CN1051702C

CN1051702C - Preparing process of amine derivative and fungusicide containing amine derivative

Info

Publication number: CN1051702C
Application number: CN89101433A
Authority: CN
Inventors: 前田铁也; 山本俊之; 高濑三夫; 佐佐本和也; 有可正; 横尾守; 桥本理惠子; 雨宫功治; 越川荣
Original assignee: Kaken Pharmaceutical Co Ltd
Current assignee: Kaken Pharmaceutical Co Ltd
Priority date: 1987-03-19
Filing date: 1989-03-17
Publication date: 2000-04-26
Anticipated expiration: 2000-06-08
Also published as: CN1035771A

Abstract

The present invention relates to a novel amine derivative used as a fungicide. The novel amine derivative has the general formula that definitions of X, Y, R1, R2, R3, R4 and R5 in the general formula are disclosed in the specification.

Description

The preparation method of Fungicidal composition

The present invention relates to the to have general formula amine derivative of (I)

X is selected from following groups in the formula:

Q be oxygen, sulfur or nitrogen-atoms and

, Q is the same; Y is selected from following groups: With

R ¹Be hydrogen atom or C ₁-C ₆(C preferably ₁-C ₄) the straight or branched alkyl; R ²Be hydrogen atom or C ₁-C ₆(C preferably ₁-C ₄) the straight or branched alkyl; R ³Be hydrogen atom, fontanelle atom (as fluorine, chlorine, bromine, iodine) or C ₁-C ₆(C preferably ₁-C ₄) the straight or branched alkyl; R ⁴Be hydrogen atom, C ₁-C ₁₀(C preferably ₁-C ₇) straight or branched alkyl, C ₃-C ₇(C preferably ₅-C ₆) cycloalkyl, haloalkyl (as trifluoromethyl) or halogen atom (as fluorine, chlorine, bromine, iodine); R ⁵Be hydrogen atom, C ₁-C ₆(C preferably ₁-C ₄) straight or branched alkyl, C ₁-C ₆(C preferably ₁-C ₄) straight or branched alkoxyl, halogen atom (as fluorine, chlorine, bromine, iodine), nitro or hydroxyl; R ⁵Be connected in arbitrary position of X, R ³Or R ⁴Be connected in arbitrary position of Y, the present invention also relates to the preparation method of these chemical compounds and with the antifungal of this compounds as active component.

It all is feasible on pharmacology that the salt of the amine of this type of tool general formula (I) has hydrogen chlorate, hydrobromate, sulfate, nitrate, acetate, oxalates, tartrate, benzene sulfonate, mesylate etc.

Chemical compound of the present invention can be with the preparation of following method: for example: (a) with the chemical compound of general formula (II)

(R in the formula ¹, R ⁵The same with the definition of X; A is an elimination group or a R ²-NH-, R ²Definition the same) with general formula be (III)

(R in the formula ³, R ⁴The same with the definition of Y; A is an elimination group or a R ²-NH-, R ²Definition the same, different in A and the formula (II)) chemical compound act on mutually;

(b) will have general formula (IV)

(R in the formula ³, R ⁴, R ⁵, X and Y definition the same; W is

R ¹, R ²Definition the same) chemical compound reduction.Collect by (a) or (b) resulting product with the form of free alkali or its acid-addition salts.

Above-mentioned (a) method and (b) method can carry out according to a conventional method.

(a) method can be reacted in aromatic hydrocarbons (as benzene, toluene), ether (as ether, dioxane) or alkyl carboxylic acid amides (as dimethyl formamide) equal solvent, reaction temperature is room temperature～solvent boiling point (preferably room temperature～60 ℃), and eliminating group A can be fontanelle atom (as chlorine, bromine), C ₁-C ₁₀Organic sulfonyloxy (as tosyloxy, mesyloxy), reaction is preferably under the existence of acid binding agent (carbonate of alkali metal hydroxide or alkaline earth metal hydroxide, alkali metal or alkaline-earth metal-as sodium carbonate, potassium carbonate) to be carried out.

(b) method can be carried out in ethers atent solvent (as ether, oxolane, dioxane), and reaction temperature is that room temperature or room temperature are between the boiling temperature of solvent; Make Reducing agent with lithium aluminium hydride reduction.

To be converted into acid-addition salts or carry out from its free alkali by the chemical compound with general formula (I) of the present invention from the available conventional method of reaction that acid-addition salts is converted into free alkali.

In order to prepare the chemical compound with formula (I) of the present invention, promptly general formula is that (II), (III) or chemical compound (IV) are easily with the conventional method preparation, no matter whether they are known compound or noval chemical compound as initiation material.Their preparation method can be exemplified below:

R wherein ¹, R ², R ³, R ⁴, R ⁵, X and Y definition the same.

Reaction is to carry out under the normal condition that adopts of this class reaction, and product can not need separate and further reacts in the middle of it; As separating, also can be undertaken by customary way.

Chemical compound of the present invention has good antifungal activity, in vitro tests when concentration is 0.003～100 μ g/ml shows antibacterial activity to Trichophyton mentagrophytes, trichophyton interdigitalis, trichophyton rubrum, canine tooth sporidiole bacteria (Microsporum gypseum), acrothesium floccosum, Cryptococcus histolyticus, Sporothrix Schenekii, Aspergillus fumigatus and Candida albicans especially.Live test to the Cavia porcellus dermatomycosis (is seen Sumio Sakai:Shinkin To Shinkinsho, has been proved also that Vol.1.252.1960) chemical compound of the present invention has good antifungal activity.

Chemical compound of the present invention can be made the antifungal of forms such as liquid preparation, ointment, butterfat.Though the consumption of active component is looked the difference of the kind of degree, chemical compound of kind, the disease of fungus and dosage form etc. and difference, by the antifungal of compound of the present invention, its concentration is generally 0.01～5%.

Following reference example, example, preparation example and test example can further be illustrated the present invention.Yet, must understand, the present invention is not limited to these examples, various variation and change can be arranged not leaving under the spiritual principles of the present invention.

Following nuclear magnetic resonance, NMR (NMR) spectrum is at CDCl ₃In be that standard substance is measured with trimethyl silane (TMS).Fusing point in each example is the hydrogen chlorate's of chemical compound a fusing point, and the NMR spectrum is used the free alkali of chemical compound.

The preparation of reference example 1[4-iodo-1 chloromethyl naphthalene]

The mixture of 17.8 gram 1-iodo-naphthalenes, 4,4 gram paraformaldehydes, 10.4 milliliters of acetic acid, 14.6 milliliters of concentrated hydrochloric acid and 6.6 milliliters of phosphoric acid is stirred down, and then add 20 milliliters of concentrated hydrochloric acid in addition at 80-85 ℃, stir each 1 hour at interval 8 times.In reactant mixture impouring water, use benzene extraction, steaming obtains 18.5 gram 4-iodo-1 chloromethyl naphthalenes after falling benzene.NMR?δ(CDCl ₃)：

8.08～6.86(m，6H)，4.78(S，2H)

Prepared following chemical compound with identical method

4-bromo-1 chloromethyl naphthalene fusing point: 82～83.5 ℃ of NMR δ (CDCl ₃):

8.33～7.15(m，6H)，4.86(S，2H)

The preparation of reference example 2[N-methyl-4-tert-butyl group benzyl amine]

The mixture of 178 gram uncle's 4-ar-Toluic acids and 360 gram thionyl chlorides was stirred 5 hours down in 50 ℃.After under reduced pressure remaining thionyl chloride being steamed, the dropwise reaction product in 300 milliliter of 40% methylamine water solution, restir 3 hours.Use hcl acidifying, obtain 171 gram N-methyl-4-tert-butyl benzene Methanamide precipitations (fusing point: 99～100 ℃).

The amide that obtains is added in the mixture of 30.4 gram lithium aluminium hydride reductions and 1 liter of absolute ether, refluxed 6 hours.Put cold after, drip entry to decompose remaining lithium aluminium hydride reduction, tell ether layer and wash with water, use anhydrous sodium sulfate drying.Carry out distilling under reduced pressure after steaming ether, obtain N-methyl-tert-butyl benzene methylamine colourless liquid (93～95 ℃ of boiling points/6mmHg).NMR?δ(CDCl ₃)：

7.26 (S, 4H), 3.68 (S, 2H), 2.42 (S, 3H), 1.29 (S, 9H) hydrochlorate fusing points: 208.5～209.5 ℃

The preparation of reference example 3[N-propyl group-1-naphthyl methylamine]

Drip 25 gram 1-naphthoyl chlorides in 116 gram propylamine, resulting mixture was stirred 3 hours, leach with formed crystallization after the salt acidify and wash with water.Resulting 26.8 gram N-propyl group-1-naphthalenecarboxamides are added in the mixture of 14.1 gram aluminium hydroxide lithiums and 300 milliliters of absolute ethers, refluxed 11 hours, put cold back dropping water remaining lithium aluminium hydride reduction is decomposed.Steam ether, and then distilling under reduced pressure, colourless liquid N-propyl group-1-naphthyl methylamine 16.6 grams obtained, 133～134 ℃/1.5mmHg of boiling point.NMR?δ(CDCl ₃)

8.2～7.2 (m, 7H), 4.20 (s, 2H), 2.69 (t, J=7Hz), 1.86～1.15 (m, 2H), 0.90 (t, J=7Hz, 3H) (t, J=7H 3H) in kind produce following compounds:

N-methyl isophthalic acid-naphthyl methylamine

N-ethyl-1-naphthyl methylamine

N-butyl-1-naphthyl methylamine

The preparation of reference example 4[N-methyl-N-(1-naphthyl methyl)-4-cumene Methanamide]

0.99 gram 4-isopropyl acid and 3.6 gram thionyl chloride mixture were stirred 4 hours down at 50 ℃, and remaining thionyl chloride is removed in decompression then.Resulting carboxyl acyl chloride is dissolved in 5 milliliters of anhydrous benzene.Then benzole soln is added dropwise in the mixture of 1.03 gram N-methyl isophthalic acid-naphthyl methylamines, 2 milliliters of triethylamines and 15 milliliters of anhydrous benzene and stirred 3 hours, then with in the reactant mixture impouring water, with the benzene extraction, in succession with 5% aqueous hydrochloric acid solution, 3% sodium bicarbonate aqueous solution and water washing extract.Obtain sticking N-methyl-N-(1-naphthyl methyl)-4-isopropyl Methanamide after steaming benzene.NMR δ (CCl ₄, n-compound TMS)

8.0～7.0(m，11H)，5.03(s，2H)，

2.80(S，3H)，3.1～2.6(m，1H)，

1.18(S，J＝7H ₂，6H)

Prepared following compounds with identical method:

N-methyl-N-(1-naphthyl methyl)-4-ethyl benzamide NMR δ (CCl ₄N-compound TMS):

8.0?to?6.95(m，11H)，5.07(s，2H)，2.78(s，3H)，

2.75(q，J＝7.6Hz，2H)?and?1.15(t，J＝7.6Hz，2H)

N-methyl-N-(1-naphthyl methyl)-4-butyl benzamide NMR δ (CCl ₄, n-compound TMS):

8.0?to?6.9(m，11H)，5.02(s，2H)，2.79(s，3H)，

2.79(s，3H)，2.54(t，J＝7Hz，2H)，1.7?to?1.15

(m，4H)?and?0.88(t，J＝7Hz，3H)

N-methyl-N-(1-naphthyl methyl)-3,4-dimethyl benzamide NMR δ (CCl ₄, n-compound TMS):

8.0?to?6.8(m，10H)，4.99(s，2H)，2.76(s，3H)

and?2.13(s，6H)

N-methyl-N-(1-naphthyl methyl)-3,5-dimethyl benzamide NMR δ (CCl ₄, n-compound TMS):

8.0?to?6.8(m，10H)，5.00(s，2H)，2.72(s，3H)

and?2.15(s，6H)

N-methyl-N-(1-naphthyl methyl)-4-iodobenzene Methanamide

Fusing point: 136.5～138.5 ℃

NMR δ (CCl ₄, n-compound TMS):

8.0?to?7.01(m，11H)，5.03(s，2H)?and?2.80(s，3H)

The preparation of reference example 5[N-(4-tert-butyl group benzyl)-N-methyl-2-ethyoxyl carboxyl-1-naphthalenecarboxamide]

Dissolving 7.52 gram 2-hydroxyl-1-naphthoic acids in sodium hydrate aqueous solution (3.63 gram sodium hydroxide add 71.5 ml waters), drip 9.59 gram chloro ethyl formates down in cooling, at room temperature mixture was stirred 1 hour, in the impouring water, extract with benzene then, extract is with water washing, use anhydrous sodium sulfate drying, remove sodium sulfate after the drying, add 5.24 gram thionyl chlorides, react on and carried out under 40 ℃ 3 hours, again resulting carboxyl acyl chloride is added dropwise in the mixture of 7.08 gram N-methyl-4-tert-butyl benzene methylamines and 8 gram pyridines and stirred 3 hours, then will be in the reactant mixture impouring water and with the benzene extraction, in succession with 3% aqueous hydrochloric acid solution and water washing benzole soln and usefulness anhydrous sodium sulfate drying it.Obtain oily N-(4-tert-butyl group benzyl)-N-methyl-2-ethoxy carbonyl-1-naphthalenecarboxamide 6.6 grams after steaming benzene.

Example 1

With 1.94 gram 1 chloromethyl naphthalenes, 1.77 gram N-methyl-4-tert-butyl benzene methylamines, 1.17 gram sodium carbonate and 10 milliliters of N, the N-diformamide stirred 14 hours down at 50 ℃, then with in the reactant mixture impouring water, extract with benzene, extraction solution is with water washing, benzene is steamed, add 1.5 milliliters of concentrated hydrochloric acid, remaining concentrated hydrochloric acid is removed in decompression again.Add acetone in a small amount, obtain white crystal 2.75 grams, leach crystal, recrystallization in acetone obtains tabular N-(4-tert-butyl group benzyl)-N-methyl isophthalic acid-naphthalene methylamine hydrochloric salt of white.Fusing point: 211～213 ℃

NMR?δ：

8.3?to?7.3(m，11H)，3.91(S，2H)，

3.56 (S, 2H), 2.19 (S, 3H) and 1.33 (S, 9H); M S (m/e):

317 (M ⁺), 190,176,170,147 and 141 (base)

Example 4

1.23 gram 1-chloromethyl-4-fluoronaphthalenes and 1.15 gram N-methyl-4-tert-butyl benzene methylamines are reacted, obtain N-(4-tert-butyl group benzyl)-N-methyl-4-fluoro-1-naphthalene methylamine (2.0 gram)

Example 9

1.20 gram 1-(1-chloroethyl) naphthalenes and 1.15 gram N-methyl-4-tert-butyl benzene methylamines are reacted, obtain N-(4-tert-butyl group benzyl)-N-methyl isophthalic acid-(1-naphthyl) ethamine (1.33 gram).

Example 12

1.11 gram 1 chloromethyl naphthalenes and 1.15 gram N-methyl-4-tert-amyl benzene methylamines are reacted, obtain N-methyl-N-(4-tertiary pentyl benzyl)-1-naphthalene methylamine (1.65 gram).

Example 22

1.11 gram 1 chloromethyl naphthalenes and 0.98 gram N-methyl-4-cumene methylamine are reacted, obtain N-(4-isopropyl benzyl)-N-methyl isophthalic acid-naphthalene methylamine (1.47 gram).

Example 29

0.89 gram 3-chloromethylbenzene [b] thiophene and 0.91 gram N-methyl-4-tert-butyl benzene methylamine are reacted, obtain N-(4-tert-butyl group benzyl)-N-methyl-3-benzene [b] thienyl methylamine (1.4 gram).

Example 2～71

Produce the hydrochlorate of various amine derivatives by the method for example 1.The fusing point of each chemical compound is listed in the table 1.

Table 1

Table 1 (continuing)

Table 1 (continuing)

Table 1 (continuing)

Table 1 (continuing)

Table 1 (continuing)

Table 1 (continuing)

Table 1 (continuing)

Table 1 (continuing)

Table 1 (continuing)

Table 1 (continuing)

Be the NMR and MS (m/e) data of example 2～71 each chemical compound below:

Example 2NMR δ:

8.35?to?7.23(m，10H)，3.97(s，2H)，3.54(s，2H)，

2.57(s，3H)，2.17(s，3H)?and?1.28(s，9H)MS(m/e)：

331(M ⁺)，176，152(base)?and?147

Example 3NMR δ:

8.4?to?7.3(m，10H)，3.88(s，2H)，3.53(s，2H)，

2.63(s，3H)，2.13(s，3H)?and?1.28(s，9H)MS (m/e)：

331(M ⁺)，184，176，152(base)?and?147

Example 4NMR δ:

8.3?to?6.8(m，10H)，3.84(s，2H)，3.52(s，2H)，

2.18(s，3H)?and?1.30(s，9H)

MS (m/e)：

335(M ⁺)，188，176，154?(base)?and?147

Example 5NMR δ:

8.3?to?7.3(m，10H)，3.83(s，2H)，3.53(s，2H)，

2.17(s，3H)?and?1.30(s，9H)

MS (m/e)：

351(M ⁺)，204，176，175?(base)?and?147

Example 6NMR δ:

8.3?to?7.3(m，10H)，3.77(s，2H)，3.50(s，2H)，

2.13(s，3H)?and?1.29(s，9H)

MS (m/e)：

397(M ⁺)，395(M ⁺)，250，248，219，201，176?(base)

and?147

Example 7NMR δ:

8.3?to?7.1?(m，10H)，3.82(s，2H)，3.52(s，2H)，

2.17(s，3H)?and?1.30(s，9H)

MS (m/e)：

443(M ⁺)，296，267，217，176?(base)?and?147

Example 8NMR δ:

8.6?to?7.3(m，10H)，3.91(s，2H)，3.54(s，2H)，

2.19(s，3H)?and?1.29(s，9H)

MS (m/e)：

362(M ⁺)，215，186，176?and?147?(base)

Example 9NMR δ:

8.54?to?7.22(m，11H)，4.36(q，J＝6.6Hz，1H)，

3.63(d，J＝13Hz，1H)，?3.34?(d，J＝13Hz，1H)，

2.19(s，3H)，1.53(d，J＝6.6Hz，2H)?and

1.28(s，9H)

MS (m/e)：

331(M ⁺)，316，204，176，152?and?147?(base)

Example 10NMR δ:

7.9?to?7.3(m，11H)，3.63(s，2H)，3.53(s，2H)，

2.21(s，3H)?and?1.31(s，9H)

MS (m/e)：

317?(M ⁺)，176?(base)，170，147，142?and?141

Example 11NMR δ:

8.3?to?7.1(m，10H)，3.98(s，2H)，3.88(s，3H)，

3.55(s，2H)2.20(s，3H)?and?1.28(s，9H)

MS (m/e)：

347?(M ⁺)，200，176，171?(base)，147?and?141

Example 12NMR δ:

8.3?to?7.3(m，11H)，3.88(s，2H)，3.54(s，2H)，

2.17(s，3H)，1.61(q，J＝7.3Hz，2H)，1.26(s，6H)

and?0.67(t，J＝7.3Hz，3H)

MS (m/e)：

331?(M ⁺)，190，170，155?and?141?(base)

Example 13NMR δ:

8.3?to?7.1(m，11H)，3.90(s，2H)，4.55(s，2H)，

2.33(s，3H)?and?2.19(s，3H)

MS (m/e)：

275?(M ⁺)，170，141?(base)，134?and?105

Example 14

NMR?δ：

8.3?to?7.3(m，11H)，3.87(s，2H)，3.53(s，2H)

and?2.16(s，3H)

MS (m/e)：

329?(M ⁺)，202，188，154，142?and?141?(base)

Example 15NMR δ:

8.3?to?7.0(m，11H)，3.87(s，2H)，3.53(s，2H)，

2.29(s，3H)?and?2.15(s，3H)

MS (m/e)：

275?(M ⁺)，170，141?(base)，134?and?115

Example 16NMR δ:

8.3?to?7.0(m，11H)，3.89(s，2H)，3.54(s，2H)，

2.5(m，1H)，2.17(s，3H)?and?2?to?1.1(m，10H)

MS (m/e)：

343?(M ⁺)，202，173，170?and?141?(base)

Example 17NMR δ:

8.3?to?7.0(m，10H)，3.87(s，2H)，3.43(s，2H)

and?2.15(s，3H)

MS (m/e)：

329?(M ⁺)，202，188，170，142?and?141?(base)

Example 18NMR δ:

8.3?to?7.2(m，11H)，3.97(s，2H)，3.54(s，2H)，

2.56(q，J＝7Hz，2H)，1.24(s，9H)?and?1.02

(t，J＝7Hz，3H)

MS (m/e)：

331?(M ⁺)，316，190，147?and?141?(base)

Example 19NMR δ:

8.3?to?7.2(m，11H)，3.91(s，2H)，3.53(s，2H)，

2.59(t，J＝7Hz，2H)，1.74?to?1.47(m，2H)，

1.25(s，9H)?and?0.78(t，J＝7Hz，3H)

MS (m/e)：345?(M ⁺)，316，147?and?141?(base)

Example 20NMR δ: 8.3 to 7.2 (m, 11H), 3.94 (s, 2H), 3.53 (s, 2H), 2.48 (t, J=7Hz, 2H) and 1.24 (s, 9H)

MS (m/e)：359?(M ⁺)，316，147?and?141?(base)

Example 21NMR δ: 8.3 to 7.06 (m, 11H), 3.89 (s, 2H), 3.47 (s, 2H) and 2.15 (s, 3H)

MS (m/e)：341?(M ⁺)，339?(M ⁺)，200，198，171，169?and141?(base)

Example 22NMR δ: 8.3 to 7.0 (m, 11H), 3.90 (s, 2H), 3.54 (s, 2H), 3.80 (q, J=7.4Hz, 1H), 2.17 (s, 3H) and 1.22 (d, J=7.4Hz, 6H)

MS (m/e)：303?(M ⁺)，170，155，141?(base)?and?133

Example 23NMR δ: 8.3 to 7.0 (m, 11H), 3.88 (s, 2H), 3.54 (s, 2H), 2.59 (q, J=7Hz, 2H), 2.16 (s, 3H) and 1.19 (t, J=7Hz, 3H)

MS (m/e)：289?(M ⁺)，170，148，141?(base)?and?119

Example 24NMR δ: 8.3 to 7.0 (m, 11H), 3.88 (s, 2H), 3.55 (s, 2H), 2.58 (t, J=7Hz, 2H), 2.16 (s, 3H) and 1.9 to1.2 (m, 4H)

MS (m/e)：317?(M ⁺)，176，147?and?141?(base)

Example 25NMR δ:

8.3?to?7.05(m，10H)，4.86(s，2H)，4.51(s，2H)，

2.22(s，6H)?and?2.16(s，3H)

MS (m/e)：

289?(M ⁺)，170，148，141?(base)?and?119

Example 26NMR δ:

8.3?to?6.9(m，10H)，3.88(s，2H)，3.53(s，2H)，

2.29(s，6H)?and?2.19(s，3H)

MS (m/e)：

289?(M ⁺)，170，148，141?(base)?and?119

Example 27NMR δ:

8.3?to?6.89(m，11H)，3.83(s，2H)，3.39(s，2H)

and?2.10(s，3H)

MS (m/e)：

387?(M ⁺)，260，246，217，170?and?141

Example 28NMR δ:

7.9?to?7.15(m，10H)，4.16(s，2H)，3.63(s，2H)，

2.30(s，3H)?and?1.31(s，9H)

MS (m/e)：

333?(M ⁺)，176?(base)，153，147，128?and?120

Example 29NMR δ:

8.0?to?7.2(m，9H)，3.74(s，2H)，3.54(s，2H)，

2.21(s，H)?and?1.30(s，9H)

MS (m/e)：

147?(base)，148，176?and?232?(M ⁺)

Example 30NMR δ:

8.0?to?7.2(m，9H)，3.76(s，2H)，3.55(s，2H)，

2.54(t，J＝7.2Hz，2H)，1.28(s，9H)?and?1.07

(t，J＝7.2Hz，3H)

MS (m/e)：

147?(base)，148，190，322?and?337?(M ⁺)

Example 31NMR δ:

8.2?to?7.1(m，12H)，3.90(s，2H)，3.73(s，2H)

and?2.20(s，3H)

MS (m/e)：

141，147?(base)，148，170，176?and?317?(M ⁺)

Example 32NMR δ:

8.0?to?7.2(m，12H)，3.73(s，2H)，3.65(s，2H)

and?2.20(s，3H)

MS (m/e)：

141，142，147?(base)，148，170，176?and?317?(M ⁺)

Example 33NMR δ:

7.9?to?7.4(m，8H)，3.72(s，2H)，2.52(s，3H)，

2.20(s，2H)?and?1.29(s，9H)

MS (m/e)：

161?(base)，162，176，190?and?337?(M ⁺)

Example 34NMR δ:

7.83?to?7.23(m，9H)，3.78(s，2H)，3.53(s，2H)，

2.17(s，3H)?and?1.32(s，9H)

MS (m/e)：

147?(base)，148，176，190?and?323?(M ⁺)

Example 37NMR δ:

7.64(m，8H)，3.73(s，2H)，3.57(s，2H)，2.15

(s，3H)?and?1.31(s，9H)

MS (m/e)：

147，176?(base)，225，227，254，256?401?(M ⁺)

and?403?(M ⁺)

Example 38NMR δ:

7.28?to?7.12(m，7H)，3.47(s，4H)，2.88

(t，J＝7Hz，4H)，2.17(s，3H)，2.02(t，J＝7Hz，2H)

and?1.30(s，9H)

MS (m/e)：

131?(base)，132，147，160，176?and?307?(M ⁺)

Example 39NMR δ:

7.27?to?6.93(m，7H)，3.48，3.45(s，s，4H)，

2.95?to?2.62(m，4H)，2.13(s，3H)，1.88?to

1.67(m，4H)?and?1.32(s，9H)

MS (m/e)：

129，144?(base)，145，147，176，178?and?321?(M ⁺)

Example 40NMR δ:

7.27(s，4H)，7.03(s，3H)，3.48，3.45(s，s，4H)，

2.9?to?2.6(m，4H)，2.16(s，3H)，1.88?to?1.67

(m，4H)?and?1.29(s，9H)

MS (m/e)：

139，140，141，174，176?(base)?and?321?(M ⁺)

Example 41NMR δ:

8.15?to?6.03(m，13H)，3.91(s，2H)，3.81(s，2H)

and?2.19(s，3H)

MS (m/e)：

137，149?(base)，170，188?and?327?(M ⁺)

Example 42NMR δ:

8.15?to?6.83(m，13H)，3.91(s，2H)，3.85(s，2H)

and?2.19(s，3H)

MS (m/e)：

147，154?(base)，176，188?and?335?(M ⁺)

Example 43NMR δ:

8.36?to?6.87(m，13H)，3.90(s，2H)，3.71(s，2H)

and?2.19(s，3H)

MS (m/e)：

137，138，149?(base)，170，188?and?329?(M ⁺)

Example 44NMR δ:

8.3?to?7.1(m，13H)，3.94(s，2H)，3.87(s，2H)

and?2.21(s，9H)

MS (m/e)：

137?(base)，138，170，175，204?and?345?(M ⁺)

Example 45NMR δ:

8.35?to?7.2(m，13H)，3.84(s，2H)，3.66(s，2H)and?2.16(s，3H)

MS (m/e)：137?(base)，138，170，175，204?and?345?(M ⁺)

Example 46

NMR?δ：8.32?to?7.11(m，13H)，3.92(s，2H)，3.83(s，2H)and?2.19(s，3H)

MS (m/e)：137?(base)，138，170，219，221，248，250，389and?391?(M ⁺)

Example 47

NMR δ: (8.47 to 7.45 of dimethyl sulfoxide-d6) (m, 13H), 3.92 (s, 2H), 3.72 (s, 2H) and 2.16 (s, 3H)

MS (m/e)：137?(base)，138，170，219，221，248，250，389and?391?(M ⁺)

Example 48

NMR?δ：8.2?to?7.1(m，13H)，3.90(s，4H)，2.61(s，3H)and?2.19(s，3H)

MS (m/e)：137，146?(base)，147，170，184?and?325?(M ⁺)

Example 49

NMR?δ：8.44?to?7.3(m，13H)，3.95(s，2H)，3.74(s，2H)，2.66(s，3H)?and?2.22(s，3H)

MS (m/e)：137?(base)，138，146?(base)，147，170，184and?325?(M ⁺)

Example 50

NMR?δ：8.57?to?7.23(m，13H)，3.85(s，2H)，3.66(s，2H)and?2.16(s，3H)

MS (m/e)：137?(base)，138，170，186，215?and?356?(M ⁺)

Example 51

NMR?δ：8.55?to?7.3(m，14H)，4.40(q，J＝6.5Hz，1H)，3.70，3.63(s，s，2H)，2.21(s，3H)?and1.59(d，J＝6.5Hz，3H)

MS (m/e)：137?(base)，146，162，170，184，198，310?and325?(M ⁺)

Example 52

NMR?δ：8.37?to?7.02(m，10H)，3.85(s，2H)，3.47(s，2H)，2.81(t，J＝7Hz，4H)，2.13(s，3H)?and?2.01(t，J＝7Hz，2H)

MS (m/e)：131，137?(base)，150，170?and?301?(M ⁺)

Example 53

NMR?δ：8.0?to?6.8(m，10H)，3.73(s，2H)，3.36(s，2H)，2.9?to?2.5(m，4H)，2.07(s，3H)?and?1.8?to?1.5(s，4H)

MS (m/e)：129，137，139?(base)，172?and?315?(M ⁺)

Example 54

NMR?δ：8.26?to?6.86(m，10H)，3.80(s，2H)，3.42(s，2H)，2.8?to?2.5(m，4H)，2.11(s，3H)?and?1.9?to?1.6(m，4H)

MS (m/e)：137?(base)，139，170，174?and?315?(M ⁺)

Example 55

NMR?δ：8.09?to?6.94(m，10H)，3.91(s，2H)，3.54(s，2H)，2.9?to?2.5(m，4H)，2.51(q，J＝7Hz，2H)，1.9?to1.6(m，4H)?and?1.05(t，J＝7Hz，3H)

MS (m/e)：137，138?(base)，184，186?and?329?(M ⁺)

Example 56

NMR?δ：8.38?to?7.01(m，10H)，3.99(s，2H)，3.56(s，2H)，2.9?to?2.38(m，6H)，1.9?to?1.6(m，4H)?and1.07(t，J＝7Hz，3H)

MS (m/e)：137?(base)，139，184，188，314?and?329?(M ⁺)

Example 57

NMR?δ：8.12(m，10H)，3.94(s，2H)，3.56(s，2H)，3.0?to?2.33(m，6H)，1.9?to?1.28(m，6H)?and0.77(t，J＝7Hz，3H)

MS (m/e)：137?(base)，139，198，200，314?and?343

Example 58

NMR?δ：8.35?to?7.03(m，10H)，3.98(s，2H)，3.57(s，2H)，2.9?to?2.34(m，6H)，1.9?to?1.3(m，6H)?and0.78(t，J＝7Hz，3H)

MS (m/e)：137?(base)，139，314?and?343?(M ⁺)

Example 59

NMR?δ：8.1?to?6.9(m，10H)，3.92(s，2H)，3.55(s，2H)，2.9?to?3.33(m，6H)，1.9?to?1.0(m，8H)?and0.76(t，J＝6Hz，3H)

MS (m/e)：137?(base)，139，212，214，314?and?357?(M ⁺)

Example 60

NMR?δ：8.35?to?7.04(m，10H)，3.95(s，2H)，3.54(s，2H)，2.9?to?2.37(m，6H)，1.9?to?1.0(m，8H)?and0.79(t，J＝6Hz，3H)

MS (m/e)：137?(base)，139，314?and?357?(M ⁺)

Example 62

NMR?δ：8.14?to?7.04(m，14H)，3.95(s，4H)，2.54(q，J＝7.5Hz，2H)?and?1.07(t，J＝7.5Hz，3H)

MS (m/e)：137?(base)，138，184，310?and?325?(M ⁺)

Example 63

NMR?δ：8.37?to?7.15(m，14H)，3.90(s，2H)，3.60(s，2H)，2.49(q，J＝7Hz，2H)?and?1.00(t，J＝7Hz，3H)

MS (m/e)：1.37?(base)，138，184，310?and?325?(M ⁺)

Example 64

NMR?δ：8.12?to?7.06(m，14H)，3.97(s，4H)，2.59?to2.33(m，2H)，1.9?to?1.3(m，2H)?and?0.71(t，J＝7Hz，3H)，

MS (m/e)：137?(base)，310?and?339?(M ⁺)

Example 65

NMR?δ：8.36?to?7.2(m，14H)，3.98(s，2H)，3.68(s，2H)，2.50(t，J＝7Hz，2H)，1.7?to?1.1(m，2H)?and0.75(t，3H)

MS (m/e)：137?(base)，138，198，310?and?339?(M ⁺)

Example 66

NMR?δ：8.11?to?7.0(m，14H)，3.93(s，4H)，2.46(t，J＝6.5Hz，2H)，1.6?to?0.9(m，4H)?and0.69(t，J＝6Hz，3H)

MS (m/e)：137?(base)，138，212，310?and?353?(M ⁺)

Example 67

NMR?δ：8.4?to?7.35(m，14H)，4.06(s，2H)，3.77(s，2H)，2.54(t，J＝7Hz，2H)，1.8?to?0.9(m，4H)?and0.77(t，J＝6Hz，3H)

MS (m/e)：137?(base)，138，212，310?and?353?(M ⁺)

Example 68

NMR?δ：8.44?to?7.2(m，13H)，4.02(s，2H)，3.91(s，2H)and?2.28(s，3H)

MS (m/e)：138?(base)，170?and?312?(M ⁺)

Example 69

NMR?δ：8.4?to?6.7(m，9H)，3.95(s，2H)，3.76(s，2H)，2.25(s，3H)?and?1.33(s，9H)

MS (m/e)：137，141?(base)，144，182，190?and?323?(M ⁺)

Example 70

NMR?δ：8.13?to?7.28(m，9H)，4.11(s，2H)，3.83(s，2H)，1.74(broad?s，1H)?and?1.29(s，9H)

MS (m/e)：137?(base)，138，141，147，151?and?303?(M ⁺)

Example 71

NMR?δ：8.82?to?7.26(m，10H)，3.85(s，2H)，3.54(s，2H)，2.17(s，3H)?and?1.27(s，9H)

MS (m/e)：141?(base)，171，176，190?and?318?(M ⁺)

Example 72

Add 1.3 gram 4-tertiary pentyl benzyl chlorides in 1.03 gram N-methyl isophthalic acid-naphthyl methylamines, 0.7 gram sodium carbonate and 10 milliliters of N, in the mixture of dinethylformamide, stirred 16 hours under the room temperature, then with in the reactant mixture impouring water, extract with benzene, extract washes with water, add 1.5 milliliters of concentrated hydrochloric acid after steaming benzene, again unnecessary concentrated hydrochloric acid is removed, add small amount of acetone, generate 1.33 gram white crystals, crystal is leached, recrystallization in acetone obtains white crystal N-(4-tertiary pentyl benzyl)-N-methyl isophthalic acid-naphthalene methylamine hydrochloric salt (example 12 chemical compounds).Fusing point: 191～193 ℃ of NMR δ:

8.3?to?7.3(m，11H)，3.88(s，2H)，3.54(s，2H)，

2.17(s，3H)，1.61(q，J＝7.3Hz，2H)，1.26(s，6H)

0.67(t，J＝7.3Hz，3H)

MS (m/e)：

331 (M ⁺), 190,170,155 and 141 (base)

Example 73

With 3.43 gram N-methyl isophthalic acid-naphthalene methylamines, 3.65 gram 4-tert-butyl group benzyl chlorides, 2.33 gram natrium carbonicum calcinatum and 20 milliliters of N, the mixture of dinethylformamide stirred 16 hours down at 50 ℃.To extract with benzene in the reactant mixture impouring water then, benzole soln is with water washing.After steaming benzene, under cooling, add 3 milliliters of concentrated hydrochloric acid, under reduced pressure remove too much concentrated hydrochloric acid, add an amount of acetone again, generate white crystals (5.9 gram).Crystallization is leached, and recrystallization in acetone obtains white platelike crystal N-(4-tert-butyl group benzyl)-N-methyl isophthalic acid-naphthalene methylamine hydrochloric salt (example 1 chemical compound).Fusing point: 210～212 ℃

By the method for example 73 to produce the amine derivative hydrochlorate of example 1～71.

Example 74

1.14 gram N-methyl-4-fluoro-1-naphthyl methylamine and 1.24 gram 4-tert-butyl group benzyl chloride effects obtain N-(4-fluoro-1-naphthyl methyl)-N-methyl-4-tert-butyl benzene methylamine (1.94 gram) (example 4 chemical compounds).

Example 75

1.11 gram N-methyl isophthalic acid-(1-naphthyl) ethamine and 1.24 gram 4-tert-butyl group benzyl chloride effects obtain N-(4-tert-butyl group benzyl)-N-methyl isophthalic acid-(1-naphthyl) ethamine (1.61 gram) (example 9 chemical compounds).

Example 76

1.03 gram N-methyl isophthalic acid-naphthyl methylamine and 0.99 gram 4-isopropyl benzyl chlorine effect obtain N-(4-isopropyl benzyl)-N-methyl isophthalic acid-naphthyl methylamine (1.75 gram) (example 22 chemical compounds)

Example 77

0.98 gram N-methyl-3-benzene (b) thienyl methylamine and 1.24 gram 4-tert-butyl group benzyl chloride effects obtain N-(4-tert-butyl group benzyl)-N-methyl-benzene (b) thienyl methylamine (1.78 gram) (example 29 chemical compounds).

Example 78

3.0 gram N-methyl-N-(1-naphthyl methyl)-4-cumene Methanamides in adding the mixture of 0.48 gram lithium aluminium hydride reduction and 10 milliliters of absolute ethers, the drips of solution of 10 milliliters of absolute ethers were refluxed 24 hours, under cooling, drip water then to decompose remaining lithium aluminium hydride reduction, further use extracted with diethyl ether behind the dilute with water reactant mixture.Diethyl ether solution washes with water, add 1.5 milliliters of concentrated hydrochloric acid then, steam ether under the decompression, add small amount of acetone again, produce white crystals (1.5 gram), leach crystallization and in acetone recrystallization, obtain white platelike crystal N-(4-isopropyl benzyl)-N-methyl isophthalic acid-naphthyl methylamine hydrochloride example 22 chemical compounds).Fusing point: 195.5～197 ℃

Example 79

The mixture of 1.03 gram 1-naphthoic acids and 4.86 gram thionyl chlorides was stirred 2 hours down at 50 ℃.Remaining thionyl chloride is removed in decompression, obtain the 1-naphthoyl chloride, the 1-naphthoyl chloride that obtains is dissolved in 10 milliliters of benzene, is added drop-wise to then in the mixture of 1.06 gram N-methyl-4-tert-butyl benzene methylamines, 2 milliliters of pyridines and 10 milliliters of dried benzene, stirred 5 hours, in product impouring water, with the benzene extraction, in succession with 3% sodium bicarbonate aqueous solution, 3% hydrochloric acid solution and water washing benzole soln, reuse anhydrous sodium sulfate drying, obtain oily product (1.74 gram amide) after steaming benzene, it is left standstill crystallization.Fusing point: 106～108 ℃ (recrystallization in normal hexane/benzene)

The above-mentioned amide of 1.33 grams is dissolved in 10 milliliters of ether, be added drop-wise in the mixture of 0.38 gram lithium aluminium hydride reduction and 40 milliliters of absolute ethers, refluxed 12 hours, with the remaining lithium aluminium hydride reduction of water decomposition, the product extracted with diethyl ether, extract washes with water, adds 1 milliliter of concentrated hydrochloric acid, and steam solvent in decompression, add proper amount of acetone again and be settled out white crystal (1.3 gram).Leach crystal, recrystallization in acetone obtains white platelike crystal N-(4-tert-butyl group benzyl)-N-methyl isophthalic acid-naphthyl methylamine hydrochloride (example 1 chemical compound) fusing point: 210～212 ℃

Example 80

React with N-(4-tert-butyl group benzyl)-N-methyl-4-fluoro-1-naphthalenecarboxamide, obtain N-(4-tert-butyl group benzyl)-N-methyl-4-fluoro-1-naphthalene methylamine.

Example 81

With N-methyl-N-(4-tertiary pentyl benzyl)-1-naphthalenecarboxamide reaction, obtain N-methyl-N-(4-tertiary pentyl benzyl)-1-naphthalene methylamine.

Example 82

With N-(4-tert-butyl group benzyl)-N-methyl-3-benzene (b) thenoyl amine reaction, obtain N-(4-tert-butyl group benzyl)-N-methyl-3-benzene (b) thiophene methyl amine.

Example 83

Drip 6.5 gram N-(4-tert-butyl group benzyl)-N-methyl-2-ethyoxyl carboxyl-1-naphthalene amino acids and restrain in the mixture of lithium aluminium hydride reduction and 80 milliliters of absolute ethers, refluxed 3 hours in the solution to 6.07 of 20 milliliters of anhydrous benzene.Under cooling, drip water remaining lithium aluminium hydride reduction is decomposed, isolate the ether layer then, add 3 milliliters of dense salt in diethyl ether solution, and under reduced pressure remove remaining hydrochloric acid, and then add small amount of acetone.Leach formed white crystals (2.12 gram), just obtain N-(4-tert-butyl group benzyl)-N-methyl-2-hydroxyl-1-naphthalene methylamine hydrochloric salt white crystals (example 28 chemical compounds) fusing point through recrystallization in methanol/acetone: 181～183 ℃

Press the amine derivative hydrochlorate of the method for example 83 with preparation example 1～71.

Example 84

Under 50 ℃, 1.06 gram 4-p t butylbenzoic acids and 4.86 gram thionyl chlorides were stirred 2 hours.Under reduced pressure steam remaining thionyl chloride, obtain carboxyl acyl chloride.Carboxyl acyl chloride is suspended in 10 milliliters of dried benzos to be added drop-wise in the mixture of 1.03 gram N-methyl isophthalic acid-naphthyl methylamines, 2 milliliters of pyridines and 10 milliliters of dried benzene, at room temperature stirred 6 hours, then in the reactant mixture impouring water, extract with benzene, use 3% sodium bicarbonate aqueous solution, 3% hydrochloric acid solution and water washing in succession, the reuse anhydrous sodium sulfate drying.Just obtain oily product (1.95 gram amide) after steaming benzene.

Above amide is dissolved in 20 milliliters of absolute ethers, is added drop-wise in the mixture of 0.57 gram lithium aluminium hydride reduction and 10 milliliters of absolute ethers, refluxed 12 hours.

Drip entry, to decompose remaining lithium aluminium hydride reduction, use the extracted with diethyl ether product, again with the water washing diethyl ether solution.Under cooling, add 2 milliliters of concentrated hydrochloric acid and fall solvent, add the proper amount of acetone postprecipitation and go out white crystals in diethyl ether solution and steaming under reduced pressure.Crystallization leached and in acetone recrystallization, obtain N-(4-tert-butyl group benzyl)-N-methyl isophthalic acid-naphthalene methylamine hydrochloric salt white crystal (example 1 chemical compound).Fusing point: 210～212 ℃

Example 85

React with N-(4-fluoro-1-menaphthyl)-N-methyl-4-tert-butyl benzene Methanamide, obtain N-(4-tert-butyl group benzyl)-N-methyl-4-fluoro-1-naphthalene methylamine (example 4 chemical compounds)

Example 86

React with N-methyl-N-1-(1-naphthyl) ethyl-4-tert-butyl benzene Methanamide, obtain N-(4-tert-butyl group benzyl)-N-methyl isophthalic acid-(1-naphthyl) ethamine (example 9 chemical compounds).

Example 87

(1-naphthyl methyl-4-cumene Methanamide reacts, and obtains N-(4-isopropyl benzyl)-N-methyl isophthalic acid-naphthalene methylamine (example 22 chemical compounds) with N-methyl-N-.

Example 89

(3-benzene (b) thienyl methyl-4-tert-butyl benzene Methanamide reacts, and obtains N-(4-tert-butyl group benzyl)-N-methyl-3-benzene (b) thienyl methylamine (example 29 chemical compounds) with N-.

Preparation example 1 (liquid preparation)

50 gram macrogels 400 and 10 gram example 1 prepared N-(4-tert-butyl group benzyl)-N-methyl isophthalic acids-naphthyl methylamine hydrochlorides are added in 500 milliliters the ethanol, make its dissolving.Add 400 gram pure water to this solution again, continuing to add ethanol to its cumulative volume then is 1000 milliliters.

Preparation example 2 (ointment)

In the mixture (remaining on 80 ℃) of 400 gram white petrolatums, 180 gram hexadecanol, 50 gram sesquialter oleic acid sorbitol esters, 5 gram Laurel macrogels and 1 gram propyl p-hydroxybenzoate, add N-(4-tert-butyl group benzyl)-N-methyl isophthalic acid-naphthyl methylamine hydrochloride of 10 gram examples, 1 gained, make its dissolving with water-bath.Again with 1 gram right-methyl hydroxybenzoate adds in the 353 gram pure water and is heated to 80 ℃, and this solution is added to clear stirring in the last solution.Stop to heat and under cooling, further stirring the mixture, until solidifying.

Preparation example 3 (butterfat)

The mixture of 15 gram white petrolatums, 200 gram liquid paraffin, 50 gram octadecanols, 40 gram glycerol～stearates, 145 gram propylene glycol and the right-nipasol of 1 gram is put in the water-bath its temperature is remained on 80 ℃, make it dissolving; N-(4-tert-butyl group benzyl)-N-methyl isophthalic acid-naphthyl methylamine hydrochloride with gained in the example 1 is dissolved in wherein again.Be added to 498 gram pure water in poly-oxyl esters of 40 gram stearic acid 40 and the right-methyl hydroxybenzoate of 1 gram and make it dissolving, the solution with gained is added in the above-mentioned amine salt solution and clear stirring then, continues clear stirring until solidifying again under the cold water cooling.

Test example 1 (extracorporeal antifungal activity test)

Chemical compound of the present invention adopts the SabouraudShi agar culture medium to the antifungal activity test system of Trichophyton mentagrophytes, trichophyton interdigitalis and trichophyton rubrum.

Each chemical compound in the table 2 is dissolved in 1 milliliter of ethanol, add distilled water concentration is transferred to 1000 mcg/ml, by a series of concentration of diluting 2 times in succession of this preparation, each concentration is got in 1 milliliter of flat container that is placed in, add 9 milliliters of SabouraudShi agar culture mediums and mix, form plating medium with it.

On plating medium, inoculate 2 * 10 with little inoculator M1P-2 (Sakuma Seisakusho Co.Ltd) ⁶0.005 milliliter of each test strain of spore/milliliter 27 ℃ of following constant temperature culture 7 days, is now listed in minimum growth inhibitory concentration (M1C, μ g/ml) in the table 2.

Table 2

Test compound

The test fungus

(a) (b) (c)

Example 1 0.0125 0.006 0.003

2 0.2 0.1 0.1

″ 3 0.1 0.05 0.025

″ 4 0.025 0.006 0.006

″ 5 0.1 0.1 0.025

″ 6 0.2 0.2 0.05

″ 7 0.78 0.39 0.39

″ 8 0.1 0.05 0.025

″ 9 0.025 0.02 0.003

″ 10 1.56 1.56 0.39

″ 12 0.0125 0.0125 0.006

″ 13 25 25 12.5

″ 14 12.5 6.25 6.25

″ 15 0.78 3.13 0.39

″ 16 3.13 1.56 1.56

″ 17 1.56 1.56 1.56

″ 18 0.1 0.05 0.006

″ 19 0.78 0.2 0.2

″ 20 6.25 6.25 3.13

″ 22 0.025 0.1 0.0125

″ 23 0.1 0.2 0.1

″ 24 0.1 0.2 0.1

″ 25 0.78 0.78 0.39

″ 26 12.5 12.5 6.25

″ 28 25 12.5 6.25

″ 29 0.05 0.05

″ 30 0.78 0.78

″ 33 0.2 0.1

″ 34 0.025 0.025

″ 35 0.78 0.78

″ 39 0.39 0.39

″ 43 0.2 0.2

″ 49 0.39 0.39

″ 51 0.39 0.2

″ 54 0.1 0.1

″ 56 0.2 0.2

″ 63 0.39 0.1

″ 69 0.05 0.025

(a) Trichophyton mentagrophytes (c) peony Trichophyton mentagrophytes result of the test shows that all test compounds all have antifungal activity in the table 2 between Trichophyton mentagrophytes (b) toe.Test example 2 (Trichophyton therapeutic test)

In the back cropping of the male Cavia porcellus of the Hartley of body weight 600～700 gram everywhere, 4 square centimeters at every place rubs gently with sand paper, will take from the second filial generation Trichophyton mentagrophytes that other Cavia porcelluss cultivate and infect cropping place, every place 1 * 15 ⁵Spore.The test compound of example 1 gained is dissolved in ethanol makes 0.1% solution, be coated with 0.2 milliliter infecting part, rose once a day in 48 hours behind the self-infection, be coated with ten altogether.Two days execution animals behind last applying soln, get 10 tissue samples and place on the SabouraudShi plate and (contain D actinomycin D and kanamycin) at every place, and 27 ℃ of constant temperature culture 7 days are observed fungus and had situation, calculate suppression ratio by following formula, it is worth up to 82%.

Suppression ratio=(1-(finding the tissue sample number of tissue sample number/cultivation of fungus))

×100

Test example 3 (side reaction test)

At the male Cavia porcellus of the Hartley of body weight 600～700 gram hair two places with one's hands clasped or tied behind one's back, 4 centimetres at every place ²The side reaction of checkout facility chemical compound.Inferior daily sand paper friction cropping place is dissolved in ethanol with the test compound of gained in the example 1 and makes 0.5% solution, and with 0.2 milliliter of/day cropping place that is applied to a Cavia porcellus, the another Cavia porcellus only is coated with 0.2 milliliter/day ethanol, once-a-day, is coated with 10 days altogether.Result of the test is not observed the side reaction such as erythema and pimple.

Claims

1. the preparation method of a Fungicidal composition, it is characterized in that with the amine derivative of general formula (I) or its esters as effective ingredient and pharmaceutically be fit to or agricultural go up diluent, carrier or the mixed with excipients of general such preparation, make the Fungicidal composition of liquid preparation, ointment or cream forms; Content of effective is 0.01 to 5% (weight), and diluent, carrier or excipient content are 95-99.99% (weight);

X in the general formula (I) is selected from following groups:

Q is that oxygen, sulfur or nitrogen-atoms Y are selected from following groups:

With

R ¹Be hydrogen atom or methyl; R ²Be hydrogen atom or C ₁-C ₄Alkyl; R ³Be hydrogen atom, halogen atom or alkyl; R ⁴Be hydrogen atom, alkyl, cycloalkyl, haloalkyl or halogen atom; R ⁵Be hydrogen atom, alkyl, alkoxyl, halogen atom, nitro or hydroxyl; R ⁵Be connected on arbitrary position of X, and R ³Or R ⁴Be connected on arbitrary position of Y.