Pestic. Sci. 1998, 52, 251È257

Synthesis and Precocious-Metamorphosis-InducingActivity of 3-Pyridyl EthersEiichi Kuwano,1* Motohisa Shimizu,1 Kenshi Shimazu,1 Satoshi Nakazawa1 &Koichi Suzuki21 Department of Agricultural Chemistry, Kyushu University, Higashi-ku, Fukuoka 812, Japan2 Faculty of Agriculture, Iwate University, Ueda, Morioka 020, Japan

(Received 14 March 1997 ; revised version received 1 July 1997 ; accepted 2 October 1997)

Abstract : A new series of 5-(substituted phenoxy)pentyl 3-pyridyl ethers inducedprecocious metamorphosis in larvae of the silkworm, Bombyx mori. Both 2- and4-pyridyl ethers were inactive, indicating that the 3-pyridine moiety was essentialfor the activity. Octyl, dodecyl and farnesyl 3-pyridyl ethers had no activity.Among the compounds tested so far, 5-(4-propylphenoxy)pentyl 3-pyridyl ethershowed the highest activity. The activity fell o† with increasing or decreasinglength of the carbon chain between two oxygen atoms. Introduction of a methylgroup at the 6 position of the pyridine ring completely eliminated the activity.Precocious metamorphosis induced by 3-pyridyl ethers was fully reversible by asimultaneous application of a small amount of tebufenozide, an ecdysteroidagonist, or methoprene, a JH agonist. 1998 SCI.(

Pestic. Sci., 52, 251È257 (1998)

Key words : Bombyx mori ; 3-pyridyl ethers ; precocious metamorphosis ; tebu-fenozide

1 INTRODUCTION

It is well known that precocious metamorphosis isinduced by allatectomy or anti-juvenile hormonal com-pounds.1 We have recently reported that 1,5-dis-ubstituted imidazoles induced precocious metamor-phosis in the silkworm, Bombyx mori L., by causing atemporary deÐciency of ecdysteroid titers in the larvalhemolymph; the most e†ective compound, KK-42,inhibited ecdysteroid synthesis at very low concentra-tions in vitro in the prothoracic glands of the silkwormlarvae.2 Also, the ability of these imidazoles to induceprecocious metamorphosis could be completelycounteracted by the dietary administration of 20-hydroxyecdysone3 or the simultaneous application oftebufenozide, an ecdysteroid agonist.4

* To whom correspondence should be addressed.Contract/grant sponsor : Ministry of Education, Science andCulture, Japan ; Contract/grant number : 07556081.

In the study of the precocious-metamorphosis-indu-cing activity in B. mori larvae, we reported that the sub-stituents at both the 1 and 5 positions of the imidazolering were essential for the activity.5 However, we haverecently found that a number of 1-substituted imid-azoles induced precocious metamorphosis in B. morilarvae as well.6 This fact prompted us to examine theprecocious-metamorphosis-inducing activity of pyridinederivatives because of some similar properties betweenthe imidazole and pyridine rings (e.g. inhibitory activityfor cytochrome P-450).7 Interestingly, several pyridinederivatives have been reported to possess high juvenilehormone (JH) activity.8 Solli et al.9 Ðrst found that 3-pyridyl ethers with a terpene chain showed high JHactivity, while 2- or 4-pyridyl ethers had little activity.Recently, the 2-pyridine derivative pyriproxyfen, whichis very active against a wide range of insect species, hasbeen commercialized for Ðeld applications.10 However,there is no report in the literature of pyridine deriv-atives inducing precocious metamorphosis. We Ðnd that

2511998 SCI. Pestic. Sci. 0031-613X/98/$17.50. Printed in Great Britain(

252 Eiichi Kuwano et al.

a new series of 3-pyridyl ethers induce precocious meta-morphosis in larvae of B. mori. In the present paper wereport their synthesis, structure and biological activity.

2 MATERIALS AND METHODS

2.1 Synthetic procedures

All melting points are uncorrected. The [1H]NMRspectra were determined with a JEOL EX-400 spectro-meter, using tetramethylsilane as an internal standard,and all samples were prepared in deuterochloroform.

Compounds 1È4 were synthesized according toreported methods.9 Compounds 33 and 34 were pre-pared according to the procedures reported previously.6All (substituted phenoxy)alkyl 3-pyridyl ethers were pre-pared by WilliamsonÏs ether synthesis method as shownin Fig. 1. The following procedure for the preparation of5-(4-propoxyphenoxy)pentyl-3-pyridyl ether (21) istypical.

2.1.1 5-(4-Propoxyphenoxy)pentyl 3-pyridyl ether (21)A mixture of 4-propylphenol (1É00 g) and 1,5-dibromo-pentane (2É03 g) was heated to boiling. To the boilingsolution was added with stirring a solution of sodiumhydroxide (0É32 g) in water (8 ml) and the mixture wasstirred under reÑux until the solution became acidic.The product was extracted with diethyl ether, the ethersolution was washed with brine, and dried over sodiumsulfate. After removal of the solvent, the residue waschromatographed on silica gel by eluting withhexane] ethyl acetate (50] 1 by volume). Concentra-tion of the eluate under reduced pressure a†orded 5-(4-propylphenoxy)pentyl bromide (1É62 g ; 77É4%) as anoil. To a suspension of sodium hydride (0É15 g ; 60% inoil) in dimethylformamide (10 ml) at 0È5¡C was added3-hydroxypyridine (0É33 g) and the mixture was stirredfor 0É5 h at room temperature. To the ice-cooledmixture was added 5-(4-propylphenoxy)pentyl bromide(1É00 g). After stirring for 24 h at room temperature,water (50 ml) was added to the mixture, and theproduct was extracted with ethyl acetate. The ethylacetate solution was washed with brine and dried oversodium sulfate. After removal of the solvent, the residuewas chromatographed on silica gel by eluting withhexane] ethyl acetate (3] 1 by volume). Concentra-tion of the ethyl acetate eluate under reduced pressurea†orded 21 (0É44 g ; 41É9%), m.p. 33È34¡C. [1H]NMRd : 0É92 (3H, t, J \ 7É3 Hz), 1É55È1É75 (4H, m), 1É81È1É91

(4H, m), 2É52 (2H, t, J\ 7É8 Hz), 3É97 (2H, t,J\ 6É4 Hz), 4É03 (2H, t, J \ 6É4 Hz), 6É81 (2H, d,J\ 8É3 Hz), 7É07 (2H, d, J\ 8É3 Hz), 7É15È7É22 (2H, m),8É21 (1H, dd, J\ 2É4 and 4É4 Hz), 8É31 (1H, d,J\ 2É4 Hz). Analysis found : C, 75É99 ; H, 8É38 ; N,4É66%. Calculated for C, 76É22 ; H, 8É42 ;C19H25N1O2 :N, 4É68%.

Compounds 5È7 were prepared in the same manneras compound 21 with use of 3-(substitutedphenoxy)propyl bromide instead of 5-(4-propylphenoxy)pentyl bromide.

2.1.2 3-(4-Phenoxyphenoxy)propyl 3-pyridyl ether (5)Yield 28É1%; [1H]NMR d : 2É24È2É30 (2H, m), 4É14 (2H,t, J \ 5É9 Hz), 4É21 (2H, t, J\ 5É9 Hz), 6É78È7É05 (7H,m), 7É18È7É31 (4H, m), 8É19È8É22 (1H, m), 8É32È8É34 (1H,m).

2.1.3 3-Phenoxypropyl 3-pyridyl ether (6)Yield 36É6%; m.p. 50È51¡C; [1H]NMR d : 2É24È2É43(2H, m), 4É16 (2H, t, J\ 5É9 Hz), 4É20 (2H, t,J\ 5É9 Hz), 6É72È6É96 (3H, m), 7É19È7É29 (4H, m), 8É21(1H, dd, J\ 2É4 and 4É4 Hz), 8É31 (1H, d, J\ 2É4 Hz).

2.1.4 3-(4-Ethylphenoxy)propyl-3-pyridyl ether (7)Yield 58É6%; [1H]NMR d : 1É20 (3H, t, J\ 7É8 Hz),2É22È2É44 (2H, m), 2É57 (2H, q, J\ 7É8 Hz), 4É12 (2H, t,J\ 6É1 Hz), 4É18 (2H, t, J \ 6É1 Hz), 6É83 (2H, d,J\ 8É3 Hz), 7É10 (2H, d, J\ 8É3 Hz), 7É17È7É25 (2H, m),8É20 (1H, dd, J\ 4É4 and 2É4 Hz), 8É32 (1H, s).

In a similar manner, compounds 8È12 were preparedby reacting 3-hydroxypyridine with the corresponding(4-ethylphenoxy)alkyl bromide.

2.1.5 2-(4-Ethylphenoxy)ethyl 3-pyridyl ether (8)Yield 87É5%; m.p. 66È67¡C; [1H]NMR d : 1É21 (3H, t,J\ 7É8 Hz), 2É60 (2H, q, J\ 7É8 Hz), 4É29È4É38 (4H, m),6É88 (2H, d, J\ 8É8 Hz), 7É12 (2H, d, J\ 8É8 Hz), 7É21È7É25 (2H, m), 8É25 (1H, dd, J\ 4É4 and 2É4 Hz), 8É37(1H, d, J\ 2É4 Hz).

2.1.6 4-(4-Ethylphenoxy)butyl 3-pyridyl ether (9)Yield 63É5%; [1H]NMR d : 1É21 (3H, t, J\ 7É8 Hz),1É92È2É04 (4H, m), 2É58 (2H, q, J\ 7É8 Hz), 4É01 (2H, t,J\ 5É9 Hz), 4É07 (2H, t, J \ 5É9 Hz), 6É82 (2H, d,J\ 8É8 Hz), 7É10 (2H, d, J\ 8É8 Hz), 7É17È7É19 (2H, m),8É21 (1H, dd, J\ 4É4 and 2É4 Hz), 8É31 (1H, d,J\ 2É4 Hz).

2.1.7 5-(4-Ethylphenoxy)pentyl 3-pyridyl ether (10)Yield 38É0%; m.p. 28È29¡C; [1H]NMR d : 1É21 (3H, t,J\ 7É8 Hz), 1É64È1É69 (2H, m), 1É85È1É89 (4H, m), 2É53È

Fig. 1. Synthetic scheme for preparation of (substituted phenoxy)alkyl 3-pyridyl ethers.

Precocious-metamorphosis-inducing activity of 3-pyridyl ethers 253

2É61 (2H, m), 3É95È4É14 (4H, m), 6É81È6É86 (2H, m),7É09È7É14 (2H, m), 7É15È7É26 (2H, m), 8É21 (1H, dd,J\ 2É4 and 4É4 Hz), 8É31È8É33 (1H, m).

2.1.8 6-(4-Ethylphenoxy)hexyl 3-pyridyl ether (11)Yield 31É8%; m.p. 50È51¡C; [1H]NMR d : 1É20 (3H, t,J\ 7É8 Hz), 1É50È1É55 (4H, m), 1É71È1É94 (4H, m), 2É57(2H, q, J \ 7É8 Hz), 3É94 (2H, t, J\ 6É4 Hz), 3É99 (2H, t,J\ 6É4 Hz), 6É81 (2H, d, J \ 8É8 Hz), 7É09 (2H, d,J\ 8É8 Hz), 7É13È7É19 (2H, m), 8É19 (1H, dd, J\ 2É4and 4É4 Hz), 8É30 (1H, d, J \ 2É4 Hz).

2.1.9 7-(4-Ethylphenoxy)heptyl 3-pyridyl ether (12)Yield 33É8%; [1H]NMR d : 1É20 (3H, t, J\ 7É8 Hz),1É39È1É54 (6H, m), 1É75È1É84 (4H, m), 2É58 (2H, q,J\ 7É8 Hz), 3É93 (2H, t, J\ 6É4 Hz), 3É99 (2H, t,J\ 6É4 Hz), 6É81 (2H, d, J \ 8É8 Hz), 7É09 (2H, d,J\ 8É8 Hz), 7É13È7É19 (2H, m), 8É19 (1H, dd, J\ 2É4and 4É4 Hz), 8É30 (1H, d, J\ 2É4 Hz).

Compounds 13È20 and 22È28 were prepared in thesame manner as that used for compound 21 from thecorresponding 5-(substituted phenoxy)pentyl bromideand 3-hydroxypyridine.

2.1.10 5-Phenoxypentyl 3-pyridyl ether (13)Yield 8É6%; [1H]NMR d : 1É60È1É68 (2H, m), 1É80È1É89(4H, m), 3É92È4É00 (4H, m), 6É87È6É93 (3H, m), 7É13È7É30 (4H, m), 8É16È8É22 (1H, m), 8É30È8É32 (1H, m).

2.1.11 5-(4-Chlorophenoxy)pentyl 3-pyridyl ether (14)Yield 28É8%; m.p. 45È46¡C; [1H]NMR d : 1É53È1É60(2H, m), 1É70È1É85 (4H, m), 3É86 (2H, t, J\ 6É4 Hz), 3É93(2H, t, J\ 6É4 Hz), 6É71È6É74 (2H, m), 7É06È7É15 (4H,m), 8É11È8É12 (1H, m), 8É22È8É23 (1H, m).

2.1.12 5-(3-Chlorophenoxy)pentyl 3-pyridyl ether (15)Yield 37É6%; [1H]NMR d : 1É58È1É65 (2H, m), 1É78È1É87 (4H, m), 3É94 (2H, t, J\ 6É4 Hz), 3É97 (2H, t,J\ 6É4 Hz), 6É74È6É76 (1H, m), 6É86È6É88 (2H, m),7É12È7É18 (3H, m), 8É17È8É18 (1H, m), 8É28 (1H, s).

2.1.13 5-(2-Chlorophenoxy)pentyl 3-pyridyl ether (16)Yield 38É1%; [1H]NMR d : 1É62È1É70 (2H, m), 1É78È1É94 (4H, m), 3É98 (2H, t, J\ 6É4 Hz), 4É00 (2H, t,J\ 6É4 Hz), 6É81È6É88 (2H, m), 7É11È7É17 (3H, m), 7É30È7É32 (1H, m), 8É16 (1H, s), 8É28 (1H, s).

2.1.14 5-(2,4-Dichlorophenoxy)pentyl 3-pyridyl ether(17)Yield 35É9%; [1H]NMR d : 1É58È1É66 (2H, m), 1É78È1É86 (4H, m), 3É94 (2H, t, J\ 6É4 Hz), 3É97 (2H, t,J\ 6É4 Hz), 6É74 (1H, d, J\ 8É8 Hz), 7É06È7É14 (3H, m),7É26 (1H, d, J \ 2É4 Hz), 8É13 (1H, dd, J \ 2É0 and4É4 Hz), 8É23 (1H, J\ 2É0 Hz).

2.1.15 5-(4-Bromophenoxy)pentyl 3-pyridyl ether (18)Yield 65É1%; [1H]NMR d : 1É63È1É69 (2H, m), 1É82È1É91 (4H, m), 3É96 (2H, t, J\ 6É4 Hz), 4É03 (2H, t,J\ 6É4 Hz), 6É77 (2H, d, J\ 9É3 Hz), 7É16È7É22 (2H, m),7É35 (2H, d, J \ 9É3 Hz), 7É35 (1H, dd, J \ 2É4 and4É4 Hz), 8É30 (1H, d, J\ 2É4 Hz).

2.1.16 5-(4-(Fluorophenoxy) pentyl 3-pyridyl ether (19)Yield 43É6%; [1H]NMR d : 1É57È1É65 (2H, m), 1É77È1É86 (4H, m), 3É89 (2H, t, J\ 6É4 Hz), 3É97 (2H, t,J\ 6É4 Hz), 6É73È6É82 (2H, m), 6É85È6É96 (2H, m),7É09È7É17 (2H, m), 8É20È8É26 (1H, m), 8É27È8É30 (1H, m).

2.1.17 5-(4-Methylphenoxy)pentyl 3-pyridyl ether (20)Yield 41É7%; m.p. 46È47¡C; [1H]NMR d : 1É62È1É70(2H, m), 1É81È1É92 (4H, m), 2É28 (3H, s), 3É97 (2H, t,J\ 6É4 Hz), 4É01 (2H, t, J \ 6É4 Hz), 6É80 (2H, d,J\ 8É3 Hz), 7É07 (2H, d, J\ 8É3 Hz), 7É16È7É22 (2H, m),8É21 (1H, dd, J\ 2É4 and 4É4 Hz), 8É31 (1H, d,J\ 2É4 Hz).

2.1.18 5-(4-Isopropylphenoxy)pentyl 3-pyridyl ether (22)Yield 20É8%; [1H]NMR d : 1É14 (6H, d, J\ 6É8 Hz),1É55È1É61 (2H, m), 1É75È1É84 (4H, m), 2É75È2É80 (1H,m), 3É89 (2H, t, J \ 6É4 Hz), 3É95 (2H, t, J \ 6É4 Hz),6É70È6É77 (4H, m), 7É06 (2H, d, J \ 8É3 Hz), 8É33È8É34(2H, m).

2.1.19 5-(4-t-Butylphenoxy)pentyl 3-pyridyl ether (23)Yield 23É5%; [1H]NMR d : 1É29 (9H, s), 1É65È1É67 (2H,m), 1É83ÈÈ1É88 (4H, m), 3É97 (2H, t, J\ 6É4 Hz), 4É02(2H, t, J\ 6É4 Hz), 6É82È6É84 (2H, m), 7É17È7É30 (6H,m), 8É19È8É20 (1H, m), 8É30È8É31 (1H, m).

2.1.20 5-(4-Methoxyphenoxy)pentyl ether (24)Yield 38É7%; [1H]NMR d : 1É57È1É67 (2H, m), 1É74È1É84 (4H, m), 3É71 (3H, s), 3É89 (2H, t, J\ 6É4 Hz), 3É97(2H, t, J \ 6É4 Hz), 6É79 (4H, s), 7É11È7É16 (2H, m), 8É16(1H, dd, J\ 2É4 and 4É4 Hz), 8É27 (1H, d, J\ 2É4 Hz).

2.1.21 5-(4-Ethoxyphenoxy)pentyl 3-pyridyl ether (25)Yield 20É4%; [1H]NMR d : 1É38 (3H, t, J\ 6É8 Hz),1É63È1É69 (2H, m), 1É79È1É91 (4H, m), 3É92È4É04 (6H,m), 6É80È6É84 (4H, m), 7É17È7É26 (2H, m), 8É19È8É21(1H, m), 8É30È8É31 (1H, m).

2.1.22 5-(4-Propoxyphenoxy)pentyl 3-pyridyl ether (26)Yield 24É6%; m.p. 48È49¡C; [1H]NMR d : 1É01 (3H, t,J\ 7É3 Hz), 1É61È1É69 (2H, m), 1É75È1É89 (6H, m), 3É86(2H, t, J \ 6É4 Hz), 3É93 (2H, t, J \ 6É4 Hz), 4É02 (2H, t,J\ 6É4 Hz), 6É80È6É84 (4H, m), 7É17È7É20 (2H, m), 8É19È8É21 (1H, m), 8É30È8É31 (1H, m).

2.1.23 5-(4-Phenoxyphenoxy)pentyl 3-pyridyl ether (27)Yield 45É8%; [1H]NMR d : 1É63È1É95 (6H, m), 4É13 (2H,t, J \ 6É4 Hz), 4É20 (2H, t, J \ 6É4 Hz), 6É86È7É05 (7H,

254 Eiichi Kuwano et al.

TABLE 1Precocious-Metamorphosis-Inducing Activity of 3-Pyridyl Ethers and Pyriproxyfen against

the 4th-instar Larvae of Bombyx mori

Activity (%)No. R Dose (160 kg per larva)

1 0

2 0

3 0

4 0

5 0

6 20

7 30

0

m), 7É17È7É30 (4H, m), 8É20È8É22 (1H, m), 8É32È8É33 (1H,m).

2.1.24 5-(4-Benzyloxyphenoxy)pentyl 3-pyridyl ether(28)Yield 24É0%; m.p. 46È47¡C; [1H]NMR d : 1É62È1É71(2H, m), 1É83È1É94 (4H, m), 3É91 (2H, t, J\ 6É3 Hz), 4É13(2H, t, J\ 6É3 Hz), 5É02 (2H, s), 6É82È6É84 (2H, m),6É88È6É92 (2H, m), 7É15È7É22 (2H, m), 7É29È7É43 (5H,m), 8É20 (1H, dd, J\ 2É4 and 4É4 Hz), 8É31 (1H, d,J\ 2É4 Hz).

Compounds 29È32 were prepared in the samemanner as 21 with use of 2-hydroxypyridine, 4-hydroxypyridine, 5-hydroxy-2-methylpyridine andphenol respectively, instead of 3-hydroxypyridine.

2.1.25 5-(4-Propylphenoxy)pentyl 2-pyridyl ether (29)Yield 22É5%; [1H]NMR d : 0É91 (3H, t, J\ 7É3 Hz),1É48È1É64 (4H, m), 1É77È1É88 (4H, m), 2É51 (2H, t,J\ 7É3 Hz), 3É91È3É96 (4H, m), 6É11È6É15 (1H, m), 6É54È6É80 (1H, m), 7É06 (2H, d, J\ 8É8 Hz), 7É22È7É32 (4H,m).

2.1.26 5-(4-Propylphenoxy)pentyl 4-pyridyl ether (30)Yield 17É5%, [1H]NMR d : 0É84 (3H, t, J\ 7É3 Hz),1É47È1É60 (4H, m), 1É73È1É82 (4H, m), 2É43 (2H, t,

J\ 7É3 Hz), 3É88 (2H, t, J\ 6É4 Hz), 3É93 (2H, t,J\ 6É4 Hz), 6É69È6É74 (4H, m), 6É99 (2H, d, J\ 8É3 Hz),8É32È8É33 (2H, m).

2.1.27 5-(4-Propylphenoxy)pentyl 2-methyl-5-pyridylether (31)Yield 18É8%; [1H]NMR d : 0É92 (3H, t, J\ 7É3 Hz),1É54È1É64 (4H, m), 1É76È1É97 (4H, m), 2É48 (3H, s), 2É51(2H, t, J \ 7É8 Hz), 3É97 (2H, t, J \ 6É4 Hz), 3É99 (2H, t,J\ 6É4 Hz), 6É86 (2H, d, J\ 8É8 Hz), 6É93È7É08 (4H, m),8É18 (1H, s).

2.1.28 Phenyl 5-(4-propylphenoxy)pentyl ether (32)Yield 82É2%; [1H]NMR d : 0É92 (3H, t, J\ 7É3 Hz)1É55È1É67 (4H, m), 1É80È1É86 (4H, m), 2É51 (2H, t,J\ 7É8 Hz), 3É93È3É98 (4H, m), 6É80 (2H, d, J\ 8É3 Hz),6É87È6É94 (3H, m), 7É06 (2H, d, J\ 8É3 Hz), 7É20È7É28(2H, m).

2.2 Biological evaluations

B. mori (Shunrei ] Shougetsu strain) larvae were rearedon artiÐcial diets as previously described.3 The pyridine

Precocious-metamorphosis-inducing activity of 3-pyridyl ethers 255

compounds, methoprene and tebufenozide in acetonesolution (1È4 kl per larva) were applied topically tonewly molted 4th-instar larvae and 24-h-old 3rd-instarlarvae. The activity was evaluated in terms of inductionof precocious metamorphosis as described by Kuwanoet al.11 : spinning a cocoon and subsequent pupationfrom the 4th-instar (penultimate) larval period. The pre-cocious pupae caused by applying pyridine compoundsmolted to miniature adults.

3 RESULTS AND DISCUSSION

Since 1-decyl- or 1-dodecylimidazole induced preco-cious metamorphosis in the 4th-instar larvae of the silk-worm,6 we Ðrst synthesized several alkyl 3-pyridylethers and evaluated their activity (Table 1). In contrastto 1-substituted imidazoles, simple alkyl 3-pyridylethers such as octyl (1) or dodecyl (2) ether showedinsecticidal activity in B. mori larvae and did not induceprecocious metamorphosis. Farnesyl 3-pyridyl ether (3),which has a similar structure to pyridyl terpenoid etherwith high JH activity,8 did not induce precocious meta-morphosis even at a high dose of 160 kg per larva.Compounds 4 and 5, with a phenoxyphenyl substituent,showing similarity to some JH mimics, had no activityat 160 kg per larva, either. Pyriproxyfen showed noactivity against the 4th-instar larvae of silkworm exceptfor a slight prolongation of the 4th-instar period. Only3-phenoxypropyl 3-pyridyl ether (6) and its 3-(4-ethyl-phenoxy)propyl analog (7) induced precocious meta-morphosis in the silkworm, and thus a modiÐcation wasmade by replacing the propyl group of the compound 7with other alkyl groups (Table 2). Among a series of (4-ethylphenoxy)alkyl 3-pyridyl ethers, the 5-(4-ethyl-phenoxy)pentyl analog (10) showed the highest activity.The activity decreased with increasing or decreasinglength of the carbon chain between the two oxygenatoms. Interestingly, the compounds with an even-

TABLE 2Precocious-Metamorphosis-Inducing Activity of (4-Ethyl-phenoxy)alkyl 3-Pyridyl Ethers against the 4th-Instar Larvae

of Bombyx mori

Activity (%)No. n Dose 160 (kg per larva)

8 2 07 3 309 4 0

10 5 7011 6 012 7 30

number alkyl chain had little precocious-metamorphosis-inducing activity.

Table 3 lists the values of some 5-ED50phenoxypentyl 3-pyridyl ether analogs with di†erentsubstituents on the benzene ring. The unsubstitutedphenyl compound (13) did not induce precocious meta-morphosis at 160 kg per larva. The introduction of achloro substituent at the para position on the benzenering (compound 14) increased the activity in compari-son with that of compound 10, while the 3- and 2-chlorophenyl analogs (15 and 16) gave much loweractivity. 2,4-Dichloro and 4-bromophenyl analogs (17and 18) had almost the same activity as that of com-pound 10, whereas the 4-Ñuorophenyl analog (19)showed much lower activity. The 4-propylphenyl analog(21) was twice as active as the 4-ethylphenyl analog (10),while the 4-isopropylphenyl analog (22) showed verylow activity in comparison with the activity observedfor compound 21. The 4-tert-butylphenyl analog (23)was inactive at 160 kg per larva, indicating that the sizeof the alkyl substituent on the benzene ring plays animportant role for activity. The 4-ethoxyphenyl analog(25) showed higher activity than compound 10, whilethe 4-methoxy- and 4-propoxyphenyl analogs (24 and26) had considerably lower activity. The introduction ofa phenoxy or benzyloxy group into the benzene ring (27and 28) completely eliminated the activity at 160 kg perlarva. Among the compounds tested so far, 5-(4-propylphenoxy)pentyl 3-pyridyl ether (21) was the most

TABLE 3Precocious-Metamorphosis-Inducing Activity of 5-(Substituted Phenoxy)pentyl 3-pyridyl Ethers against the 4th-

instar Larvae of Bombyx mori

No. R ED50 (kg per larva)a

13 H [160 (0)14 4-Cl 4015 3-Cl [160 (0)16 2-Cl [160 (10)17 2,4-Cl2 6118 4-Br 7119 4-F [160 (20)20 4-CH3 [80 (40)10 4-C2H5 6721 4-n-C3H7 3222 4-i-C3H7 [80 (10)23 4-t-C4H9 [160 (0)24 4-OCH3 [160 (10)25 4-OC2H5 4326 4-O-n-C3H7 [160 (30)27 4-OC6H5 [160 (0)28 4-OCH2C6H5 [160 (0)

a Numbers in parentheses show percentage precociouspupation at speciÐed doses.

256 Eiichi Kuwano et al.

e†ective of the analogs tested on the 4th-instar larvae ofB. mori.

For the 5-(4-propylphenoxy)pentyl 3-pyridyl ether(21), replacement of the 3-pyridyl group by a 2-pyridyl(29), 4-pyridyl (30) or phenyl (32) group gave analogswith negligible precocious-metamorphosis-inducingactivity (Table 4). This result indicates that the presenceof a 3-pyridyl group is essential for activity. In contrastto the results found in 3-pyridyl terpenoid ethers withJH activity,9 the introduction of a methyl group on the6-position of the pyridine ring (31) led to a drasticdecrease in precocious-metamorphosis-inducing activ-

TABLE 4Precocious-Metamorphosis-Inducing Activity of PyridylEthers and Related Compounds against the 4th-instar Larvae

of Bombyx mori

No. R ED50 (kg per larva)a

21 32

29 [160 (0)

30 [160 (0)

31 [160 (0)

32 [160 (0)

33 [160 (0)

34 34

a Numbers in parentheses show percentage precociouspupation at speciÐed doses.

ity. It is noteworthy that 1-[5-(4-propylphenoxy)hexyl]imidazole (34) showed activity comparable to that ofcompound 21, whereas the 1,2,4-triazole derivative withthe same substituent (33) did not induce precociousmetamorphosis even at a high dose of 160 kg per larva.

It has been reported that a variety of 1,5-dis-ubstituted imidazoles showed precocious-metamorphosis-inducing activity against 3rd-instarlarvae as well as against 4th-instar larvae. Table 5shows the e†ect of representative compounds 14 and 21on 24-h-old 3rd-instar larvae of B. mori. Third-instarlarvae were less sensitive than 4th-instar larvae to the3-pyridyl ethers. Compounds 14 showed no activityeven at a dose of 160 kg per larva, while compound 21induced precocious metamorphosis against 3rd-instarlarvae, though the activity was weak. In this case, pre-cocious metamorphosis occurred in the 4th(penultimate) larval stage. None of the treated 3rd-instar larvae metamorphosed into precocious pupae inthe same larval stage by a single topical application ofcompound 21, which is similar to the e†ect of 1,5-dis-ubstituted imidazoles.

In the 4th-instar larvae, precocious metamorphosisinduced by compounds 14 and 21 was completely pre-vented not only by a simultaneous application of 10 kgof methoprene, a JH mimic, but also by 0É01 kg of tebu-fenozide, an ecdysteroid agonist (Table 6). The latterresult suggests that these 3-pyridyl ethers, as well as 1,5-disubstituted imidazoles and 1-substituted imidazoles,temporarily depress the ecdysteroid titer in the larval

TABLE 5Precocious-Metamorphosis-Inducing Activity of 3-Pyridyl

Ethers against 24-h-old 3rd-instar Larvae

Compound Dose (kg per larva) Activity (%)

14 20 014 40 014 80 014 160 0

21 20 021 40 1021 80 1521 160 40

TABLE 6E†ects of Methoprene and Tebufenozide on Precocious Metamorphosis Induced by 3-Pyridyl

Ethers against the 4th-instar Larvae of Bombyx mori

Precocious metamorphosis (%)

Compound Dose ]Methoprene ]T ebufenozideNo. (kg per larva) Alone (10 kg) (0É01 kg)

14 80 65 0 021 80 80 0 0

Precocious-metamorphosis-inducing activity of 3-pyridyl ethers 257

hemolymph to induce precocious metamorphosis.However, counteraction by methoprene suggests someinteraction with JH biosynthesis or action as well. Onthe basis of the preliminary biological data described inthis article, it is concluded that 3-pyridyl ethers rep-resent reasonable leads for the development of newinsect growth regulators.

ACKNOWLEDGEMENT

We thank Prof. Lawrence G. Harshman of Universityof Nebraska for his critical reading and improvement ofthis manuscript. This work was supported in part bygrant-aid for scientiÐc research (No. 07556081) from theMinistry of Education, Science and Culture of Japan.

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