High concentration topical insecticide containing pyriproxyfen

<u>BACKGROUND OF INVENTION</u>

0001The invention relates generally to insecticides and more particularly to a topical insecticide, such as one suitable to use on house pets such as cats and dogs.

0002The infestation of animals with fleas, ticks, flies is highly undesirable. Accordingly, it has become common to administer both topical and internal insecticides to livestock and pets. Topical applications can be desirable, in that many insecticides are acceptably safe when used topically, but not when used internally.

0003Various topical insecticides have drawbacks. Some require a large volume to be applied to the animal. This can cause considerable mess and can lead to an unpleasant smell. Also, when the animal is a house pet, there is a further complication in that the insecticide should be safe for human contact. It should also not lead to staining of furniture, carpeting. Finally, even if safe, topical insecticides for house pets should not be irritating or lead to rashes, hair loss or exhibit other unpleasam side effects.

0004Accordingly, it is desirable to provide an improved topical insecticide, which overcomes drawbacks of the prior art.

<u>SUMMARY OF THE INTENTION</u>

0005Generally speaking, in accordance with the invention, a topical insecticide is provided which can be safe to use and avoids many common deleterious side effects of conventional topical insecticides. In one preferred embodiment of the invention, the active ingredient of the insecticide formulation is an amine derivative, having a nitro-methylene group, a nitroamino group or a cyanoamino group, which can be formulated to have low toxicity and excellent insecticidal activity. Active ingredients of insecticides and their method of formation in accordance with the preferred embodiments of the invention are discussed in <patcit id="pcit0001" dnum="US5532365A"><text>U.S. Patent No. 5,532,365</text></patcit> and <patcit id="pcit0002" dnum="US5434181A"><text>5,434,181</text></patcit>. One particularly suitable insecticide is 1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine (dinotefuran). Dinotefuran is an aldulticide that will kill adult fleas.

0006<patcit id="pcit0003" dnum="EP1212943A1"><text>EP 1 212 943 A1</text></patcit> teaches ectoparasite control compositions comprising 1-methyl-2-nitro-3-[(3-tetrahydrofuryl)methyl]guanidine (dinotefuran) and a solvent comprising mainly N-methyl-2-pyrrolidone. Additional pesticidal compounds included in said compositions are also disclosed, such as pyriproxyfen.

0007<patcit id="pcit0004" dnum="EP0976328A2"><text>EP 0 976 328 A2</text></patcit> teaches ectoparasite controlling agents for animals comprising dinotefuran, pyriproxifen and a glycol monoalkyl ether.

0008<patcit id="pcit0005" dnum="EP0979606A1"><text>EP 0 979 606 A1</text></patcit> teaches compositions for the extermination of harmful arthropods comprising dinotefuran, pyriproxyfen and a carrier.

0009<patcit id="pcit0006" dnum="WO9941986A"><text>WO 99/41986</text></patcit> teaches aqueous formulations of parasiticides for skin application. Said formulations comprise an agonist or antagonist of nicotinic acetylcholine receptors of insects and a solvent, in particular benzyl alcohol.

0010<patcit id="pcit0007" dnum="EP1212943A"><text>EP 1 212 943</text></patcit>, <patcit id="pcit0008" dnum="EP0976328A"><text>EP 0 976 328</text></patcit>, <patcit id="pcit0009" dnum="EP0979606A"><text>EP 0 979 606</text></patcit> and <patcit id="pcit0010" dnum="WO9941986A"><text>WO 99/41986</text></patcit> do not disclose an insecticidal composition comprising an insecticidal (tetra-3-furanyl) methylamine derivative in a solvent comprising pyriproxyfen and phenyl methanol as in the present invention.

0011In one preferred embodiment of the invention, the active portion of the insecticide formulation comprises (tetrahydro-3-furanyl)methylamine derivatives of following formula (1). <chemistry id="chem0001" num="0001"><img file="EP1538905B1_D0001.tif" /></chemistry>

0012Active ingredients and insecticides in accordance with preferred embodiments of the invention are generally available as crystals and solids. Therefore, they need to be dissolved or otherwise put into a liquid form for use as topical spot products on animals. Topical spot products are more advantageous if the amount of liquid applied can be minimized. This must be balanced with the need for appropriate dosage to achieve the desired insecticidal effect Therefore, it is desirable to use a solvent that will allow the solubilization of a high concentration of insecticide.

0013It is also desirable that the resulting formulation be stable (i.e., no crystallization) when stored at -17.8°C (0°F) and 4.4°C(40° F) for 1 month, which is important because these conditions can be met in commerce. The crystallization would reduce the amount of insecticide in solution and reduce the efficacy of the solution applied to the animal.

0014Phenyl methanol, is an alcohol, also known as benzyl alcohol, and is a liquid, somewhat soluble in water. It is routinely used in perfumes, flavors, photographic developers, dyes, films and inks and has other uses. It was surprisingly discovered that a relatively high concentration of the dinotefuran could be solubilized in phenyl methanol.

0015Pyriproxyfen is an insecticide that acts as an insect growth regulator that prevents flea eggs from hatching. It was unexpectedly determined that pyriproxyfen can act as a solvent for the amine derivative insecticides such as dinotefuran, discussed above. For example, the addition of pyriproxyfen to the dinotefuran formulations with phenyl methanol allowed the preparation of more highly concentrated solutions of dinotefuran that do not crystallize at -17.8°C(0°F).

0016In one aspect of the current invention, the dinotefuran is dissolved in solvent containing pyriproxyfen to a concentration range of 5 - 25%, more preferably 9 - 20% and most preferably 12.5 to 19.2%, with 15.7% as a preferred example. All percentages, unless otherwise evident, are on a weight basis.

0017Accordingly, it is an object of the invention to provide an improved topical insecticide, which overcomes drawbacks of the prior art.

<u>DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS</u>

0018The (tetrabydro-3-furanyl)methylamine derivatives of the formula (1) have an excellent insecticidal activity even in the absence of a pyridylmethyl group or a thiazolylmethyl group in their molecular structure. According to the present invention, there are provided (tetrahydro-3-furanyl)methylamine derivatives represented by formula (1), where X₁, X₂, X₃, X₄, X₅, X₆ and X₇ represent each a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; R₁ represents a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, an alkenyl group having 3 carbon atoms, a benzyl group, an alkoxyalkyl group having from 2 to 4 carbon atoms (in its whole group), an alkyloxycarbonyl group having from 1 to 3 carbon atoms, a phenoxy carbonyl group, an alkylcarbonyl group having from 1 to 6 carbon atoms, an alkenylcarbonyl group having from 2 to 3 carbon atoms, a cycloalkylcarbonyl group having from 3 to 6 carbon atoms, a benzoyl group, a benzoyl group substituted by alkyl group(s) having from 1 to 4 carbon atoms, a benzoyl group substituted by halogen atom(s), a 2-furanylcarbonyl group or an N,N-dimethylcarbamoyl group; R₂ represents a hydrogen atom, an amino group, a methyl group, an alkylamino group having from 1 to 5 carbon atoms, a di-substituted alkylamino group having from 2 to 5 carbon atoms (in its whole group), a 1-pyrrolidinyl group, an alkenylamino group having 3 carbon atoms, an alkynylamino group having 3 carbon atoms, a methoxyamino group, an alkoxyalkylamino group having from 2 to 4 carbon atoms (in its whole group), a methylthio group or -N(Y₁)Y₂ (where Y₁ represents an alkyloxycarbonyl group having from 1 to 3 carbon atoms, a phenoxycarbonyl group, an alkylcarbonyl group having from 1 to 6 carbon atoms, an alkenylcarbonyl group having from 2 to 3 carbon atoms, a cycloalkylcarbonyl group having from 3 to 6 carbon atoms, a benzoyl group, a benzoyl group substituted by alkyl group(s) having from 1 to 4 carbon atoms, a benzoyl group substituted by halogen atom(s), a 2-furanylcarbonyl group, an N,N-dimethylcarbamoyl group, a (tetrahydro-3- furanyl)methyl group or a benzyl group, and Y₂ represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms); and Z represents =N-NO₂, =CH-NO₂ or =N-CN; insecticides containing the derivatives as an effective ingredient; and intermediates for producing the compounds of the formula (1) represented by a formula (2): <chemistry id="chem0002" num="0002"><img file="EP1538905B1_D0002.tif" /></chemistry> where X₁, X₂, X₃, X₄, X₅, X₆ and X₇ represent each a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; R₁₀ represents an alkyl group having from 1 to 5 carbon atoms or a benzyl group; and R₁₁ represents an alkyl group having from 1 to 5 carbon atoms or a benzyl group.

0019The (tetrahydro-3-furanyl)methylamine derivatives of the formula (1) and formula (2) according to the invention are excellent compounds having a high insecticidal power and broad insecticidal spectrum. Further, agricultural chemicals containing the novel (tetrahydro-3- furanyl)methylamine derivatives of the formula (1) and (2) according to the invention have outstanding characteristics as insecticides and hence are useful.

0020Specific examples of the alkyl group for X₁, X₂, X₃, X₄, X₅, X₆ and X₇ in the above formulae (1) and (2) include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, a tert-butyl group, preferably a methyl group.

0021Specific examples of the alkyl group for R₁ include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n- butyl group, an iso-butyl group, a see-butyl group, a tert-butyl group, an n-pentyl group.

0022Specific examples of the alkenyl group for R₁ include a 1-propenyl group, a 2-propenyl group.

0023Specific examples of the alkoxyalkyl group for R₁ include a methoxymethyl group, an ethoxymethyl group, an n-propoxymethyl group, an iso-propoxymethyl group, a methoxyethyl group, an ethoxyethyl group.

0024Specific examples of the alkyloxycarbonyl group for R₁ include a methyloxycarbonyl group, an ethyloxycarbonyl group, an n-propyloxycarbonyl group, an isopropyloxycarbonyl group.

0025Specific examples of the alkylcarbonyl group for R₁ include a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an iso-propylcarbonyl group, an n-butylcarbonyl group, an iso-butylcarbonyl group, a sec-butylcarbonyl group, a tert-butylcarbonyl group, an n-pentylcarbonyl group, an n-hexylcarbonyl group.

0026Specific examples of the alkenylcarbonyl group for R1 include a vinylcarbonyl group, a 1-methylvinylcarbonyl group.

0027Specific examples of the cycloalkylcarbonyl group for R₁ include a cyclopropylcarbonyl group a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group.

0028Specific examples of the benzoyl group substituted by alkyl group(s) for R₁ include a 2-methylbenzoyl group, a 3-methylbenzoyl group, a 4-methylbenzoyl group, a 4-tert-butylbenzoyl group.

0029Specific examples of the benzoyl group substituted by halogen atom(s) for R1 include a 2-chlorobenzoyl group, a 3-chlorobenzoyl group, a 4-chlorobenzoyl group, a 3,4-dichloro-benzoyl group, a 4- fluorobenzoyl group.

0030Although R₁ can take various substituents as described above, it is preferably a hydrogen atom, an alkylcarbonyl group having from 1 to 4 carbon atoms or a cyclopropylcarbonyl group.

0031Specific examples of the alkylamino group for R₂ include a methylamino group, an ethylamino group, an n-propyl-amino group, an iso-propylamino group, an n-butylamino group, an iso butylamino group, a sec-butylamino group, a tert-butylamino group, an n-pentylamino group, preferably a methylamino group.

0032Specific examples of the di-substituted alkylamino group for R₂ include a dimethylamino group, a diethylamino group, an N-methyl-N-ethylamino group, an N-methyl-N-n-propylamino group, an N-methyl-N-n-butylamino group, preferably a dimethylamino group.

0033Specific examples of the alkenylamino group for R₂ include a 1-propenylamino group, a 2-propenylamino group.

0034Specific examples of the alkynylamino group for R₂ include a propargylamino group.

0035Specific examples of the alkoxyalkylamino group for R₂ include a methoxymethylamino group, an ethoxymethylamino group, an n-propoxymethylamino group, an iso-propoxymethylamino group, a methoxyethylamino group, an ethoxyethylamino group.

0036Specific examples of the alkyloxycarbonyl group denoted by Y₁ for R₂ include a methyloxycarbonyl group, an ethyloxy-carbonyl group, an n-propyloxycarbonyl group, an isopropyloxy-carbony) group.

0037Specific examples of the alkylcarbonyl group denoted by Y₁ for R₂ include a methyl carbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an iso-propylcarbonyl group, an n-butylcarbonyl group, an isobutylcarbonyl group, a sec-butylcarbonyl group, a tertbutylcarbonyl group, an n-pentylcarbonyl group, an n-hexylcarbonyl group, preferably a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an iso-propylcarbonyl group, an n-butylcarbonyl group, an iso-butylcarbonyl group, a sec-butylcarbonyl group and a tert-butylcarbonyl group.

0038Specific examples of the alkenylcarbonyl group denoted by Y₁ for R₂ include a vinylcarbonyl group, a 1-methyl-vinylcarbonyl group.

0039Specific examples of the cycloalkylcarbonyl group denoted by Y₁ for R₂ include a - cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group, preferably a cyclopropyl-carbonyl group.

0040Specific examples of the benzoyl group substituted byalkyl group(s) denoted by Y₁ for R₂ include a 2-methylbenzoyl group, a 3-methylbenzoyl group, a 4-methylbenzoyl group, a 4-tert-butylbenzoyl group.

0041Specific examples of the benzoyl group substituted by halogen atom(s) denoted by Y₁ for R₂ include a 2-chlorobenzoyl group, a 3-chlorobenzoyl group, a 4-chlorobenzoyl group, a 3,4-dichlorobenzoyl group, a 4-fluoro benzoyl group.

0042Specific examples of the alkyl group denoted by Y₂ for R₂ include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, preferably a methyl group.

0043In the formula (1), compounds in which R₁ and Y₁ are concurrently an alkylcarbonyl group having from 1 to 4 carbon atoms or a cyclopropylcarbonyl group are preferred from the viewpoint of both insecticidal activity and production method.

0044In the development of a formulation for use on animals, there are several parameters that must be considered. These are: <ol id="ol0001"><li>(a) Concentration high enough to minimize the volume of the topical applied to the animal (one would not want to put 20 ml, e.g., onto a small cat).</li><li>(b) The formulation should be stable for one month at 54.4°C (130°F), 43.3°(110°F), 4 .4°C(40°F), room temperature and (-17.8°C) (0°F). This helps ensure that the formulation remains stable under the conditions that it could meet in commerce.</li><li>(c) Safe to use on the animal - particularly non-irritating since the product is applied to the skin. Also safe if ingested by the animal; ingestion can occur when cats groom themselves.</li><li>(d) Safe to use by the consumer.</li><li>(e) Efficacious in use - should kill greater than 90% of the fleas up to 28 days.</li><li>(f) Efficacy would be reduced if crystallization occurred in the package.</li><li>(g) Needs to be aesthetically pleasing - "no oily drop" on the animal when applied.</li><li>(h) Fast drying to reduce the chance of the animal shaking off the liquid thereby reducing efficacy.</li><li>(i) Microbiologically stable.</li></ol>

0045The above-referenced patents recognize different possible solvents, but do not provide information on how to formulate insecticide in a non-irritating manner. No examples were given in which the compounds were used on animals. Additionally, in all of the examples given the compounds were dissolved into solvents that are undesirable to use on animals. Specifically, acetone, used in all but one of the examples, is very irritating by both inhalation and skin contact, due to de-fatting action on skin and mucous membranes. It is also very irritating to the eyes. Accordingly, there is a need to develop a different solvent for these compounds that can be used on animals. The present formulation satisfies the parameters detailed above.

0046In one aspect of the current invention, the dinotefuran is dissolved in solvent containing pyriproxyfen to a concentration range of 5 - 25%, more preferably 9 - 20% and most preferably 12.5 to 19.2%, with 15.7% as a preferred example. All percentages, unless otherwise evident, are on a weight basis. Pyriproxyfen is advantageously included as over 0.1%, advantageously 0.1 to 3%.

0047The following examples are given for purposes of illustration only and are not intended to be construed in a limiting manner.

EXAMPLE 1 -Preparation of 1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine (dinotefuran)

0048A mixture comprising 10.0 g of (tetrahydro-3-furanyl)methanol, 29. 5 g of trifluoromethanesulfonic anhydride, 10.0 g of pyridine and 200 ml of dichloromethane was stirred for an hour at room temperature. Water was poured into the reaction solution to separate the organic layer, which was washed with 1 N hydrochloric acid, water and a saturated saline solution, dried, and concentrated to obtain 20 g of 3-tetrahydro-furanylmethyl triflate. 3.25 g of 60% sodium hydride were added to 12.5 g of 1,5-dimethyl-2-nitroiminohexahydro-1,3,5-triazine and 60 ml of DMF at room temperature, followed by stirring for an hour. 20.0 g of the 3-tetrahydrofuranylmethyl triflate were added thereto, and the mixture was stirred at 50° C for 2 hours. After cooling the mixture to room temperature, 50 ml of 2N hydrochloric acid were added thereto, followed by stirring at 50° C for 2 hours. The resultant mixture was neutralized with sodium bicarbonate and extracted with dichloromethane, and the extract was dried and concentrated. The residue thus obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1) to obtain 7.8 g of 1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine (dinotefuran).

EXAMPLE 2- Preparation of Insecticide Formulation Containina Dinotefuran and Phenol Methanol

004915 g (i.e., 12.5% (weight/weight)) of dinotefuran was dissolved into 100 ml of phenyl methanol. The resulting solution can be spot applied to companion animals, such as dogs and cats and will kill fleas, ticks and other insects.

EXAMPLE 3- Preparation of Insecticide Formulation Containing Dinotefuran. Pyriproxyfen and Phenyl Methanol

005020 g of dinotefuran was added to 100 ml phenyl methanol with stirring until it dissolves 3g of pyriproxyfen was added to the solution with stirring to produce a clear, homogeneous solution.

EXAMPLE 4- Preparation of Insecticide Formulation Containing Dinotefuran. Pyriproxyfen and Phenyl Methanol

005125 g of dinotefuran was added to 100 ml phenyl methanol with stirring until it dissolved. I g of pyriproxyfen was added to the solution with stirring to produce a clear, homogeneous solution of high insecticide concentration.

0052The resulting solution can be spot applied to companion animals, such as dogs and cats and will kill fleas, ticks and other insects.

EXAMPLE 5-

Stability of Dinotefuran/Pyriproxyfen Formulations

0053Table I demonstrates that an approximate 50% increase in concentration can be achieved for dinotefuran by including pyriproxyfen at low levels in the formulation based on the criterion of no crystal formation at -17·8°C (0° F) during a 1 month period. <tables id="tabl0001" num="0001"><table frame="all"><title><b><u>Table 1: Formulation Stability Studies (% are w/w)</u></b></title><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="23mm" /><colspec colnum="2" colname="col2" colwidth="25mm" /><colspec colnum="3" colname="col3" colwidth="30mm" /><colspec colnum="4" colname="col4" colwidth="15mm" /><thead><row><entry align="center" valign="top"><b>Dinotefuran</b></entry><entry align="center" valign="top"><b>Pyriproxyfen</b></entry><entry align="center" valign="top"><b>Phenyl Methanol</b></entry><entry align="center" valign="top"><b>Stable</b></entry></row></thead><tbody><row><entry align="center">12.5</entry><entry align="center">0</entry><entry align="center">87.5</entry><entry>Yes</entry></row><row><entry align="center">14.7</entry><entry align="center">0</entry><entry align="center">85.3</entry><entry>No*</entry></row><row><entry align="center">15.7</entry><entry align="center">2.4</entry><entry align="center">81.9</entry><entry>Yes</entry></row><row><entry align="center">15.9</entry><entry align="center">0.8</entry><entry align="center">83.3</entry><entry>Yes</entry></row><row><entry align="center">19.2</entry><entry align="center">0.8</entry><entry align="center">80.0</entry><entry>Yes</entry></row></tbody></tgroup><tgroup cols="4" rowsep="0"><colspec colnum="1" colname="col1" colwidth="23mm" /><colspec colnum="2" colname="col2" colwidth="25mm" /><colspec colnum="3" colname="col3" colwidth="30mm" /><colspec colnum="4" colname="col4" colwidth="15mm" /><tbody><row><entry namest="col1" nameend="col4" align="justify">*Crystallizes at -17.8° F (0° F).</entry></row></tbody></tgroup></table></tables>

EXAMPLE 6-

<i>In Vivo</i> Activity of a Flea Dermal Treatment Against the Cat Flea <i>(Ctenocephalides felis)</i> on Cats

0054Eighteen cats were separated into three groups each containing 6 cats. Group 1 (6 cats each weighing 4.1kg (9 lbs) or less) remained untreated as Non-Treated Controls. Group 2 (6 cats each over 4.1kg (9 lbs) were treated with 3.4 ml of the dinotefuran insecticide formulation (5.71% w/w). Group 3 (6 cats each weighing 4.1kg (9 lbs)or less) were treated with 1.5 ml of the dinotefuran insecticide formulation (5.71% w/w)

0055Approximately 18 hours prior to treatment the cats were infested with 100 cat fleas (Ctenocephalides felis) which were applied to the animal's back. Cats in Groups 2 and 3 were then treated with the indicated volume of insecticide by dispensing the liquid at skin level between the shoulder blades. Flea counts were taken at day 1 (i.e., 24 hours post-treatment), day 8. day 15, day 22 and day 29. Cats were re-infested with 100 fleas on days 7. 14, 21, and 28. To determine the efficacy of the dermal treatment, the number of fleas found on treated cats was compared to the number of fleas found on untreated cats. Percent reduction was determined as follows and the results are summarized in Table 2: <maths id="math0001"><math display="block"><mfrac><mrow><mi>Mean Number of fleas on Untreated Cats</mi><mo>-</mo><mi>Mean Number of fleas on Treated Cats</mi></mrow><mi>Mean Number of fleas on Untreated Cats</mi></mfrac><mspace width="1em" /><mi>X</mi><mo>⁢</mo><mn>100</mn><mo>%</mo></math><img file="EP1538905B1_D0003.tif" /></maths>

0056As shown in Table 2 the results demonstrate that the dosages used on Groups 2 and 3 are both effective at reducing the number of adult fleas on cats through at least 29 days and thus are effective as a one month dermal treatment. <tables id="tabl0002" num="0002"><table frame="all"><title><b><u>Table 2: Controlled Percent Reduction in Flea Population</u></b></title><tgroup cols="6"><colspec colnum="1" colname="col1" colwidth="24mm" /><colspec colnum="2" colname="col2" colwidth="15mm" /><colspec colnum="3" colname="col3" colwidth="15mm" /><colspec colnum="4" colname="col4" colwidth="15mm" /><colspec colnum="5" colname="col5" colwidth="15mm" /><colspec colnum="6" colname="col6" colwidth="15mm" /><thead><row><entry valign="top" /><entry valign="top">Day 1</entry><entry valign="top">Day 8</entry><entry valign="top">Day 15</entry><entry valign="top">Day 22</entry><entry valign="top">Day 29</entry></row></thead><tbody><row><entry>Control Group</entry><entry>0</entry><entry>0</entry><entry>0</entry><entry>0</entry><entry>0</entry></row><row><entry>Group 2</entry><entry>100</entry><entry>100</entry><entry>99</entry><entry>99</entry><entry>96</entry></row><row><entry>Group 3</entry><entry>100</entry><entry>98</entry><entry>95</entry><entry>95</entry><entry>91</entry></row></tbody></tgroup></table></tables>