groWth retardant in turf, peanuts, ?oWers and
collected from the Wound. The air-dried latex is opium Which
to inhibit neW tWig elongation of fruit trees.
contains alkaloids. In Work leading up to the present invention, the inventors
In a second method, the mature poppy capsules and the unexpectedly found that the application of certain plant
poppy capsule stems are collected, and threshed to remove the 30 groWth regulators, such as acylcyclohexanedione compounds
seeds and form a straW. When necessary, the straW is dried to and methyl jasmonate, in combination or individually, to
a Water content beloW 16%. Extraction by solvent or Water or poppy plants altered the alkaloid composition of a poppy
super critical ?uid, such as CO2, is usually employed to plant, in particular by decreasing the proportion of morphine
remove the alkaloids from the straW to produce a “concentrate and increasing the proportion of thebaine and oripavine in
of poppy straW”. 35 poppy plants When compared to control plants to Which the
While thebaine has no direct medical use, during recent plant groWth regulators had not been applied.
years, demand for this alkaloid has increased as it is the raW
material for the production of semi-synthetic drugs having
SUMMARY OF THE INVENTION
analgesic, antitussive and sedative properties. Hydrocodone,
thebacon, oxycodone and drotebanolare are other useful 40 The present invention noW provides a method of altering
drugs that may be derived from thebaine. Naloxone made the alkaloid composition of a poppy plant comprising the step
from thebaine is used as an antagonist in the treatment of of applying an effective amount of an acylcyclohexanedione
morphine and heroin addicts. Etorphine and some of its ana compound or agriculturally acceptable salt or ester thereof to
lo gues knoWn as Bentley compounds prepared from thebaine
said poppy plant or a locus thereof.
have a much greater activity than morphine and are used in 45 Another aspect of the invention provides a method of
veterinary medicine and in capturing Wild animals. The decreasing the proportion of morphine and/or increasing the
Diels-Adler adducts of thebaine are easily prepared in high proportion of thebaine and/or oripavine in a poppy plant
yields and are of great interest. comprising the step of applying an effective amount of an
The availability of thebaine is limited and its cost high. One acylcyclohexanedione compound or agriculturally accept
reason for the limited availability of thebaine, and its high 50 able salt or ester thereof to said poppy plant or a locus thereof.
cost, is that total synthesis is dif?cult. Yet, the demand for Yet another aspect of the invention provides a method of
thebaine remains. A second reason for the limited availability producing thebaine and/or oripavine comprising the steps of:
of thebaine, and its high cost, is that the primary source of (i) applying an effective amount of an acylcyclohexanedi
thebaine is by extraction from the poppy plant, Papaver som one compound or agriculturally acceptable salt or ester
nlferum. thereof to a poppy plant or locus thereof;
Morphine, is the major alkaloid that accumulates in cap (ii) harvesting poppy capsules to produce a straW from the
sules of Papaver somniferum. Moreover, according to the poppy plant; and
Merck Index, 11th edition, air dried latex contains alkaloids (iii) extracting thebaine and/ or oripavine from the straW.
in the amounts shoWn in Table I. Still yet another aspect of the invention provides a method
TABLE I of producing thebaine and/or oripavine comprising the steps
of:
opium straw
(i) applying an effective amount of an acylcyclohexanedi
morphine, % 10-16 l-3 one compound or agriculturally acceptable salt or ester
codeine, % 0.8-2.5 0.05—0.3
thereof to a poppy plant or locus thereof;
oripavine, % 0—0.l 0—0.05
(ii) collecting and drying immature poppy capsules from
thebaine, % 0.5-2 0.15-0.65
the poppy plant to produce opium; and
(iii) extracting thebaine and/ or oripavine from the opium.
US 8,377,851 B2
3 4
In a preferred embodiment, the acylcyclohexanedione and the like. An alkyl group may be further optionally sub
compound or agriculturally acceptable salt or ester thereof is stituted by one or more optional substituents as herein
trinexapac-ethyl or prohexadione-calcium. de?ned. Some preferred substituted alkyl include alkoxyalkyl
Preferably, the step of extraction in (iii) comprises either (such as alkoxymethyl), alkylthioalkyl (such as alkylthiom
solvent or aqueous extraction to form a concentrate of poppy ethyl), phenylalkyl (such as phenylmethyl (benZyl) or phe
straW. nylethyl, and Wherein the phenyl group may be further sub
In yet another aspect of the invention there is provided a stituted), thienylalkyl (such as thienylmethyl), haloalkyl, and
method of altering the alkaloid composition of a poppy plant, aryloxyalkyl (such as phenoxymethyl). When used as a speci
comprising the step of applying an effective amount of methyl ?ed radical for any of R, R1, R2, R3 or R4. These may be
jasmonate or agriculturally acceptable salt or ester thereof to further optionally substituted as described herein.
said poppy plant or a locus thereof. The term “alkenyl” as used herein denotes groups formed
In still yet another aspect of the invention, there is provided
from straight chain, branched or cyclic hydrocarbon residues
method of decreasing the proportion of morphine and/or
containing at least one carbon to carbon double bond includ
increasing the proportion of thebaine and/or oripavine in a
ing ethylenically mono-, di- or poly-unsaturated alkyl or
poppy plant comprising the step of applying an effective
cycloalkyl groups as previously de?ned, preferably C2_2O alk
amount of methyl jasmonate or agriculturally acceptable salt
enyl (eg C2_1O or C2_6). Examples of alkenyl include vinyl,
or ester thereof to said poppy plant or a locus thereof.
allyl, l-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-bute
Yet another aspect of the invention provides a method of
nyl, l-pentenyl, cyclopentenyl, l-methyl-cyclopentenyl,
producing thebaine and/or oripavine comprising the steps of:
l-hexenyl, 3-hexenyl, cyclohexenyl, l-heptenyl, 3-heptenyl,
(i) applying an effective amount of a methyl jasmonate or 20
l-octenyl, cyclooctenyl, l-nonenyl, 2-nonenyl, 3-nonenyl,
agriculturally acceptable salt or ester thereof to a poppy
l-decenyl, 3-decenyl, 1,3-butadienyl, 1-4, pentadienyl, 1,3
plant or locus thereof;
cyclopentadienyl, 1,3-hexadienyl, l,4-hexadienyl, 1,3-cyclo
(ii) harvesting poppy capsules to produce a straW from the
hexadienyl, l,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,
poppy plant; and
(iii) extracting thebaine and/or oripavine from the straW. 25 5-cycloheptatrienyl and l,3,5,7-cyclooctatetraenyl. An
Preferably, the step of extraction in (iii) comprises either alkenyl group may be optionally substituted by one or more
solvent or aqueous extraction to form a concentrate of poppy optional substituents as herein de?ned.
As used herein the term “alkynyl” denotes groups formed
straW.
Still yet another aspect of the invention provides a method from straight chain, branched or cyclic hydrocarbon residues
of producing thebaine and/or oripavine comprising the steps 30 containing at least one carbon-carbon triple bond including
of: ethynically mono-, di- or poly-unsaturated alkyl or cycloalkyl
(i) applying an effective amount of a methyl jasmonate or groups as previously de?ned. The term preferably refers to
C2_2O alkynyl more preferably C2_1O alkynyl. Examples
agriculturally acceptable salt or ester thereof to a poppy
include ethynyl, l-propynyl, 2-propynyl, and butynyl iso
plant or locus thereof;
(ii) collecting and drying immature poppy capsules from 35 mers, and pentynyl isomers. An alkynyl group may be further
the poppy plant to produce opium; and optionally substituted by one or more optional substituents as
(iii) extracting thebaine and/or oripavine from the opium. herein de?ned.
The term “aryl” used either alone or in compound Words
BRIEF DESCRIPTION OF THE FIGURES denotes single, polynuclear, conjugated or fused residues of
40 aromatic hydrocarbons (carboaryl) or aromatic heterocyclic
FIG. 1 structurally depicts a number of metabolic products (heteroaryl) systems Where one or more carbon atoms (and
derived from trinexapac -ethyl. Where appropriate hydrogen atoms attached thereto) of a
cyclic hydrocarbon residue are replaced to provide an aro
DETAILED DESCRIPTION OF THE INVENTION matic heterocyclic residue. Suitable heteroatoms include O,
45 N and S. Examples of carboaryl include phenyl, biphenyl,
Throughout this speci?cation and the claims Which folloW, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl,
unless the context requires otherWise, the Word “comprise”, anthracenyl, dihydroanthracenyl, benZanthracenyl, diben
and variations such as “comprises” and “comprising”, Will be Zanthracenyl, phenanthrenyl, ?uorenyl, pyrenyl, idenyl, aZu
understood to imply the inclusion of a stated integer or step or lenyl and chrysenyl. Preferred carboaryl groups include phe
group of integers or steps but not the exclusion of any other 50 nyl and naphthyl, particularly phenyl. Examples of heteroaryl
integer or step or group of integers or steps. include pyridyl, thienyl, furyl, pyrrolyl, indolyl, pyridaZinyl,
The reference to any prior art in this speci?cation is not, pyraZolyl, pyraZinyl, thiaZolyl, pyimidinyl. Preferred het
and should not be taken as, an acknowledgment or any form eroaryl include pyridyl, thienyl, furyl and pyrrolyl. An aryl
of suggestion that that prior art forms part of the common group may be further optionally substituted by one or more
general knowledge in Australia. 55 optional substituents as herein de?ned.
As used herein, the term “alkyl”, used either alone or in The term “heterocyclyl” used either alone or in compound
compound Words, denotes saturated straight chain, branched Words includes cyclic hydrocarbon residues, preferably
or cyclic hydrocarbon groups, preferably C L20 alkyl, eg C 1_ 10 C3-C2O (e.g. C3_1O or C3_6) Wherein one or more carbon atoms
or C1_6. Examples of straight chain and branched alkyl (and Where appropriate, hydrogen atoms attached thereto) are
include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert 60 replaced by a heteroatom so as to provide a non-aromatic
butyl, n-pentyl and branched isomers thereof, n-hexyl and residue. Suitable heteroatoms include N, O and S. Where tWo
branched isomers thereof, n-heptyl and branched isomers or more carbon atoms are replaced, this may be by tWo or
thereof, n-octyl and branched isomers thereof, n-nonyl and more of the same heteroatom or by different heteroatoms.
branched isomers thereof, and n-decyl and branched isomers Suitable examples of heterocyclic groups may include pyrro
thereof. Examples of cyclic alkyl include mono- orpolycyclic 65 lidinyl, pyrrolinyl, piperidyl, piperaZinyl, morpholino, indoli
alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, nyl, imidaZolidinyl, pyraZolidinyl, thiomorpholino, dioxanyl,
cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl etc.
US 8,377,851 B2
5 6
A heterocyclyl group may be further optionally substituted by rylamino, benZylamino, dibenZylamino, acyl, alkenylacyl,
alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy,
one or more optional substituents as herein de?ned.
The term “acyl” either alone or in compound Words alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, hetero
cycloxy, heterocyclamino, haloheterocyclyl, alkylsulphenyl,
denotes a group containing the moiety C:O (and not being a
arylsulphenyl, carboalkoxy, carboaryloxy mercapto, alky
carboxylic acid, ester or amide) Preferred acyl includes
lthio, benZylthio, acylthio, cyano, nitro, sulfate and phosphate
C(O)iR, Wherein R is hydrogen or an alkyl, alkenyl, alky
nyl, aryl, or heterocyclyl, residue as de?ned above, preferably groups.
Examples of optional substituents include alkyl, (eg
a Cl_2O residue. Examples of acyl include formyl; straight
Cl_6alkyl such as methyl, ethyl, propyl, butyl, cyclopropyl,
chain or branched alkanoyl such as, acetyl, propanoyl,
cyclobutyl, cyclopentyl or cyclohexyl), hydroxyalkyl (eg
butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpro
hydroxymethyl, hydroxyethyl, hydroxypropyl), alkoxyalkyl
panoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl,
(eg methoxymethyl, methoxyethyl, methoxypropyl,
undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, penta
ethoxymethyl, ethoxyethyl, ethoxypropyl etc) alkoxy (eg
decanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nona
Cl_6 alkoxy such as methoxy, ethoxy, propoxy, butoxy, cyclo
decanoyl and icosanoyl; cycloalkylcarbonyl such as cyclo propoxy, cyclobutoxy), alkylthio, halogen (F, Cl, Br, I), trif
propylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl luoromethyl, trichloromethyl, tribromomethyl, hydroxy,
and cyclohexylcarbonyl; aroyl such as benZoyl, toluoyl and phenyl (Which itself may be further optionally substituted),
naphthoyl; aralkanoyl such as phenylalkanoyl (e.g. pheny benZyl (Wherein benZyl itself may be further optionally sub
lacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, stituted), phenoxy (Wherein phenyl itself may be further
phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl optionally substituted), benZyloxy (Wherein benZyl itself may
(e. g. naphthylacetyl, naphthylpropanoyl and naphthylbu 20 be further optionally substituted), amino, alkylamino (eg
tanoyl]; aralkenoyl such as phenylalkenoyl (e.g. phenylpro Cl_6alkyl, such as methylamino, ethylamino, propylamino
penoyl, phenylbutenoyl, phenylmethacryloyl, phenylpen etc), dialkylamino (eg Cl_6alkyl, such as dimethylamino,
tenoyl and phenylhexenoyl and naphthylalkenoyl (e.g. diethylamino, dipropylamino), acylamino (eg NHC(O)CH3),
naphthylpropenoyl, naphthylbutenoyl and naphthylpen phenylamino (Wherein phenyl itself may be further substi
tenoyl); aryloxyalkanoyl such as phenoxyacetyl and phenox 25 tuted), nitro, for'myl, 4C(O)-alkyl (eg Cl_6 alkyl, such as
acetyl), OiC(O)-alkyl (eg Cl_6alkyl, such as acetyloxy),
ypropionyl; arylthiocarbamoyl such as phenylthiocarbamoyl;
benZoyl (Wherein the phenyl group itself may be further
arylglyoxyloyl such as phenylglyoxyloyl and naphthylgly
optionally substituted), replacement of CH2 With C:O,
oxyloyl; arylsulfonyl such as phenylsulfonyl and napthylsul
COZH, CO2alkyl (eg Cl_6 alkyl such as methyl ester, ethyl
fonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as
ester, propyl ester, butyl ester), CO2phenyl (Wherein phenyl
thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpen
30 itself may be further substituted), CONH2, CONHphenyl
tanoyl, thienylhexanoyl, thiaZolylacetyl, thiadiaZolylacetyl
(Wherein phenyl itself may be further substituted), CONH
and tetrazolylacetyl; heterocyclicalkenoyl such as heterocy
benZyl (Wherein benZyl itself may be further substituted),
clicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl
CONHalkyl (eg C1_6 alkyl such as methyl ester, ethyl ester,
and heterocyclichexenoyl; and heterocyclicglyoxyloyl such propyl ester, butyl amide), CONHdialkyl (eg C l_6all<yl), thie
as thiaZolyglyoxyloyl and thienylglyoxyloyl. 35 nyl, furyl, pyridyl and methylenedioxy.
The terms alkoxy, alkenoxy alkynoxy, aryloxy, heteroary As used herein, an “acylcyclohexanedione compound”
loxy, heterocyclyloxy and acyloxy respectively denote alkyl, refers to a 1,3-cyclohexanedione bearing an acyl group (or
alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and acyl enol form thereof) at the 2-position and a carboxylic acid,
groups as hereinbefore de?ned When linked by oxygen. carboxylic ester or carboxylic amide at the 5-position, as Well
The term thioalkyl refers to an alkyl group When linked by 40 as agriculturally acceptable salts, esters and metabolic prod
sulfur. ucts thereof. It Will be appreciated that, as noted above, tau
“Halogen” or “halo” refers to ?uorine, chlorine, bromine tomeric forms are also intended to be encompassed by the
invention.
or iodine.
The term “carboxylic acid” refers to the group COZH and As used herein an “enol form” of a 1,3-cyclohexanedione
compound having an acyl group at the 2-position refers to the
“carboxylic ester” or “ester” refers to the group COZR 45
enol Which can be formed as a result of abstraction of the
Wherein R is any group not being H. Preferred R includes
alkyl, alkenyl, alkynyl and aryl (carbaryl and heteroaryl) and hydrogen atom located at C2 of the 1,3-cyclohexanedione
ring. It Will be understood that the enol can be formed With
heterocyclyl, each of Which may be optionally substituted.
either of the carbonyl groups of the 1,3-cyclohexanedione
Some examples include CO2Cl_2Oalkyl, CO2aryl (eg. CO2
ring or With the carbonyl group of the C2 acyl group, prefer
phenyl) and COZaralkyl (eg. COZbenZyl).
50 ably With carbonyl of the C2 acyl group.
The terms “amino” and “carboxylic amide” refer to groups Exemplary acylcyclohexanedione compounds and meth
NRR' and CONRR' respectively, Wherein R and R" can inde
ods ofmaking such are disclosed in Us. Pat. No. 6,083,882,
pendently be H, alkyl, alkenyl, alkynyl, aryl (carboaryl and
U.S. Pat. No. 4,693,745 and Us. Pat. No. 4,560,403, Which
heteroaryl), acyl and heterocyclyl, each of Which may be are incorporated herein by reference in their entireties for all
optionally substituted. Some examples include NH2NHCl_2O 55 purposes.
alkyl, NHaryl, NdiCl_2Oalkyl, NHCOC1_2Oalkyl, NHCOaryl
In one embodiment of the invention, the acylcyclohex
(eg. NHCOphenyl), CONH2, CONHCl_2Oalkyl, CONHaryl anedione compound is a compound of formula (I)
(eg. CONHbenZyl), and CONHdiCl_2Oalkyl.
In this speci?cation “optionally substituted” is taken to
mean that a group may or may not be further substituted or 60 (1)
fused (so as to form a condensed polycyclic group) With one
or more groups selected from alkyl, alkenyl, alkynyl, aryl,
halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy,
R1
alkoxy, alkenyloxy, aryloxy, benZyloxy, haloalkoxy, haloalk
enyloxy, haloaryloxy, nitro, nitroalkyl, nitroalkenyl,
65
nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino,
dialkylamino, alkenylamino, alkynylamino, arylamino, dia
US 8,377,851 B2
7
wherein R is selected from the group consisting of hydrogen, -continued
optionally substituted alkyl optionally substituted alkenyl,
optionally substituted alkynyl and optionally substituted aryl; R R1
and
Bun Me
R1 is optionally substituted alkyl or optionally substituted Pr, Me
aryl; Pr" Me
or an agriculturally acceptable salt or ester thereof.
In a preferred embodiment, R1 is optionally substituted Prohexadione, CAS Registry No. 127277-53-6, also
al 1. knoWn as 3,5-dioxo-4-propionylcyclohexanecarboxylic acid,
kfi1 another preferred embodiment R is hydrogen or option 3,5-dioxo-4-(l-oxopropyl-)cyclohexanecarboxylic acid, and
ally substituted alkyl or optionally substituted aryl. also 3-hydroxy-4-prionyl-5-oxo-3-cyclohex-ene carboxylic
One preferred subgroup of formula (I) is (Ia): acid is one particularly preferred compound for use in the
present invention and is represented beloW:
(15)
R1
R0 20 HO
0 O
Wherein R is selected from the group consisting of hydrogen, Desirable prohexadione salts include chloride, sulfate,
25
an optionally substituted alkyl group, an optionally substi metrab, acetate, carbonate, hydride, hydroxide, sodium,
tuted alkylthioalkyl group, or an optionally substituted phe potassium, calcium, magnesium, barium, aluminum, nickel,
nyl group, and R1 is selected from the group consisting of an copper, manganese, cobalt, Zinc, iron and silver salts, With
optionally substituted alkyl group, an optionally substituted prohexadione-calcium, shoWn beloW, as a preferred salt.
phenethyl group, an optionally substituted benZyl group, an
30
optionally substituted phenoxymethyl group, an optionally
substituted 2-thienylmethyl group, an optionally substituted
alkoxymethyl group or an optionally substituted alkylthiom
ethyl group.
Some particular examples of compounds of Formula (I)
35
contemplated by the present invention are depicted beloW in
Table 2. Other speci?c examples are depicted in Table I of
Us. Pat. No. 4,560,403.
1/20212+
40
R R 1 In another embodiment of the invention, the acylcyclohex
anedione compound is a compound of formula (II)
Et CH(Me)Et
Et Bu,
Bu, Bun
Me Pr, 45
(11)
CHEt2 Pr"
Et Me
Bu, Et
Me Me
Et (CH2)7Me
Et (CH2)6Me 50
Et (CH2)5Me
Et (CH2)4Me
Et Bu, 0
Et Bun
Et Pr,
(CH2)2CHMe2 Pr" 55 wherein R1 is optionally substituted alkyl or optionally sub
CH(Me)Et Pr" stituted aryl; and
Bu , Pr"
Bun Pr" A is OR2 or NR3R4 Wherein R2 is selected from the group
Pr, Pr" consisting of hydrogen, optionally substituted alkyl, option
Pr" Pr" ally substituted alkenyl, optionally substituted alkynyl and
Et Pr" 60 optionally substituted aryl; and
Me Pr"
R3 and R4 are independently selected from hydrogen, option
Pr, Et
ally substituted alkyl, optionally substituted alkenyl, option
Pr" Et
Et Et ally substituted alkynyl and optionally substituted aryl; or
Me Et one of R3 or R4 is alkoxy and the other as de?ned above or R3
Bu, Me
CH(Me)Et Me 65 and R4 together With the nitrogen atom to Which they are
Bu’ Me attached form a 5- or 6-membered heterocyclic ring Which
may contain an additional oxygen or sulfur atom;
US 8,377,851 B2
10
or an agriculturally acceptable salt or ester thereof. able salt or ester thereof, Which may be used alone or in
In a preferred embodiment, R1 is optionally substituted conjunction With acylcyclohexadiones described herein.
alkyl.
A preferred subgroup of formula (II) is formula (Ila):
(Ila)
O OH
cozcn3
/ Rl
The acylcyclohexadione compounds and methyl jas
A O monate may be applied as salts or esters.
By the term “agriculturally acceptable salts” is meant salts
O the cations or anions of Which are knoWn and accepted in the
art for the formation of salts for agricultural or horticultural
wherein: use. Preferably the salts are Water-soluble. Suitable salts With
R1 is alkyl, preferably C3-C6 cycloalkyl; and bases include alkali metal (e. g. sodium and potassium), alka
A is OR2 or NR3R4; line earth metal (e.g. calcium and magnesium), ammonium
R2, R3, and R4 are each independently hydrogen, C l-C6 alkyl, and amine (e.g. diethanolamine, triethanolamine, octy
20
Cl-C6 haloalkyl, C2-Cl0 alkoxyalkyl, C2-Cl0 alkylthioalkyl; lamine, morpholine and dioctylmethylamine) salts. Suitable
C3 -C6 alkenyl, Which is unsubstituted or substituted by halo acid addition salts, formed by compounds containing an
gen, C l-C4 alkoxy or C l-C4 alkylthio; C3 -C6 alkynyl; phenyl nitrogen atom With an available lone pair, include salts With
or C 1 -C6 aralkyl, Wherein the phenyl nucleus is unsubstituted inorganic acids, for example hydrochlorides, sulfates, phos
or substituted by halogen, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4
phates and nitrates and salts With organic acids, for example
haloalkyl, nitro or cyano; and acetic acid. Suitable metal and alkaline earth metal hydrox
one of R3 and R4 is methoxy; or R3 and R4, together With the
ides as salt formers include the salts of barium, aluminum,
nitrogen atom to Which they are attached, form a 5 - or 6-mem nickel, copper, manganese, cobalt Zinc, iron, silver, lithium,
bered heterocyclic ring system Which may contain an addi
sodium, potassium, magnesium or calcium. Additional salt
tional oxygen or sulfur atom in the ring. 30 formers include chloride, sulfate, metrab, acetate, carbonate,
Speci?c compounds of the immediately above noted for hydride, and hydroxide.
mula, for use in practicing embodiments of the invention By the term “agriculturally acceptable esters” is meant
include trinexapac, also knoWn as 4-cyclopropyl(hydroxy)
those esters of the carboxylic acid group(s) Which have an OR
methylene-3,5-dioxocyclohexanecarboxylic acid, and its
moiety that is not itself signi?cantly herbicidal to any crop
ethyl ester, trinexapac-ethyl, also knoWn as ethyl 4-cyclopro
being treated and not signi?cantly deleterious to the applica
pyl (hydroxy)methylene-3 ,5 -dioxocyclohexanec arboxylate,
tor, the environment, or the ultimate user of any crop being
both shoWn beloW.
treated.
By the term “metabolic products” is meant those com
pounds produced as a result of the metabolism or degradation
O OH 0 of acylcyclohexane compounds preferably Within the poppy
plant. Possible metabolites are presented in FIG. 1.
/
The plant groWth regulators, such as acylcyclohexadione
compounds and methyl jasmonate, may be applied unformu
lated or formulated into a composition. Preferably the com
HO O
pounds are applied in the form of a composition comprising
the compound and one or more agriculturally acceptable
O 0 OH additives and/or active ingredients. Compositions may con
tain the acylcyclohexanedione and/or methyl jasmonate in a
/
range from 0.1 parts to 100 parts by Weight.
Compositions for use in the invention may contain a car
\—o o rier. The carrier may be any natural or synthetic organic or
inorganic ingredient that facilitates dispersion of the compo
sition or compound and contact With the plant. The carrier
0
may be solid (e.g. clays, synthetic silicates, silica, resins,
Waxes, kaolin, bentonite, dolomite, calcium carbonate, talc,
Some Examples of Formula (11) include those depicted
poWdered magnesia, Fuller’s earth, gypsum, diatomaceous
beloW in Table 3. Other speci?c examples are described in
earth, China clay, and combinations thereof); liquid (eg
US. Pat. No. 4,693,745:
Water, aqueous solutions, N-methylpyrrolidone, kerosene,
cyclohexanone, methylethyl ketone, acetonitrile, methanol,
TABLE 3 ethanol, isopropyl alcohol, acetone, butyl cellosolved,
2-ethyl-lhexanol, cyclohexanone, methyl cellulose, polyvi
A R1
nyl alcohol, sodium lignin sulfonates, polymeric alkyl naph
Et Me thalene sulfonates, sodium naphthalene sulfonate, polymeth
Bu 1 Pr" ylene bisnaphthalenesulfonate, sodium N-methyl-N-(long
5 chain acid) laureates, hydrocarbons and other Water-immis
Another compound useful in the present invention is cible ethers, esters and ketones, and combinations thereof); or
methyl jasmonate as shoWn beloW or agriculturally accept a combination of solid and liquid carriers.
US 8,377,851 B2
11 12
Compositions useful in the present invention may also components that may be added include antifoaming agents
contain one or more surfactants to increase the biological including silicone based antifoaming agents; thickening
effectiveness of the active ingredient. Suitable surface active agents such as fumed silica; antimicrobial agents; antioxi
ingredients include surfactants, emulsifying agents, and Wet dants; buffers; dyes; perfumes; stabiliZing agents; and anti
ting agents.A Wide range of surfactants is available and canbe freeZing agents. Exemplary antifreeZing agents include but
selected readily by those skilled in the art from “The Hand are not limited to, glycols such as propylene glycol and eth
book of Industrial Surfactants,” 2nd Edition, GoWer (1997), ylene glycol, N-methylpyrrolidone, cyclohexanone, and
Which is incorporated herein by reference in its entirety for all
alcohols such as ethanol and methanol.
purposes. There is no restriction on the type or chemical class
The compounds used in the present invention may be
of surfactant(s) that can be used. Nonionic, anionic, cationic
present in any effective formulation, including, but not lim
and amphoteric types, or combinations of more than one of
ited to, dusting poWders or granules; dispersible poWders,
these types, may all be useful in particular situations.
granules or grains; aqueous dispersions; emulsions or micro
Among nonionic surfactants, exemplary classes include
encapsulation.
polyoxyethylene alkyl, alkyne, alkynyl or alkylaryl ethers,
PoWders, including dusting poWders or granules and dis
such as polyoxyethylene primary or secondary alcohols,
alkylphenols or acetylenic diols; polyoxyethylene alkyl or persible poWders, granules or grains contain at least one
alkyne esters, such as ethoxylated fatty acids; sorbitan alky active ingredient and an inert solid extender or carrier, such as
lesters, Whether ethoxylated or not; glyceryl alkylesters; kaolin, bentonite, dolomite, calcium carbonate, talc, poW
sucrose esters; and alkyl polyglycosides. Exemplary anionic dered magnesia, Fuller’s earth, gypsum, diatomaceous earth
surfactant classes include fatty acids, sulfates, sulfonates, and 20 and China clay. Dispersible poWders, granules and grains
phosphate mono- and diesters of alcohols, alkylphenols, typically also include one or more Wetting and dispersing
polyoxyethylene alcohols and polyoxyethylene alkylphe agents, such as surfactants.
nols, and carboxylates of polyoxyethylene alcohols and poly The aqueous dispersions or emulsions may be prepared by
oxyethylene alkylphenols. These can be used in their acid dissolving the active ingredient(s) in an organic solvent
form but are more typically used as salts, for example sodium, 25 optionally containing Wetting, dispersing or emulsifying
potassium or ammonium salts. agent(s) and then adding the mixture to Water Which may also
Cationic surfactants classes include polyoxyethylene ter contain Wetting, dispersing or emulsifying agents (s). Suitable
tiary alkylamines or alkenylamines, such as ethoxylated fatty organic solvents are kerosene, cyclohexanone, methylethyl
amines, quaternary ammonium surfactants and polyoxyeth ketone, acetone, methanol, acetonitrile, and the like. The
ylene alkyletheramines. Representative speci?c examples of 30 compositions may also be in the form of liquid preparations
such cationic surfactants include polyoxyethylene (5) for use as dips or sprays Which are generally aqueous disper
cocoamine, polyoxyethylene (15) talloWamine, distearyldim sions or emulsions containing the active ingredient in the
ethylammonium chloride, N-dodecylpyridine chloride and presence of one or more of Wetting agent(s), dispersing
polyoxypropylene (8) ethoxytrimethylammonium chloride. agent(s), emulsifying agent(s) or suspending agent(s).
Many cationic quaternary ammonium surfactants of diverse 35 Typical liquid solutions include the active ingredient, a
structures are knoWn in the art to be useful in combination carrier, and optionally, a surface active agent. The dilute solu
With herbicides and can be used in compositions contem tions of the present compositions generally contain about 0.1
plated herein. to about 50 parts active ingredient, about 0.25 to about 50
Suitable emulsifying agents and Wetting agents include, parts carrier, and about 0 to about 94 parts surface active
but are not limited to, ionic and nonionic types such as poly 40 agent, all parts being by Weight based on the total Weight of
acrylic acid salts, lignosulphonic acid salts, phenolsulphonic the composition. Similarly, the concentrated compositions
or naphthalenesulphonic acids, products of polycondensation typically include about 40 to about 95 parts active ingredient,
of ethylene oxide With fatty alcohols, fatty acids or fatty about 5 to about 25 parts carrier, and about 0 to about 20 parts
amines, substituted phenols (especially alkylphenols or surface active agent.
arylphenols), sulphonosuccinic acid ester salts, taurine 45 Emulsi?cations are usually solutions of active ingredients
derivatives (especially alkyl taurates), phosphoric esters of in Water-immiscible or partially Water-immiscible solvents as
alcohols or products of polycondensation of ethylene oxide the carrier together With at least one surface active agent.
With phenols, esters of fatty acids With polyhydric alcohols, Suitable solvents for the active ingredients of this invention
and derivatives having sulphate, sulphonate and phosphate include, but are not limited to, hydrocarbons and Water-im
groups, of the compounds above. 50 miscible ethers, esters or ketones. The emulsi?cation compo
The methods of the invention may also be used in conjunc sitions generally contain from 5 to 95%, preferably 20 to 70%
tion With the application of other active agents, for example by Weight of the active compound of this invention as active
fertilizers such as ammonium nitrate, urea, potash, and super ingredient; 1 to 40%, preferably 5 to 20% by Weight of sur
phosphate; phytotoxicants and plant groWth regulators; factant; and 4 to 94%, preferably 10 to 75% by Weight of
methyl jasmonate; safeners; fungicides; pesticides and other 55 liquid carrier.
alkaloid altering compositions such as thidiaZuron or clopy The compounds useful in the present invention may be
ralid. These additional agents may be used in combination readily synthesiZed using techniques generally knoWn to syn
(either together, separately or sequentially) With the above thetic organic chemists. In general, the compounds and com
described compositions. Thus, compositions used in the positions may also be purchased commercially. In this regard,
invention may also contain one or more active agents. Alter 60 examples of commercial formulations of trinexapac-ethyl are
natively, the poppy plant(s) may be treated With other active ModdusTM, PrimoTM, Primo MAXXTM, Which are manufac
agents before or after applying the acylcyclohexandione or tured by Syngenta and an example of commercial formula
methyl jasmonate. Alternatively, a separate composition con tion of prohexadione-calcium is BAS125 10WTM, RegalisTM
taining the active agent may be applied concurrently. and ApogeeTM all of Which are manufactured by BASFTM.
Other optional components may be admixed With the 65 The compositions may be prepared in knoWn manner, for
present compositions to facilitate the application and/or example by homogeneously mixing or grinding the active
effectiveness of the active ingredient. To this end, optional ingredients With other ingredients. Additional components
US 8,377,851 B2
13 14
may be admixed With the composition at any point during the per hectare, 6.5 kg per hectare, 7 kg per hectare, 7.5 kg per
process, including during and/or after any mixing. hectare, 8 kg per hectare, 8.5 kg per hectare, 9 kg per hectare,
The term “alkaloid” encompasses a class of organic com 9.5 kg per hectare, 10 kg per hectare, 10.5 kg per hectare, 11
pounds containing nitrogen, isolated from plants, particularly kg per hectare, 11.5 kg per hectare and 12 kg per hectare are
poppy plants and includes thebaine, oripavine, neopinone, all suitable rates of application.
codeinone, morphinone, codeine and morphine. Preferably, Further, suitable concentrations of a composition compris
the alkaloid is selected from the group consisting of mor ing methyl jasmonate are for example greater than 95% pure
phine, thebaine and oripavine. The term “altering” encom methyl jasmonate. Suitable rates of application of a compo
passes the decrease in the proportion of morphine, and/or sition comprising greater than 95% pure methyl jasmonate
increase in the proportion of thebaine and/ or oripavine When include 10 ml per hectare to 1.0 L per hectare. Preferable rates
compared to a poppy plant Which has not been treated in range from 20 ml per hectare to 1.0 L per hectare. Further
accordance With the invention. suitable rates include 20 ml per hectare, 30 ml per hectare, 40
Preferably, the alteration of the alkaloid content involves ml per hectare, 50 ml per hectare, 100 ml per hectare, 150 ml
either the decrease in morphine yield and/ or increase in the per hectare, 200 ml per hectare, 250 ml per hectare, 300 ml per
baine and/ or oripavine yield. The terms “decrease” or hectare, 350 ml per hectare, 400 ml per hectare, 450 ml per
“increase” are relative to those levels of alkaloid content in hectare, 500 ml per hectare, 550 ml per hectare, 600 ml per
poppies Which have not been treated in accordance With the hectare, 650 ml per hectare, 700 ml per hectare, 800 ml per
invention. hectare, 900 ml per hectare, and 1 .0 L per hectare. A desirable
An “effective amount” of a compound Will vary according rate of application is 300 ml per hectare. Another desirable
to the prevailing conditions such as Weather, plant species, 20 rate is 600 ml per hectare. Another desirable rate is 1.0 L per
feed pressure, groWth stage, mode of application, cultivation hectare.
practice and the like. In general, “effective amount” means Desirably, the alkaloid altering effects result in an increase
the amount of the compound needed to achieve a detectable or decrease in the amount of a particular alkaloid produced
alteration in alkaloid composition. Suitable rates of the acyl When compared With a control. Desirably the application of
cyclohexanedione compound (active ingredient) may range 25 the compound or salt produces an increase or decrease in
from about 4 g a.i. per hectare to about 1750 g a.i. per hectare. alkaloid amount When compared With a control. The term
As used herein “a.i.” means active ingredient. Preferable rates “control” refers to the same type, variety, or cultivar of poppy
of trinexapac-ethyl range from 125 g a.i. per hectare to 250 g plant Which has not been subjected to any alkaloid composi
a.i. per hectare and from 250 g a.i. to 500 g a.i. per hectare. tion altering treatment or is not the result of any alkaloid
Even more desirable is 500 g a.i. per hectare. Desirable rates 30 composition altering treatment and has been subjected to
of prohexadione-calcium are 5 g a.i. per hectare to 300 g a.i. exactly the same set of conditions but for application of an
per hectare. alkaloid composition altering treatment. Even more desirable
A suitable concentration of a composition comprising is a decrease in morphine amount ranging from 60% to 90%
trinexapac-ethyl ranges from 100 g a.i./L to 300 g a.i./L. When compared to a control. Also preferred is an increase in
Desired concentrations are 120 g a.i./L and 250 g a.i./L. 35 thebaine amount ranging from 50% to 1900%. An increase in
Where the concentration of a composition of trinexapac-ethyl oripavine amount ranging from 20% to 1800% is desirable.
used is 250 g a.i./L, a suitable rate of application ofa com One of ordinary skill in the art Will recogniZe that the potency
position comprising trinexapac-ethyl is at least 40 ml per and, therefore, an “effective amount,” can vary for the various
hectare. A suitable rate of application of composition com compounds/ compositions used in the invention.
prising trinexapac-ethyl ranges from 40 mL per hectare to 7.0 40 The term “poppy plant” refers to the Papaver somniferum
L per hectare. Further suitable rates of application are for as Well as any part of a Papaver somniferum plant including,
example 50 mL per hectare, 100 mL per hectare, 0.5 L per but not limited to, bud stem, seed, capsules, ?oWers, and
hectare, 0.75 L per hectare, 1.0 L per hectare, 1.25 L per leaves.
hectare, 1 .5 L per hectare, 2.0 L per hectare, 2.5 L per hectare, The term “morphine variety” encompasses a plant or strain
3.0 L per hectare, 3.5 L per hectare, 4.0 L per hectare, 4.5 L 45 of poppy Wherein the amount of morphine and codeine pro
per hectare, 5.0 L per hectare, 5.5 L per hectare and 6.0 L per duced is greater than the amount of thebaine and oripavine.
hectare. Desirably the rate of trinexapac -ethyl applied is 0. 5 L The term “thebaine variety” encompasses a plant or strain
to 2.0 L per hectare. Even more desirable is the range of 1.0 L Wherein the amount of morphine and codeine produced is less
per hectare to 2.0 L per hectare When applied to increase the than the amount of thebaine and oripavine. The methods of
proportion of thebaine. Also preferable is the range of 0.5 L to 50 the present invention relate especially to altering the alkaloid
1.0 L per hectare When applied to increase the proportion of composition in the capsule and/ or stem of the poppy plant.
oripavine. Preferably, When a decrease in morphine is to be achieved,
In addition, an example of a suitable range of concentration a composition comprising an acylcyclohexadione is applied
of a composition comprising prohexadione-calcium, Which to a morphine or thebaine variety. Preferably, When an
may be further diluted for application, is 50 g a.i./kg to 300 g 55 increase in thebaine is to be achieved, a composition com
a.i./kg. Preferred concentrations of prohexadione-calcium prising trinexapac-ethyl or prohexadione-calcium is applied
are 100 g a.i./kg and 275 g a.i./kg respectively. Where the to a morphine or thebaine variety. Even more preferable is if
concentration of a composition of prohexadione-calcium the composition is applied to a thebaine variety. Preferably,
used is 100 g a.i./kg, a desirable rate of application is at least When an increase in oripavine is to be achieved, a composition
40 g of composition per hectare. Even more preferable is the 60 comprising trinexapac-ethyl or prohexadione-calcium is
range of 50 g per hectare to 12 kg per hectare. Even more applied to a morphine or thebaine variety. Even more prefer
preferable is a range of 50 g per hectare to 6 kg per hectare. able is if the composition is applied to a morphine variety. In
Even more desirable is a rate of at least 3 kg per hectare. order to maximise the proportion of oripavine and minimiZe
HoWever, the rates of 50 g per hectare, 100 g per hectare, 1 kg the proportion of morphine it is preferable that the composi
per hectare, 1.5 kg per hectare, 2 kg per hectare, 2.5 kg per 65 tion is applied to a thebaine variety. HoWever, a maximal
hectare, 3 kg per hectare, 3.5 kg per hectare, 4 kg per hectare, amount of oripavine may be achieved if the composition is
4.5 kg per hectare, 5 kg per hectare, 5.5 kg per hectare, 6 kg applied to a morphine variety.
US 8,377,851 B2
15 16
As used throughout, the term “applying”, or variations the growth stages selected from the group consisting of
thereof such as “application”, is used to mean that the poppy ground cover, run-up, bud emergence, hook and early ?ow
plant or locus thereof has contact with the described com ering is also desirable to increase the proportion of thebaine in
pound(s) or composition(s) thereof by application methods a poppy plant or part thereof. Further, a composition com
known in the art. As such, the compounds (and their salts) of prising methyl jasmonate may be applied for example during
the present invention can be applied in a number of ways, for the growth stages including run up, bud-emergence, hook and
example, they can be applied, formulated or unformulated, ?owering. A preferred growth stage for the application of a
directly to the foliage of the plant or they can be sprayed on, composition comprising methyl jasmonate is early ?owering.
broadcast, dusted on or applied as a cream or paste formula When operating in accordance with the present invention,
tion or they can be applied as slow release granules (ie by the poppy plants or area proximate to the poppy plants is
injecting, shanking, chiseling or working into the soil). Com
contacted with an effective amount of the compound or com
positions may be applied in a single application. Multiple, or position of the present invention. The application of such
separate or sequential applications of the compound(s) or compositions to terrestrial plants can be carried out by con
composition(s) used in the invention are preferred to decrease ventional methods, e. g. power dusters, boom and hand spray
the proportion of morphine and increase the proportion of
ers and spray dusters.
thebaine and/ or oripavine. “Locus thereof ’ refers to the gen Papaver somniferum is postulated to have two biosynthetic
eral area in which the poppy plant(s) are grown to which pathways from thebaine to morphine as shown in the scheme
application of compound(s) used in the invention achieve the below.
effect of altering the alkaloid composition in the poppy
plant(s) or parts thereof. Thus, for example, the locus, can 20
refer to the surrounding soil in which the plants are grown and Theb aine
may encompass the whole or part of the planted area. Also
Pathway 1/ \Pathway 2
compounds used in the invention may also be applied to
fertilizer or poppy seed and placed in the soil at sowing time.
neopinone orip avine
In addition, a (jet stream) of compound or chemical used in 25
the invention may be directed at a point into the ground next
to the poppy plant(s) and allowed to diffuse through the soil
and be taken up by the roots of the poppy plant(s). The locus
codeinone morphinone
can also refer to the air surrounding the plant(s), when the
compound or composition used in the invention can be 30 l / C(RoeNddAeuDictnPaoHsn)ee l
applied in the form of a spray or vapour.
Poppy plants are normally grown from seed until they
mature to produce capsules. Once the plant has matured the
capsules and a part of the stem are harvested. After the seeds codeine —> morphine
are collected for culinary use the deseeded capsules and stem 35
(together known as “straw”) are processed in order to extract
useful chemicals such as plant alkaloids. The most valuable By the methods herein, varieties of Papaver somniferum
part of the plant is the capsule containing the majority of the were obtained having reduced morphine or codeine. Without
total plant alkaloids. Stems and other parts of the plant also wishing to limit the invention to one theory, it is believed, that
contain the alkaloids although in lower concentration. 40 the production or activity of codeinone reductase (NADPH)
During the growth from seed, poppy plants go through is substantially inhibited by the application of an acyclocy
several developmental stages which are herein designated by clohexadione compound, particularly, trinexapac-ethyl or
the following terms: 4-6 leaf stage (early post emergent), 6-8 prohexadione-calcium, to a poppy plant.
leaf stage, 8-10 leaf stage, 10-12 leaf stage (row cover), The term “opium” encompasses the air dried latex or the
ground cover (12-14 leaf), run up, bud emergence, bud to 45 milky exudate from an immature or unripe (green) capsule of
hook, hook and lastly ?owering. Maturity and harvesting a poppy plant. The term “poppy straw” encompasses mature
occur 6-8 weeks post ?owering. The ground cover stage is or ripe (dry) poppy capsules and stems which have been
where plants have 12-14 leaves, are in a rosette habit and, as treated to remove the seeds, and form a straw.
the term implies are covering the ground such that the bare The term “concentrate of poppy straw” includes the mate
ground is not easily visible when the plants have the normal 50 rial arising when poppy straw has entered into a process for
row spacing of 15-20 cm. Run-up includes both early run-up the concentration of its alkaloids, when such material is made
and late run-up. Early run-up is the emergence of the stem available in trade, (Multilingual Dictionary Of Narcotic
from the rosettes. Late run-up is the beginning of the emer Drugs And Psychotropic Substances Under International
gence of the buds as the stem is elongated. Clearly not all the Control, United Nations, New York, 1983). Not inconsistent
plants in any given crop will be at the same growth stage 55 with the foregoing de?nition, concentrate of poppy straw is
however the terms used herein refer to the growth stage of the de?ned as “the crude extract of poppy straw in either liquid,
leaves of the majority of the plants or of the majority of solid or powder form which contains the phenanthrene alka
primary buds once they have appeared. loids of the opium poppy,” 45 US. Federal Register 77466,
The compositions for use in the present invention, com Nov. 24, 1980. When in liquid form, the liquid is preferably
prising for example acylcyclohexanedione, may be applied 60 concentrated before entering into commerce. The generally
anytime up to ?owering, but application during 10-12 leaf preferred concentrate of poppy straw is the powder form
stage, ground cover, run up, bud emergence or hook growth which results from simply removing the solvent or water
stages is preferred in order to decrease the proportion of following extraction of the poppy straw.
morphine and increase the proportion of thebaine or oripa Recovering thebaine and/ or oripavine from either the dried
vine. Application at an early growth stage, for example at the 65 straw or from the opium of Papaver somniferum is a process
10-12 leaf stage or early run-up is also desirable to increase well established in the art. Until now, thebaine has been
the proportion of oripavine. Application during at least one of extracted from this plant as a part of the process of extracting