CN1040792A - Antifungal agents based on amides containing phenyl group - Google Patents

Abstract

The CYCLE that centered on by semi-ring in the compound formula of formula (I) representative contains carbocyclic ring or heterocycle, and it is connected with two carbon atoms, is having-C between two carbon atoms of (Z)-Y base and phenyl to have an alkene type key or aromatics key at least, and Y is oxygen or S, and Z is NR ₁R ₂, R ₁And R ₂Represent substituted alkyl, alkoxyl group or cycloalkyl separately; Alkenyl or alkynyl;-NR ₁R ₂Represent heterocycle; R ₃, R ₄And R ₅Represent hydrogen atom or halogen atom separately; The amino that can replace arbitrarily etc.; Or R ₃And R ₄(in 3-position and 4-position) forms a single divalent group together, and this compound can be effective as the mycocide on the agricultural.

Description

Antifungal agents based on amides containing phenyl group

The present invention seeks in order to introduce a series of new phenyl and the derivative (or its analogue) of acid amides, and their preparation, they avoid the application of the active material of fungi infestation as protective plant, are required intermediate and its preparation method of its preparation.

In introducing now, all kinds molecule (structure) formula of being quoted from all is listed in the ending (before the claim fund) of this paper together.Below be used for those terms that contain the carbochain group and mean that this carbochain has 1-4 carbon atom (or 2-4 carbon atom arranged at unsaturated carbon chains).

Product innovation according to the present invention is to have as formula I feature at compound, wherein:

* two carbon atoms that connected by " Cycle " symbol that semi-ring enclosed and this semi-ring are represented a carbocyclic ring with 4-7 chain link (preferably 5 or 6), at random are heterocycle, it

Have a unsaturated link(age) alkene or aroma properties in the middle of two carrier carbon atoms of group and phenyl at least, described ring may by maximum 30 carbon atoms of tool organic group replaced.

* Y is oxygen or sulphur atom.

Z is a chlorine atom, group OW ', a NHR ₁Or NR ₁R ₂(when being used for resisting plant disease, Z preferentially is NR in these compound molecule formulas ₁R ₂, and Z is a chlorine atom, an OW ' group or a NHR in the formula ₁Those compounds of group mainly are used as chemical intermediate.

* W ' is a hydrogen atom; Or a low alkyl group, or basic metal or alkaline-earth metal.

* R ₁And R ₂, identical or different, its representative:

-one low alkyl group or lower alkoxy are (at R ₁And R ₂In to have one at least be not alkoxyl group), or the cycloalkyl of 3-7 carbon atom, these groups perhaps by at least one hydrogen and/or hydroxyl or lower alkoxy or alkoxyl group (rudimentary)-alkyl (rudimentary) or acyloxy (rudimentary) or phenyl or contain 1 or 2 heteroatoms (O, N or S) the 4-6 annular atoms heterocyclic radical replaced by the low alkyl group list or disubstituted amino etc. replace.

The alkenyl or the alkynyl of-one a tool 3-7 carbon atom.

* or R ₁And R ₂Link to each other together with nitrogen-atoms and to form a saturated or undersaturated heterocycle, it contains 4-7 chain link (being preferably 5 or 6) and 1,2 or 3 heteroatoms (O, N or S, this heterocycle can be by low alkyl group or lower alkoxy, or hydroxyl, or oxo group, or one or several halogen atom, or alkoxyl group-(rudimentary) alkyl replaces.

* R ₃, R ₄And R ₅, identical or different, its representative:

* hydrogen atom or halogen atom, and R at least ₃, R ₄And R ₅One of group is not a hydrogen atom or halogen atom.

* amino that is perhaps replaced by one or two low alkyl group.

* low alkyl group or lower alkoxy or alkyl (rudimentary)-alkoxyl group (rudimentary) or low alkyl group sulfo-, perhaps halo or hydroxylated.

* R ₃And R ₄(position and contraposition) can form a unique group of divalence with 3 or 4 chain links together, and it comprises 1 or 2 non-conterminous Sauerstoffatom.

The present invention more peculiarly relates to those compounds that is used for resisting mycotic infection of plant especially, and in the clear and definite as described above compound, Z is NR ₁R ₂, wherein different groups and substituting group are being allowed a choice aspect its character and their positions, so that in the scope of decimal logarithm (logP) between 2 and 5 of their n-Octanol/water partition coefficient (P), are preferably between 2.5 and 4.5.

N-Octanol/the water partition coefficient of a chemical product can be measured according to the method that everybody is familiar with.

According to experiment, this coefficient is that a kind of material is dissolved in a two-phase system by two kinds of immiscible solvent compositions, promptly by the ratio of equilibrium concentration in the two-phase system that descends hot alcohol and water to form, that is to say:

P=(C n-Octanol)/(C water)

Measure out of phase three different concns and ratio at 20 ℃, in order to draw identical P value from three phase ratios of these three phase concentrations.

If it is more water-soluble to relate to a product, three concentration of aqueous solution that then prepare this product, be 0.25g/l, 0.5g/l and 1g/l, the solution of each concentration mixes by following proportional and n-Octanol then, the volume ratio that is product water solution/n-Octanol is respectively 80/20,90/10,95/5.Stir these mixtures then, inclining the upper strata, and is dissolved in every product amount in mutually with high-performance liquid chromatogram determination, and according to the formula calculation of distribution coefficient of above introduction.

On the contrary, more be dissolved in n-Octanol and product if relate to one, three different concns n-Octanol solution that then prepare this product, be 0.25g/l, 0.5g/l and 1g/l, each solution is measured in proportion with water and is mixed then, the volume ratio that is the n-Octanol solution/water of product is respectively 80/20,90/10,95/5.

If product is seldom water-soluble or n-Octanol, thereby all can not reaches with any mode solution and to be equivalent to 0.25,0.5 and the concentration level of 0.1g/l, then can operate, for example 0.05,0.1 and 0.2g/l or lower concentration grade again by the low concentration grade.

In any case, three P values that obtain under these conditions should be consistent (if these values are inequality, should seek lower concentration, to allow to reach three identical values), and this is that three common, unique values of mensuration are equivalent to partition ratio P(or its logarithm log P), this is the peculiar character of this product.

But, in fact, calculate its partition ratio value according to molecular structure and replace its mensuration to become more common.The utilization of these method of calculation is provided by C.Hansch and A.Leo institute in " the applied substituent constant of correlation analysis in the chemistry and biology " book (Ed.John Wiley, 1979, Page 18-43).This method is slowly development in recent years, but towards purified direction evolution more, that is to say, and is more and more approaching to the actual value that direct mensuration obtains.Therefore, the method for calculation of partition ratio, correlative factor when interacting, improve (A.Leo, J.Chom Pdrkin Trans, II P P825-838,1983) for explanation.For the ease of these calculating, computer program commercialization, it can directly carry out the calculating of partition ratio (log P) voluntarily.Equally, we have utilized the data that " Medchem " program provides in this article, this program is described in " Medchem Software Manual; release 3.52 " book (in November, 1987 version is edited by the Pomona College of California state Claremont).

Even a computer program like this also will further develop in the future, its differentiation also will be carried out towards the direction of accuracy more, that is to say, more will approach the experimental value of log P.

It is so common replacing the principle of its measured value by the calculated value of log P, so that this method is accepted by USEPA (Environmental Protection Agency).

In this article, we have adopted as the log P calculated value that shows above.

Then, when we indicated the implication of multiple group, for example (R) n that is to say n R group, and it can be identical or different then being understood to various R groups according to complete general mode, comes to this for all types of groups and substituting group.

In the big class of formula I compound, it is particularly advantageous returning the different subclass of branch.

So, pay the utmost attention to have following this or that or several characteristic:

-R ₁And R ₂Representative:

* low alkyl group; Cycloalkyl with 3-7 carbon atom; The alkenyl or the alkynyl of a tool 3-7 carbon atom; The alkoxyalkyl of a tool 3-8 carbon atom.

* or R ₁And R ₂Can link to each other together with nitrogen-atoms and form a saturated or undersaturated heterocycle, it comprises 4-7 chain link and 1 or 2 heteroatoms (O, N, S), and the alcoxyl alkyl alkyl that this heterocycle can be had the alkyl of 1-3 carbon atom or have a 2-3 carbon atom replaces.

-R ₃, R ₄And R ₅Position, contraposition and a position between laying respectively on the phenyl that replaces CYCLE (these positions be with the valence link that above-mentioned phenyl is connected with above-mentioned CYCLE in conjunction with making comparisons and localized).

* R ₃, R ₄And R ₅Represent a hydrogen atom or halogen atom (having one at least in these three groups is not hydrogen atom or halogen atom); Or a low alkyl group or a lower alkoxy; Or alkoxyalkyl with 2-4 carbon atom; Or low alkyl group sulfo-; Or hydroxyl; Or one perhaps replaced or disubstituted amino by the low alkyl group list.

* R ₃And R ₄(position and contraposition between being in) can form a unique divalent group with 3 or 4 chain links together, and it comprises 1 or 2 non-conterminous Sauerstoffatom.

Symbol CYCLE is enclosed by a semi-ring, and it represents a divalent group-K ₆-K ₇-K ₈-K ₉-or-K ₆-K ₇-K ₁₀-, so that and its two carbon atoms that connected constitute a tool 5-6 chain link ring [as molecular formula (I a) and use in (I b) scheme indicated], group K ₆, K ₇, K ₈, K ₉And K ₁₀Be like this:

K ₆Representative-N=or-C(R ₆)=

K ₇Representative-N=or-C(R ₇)=

K ₈Representative-N=or-C(R ₈)=

K ₉Representative-N=or-C(R ₉)=

K ₁₀Representative-N=or-C(R ₁₀)=

In addition, as the CYCLE symbology K that is surrounded by a semi-ring ₆, K ₇, K ₁₀The time, these groups K ₆, K ₇And K ₁₀Can also be like this:

K ₆Representative-N(R ₆)-or-C(R ₆) ₂-or-O-or-S(O) n

K ₇Representative-N(R ₇)-or-C(R ₇) ₂-or-O-or-S(O) n

K ₁₀Representative-N(R ₁₀)-or-C(R ₁₀) ₂-or-O-or-S(O) n or-CO-n equals 0,1 or 2 integer, at CYCLE symbology-K ₆-K ₇-K ₈-K ₉With-K ₆-K ₇-K ₁₀Two kinds of situations under be understood to: at K ₆And K ₇In have a group representative-(R at least ₆)=or-(R ₆) ₂-or-C(R ₇)=or-C(R ₇) ₂, in addition, these divalent group-K ₆-K ₇-K ₈-K ₉-and-K ₆-K ₇-K ₁₀-in its main chain, only comprise 0,1 or 2 heteroatoms (N, O or S), and without any-O-O-or-the S-S-chain connects.

(it may be noted that in fact-K ₆-K ₇-K ₈-K ₉Form a ring) with fragrance characters

-R ₆, R ₇, R ₈, R ₉Or R ₁₀, wherein each is identical or is different from other groups, their representatives:

* hydrogen atom or halogen atom are at R ₆Or R ₇In to have a group at least be not hydrogen atom.

* cyano group, nitro, thiocyano, hydroxyl or carboxyl.

* alkyl, cycloalkyl, alkenyl, alkynyl, the n(n=0 of alkyl-S(O), 1 or 2), alkoxyl group has the cycloalkyloxy of 3-8 carbon atom, alkenyloxy, alkynyloxy group; These groups preferably have 1-8 carbon atom, are perhaps replaced by one or several halogen atom.

* phenyl, naphthyl, the n(n=0 of phenyl-S(O), 1 or 2), phenoxy group, phenylalkyl (low alkyl group), the n(low alkyl group of phenylalkyl-S(O)); N=0,1 or 2), phenyl alkoxyl group (lower alkoxy) or the heterocyclic radical that 5-6 chain link and band 1-3 heteroatoms (being selected in oxygen, sulphur and nitrogen group) are arranged, it perhaps is that replace, saturated or unsaturated, each contained benzene nucleus or heteronucleus can be replaced by at least one substituting group in these groups, and this substituting group is selected in following group:

* halogen atom,

* nitro, cyano group, carboxyl, hydroxyl, sulfydryl, thiocyano, alkoxyl group (rudimentary) carbonyl ,-CO-NR ' R ", NR ' R " and ,-N(R ')-CO-R " ,-O-CO-R ' ,-O-CO-NR ' R ", or

* low alkyl group, lower alkoxy, alkyl (rudimentary)-S(O) n(n=0,1 or 2), cycloalkyl (3-7 carbon atom), phenyl, phenoxy group, the n(n=0 of phenyl-S(O), 1 or 2), the benzene alkyl, the phenyl alkoxyl group, the n(n=0 of phenylalkyl-S(O), 1 or 2), these groups may be by halo, and moieties has 1-4 carbon atom.

* an alkoxyl group (rudimentary)-carbonyl, CONR ' R ", NR ' R " and, N(R ') COR ", O-CO-R ', O-CONR ' R ".

* R ' and R ", identical or different, respectively be a hydrogen atom; A low alkyl group; The cycloalkyl of 3-7 carbon atom; May be by halogenated phenyl; May be by halogenated phenylalkyl (low alkyl group); Alkenyl or an alkynyl with 3-7 carbon atom; Alkoxyalkyl with 3-8 carbon atom.

* work as K ₆And K ₇Representative-C(R ₆)-or-C(R ₆) ₂-or-C(R ₇)-or-C(R ₇) ₂-time, then R ₆And R ₇, perhaps R ₆One and R in the base ₇Energy and carrier band R in the base ₆And R ₇Two carbon atoms form a carbocyclic ring, or saturated or unsaturated heterocycle with 5 or 6 chain links and 0,1 or 2 non-conterminous heteroatoms (O, N or S).

* work as K ₆Or K ₇Or K ₈, K ₉Or K ₁₀For-N(R ₆)-,-N(R ₇)-N(R ₈)-,-N(R ₉)-,-N(R ₁₀) in one, so, corresponding group, i.e. R ₆, R ₇, R ₈, R ₉Or R ₁₀(but R in the following connotation is arranged ₆Or R ₇In to have a group at least must not be hydrogen atom):

Hydrogen atom; The alkyl of 1-6 carbon atom; Phenyl or phenylalkyl (low alkyl group), it may be by one or several halogen atom, or by cyano group, or nitro, or by low alkyl group, or lower alkoxy replaces.

According to introducing just now the front, formula (I a) and the compound of (I b) constituted special several big class products among the present invention.

Belong to the formula I of the scope of the invention, (I is a) or in all cpds of (I b), and different, special subclass compound makes us especially interest, especially in the properties of resultant product and all the more so aspect easy to prepare.These subclass compounds are classified with following more definite mode, are especially determined according to the mode of formula II, (III), (IV), (V), (VI) and (VII).

In these subclass compounds, during the general sense of those groups that provided when the reference front, no matter this is for common definition, or all benefits with the implication of getting property earlier that mode of priority is made for those.

Equally, for useful product, especially can be used to prevent and treat the product of mycotic infection of plant, those have the compound of a front undefined log P value our priority application.

According to the present invention, product first subclass is made of the formula II product, wherein:

* K ₁₁₀It is a Sauerstoffatom; A S(O) _N1-wherein _N1Be one and equal 0,1 or 2 integer; Or NR ₁₁₀Or C(R ₁₁₀) group, or an oxo group.

* Z ₁Be a halogen atom or an OW ₁Base (wherein, W ₁Have one of implication to aforementioned W ') or a NHR ₁₁, or NR ₁₁R ₁₂Base, wherein R ₁₁And R ₁₂, identical or different, have respectively to aforesaid R ₁And R ₂One of implication.

* R ₁₃-R ₁₅, identical or different, have to aforementioned R ₃, R ₄And R ₅One of implication.

* R ₁₃And R ₁₄Can form a methylene-dioxy or ethylenedioxy together equally, their carbon atom itself can be replaced by low alkyl group or halogen atom.

* R ₁₆-R ₁₉, identical or different, have to aforementioned R ₆-R ₉One of implication.

If K * ₁₁₀Be=C(R ₁₁₀)-or-C(R ₁₁₀) ₂-time, then R ₁₁₀Represent a hydrogen atom or low alkyl group or a benzyl or a hydroxyl, or a lower alkanoyloxy (for example acetoxyl group) or a lower alkoxy.

If K * ₁₁₀Be-N(R ₁₁₀)-, be R then ₁₁₀Represent a hydrogen atom or a low alkyl group or a benzyl.

Work as Z ₁Be a NR ₁₁R ₁₂Base, then these derivatives have formula (II ') structure, and work as Z ₁Be OW ₁During base, those derivatives have formula (II ") structure.

In molecule formula II derivative, pay the utmost attention to the derivative of following constructional feature:

* K ₁₁₀Be a Sauerstoffatom, sulphur atom, or representative-N(R ₁₁₀)-or-C(R ₁₁₀) ₂-.

* Z ₁Be an OW ₁Group, implication as described above; A NHR ₁₁Or NR ₁₁R ₁₂Base, wherein R ₁₁And R ₁₂Be low alkyl group, as R ₁₁And R ₁₂Comprise 6 carbon atoms altogether at most, perhaps form a morpholino or parathiazan generation together.

* R ₁₃-R ₁₅Have as R ₃, R ₄, R ₅Identical meanings.

The formula II derivative of following feature is given special priority for:

* Z ₁Be OW ₁Group, implication as described above; Perhaps NR ₁₁R ₁₂Group, it is a morpholino, parathiazan generation, N-methyl-N-ethylamino or N, the N-diethylin.

* R ₁₃-R ₁₅, identical or different, be a hydrogen atom or halogen atom, a low alkyl group, a lower alkoxy, a low alkyl group sulfo-.

* R ₁₆, R ₁₈, R ₁₉Be a hydrogen atom or fluorine atom.

* R ₁₇Be hydrogen or halogen atom; A low alkyl group, lower alkoxy, low alkyl group sulfo-, low-grade halogenated alkyl, elementary halogenated alkoxy, low-grade halogenated alkyl sulfo-; A nitro, cyano group; A low-grade alkenyl, a low-grade alkynyl, or an alkoxyl group (rudimentary)-carbonyl.

In addition, for the application of agricultural chemicals, the above-mentioned product that has log P and be 2.5-4.0 gives special priority for.

In belonging to formula I all cpds of the present invention, make us the interested especially second subclass derivative and be being constituted by the phenyl amide of formula III, wherein:

* Z ₂Representative:

-one halogen atom, or

-OW ₂Group (W wherein ₂Have one of implication to W ') or a NHR

Base, or

-one NR ₂₁R ₂₂Base, wherein R ₂₁And R ₂₂, identical or different, have to R respectively ₁And R ₂One of implication.

* R ₂₃-R ₂₅, identical or different, have to R respectively ₃, R ₄, R ₅One of implication.

* R ₂₃And R ₂₄Can form a methylene-dioxy or ethylenedioxy together equally, the carbon atom in these groups itself can be replaced by some low alkyl groups or halogen atom.

* R ₂₆And R ₂₇, identical or different, have to R respectively ₆, R ₇One of implication, condition is R ₂₆And R ₂₇Can not be a hydrogen atom simultaneously.

* R ₂₈And R ₂₉, identical or different, can be hydrogen or halogen atom; Hydroxyl; A low alkyl group; Lower alkoxy; Alkoxyl group (rudimentary)-alkyl (rudimentary); Alkoxyl group base (rudimentary)-carbonyl.

In formula III derivative, pay the utmost attention to the compound of following feature:

* Z ₂Be an OW ₂Group (W wherein ₂Has one of implication to W '); A NHR ₂₁Base or a NR ₂₁R ₂₂Base, wherein R ₂₁And R ₂₂Be low alkyl group, as R ₂₁And R ₂₂Comprise altogether mostly being most 6 carbon atoms, perhaps form a morpholino or parathiazan generation jointly.

* R ₂₃-R ₂₅, identical or different, have R ₃, R ₄And R ₅Identical meanings.

* R ₂₈And R ₂₉, identical or different, can be a hydrogen atom or halogen atom or a hydroxyl.

Following structural formula III derivative gives special priority for:

* Z ₂Be OW ₂Group, as above definite, perhaps NR ₂₁R ₂₃-Ji, it is a morpholino, parathiazan generation, N-methyl-N-ethylamino or N, N-diethylin.

* R ₂₃-R ₂₅, identical or different, be a hydrogen atom or halogen atom, a low alkyl group, a lower alkoxy, a low alkyl group sulfo-.

* R ₂₆-R ₂₇, identical or different, be a hydrogen atom or halogen atom, a low alkyl group, a low-grade alkenyl, a lower alkoxy, a low alkyl group sulfo-, a low-grade halogenated alkyl, elementary halogenated alkoxy or low-grade halogenated alkyl sulfo-.

* R ₂₈And R ₂₉, identical or different, be a hydrogen atom or fluorine atom.

In addition, for the product that agricultural chemicals is used, pay the utmost attention to and have the above-mentioned product that log P is 2.5-4.0.

In belonging to the formula I compound of this patent, make us interested especially the 3rd subclass and be being constituted by the nicotinic acid derivates of formula IV, wherein:

* Z ₃Representative:

-one halogen atom, or

-one OW ₃Group (W wherein ₃Have one of implication to W ') or a NHR ₃₁The base or

-one NR ₃₁R ₃₂, R wherein ₃₁And R ₃₂, identical or different, have to R respectively ₁And R ₂One of implication.

* R ₃₃-R ₃₅, identical or different, have to R respectively ₃, R ₄And R ₅One of implication.

* R ₃₃And R ₃₄, can form a methylene-dioxy or ethylenedioxy jointly equally,

The carbon atom of these groups itself can be replaced by some low alkyl groups or halogen atom.

* R ₃₇Have to R ₇One of implication, but be limited to R ₇It or not a hydrogen atom.

* R ₃₈And R ₃₉, identical or different, can be a hydrogen atom or halogen atom, a low alkyl group, lower alkoxy, alkoxyl group (rudimentary)-alkyl (rudimentary) or elementary alkoxy carbonyl, perhaps a cyano group.And, work as R ₃₇When being phenyl, R ₃₈Energy and the ortho position R that links to each other with pyridine nucleus ₃₇Carbon atom form a Y ₃-(CH ₂) n ₃Chain, wherein Y ₃Be Sauerstoffatom or sulphur atom or methylene radical and n ₃Be 0,1 or 2.

In the formula IV compound, pay the utmost attention to the compound of following structural formula: R wherein ₃₃-R ₃₅, identical or different, be a hydrogen atom or halogen atom (having one at least in these three groups is not hydrogen atom or halogen atom), perhaps low alkyl group, a lower alkoxy, or low alkyl group sulfo-.

In belonging to formula I compound of the present invention, make us interested especially the 4th subclass and constituted by the formula with following characteristics (V) derivative:

Z ₄Representative:

* halogen atom, or

* OW ₄Group 9 is W wherein ₄Have one of implication to W '), a NHR ₄₁Base or NR ₄₁R ₄₂Base, wherein R ₄₁And R ₄₂, identical or different, have respectively

Give R ₁And R ₂One of implication.

* R ₄₃, R ₄₄, R ₄₅, identical or different, have to R respectively ₃, R ₄, R ₅One of implication.

* R ₄₇Have to R ₇One of implication, but be not hydrogen atom.

* R ₄₉Can be a hydrogen atom or a low alkyl group.

In formula (V) derivative, following structural compounds is for paying the utmost attention to:

* Z ₄Be an OW ₄Group (W wherein ₄Have to one of W ' implication), a NHR ₄₁Base or a NR ₄₁R ₄₂Base, wherein R ₄₁And R ₄₂Be low alkyl group, i.e. R ₄₁And R ₄₂Comprise maximum 6 carbon atoms altogether, perhaps form a morpholino or parathiazan generation jointly.

* R ₄₃-R ₄₅, identical or different, be hydrogen atom or halogen atom, a low alkyl group, a lower alkoxy, a low alkyl group sulfo-.

* R ₄₉It is a hydrogen atom.

Product the 5th subclass by formula I is made of the formula VI product, wherein:

* Z ₅Represent a halogen atom or an OW group (W ₅Have one of implication to W '),

Perhaps NHR ₅₁Base or a NR ₅₁R ₅₂Base, wherein R ₅₁And R ₅₂, identical or different, have to R respectively ₁And R ₂One of implication.

* R ₅₃, R ₅₄, R ₅₅, identical or different, have to R respectively ₇, R ₄, R ₅One of implication.

* R ₅₃And R ₅₄Can form methylene-dioxy or ethylenedioxy jointly equally, the carbon atom of these groups itself can be replaced by some low alkyl groups or halogen atom.

* R ₅₆And R ₅₇Have to R ₆And R ₇One of implication, but be limited to R ₆And R ₇Can not be a hydrogen atom simultaneously.

* R ₅₉Can be hydrogen or halogen atom, a low alkyl group, a hydroxyl, lower alkoxy, or low-grade alkoxy alkyl, these groups can be by halo.

In the formula VI compound, top-priority compound, R in its formula ₅₃-R ₅₅, identical or different, be a hydrogen atom or halogen atom, or a low alkyl group, a lower alkoxy, or a low alkyl group sulfo-.

R ₅₉Be a hydrogen atom or a low alkyl group.

Product the 6th subclass according to logical formula I is made of formula (VII) product, wherein:

* Z ₆Representative:

-one halogen atom,

-one OW ₆Group (W wherein ₆Have one of implication to W ') NHR ₆₁Base or a NR ₆₁R ₆₂Base, wherein R ₆₁And R ₆₂, identical or different, have to R respectively ₁And R ₂One of implication.

* K ₆₆In a substituted nitrogen atom-N(R ₆₆)-, or-N=, or sulphur atom or Sauerstoffatom, or an alternate c atoms=C(R ₆₆)-.

* K ₆₇Be a sulphur atom or Sauerstoffatom, or a substituted nitrogen atom-N(R ₆₇)-, or-N=, or alternate c atoms=C(R ₆₇)-, but K ₆₆And K ₆₇Can not be simultaneously-N(R ₆₆)-and-N(R ₆₇)-.

* K ₆₁₀Be a substituted nitrogen atom-N(R ₆₁₀)-, or-N=, or sulphur atom or Sauerstoffatom, or an alternate c atoms=C(R ₆₁₀)-, but K ₆₁₀And K ₆₇Can not be simultaneously-N(R ₆₁₀) and N(R ₆₁)-.

* R ₆₃-R ₆₅, identical or different, have to R ₃, R ₄, R ₅One of implication.

* R ₆₆, R ₆₇And R ₆₁₀, identical or different, have to R respectively ₆, R ₇, R ₁₀One of implication.

In formula (VII) derivative, pay the utmost attention to the compound of following characteristics:

* Z ₆Be an OW ₆Group (W wherein ₆Have to one of W ' implication), a NHR ₆₁Base or a NR ₆₁R ₆₂Base, wherein R ₆₁And R ₆₂Comprise maximum 6 carbon atoms altogether, perhaps form a morpholino or parathiazan generation jointly.

* K ₆₆Be the nitrogen-atoms-N(R of a replacement ₆₆)-.

* K ₆₇Be a nitrogen-atoms-N=or an alternate c atoms=C(R ₆₇).

* K ₆₁₀Be a carbon atom=CH-.

* R ₆₃, R ₆₄, R ₆₅, identical or different, be a hydrogen atom or halogen atom, perhaps low alkyl group, a lower alkoxy, a low alkyl group sulfo-.

* R ₆₆And R ₆₇Be a hydrogen atom, an alkyl, phenyl, the benzene alkyl that may be replaced by halogen or haloalkyl, but R ₆₆And R ₆₇Can not be a hydrogen atom simultaneously.

Making us interested especially according to derivative of the present invention is, as intermediate and because the antimycotic character of their brilliances, especially agriculturally, and as derivative synthetic intermediate, other derivatives of formula I especially.

(a) compound and formula (I b) compound, other all is a preferred compound of the present invention to I except following formula.

* (I product a), wherein Y is a Sauerstoffatom to formula, simultaneously K ₈And K ₉Or-CH=, perhaps one of them is-N=, another is-CH=, and while K ₆And K ₇Common form a unsaturated carbocyclic, and be connected to and comprise K ₁₀The ring with 5 chain links.

* the product of formula (I b), wherein Y is a Sauerstoffatom, simultaneously K ₁₀Be O, S or SO or SO ₂Or NR ₁₀(R ₁₀Have the above implication that provides), or CH ₂CO, and while K ₆And K ₇Common form a unsaturated carbocyclic, and be connected to and comprise K ₁₀The ring with 5 chain links.

The preparation method:

Can be prepared with SOME METHODS according to derivative of the present invention.

The below preparation of narration formula II compound.

According to first method (method A), it is specially adapted to formula II compound, wherein K ₁₁₀Be-O--S-or NR ₁₁₀, be raw material with the benzophenone of a molecular formula (XII '), at XII ' middle R ₁₃-R ₁₉Implication (comprise top-priority implication) as hereinbefore, and A ₁Be a commutable halogen atom (, or paying the utmost attention to chlorine or fluorine) or a nitro as bromine, with XII ' and the derivative of a following molecular formula react: H-K ₁₁₀-CH ₂-CO-Z ₁, K wherein ₁₁₀And Z ₁Have aforementioned identical meanings, pass through A ₁Displacement and cyclisation and obtain the derivative of formula II.

This reaction is preferably in alcohol solvent (for example low-level chain triacontanol) at corresponding alkanoate (CH for example ₃ONa, C ₂H ₅ONa, C ₃H ₇ONa) or a kind of organic bases, as preferably selecting a tertiary amine (triethylamine), or a kind of mineral alkali,, under existing, carbonate or supercarbonate (these mineral alkalis are derivatives of basic metal such as sodium, potassium or calcium or alkaline-earth metal) carry out as oxyhydroxide.

Reaction equally can be in a non-proton dipolar nature solvent such as methyl-sulphoxide in the presence of above alkali, dimethyl formamide, and N,N-dimethylacetamide, N-methyl-pyrrolidone, or carry out in the hexamethylphosphorictriamide etc.

Formula (in II ") the derivative example, methods availalbe G is translated into formula (II ') derivative, promptly according to following formula with II " and excess amine HNR ₁₁R ₁₂In 100-200 ℃ of heating, perhaps carry out ∷ adding to depress sometimes

（Ⅱ″） ¹HNR ₁₁R ₁₂→Ⅱ′+W ₁OH

(when W was a hydrogen atom in the II "), these derivatives at first carried out the activation of (functional acid), can be at II ' and amine HNR in formula ₁₁R ₁₂Use thionyl chloride (SOCl before the reaction ₂), phosphoryl chloride (POCl ₃), trichlorine or five phosphorus oxide (PCl ₃, PCl ₅), dicyclohexyl carbodiimide, diimidazole base phosphinylidyne, reagent such as Vinyl chloroformate or trifluoroacetic anhydride are handled in tetrahydrofuran (THF) (THF) or chlorinated solvent (especially aliphatic series or aromatic hydrocarbon) in 0-50 ℃, and are preferably in excess amine HNR ₁R ₁₂, or a kind of inorganic or organic bases (as triethylamine) reacts under existing.

Set out by formula (II ') derivative, might come other derivatives of preparation formula (II ') with modified with functional group method classical in the organic chemistry.

As preparing nitro substitutive derivative (R in formula II ₁₆Or R ₁₇Or R ₁₈Or R ₁₉Be NO ₂) example in, it can be reduced into amination derivative (method B), used reductive agent such as metal (iron, tin) or its esters (as tin chloride) are in mineral acid (HCl, H ₂SO ₄), or reduce in organic acid (ethanol or carboxylic acid, the especially an acetate) medium.As reductive agent, also can use hydrogen (will pressurize sometimes) equally, or its precursor (sodium borohydride, carboxylic acid derivatives, cyclic ethylene) reduces in the presence of transition metal as palladium.In this case, preferably adopt vinyl acetic monomer, acetate or alcohol (as ethanol) as solvent.

Resulting amination derivative (R in the formula II ₁₆Or R ₁₇Or R ₁₈Or R ₁₉Be NH ₂) can itself stand acidylate (method C) or diazotization reaction.Anti-ization of acidylate is that nationality helps carboxylic acid derivative (acyl chlorides or acid anhydrides) at organic bases (triethylamine; pyridine) or mineral alkali (alkali-metal oxyhydroxide; carbonate or supercarbonate) exist down in aprotic solvent such as chlorinated solvent (methylene dichloride, chloroform) or aromatic hydrocarbons (benzene, toluene) or aliphatic ether (ether, tetrahydrofuran (THF); 1,2-glycol dimethyl ether) carries out in.

Diazotization (method D) reaction promptly uses alkali-metal nitrite (Sodium Nitrite) to handle a kind of amination derivative (R in the formula II under-10-15 ℃ temperature ₁₆Or R ₁₇Or R ₁₈Or R ₁₉Be NH ₂) solution in a kind of strong inorganic acid (hydrochloric acid, bromine hydracid, sulfuric acid).The diazonium salt that so obtains under+5 °-+100 ℃ temperature in different reagent such as cuprous chloride, cuprous bromide, potassiumiodide, decompose under the existence such as Red copper oxide or ethyl sulfuration potassium xanthonate, can obtain different derivatives respectively, promptly wherein amino by chlorine atom, bromine atoms, iodine atom, hydroxyl or sulfydryl are replaced.

In introducing the example of bromine atoms, can be with a boric acid R ₁₇B(OH) ₂Realize aryl linked reaction (method E), wherein R ₁₇(these groups can be as R to can be a heterocycle or phenyl or a vinyl ₇Show in the definition and be substituted like that), can generate like this according to other derivatives of the present invention.

This reaction for Z ₁=OW ₁(W ₁=H or alkyl, or basic metal) or and Z ₁-NR ₁₁R ₁₂Compound can realize too.

As catalyzer, can utilize commercial palladium mixture-four [triphenyl phosphine] to close palladium: Pd[P(C ₆H ₅) ₃] ₄, perhaps make raw material and make freshly by palladium salt such as palladium and a kind of phosphine such as triphenyl phosphine or 3-O-tolylphosphine.As alkali, can utilize a kind of as alkali-metal carbonate or supercarbonate (Na ₂CO ₃, NaHCO ₃) mineral alkali, or a kind of organic bases as amine (triethylamine).Reacting available a kind of mineral alkali carries out in comprising the heterogeneous medium of an organic phase, this organic phase can be the solvent such as the benzene of a hydrocarbonaceous, or toluene, or high boiling point ether such as glyme or its higher derivative diglyme, triglyme, another is alkaline aqueous solution mutually.Equally, react also available organic bases and carry out in equal phase medium in the presence of a solvent, this solvent is as dimethyl formamide or N-methyl-pyridine alkane ketone.Used boric acid can be commercial compound, perhaps uses a kind of Organometallic derivatives R ₁₇M ₁, R wherein ₁₇Has implication (M as the aforementioned ₁=Li or MgX, X=Cl is Br) with a boric acid alkyl ester B(OR ') ₃(R '=CH ₃, C ₂H ₅, C ₃H ₇, i-C ₃H ₇, C ₄H ₉) interact, according to Organic Synthesis Coll Vol 4P.68 or J.Org.Chem.49, P5237-5243(1984) working method of Jie Shaoing is carried out acidic hydrolysis then.The proportioning of agents useful for same is as follows:

Boric acid R ₁₇B(OH) ₂: the 1.05-1.50 equivalent

Alkali: 4.00-6.00 equivalent

Catalyzer: 0.005-0.03 equivalent

Formula II " ' Substrate: 1.00 equivalents

Be reflected under 50-150 ℃ the temperature and carry out, preferably allow reaction mixture refluxed, the reaction times continues 2-48 hour.Formula (II " ') derivative separates with ordinary method, extracts, or adds water and make in the reaction mixture and separate out solid, carries out purifying with a kind of suitable solvent recrystallization or with chromatography then.

In another method (method F), i.e. the version of method D promptly heats under the temperature between 40 ℃ and the solvent boiling point, makes formula II compound (wherein, substituent R ₁₆-R ₁₉One of be unsubstituted amino, and Z ₁, R ₁₃-R ₁₅Implication as preceding showing) and a kind of nitrous acid low alkyl group such as nitrite tert-butyl react at a kind of solvent such as tetrahydrofuran (THF) or dimethyl formamide, wherein amino to obtain a kind of formula II derivative, and Z by a hydrogen atom displacement ₁And R ₁₃-R ₁₉Has the implication as preceding showing.

Formula (XII ') derivative can react with Friedel-Crafts and prepare, as shown in the formula:

（Ⅻ″′） ¹（Ⅻ″）→（Ⅻ′）

A wherein ₁And R ₁₃-R ₁₉Have implication as preceding showing, compound (XII " ') and (XII ") know.

This is reflected at lewis' acid (the Fe Cl of catalytic amount or stoichiometric quantity ₃, Al Cl ₃, Zn Cl ₂, Sn Cl ₄) exist down and carry out having under solvent or solvent-free (solvent such as oil of mirbane, aliphatic chlorinated solvent, the dithiocarbonic anhydride).Reaction is carried out in-10-200 ℃ scope according to used experiment condition.

According to other method (method G), this method is suitable for the K of formula II compound-wherein especially ₁₁₀Be a C(R ₁₁₀) ₂Base, and R ₁₃-R ₁₉Have identical meanings (comprising the priority implication) as described above, can be with the benzophenone of a kind of formula (X XII ') (Z wherein ₁=OH, and R ₁₃-R ₁₉Have identical meanings as described above, comprise that the priority implication is also like this) and thionyl chloride (SOCl ₂), phosphoryl chloride (POCl ₃), phosphorus trichloride (PCl ₃) or phosphorus pentachloride (PCl ₅) react, to obtain a kind of benzophenone of formula (X XII '), wherein Z ₁=Cl, and R ₁₃-R ₁₉Has identical meanings as described above.

Generally, the compound that so obtains can not separate; The lower alkyl esters of it and propanedioic acid (preferably paraffinic acid magnesium, as magnesium ethylate) in the presence of alkali reacts.The formula that the so obtains (W of X XII ") compound-wherein ₁It is a low alkyl group, use the alkanoate of a kind of alkali such as basic metal or alkaline-earth metal then, or a kind of mineral alkali such as alkali-metal oxyhydroxide or carbonate are in water-based or alcohol medium, or at a kind of non-proton dipolar nature solvent such as methyl-sulphoxide, dimethyl formamide, react in N-methyl-pyrrolidone, to obtain a kind of formula II compound, wherein K ₁₁₀Be oxo group, and R wherein ₁₃-R ₁₉Have as aforesaid implication, and Z ₁Be an OW ₁Group, wherein W is a low alkyl group.

With this compound and excessive amine HNR ₁₁R ₁₂In that solvent or solvent-free heating under 100-200 ℃ are down arranged, need add sometimes and depress reaction, can obtain the formula II compound, wherein K ₁₁₀Be oxo group, and R wherein ₁₃-R ₁₉Have following with aforesaid implication, and Z ₁Be to have determined NR ₁₁R ₁₂Base.This latter compound can as existing down in cerous compounds with sodium borohydride, react in a kind of alkanol such as ethanol with the reduction of suitable reductive agent, to obtain the formula II compound, and K wherein ₁₁₀Be CH(OH) base, and Z ₁Be clear and definite NR ₁₁R ₁₂Base.

Back two class products can stand classical organic chemical reactions (for the first kind, by a kind of addition of organometallic compound; And for second class, by acidylate or alkylated reaction) make other derivatives of formula II.

According to another kind of method (method H), the special fortune of this method should be in the K of formula II compound-wherein ₁₁₀Be C(R ₁₁₀) ₂Base, and R wherein ₁₃-R ₁₉Have as aforesaid implication (comprising top-priority implication), with the Z of a kind of derivative of formula (XX XII ')-wherein ₁Be an OW ₁Or NR ₁R ₂Base, the R of the benzyl halide of a formula (XX XII ')-wherein ₁₆-R ₁₁₀Have as aforesaid implication, and wherein Hal shows a halogen atom such as chlorine or bromine, interact.This is reflected at the alkanoate that a kind of alkali exists following-preferably a kind of basic metal or alkaline-earth metal, or in the presence of a kind of mineral alkali such as alkali-metal oxyhydroxide in the alkanol medium or at a kind of non-proton dipolar nature solvent such as methyl-sulphoxide, carry out in dimethyl formamide or the N-Methyl pyrrolidone, to obtain the formula (R of XX XII ") compound-wherein ₁₃-R ₁₉Have as aforesaid implication with Z.With organic acid or mineral acid, being preferably Tripyrophosphoric acid is having solvent (toluene, dimethylbenzene) or solvent-freely down above-claimed cpd is being handled under 0-150 ℃ of temperature, can obtain the K of a kind of formula II derivative-wherein ₁₁₀Be C(R ₁₁₀) ₂Base, and R ₁₃-R ₁₉Have as aforesaid implication.If Z ₁=OW ₁(W ₁Be low alkyl group or hydrogen atom) derivative obtained, then can be used on the classical technique of organic chemistry of introducing in the first method, be translated into Z ₁=NR ₁R ₂Derivative.

Be suitable for the K of formula II compound-wherein especially according to another ₁₁₀Be C(R ₁₁₀) ₂, and R wherein ₁₃-R ₁₉Have as the aforesaid implication method of (comprising top-priority implication) (method 1, the just capitalization of i), can be with the Z of formula (XX XII ') derivative-wherein ₁Be OW ₁Base or NR ₁₁R ₁₂Base and one are by R ₁₆, R ₁₇, R ₁₈Or R ₁₉The phenyl aldehyde that replaces Deng group reacts.This is reflected in a kind of solvent and realizes, this solvent can be a kind of aromatic hydrocarbons or a kind of carboxylic acid in the presence of a kind of catalyzer-this catalyzer preferably two replaces amine such as piperidines, thereby obtain the R of a kind of formula (XXX XII ') compound-wherein ₁₃-R ₁₅And Z ₁All have as aforesaid implication.This compound appropriate reductant as sodium borohydride, is reacted under the chlorination existence of having introduced in above second method then.The vinyl carbinol of mentioning, with a catalytic amount be higher than the organic acid of stoichiometric quantity or mineral acid having under solvent (toluene, dimethylbenzene) or the condition of no solvent, under 0-150 ℃, handle, can cyclisation obtain the K of a formula II derivative-wherein ₁₁₀Be CH ₂, and R ₁₃-R ₁₉Have as aforesaid implication.If obtain Z ₁=OW ₁Derivative, W is low alkyl group or hydrogen atom, then can be used on the classical technique of organic chemistry of introducing in the first method and is translated into Z ₁-NR ₁R ₂Derivative.

Below introduce the preparation of formula III compound:

According to also belonging to a kind of method of the present invention, the preparation of formula III compound is by a boric acid R ₂₇B(OH) ₂[R wherein ₂₇Can be a heterocycle, (these groups can be substituted, as at R for phenyl or vinyl ₇Definition in indicated like that] and the bromo derivative of a formula (X III ') between the aryl linked reaction finish, thereby other any substituting groups can not be bromine atoms or iodine atom simultaneously.This aryl linked reaction formula is as follows:

This reaction is implemented in Z equally ₂=OW ₂(W ₂=H or alkyl, or basic metal) and Z ₂=NR ₂₁R ₂₂Example.

As catalyzer, can use commercial palladium mixture four [triphenyl phosphines] and close palladium: Pd[P(C ₆H ₅) ₃] ₄Or make raw material by a kind of palladium salt such as palladium and a kind of phosphine such as triphenyl phosphine or 3-O-tolylphosphine and prepare freshly.As alkali, can use mineral alkali such as alkali-metal carbonate and supercarbonate (Na ₂CO ₃, Na HCO ₃), or organic bases such as amine (triethylamine).This reaction is carried out in the heterogeneous medium that contains an organic phase and an alkaline water with mineral alkali, its organic phase can be a kind of hydrocarbon solvent such as benzene or toluene of containing, or high boiling point ether such as glyme or its higher derivative such as diglyme, triglyme.Carry out in the same equal phase medium of available a kind of organic bases in the presence of a kind of solvent such as dimethyl formamide or N-Methyl pyrrolidone of this reaction.Used boric acid can be commercial prod or with a kind of Organometallic derivatives R ₂₇M ₂(R wherein ₂₇Have as aforesaid implication, M ₂=Li or Mg X, X=Cl, Br) and a boric acid alkyl ester B(OR ') (R '=CH wherein ₃, C ₂H ₃, C ₃H ₇, i-C ₃H ₇, C ₄H ₉) react, then according to Org, Synth, Coll, Vol 4P.68 or J.Org.Chem.49.pp.5237-5243(1984) operating method narrated carries out acidic hydrolysis.The agents useful for same proportioning is as follows: boric acid R ₂₇B(OH) ₂: the 1.05-1.50 equivalent

Alkali: 4.00-6.00 equivalent

Catalyzer: 0.005-0.03 equivalent

Or X III ' Substrate: 1.00 equivalents

Be reflected under 50-150 ℃ and carry out, best reaction mixture refluxed, time remaining 2-48 hour.The formula III derivative separates with ordinary method, extracts, or water is added to product is precipitated out, and available then a kind of appropriate solvent carries out recrystallization or chromatographic separation is come purifying.

The bromo derivative of formula (X III ') can (the heavy helium reaction of the amine of X III ") obtains with formula.

This reaction can be implemented in Z in the formula equally ₂=OW ₂(W ₂=H or alkyl) derivative, or Z in the formula ₂-NR ₂₁R ₂₂Derivative.By with amination derivative (X III ') at a kind of strong inorganic acid (sulfuric acid or bromine hydracid), also contain sometimes in the organic acid (acetate) with a kind of basic metal ite (Sodium Nitrite) and under-10-+10 ℃ temperature, handle and realization response.The heavy helium salt that so obtains decomposes in 5-90 ℃ in the presence of bromine hydracid and bromize alpha ketone.

Formula (X III ') product separates with ordinary method, extracts or adds water in reaction mixture product to be precipitated out, and carry out recrystallization or chromatographic separation is carried out purifying with a kind of suitable solvent.

Amine (the available formula A of X III ") ₂By R ₂₃, R ₂₄, R ₂₅Suitably the phenyl-boron dihydroxide of Qu Daiing and a kind of formula (halo (bromine or iodine) of X III ") (and prepare with the aryl linked reaction before the derivative, as shown in the formula:

Wherein, group Z ₂, R ₂₆, R ₂₈And R ₂₉Have as aforesaid implication, but condition is R ₂₆R ₂₈And R ₂₉Can not be a bromine atoms or iodine atom simultaneously, get and Hal represents a halogen atom, particularly bromine or iodine.

Reaction also is implemented in Z ₂=OW ₂(W ₂=H or alkyl/or basic metal) and Z ₂=NR ₂₁R ₂₂Reaction conditions is same as the aforementioned situation that carries out the transition to (III) from (X III ').

Amine (X III) can through type (X III " ") contain also obtaining originally of nitro-derivative.

This reaction also can be implemented in Z ₂=OW ₂(W ₂=H or alkyl) derivative and Z ₂=NR ₂₁R ₂₂Derivative.As reductive agent, the salt (for example tin chloride) that can use a kind of metal (for example iron, tin) or these metals is at mineral acid (HCl, H ₂SO ₄) or organic acid (acetic acid) medium in react.Can use equally hydrogen as reductive agent (pressurization) possibly or its precursor (sodium borohydride, carboxylic acid derivatives, tetrahydrobenzene) in the presence of a kind of transition metal such as palladium or platinum.In this example, the most handy Methane Carboxylic Acid solvent, acetic acid or alcohol as ethanol as solvent.Formula (X III " ') product separates with ordinary method.Extract or add water and make in the reaction solution and separate out precipitation, and available a kind of suitable solvent carries out recrystallization or carries out purifying with chromatography.The derivative of formula (X III " ') type is a known compound.

(compound of III ") and (X III ') is if obtain wherein Z for formula ₂=OW ₂Derivative, might be translated into Z with the technology of modified with functional group classical in the organic chemistry ₂-NR ₂₁R ₂₂Derivative.Therefore, work as Z ₂Be OW ₂(W ₂-alkyl), might under 100-200 ℃ of temperature, (pressurize possibly) and a kind of excess amine HNR ₂₁R ₂₂Reacting by heating and be converted into Z ₂=NR ₂₁R ₂₂Derivative, as shown in the formula:

From formula (III "), (X III ') or (the X III " initial (Z wherein of the compound of ") ₂Equal OW ₂, W ₂=alkyl), can obtain Z in the formula equally ₂Equal OM ₂(M wherein ₂Be a kind of basic metal) compound, promptly by a kind of and saponification reaction mineral alkali, mineral alkali such as soda alcohol or alcoholic potash.These compounds can obtain (III), (X III ') or (X III " ") (Z respectively with a kind of mineral acid example hydrochloric acid, vitriolization ₂=OH) derivative.

From Z wherein ₂The formula III of=OH, the derivative of (X III ') or (X III " ") is initial can to obtain wherein Z equally ₂=NR ₂₁R ₂₂Compound, promptly with thionyl chloride (SOCl ₂), phosphoryl chloride (POCl ₃), phosphorus trichloride (PCl ₃), or phosphorus pentachloride (PCl ₅) dicyclohexyl carbodiimide, after diimidazole base phosphinylidyne, alkyl chloroformate or trifluoroacetic anhydride activate carboxylic-acid functional and amine HNR ₂₁R ₂₂In the presence of organic or inorganic alkali in a kind of organic solvent as reacting among chloro or aromatic solvent or the etherificate THF.

The below preparation of narration formula IV compound:

The preparation of formula IV compound, for example the cyclisation of through type (X IV ') derivative realizes

Ar wherein ₃Be that (group of X IV ") that is to say by R a formula ₃₃, R ₃₄And R ₃₅The phenyl that replaces, and Z ₃, R ₃₃-R ₃₉Have as aforesaid implication, this is reflected in the acidic medium provides the body existence to be undertaken by heating down in a kind of ammonia.

The midbody derivant of formula (X IV ') is to belong to new compound of the present invention.It can prepare according to a kind of method, and this method is characterised in that 3-acetone and a kind of benzoyl acetate of suitable replacement or the reaction of ethanamide in the presence of a kind of strong inorganic base and a kind of solvent.As shown in the formula:

Z wherein ₃With R -R ₃₇Has the middle identical meanings of formula (X IV) as described above, T ₃Appointment is that a leavings group is as a halogen atom or quaternary ammonium.

Work as T ₃Be under the situation of a quaternary ammonium, can be with a kind of Mannich alkali derivant, promptly a kind of formula: Derivative and a kind of formula

Ar ₃-CO-CH ₂-CO-Z ₃Derivative reacts under a ferment kind solvent exists in alkaline medium.

These derivatives of the latter are known.

Formula IV derivative (Z wherein ₃Be the OH base, formula (IV ") derivative, wherein W just ₃=H), also can be according to so that (IV ") formula ester (W wherein ₃Be low alkyl group) saponification reaction is that the method for feature makes through acidifying then.

At last, can be with formula (IV ") derivative (W ₃=low alkyl group) is converted into (IV ') formula derivative (Z wherein ₃Be NR ₃₁R ₃₂), promptly, as illustrated in the past, then these sour halogenations are become corresponding acyl halide, again with formula HNR by saponification ₃₁R ₃₂Amine (R wherein ₃₁And R ₃₂Have as aforesaid implication) react and get.

The preparation of following narrative (V) product:

According to first method, can be with as shown in the formula (the ketenes of X V ")

X ₄

O＝C-C＝C-R ₄₉（ⅩⅤ′）

Z ₄CO

Ar ₄

Ar wherein ₄Has formula (X V ")

R ₄₃, R ₄₄, R ₄₅, R ₄₉And Z ₄Have with the formula V in identical meanings

X is the amidine R of a dialkyl group (rudimentary)-amino or alkoxyl group (rudimentary) and a kind of following formula ₄₇-C=NH or its salt

NH ₂R ₄₇-C＝N ⁺H ₂

NH ₂Negatively charged ion ^-

(R wherein ₄₁Have as aforesaid implication), in the presence of a kind of solvent, in alkaline medium, react.This reaction is preferably in organic solvent, be preferably alcohol solvent example methyl alcohol, ethanol, propyl alcohol, and at corresponding alcoholate or a kind of organic bases such as amine, be preferably tertiary amine, or the oxyhydroxide of a kind of mineral alkali such as metal, alkaline-earth metal, carbonate or supercarbonate such as sodium salt, sylvite or calcium salt carry out under existing.This reaction can be carried out under above-mentioned mineral alkali exists in water equally.In the example of formula (V ') derivative, that is to say (V) formula compound, wherein Z ₄Be a NR as former clear and definite implication ₄₁R ₄₂, can be with a kind of formula (V ") derivative, just formula (V) derivative (Z wherein ₄Be OW ₄Group was as in the past clear and definite) and a kind of formula HNR ₄₁R ₄₂Amine react, and lose W ₄OH.As formula (W in the V ") ₄When being a Sauerstoffatom, these derivatives are at first used dicyclohexyl carbodiimide, diimidazole base carboxylic acyl, oxygen ethyl formate and trifluoro acid anhydrides, thionyl chloride (SOCl ₂), phosphoryl chloride (POCl ₃), phosphorus trichloride (PCl ₃) or phosphorus pentachloride (PCl ₅) wait reagent to activate functional acid, use amine HNR then ₄₁R ₄₂In the presence of a kind of organic bases, in a kind of organic solvent such as chlorinated solvent or aromatic solvent (especially a kind of hydro carbons) or a kind of ether such as THF, react.

Initial from formula (V ') derivative, by modified with functional group technology classical in the organic chemistry, might other derivatives of preparation formula (V ').

Formula (X V ') derivative can be according to preparing as this method, is about to formula (X V " ') derivative:

(Ar wherein ₄, R ₄₃, R ₄₄And R ₄₅And Z ₄Have as aforesaid implication) and a kind of formula (X V) derivative

(X V " ") (R wherein ₄₉And X ₄Have as aforesaid implication, R ₄₁₀Be a low alkyl group) one react.

Second kind of preparation method, R therein according to preparation formula (V) derivative ₄₇Not under the situation of an alkyl or benzyl-sulfinyl or alkylsulfonyl, can be a kind of formula (XX V ') derivative (R wherein ₄₃-R ₄₅, R ₄₉And Z ₄Have as aforesaid implication, and A ₄Be alkyl (rudimentary) alkylsulfonyl or benzyl alkylsulfonyl] and a kind of formula R ₄₇H(is R wherein ₄₇Be and R ₇Identical meanings is arranged, just at R ₄₇The middle valency chain that connects a hydrogen atom can connect a heteroatoms such as O, Sn or HR equally ₄₇

This has been reflected in solvent and the alkaline medium and has carried out, and is preferably in proton or the aprotic solvent, and at oxyhydroxide, carbonate, the supercarbonate of a kind of organic or inorganic alkali such as basic metal or alkaline-earth metal, for example there are reaction down in its sodium, potassium or calcium salt.

Some formulas (XX V ') but the oxidizing reaction of derivative through type (V) derivative makes (R in (V) ₄₇Be a low alkyl group sulfo-or dibenzylsulfide generation), promptly by means of a kind of oxygenant, for example hydrogen peroxide and some are crossed (oxygen) acid as peracetic acid, metachloroperbenzoic acid or the adjacent magnesium formiate of mistake.

The below preparation of narration formula VI compound:

According to this method, with the 2-alkene benzophenone and a kind of β-carbonyl ester or the acid amides of a kind of formula (X VI), promptly formula is R ₅₉-CO-CH ₂-COZ ₅, R wherein ₅₃-R ₅₇And Z ₅Have as aforesaid implication, in the presence of a kind of organic or inorganic alkali, the barium oxide of for example using partial dehydration reacts (Michael reaction) in temperature range between 0 ℃ and the solvent for use boiling point in low-level chain triacontanol such as ethanol.Gained formula (the R of X VI ") compound-wherein ₅₃-R ₅₇And Z ₅Have as aforesaid implication, in the carboxylic acid medium, be preferably acetate, and provide (as ammonia or a kind of organic or inorganic ammonium salt) in the presence of the body reagent, simply heat down until solvent refluxing, thereby cyclization takes place in 40 ℃ at a kind of ammonia.Thereby obtain a kind of formula (compound of V ") or (VI '), wherein Have as aforesaid implication, and

Dividing in addition is OW ₅And NR ₅₁R ₅₂

If the formula VI derivative is obtained, the vitochemical classical technology of introducing in the then available previous method is translated into formula (VI ') derivative.

The preparation of following narrative (VII) compound:

According to the compound of formula (VII), wherein K ₆₆Be O, K ₆₇Be-C(R ₆₇)=and K ₄₇Be-C(R ₆₇)=, by β. γ-dicarbapentaborane ester or acid amides (formula X VII ') are by in alcohol or carboxylic acid such as acetate, (0,1-5%) strong acid (inorganic or organic acid, for example hydrochloric acid and sulfuric acid) exists down in catalytic amount, 40-120 ℃ of down simple heating and cyclisation prepares, this reaction be according to KRAFF and DAAL at Chem.Ber, 21, p 3053(1888) in and TREBAUL and TESTE at Bull, Soch.chim, Fr.p 2272(1970) the middle general method of narrating.

By the compound of formula (VII), wherein K ₆₆Be NR ₆₆, K ₆₇Be-C(R ₆₇)=K ₆₁₀Be-C(R ₆₁₀)=, can be by β. and γ-dicarbapentaborane acid amides or ester (formula X VII ') are initial, by in acidic medium, in a kind of formula NHR ₆₆Amine (R ₆₆Have as aforesaid implication) there is heating down and cyclisation makes.As solvent, can utilize a kind of carboxylic acid such as acetate, it brings into play catalyst action simultaneously.The strong inorganic acid that also can add catalytic amount, for example hydrochloric acid or sulfuric acid.Be reflected between the boiling point of 40 ° and solvent for use and carry out under the temperature.

, obtain product and have formula (VII), wherein K with under the situation of ammonia in reaction ₆₆Be NH, K ₆₇Be-C(R ₆₇)=, K ₆₁₀Be-C(R ₆₁₀)=.This compound can be with a kind of halo derivatives R ₆₆Hal, wherein Hal is a halogen (can be a chlorine atom bromine atoms or iodine atom), in a kind of solvent such as methyl-sulphoxide, reacts in dimethyl formamide or the N-Methyl pyrrolidone in the presence of inorganic or organic bases, to obtain the derivative of a kind of formula (VII), wherein K ₆₆Be NR ₆₆, K ₆₇Be-C(R ₆₇)=, and K ₆₁₀Be-C(R ₆₁₀)=.

The dicarbapentaborane ester class and the amides of formula (X VII ') can be according to preparing as this method, and this method is characterised in that a kind of formula (X VII ') halogenated ketone (may be by R ₆₇) and R ₆₁₀The base replace) and a kind of benzoyl acetate or ethanamide of suitable replacement react by following formula:

Ar wherein ₆Be a formula ((X VII " ') group, that is to say by R ₆₃, R ₆₄And R ₆₅The phenyl that replaces, wherein Z ₆And R ₆₃-R ₆₁₀All have as aforesaid implication, Hal represents that a leavings group is as a halogen atom.

By the compound of formula (VII), wherein K ₆₆Be-N=or-N(R ₆₆)-and K ₆₇Be-N=or-N(R ₆₇)-, condition is K ₆₆And K ₆₇Can not be simultaneously-N(R ₆₆)-and N(R ₆₇)-, it can be by the ketenes of a kind of formula (XX VII ') and a hydrazine reaction and make Ar in (XX VII ') ₆Be a formula (X VII ') group, that is to say one by R ₆₃, R ₆₄And R ₆₅The phenyl that is replaced; Z ₆, R ₆₁₀Have as aforesaid implication, and X is dialkyl group (rudimentary) amino or alkoxyl group, and this hydrazine may be at most by a R ₆₆Base replaces.

Ar ₆（ⅩⅩⅦ′）

Be reflected in a kind of alkanol such as the ethanol, under a kind of inorganic or organic bases such as triethylamine exist, carry out.

At R ₆₆Be in the situation of low alkyl group or rudimentary aralkyl, might obtain two kinds of positional isomerss: formula (VII ') and (VII ") wherein is respectively: K ₆₆Be-N=and K ₆₇Be-N-(R ₆₇)-or K ₆₆Be-N(R ₆₆)-and K ₆₇Be-N=that the latter generally is a primary product.

The ketenes that is used as starting raw material is that the method according to aforementioned preparation formula (V) compound prepares.

For the compound of all formulas (VII), if Z wherein ₆=OW ₆Derivative be made, then might use in the organic chemistry classical modified with functional group technology and be translated into Z in the formula ₆=NR ₆₁R ₆₂Derivative.Therefore, work as Z ₆Be OW ₆, wherein during the W=low alkyl group, might be down and a kind of excessive amine HNR at 100-200 ℃ ₆₁R ₆₂Reacting by heating perhaps need be pressurizeed sometimes, is translated into Z ₆=NR ₆₁R ₆₂Derivative.

By (VII) compound (Z wherein ₆Be the O-alkyl) initial, can make Z in the formula equally ₆Be OM ₆(M wherein ₆Be a basic metal) compound, promptly carry out saponification reaction and get with a kind of mineral alkali such as soda alcohol liquid or alcoholic potash.This compound can generate Z with mineral acid example hydrochloric acid or vitriolization ₆The derivative of=OH (VII).

By Z ₆The formula of=OH (VII) derivative is initial, can obtain Z equally ₆Be NR ₆₁R ₆₂Compound, promptly with thionyl chloride (SOCl ₂), p chloromethylbenzoic acid (POCl ₃), phosphorus trichloride (PCl ₃) or phosphorus pentachloride (PCl ₅), dicyclohexyl carbodiimide, diimidazole base phosphinylidyne is after reagent such as alkyl chloroformate or trifluoroacetic anhydride activate carboxylic-acid functional and amine HNR ₆₁R ₆₂In the presence of a kind of organic or inorganic alkali, in a kind of organic solvent such as chloro or aromatic solvent (especially being a kind of hydrocarbon) or a kind of ether such as THF, react.

The example that following non-limited way provides has illustrated the present invention, and shows how they implement.

Compound structure is determined with nuclear magnetic resonance spectrometry in these different examples.

In these examples, we used following liquid slightly symbol: PF be fusing point ℃.If a product does not provide log P value, then this product is a chemical intermediate, and is not useful product concerning the plant anti-fungal infection.

Example 101-170 relates to a series of products of formula II subclass.

Example 101:2-(4-morpholino carbonyl)-and 5-iodo-3-(3, the 4-dimethoxy phenyl) thionaphthene-(method D; Compound n ° 101)

In 100ml round bottom alkane burns, add the 1.47g(0.0037 mole) the 2-(4-morpholino carbonyl)-5-amino-3-(3, the 4-dimethoxy phenyl) thionaphthene, 10ml distilled water and 1.0ml 98% vitriol oil.Make reaction mixture temperature remain on below 50 ℃ simultaneously or, add a kind of 0.27g(0.0039 of containing mole more gradually at 50 ℃) solution of Sodium Nitrite in 5ml water.Stirred 1 hour, and reaction mixture poured into contained 10ml water and 0.65g(0.0039 mole then) in the solution of potassiumiodide.The mixture that so obtains slowly is heated to 60 ℃, and kept 1 hour in this temperature.After the cooling, reaction mixture extracts with 3 * 50ml methane dioxide; Organic phase washes with water, and is dry on sal epsom, and boils off solvent.Use the silica gel column chromatography purifying, can get the 0.9g2-(4-morpholino carbonyl)-5-iodo-3-(3, the 4-Dimethoxyphenyl) thionaphthene, 214 ℃ of (yields 48% of fusing point; Compound n ° 101).

Example 102:2-(4-morpholino carbonyl)-5-(4-chloro-benzamido)-3-(3, the 4-dimethoxy phenyl) thionaphthene-(method C, compound n ° 102):

In the 100ml round-bottomed flask, add the 2.0g(0.005 mole in succession) the 2-(4-morpholino carbonyl)-5-amino-3-(3, the 4-dimethoxy phenyl) thionaphthene, 50ml methylene dichloride, 0.74ml(0.0052 mole) triethylamine and 0.70ml(0.0052 mole) 4-chloro-Benzoyl chloride.Stirred 1 hour at 20 ℃, boil off solvent, wash with water,, use the solid of 20ml washed with dichloromethane gained then in air drying.Obtain 1.0g(37%) the 2-(4-morpholino carbonyl)-5-(4-chloro-benzamido)-3-(3, the 4-dimethoxy phenyl) thionaphthene, 247 ℃ of fusing points (compound n ° 102).

Example 103:2-(4-morpholino carbonyl)-and 5-amino-3-(3, the 4-dimethoxy phenyl) thionaphthene-(method B; Compound n ° 103):

In the 250ml round-bottomed flask, add the 10.7g(0.025 mole in succession) the 2-(4-morpholino carbonyl)-5-nitro-3-(3, the 4-dimethoxy phenyl) thionaphthene, 100ml dehydrated alcohol, 3ml concentrated hydrochloric acid and 4.2g(0.075 mole) iron powder.Reaction mixture refluxed 2 hours, cooling then is to the 200ml saturated sodium bicarbonate solution.After with 6 * 100ml ethyl acetate extraction, organic phase is dry on anhydrous magnesium sulfate, filters, boil off solvent, obtain the 9.2g2-(4-morpholinyl carbonyl)-5-amino-3-(3, the 4-dimethoxy phenyl) thionaphthene, yield 92%, 213 ℃ of fusing points (compound n ° 103).

Example 104:2-(4-morpholino carbonyl)-and 5-nitro-3-(3, the 4-dimethoxy phenyl) thionaphthene-(method A, compound n ° 104):

In a round-bottomed flask, add the 9.0g(0.0056 mole in succession), α sulfydryl acetyl morphine, 13.8 gram (0.1 mole) salt of wormwood, 14.8 gram (0.046 mole) 2-chloro-3 ', 4 '-dimethoxy-5-nitro benzophenone and 200ml ethanol.Mixture is reflux 2 hours under agitation, is as cold as room temperature then; Pour in 1 premium on currency; Yellow mercury oxide filtrate with separating out washes with water, and is dry under airflow then.So obtain the 2-(4-morpholino carbonyl of 18.1 grams (92%))-5-nitro-3-(3, the 4-dimethoxy phenyl) thionaphthene, molten point is 144.5 ℃ (compound n ° 104).

Example 105:2-(4-morpholino carbonyl)-5-(propylene-2-yl)-3-(3, the 4-dimethoxy phenyl)-thionaphthene (method E; Compound n ° 105).

In a round-bottomed flask, under inert atmosphere, add 2.0 gram (0.005 mole) 2-(4-morpholino carbonyls in succession)-5-bromo-3-(3, the 4-dimethoxy phenyl)-thionaphthene (press A method preparation), 50ml 1, the 2-glycol dimethyl ether, 0.2 gram four [triphen phosphorus] closes palladium, 0.5 gram (0.006 mole) propylene-2-ylboronic acid and 20cm ³The 2M aqueous sodium carbonate.Mixture refluxed 8 hours, poured into then in the mixture of water and ice.By the cream-coloured product of precipitation gained, separate after filtration, wash with water and dry air, obtain n ° of 105 compounds of 1.5 grams (yield 81.5%), 135 ℃ of fusing points through the silicic acid chromatography purification.

Example 106:2-(4-morpholino carbonyl)-and the 3-(4-methoxyphenyl) thionaphthene (method F; Compound n ° 106).

In a round-bottomed flask, add 1.0 gram (0.0027 mole) 5-amino-2-(4-morpholino carbonyls down in inert atmosphere)-the 3-(4-methoxyphenyl) thionaphthene and 50ml distillatory tetrahydrofuran (THF).Mixture heating up refluxes, and drips the 0.7ml(0.0054 mole then) nitrite tert-butyl is dissolved in the solution among the 20mlTHF.After three hours, the reaction mixture water treatment is extracted with CHCl, washes with water and drying on sal epsom.After boiling off solvent and chromatography, separable n ° of 106 compounds, 131 ℃ of fusing points to 0.5 gram (yield 53%).

Example 107:2-(N, the N-diethylformamide)-3-(3, the 4-Dimethoxyphenyl) thionaphthene (method G; Compound n ° 107).

In a round-bottomed flask, add 25 gram (0.08 mole) 3-(3, the 4-dimethoxy phenyl) thionaphthene-3-carboxylic acid (preparing) according to method D, 300ml 1, the 2-ethylene dichloride, the 12ml(0.16 mole) thionyl chloride and 1ml DMF.Mixture slowly is added to backflow; Solid fuses gradually, obtains a kind of solution of yellow transparent.After 4 hours, boil off solvent, obtain 24.7 grams (yield 96%), 2-(is chloroformyl)-3-(3, the 4-dimethoxy phenyl) thionaphthene.

2.5 this product of gram (0.0075 mole), immediately and 4cm ³(0.0375 mole) N, N dimethylamine is reacted in 100ml THF, after with water treatment and ethyl acetate extraction, can obtain 2.5 gram (yield 90%) 2-(N, the N-diethylformamide)-3-(3, the 4-dimethoxy phenyl) thionaphthene, separate out crystallization with pentane development, 113 ℃ of fusing points, compound n ° 107.

Example 108:3-(3, the 4-dimethoxy phenyl)-2-ethoxy carbonyl indone (method G):

A) 25 gram thionyl chlorides are added to 15 gram 2-(7.4-dimethoxy benzoyls) in the phenylformic acid, then in 50 ℃ of heating, till gas release stops.Reaction adds some toluene after finishing, and evaporation is to remove excessive SOCl ₂The gained acyl chlorides is a kind of orange solids.

B) the enol magnesium of this acyl chlorides and excessive slightly malonic ester reacts (above-mentioned magnesium salts is made by malonic ester and magnesium ethylate) in toluene.Reaction mixture poured into use ethyl acetate extraction in the dilute acid.Wash with water and drying after, boil off solvent and obtain a kind of reddish oil, it can be used for the next step.

C) above gained reddish oil and 300ml 5% sodium carbonate solution reflux are 35 minutes.It forms a kind of red solid, and through cooling, the water-yielding stratum that inclines adds 300ml water again, reheats and refluxes 35 minutes.Cold after-filtration washes drying with water, can obtain the indone of red solid, 130 ℃ of fusing points, yield 49%(compound n ° 108).

Example 109:3-(3, the 4-dimethoxy phenyl)-2-morpholino carbonyl indone:

0.9 gram was heated 1 hour by example 108 gained indones and 10ml morpholine.Reaction mixture is poured in the dilute hydrochloric acid solution, used ethyl acetate extraction then, wash with water, concentrate.Obtain the product (71.5 ℃ of fusing points) of yield 98%, compound n ° 109.

Example 110:1-(3, the 4-dimethoxy phenyl)-2-morpholino carbonyl-3-hydroxyl indenes:

0.5 gram indone of example 100 gained is with 0.05 gram Na BH ₄Reduce in 20ml methyl alcohol with 0.5 gram Cerium II Chloride.Be reflected at end in 10 minutes, reaction mixture is poured in the water.Be adjusted to pH5 with dilute hydrochloric acid, and use ethyl acetate extraction.Wash with water, boil off solvent, obtain 0.49 gram indenols, 134 ℃ of (yield 99%) compound n of fusing point ° 110).

Example 111:2-morpholino carbonyl-3-(3, the 4-dimethoxy phenyl)-6-methoxyl group indenes (method H):

A) make 0.8 gram sodium Metal 99.5 and the reaction of 100ml dehydrated alcohol in a reactor, add 10 grams 3 then, 4-dimethoxy benzoyl acetyl morphine also stirred 15 minutes.Yet add 0.3 gram 3-methoxyl group Bian chlorine.Refluxed 1.5 hours, and concentrated reaction mixture under reduced pressure.Water and dilute hydrochloric acid are handled, and use ethyl acetate extraction, obtain an orange oil.

B) 53 gram Tripyrophosphoric acid are added in the above-mentioned 5.1 gram oil, and 70 ℃ of heating 6 hours.Water is added in the reaction mixture, stirs, use ethyl acetate extraction then until dissolving.By chromatography purification (eluent: vinyl acetic monomer).Yield 25%, 115 ℃ of fusing points (compound n ° 111).

Example 112:2-morpholino carbonyl-3-(3, the 4-dimethoxy phenyl)-5,6-methoxyl group indenes (method I):

A) with 3,4-(dimethoxy benzoyl)-acetyl morphine and veratryl aldehyde carry out condensation in the presence of piperidines and aceticanhydride in acetum.Be heated to 100 ℃, pour in the water, extract, wash organic phase with saturated potassium carbonate with Methane Carboxylic Acid.By the silicic acid chromatography purification, eluent is 10/90 mixture of pentane/vinyl acetic monomer, obtains a kind of fusing point and be 150 ℃ red solid.

B) yet, Acetolon Na BH ₄In the presence of Cerium II Chloride, in methyl alcohol, reduce.Thereby obtain the vinyl carbinol (110 ℃ of fusing points) of 83% yield.

C) put into 2.2 vinyl carbinols that obtain previously of gram and the tosic acid of catalytic amount in 80ml toluene, reflux 5 hours is removed the water that generates simultaneously in reaction.Pour in the water.Inclining, and with the washing of rare saleratus, washes with water again, can obtain the shallow maroon powder of 1.9 grams (compound n ° 112).

Following compound is to utilize one of aforesaid method to prepare.Their structure and physicochemical property and preparation method are all indicated in the following table I.

In addition, this form is also classified the structure and the character of the product of example 101-112.These compounds have formula II structure, wherein R ₁₅Be H, NR ₁₁R ₁₂It is a 4-morpholino.

The K of through type (62) ₁₁₀, R ₁₃, R ₁₄, R ₁₆, R ₁₇, R ₁₈And R ₁₉In following table, provide structure.

In addition, the table II is also sorted out the structure and the physico-chemical property of formula II compound, wherein K ₁₁₀Be a sulphur atom, R ₁₃And R ₁₄Be methoxyl group, R ₁₅, R ₁₆, R ₁₈And R ₁₉Be a hydrogen atom, R ₁₇And NR ₁₁R ₁₂As show as indicated in the II.These compounds prepare according to method G.

The table II

Compound R ₁₇NR ₁₁R ₁₂PF Log P

N°

150 H N-methylethyls amino 95 3.6

151 H two (methoxy ethyl) amino 90 3.7

107 H N-diethylaminos 113 4.1

152 H 2, the 6-thebaine is for 150 4.2

153 H piperidyls 110 4.3

154 H pyrrolidyls 119 3.7

155 H N-dimethylaminos 128 3.1

156 H N-methyl hydroxyethyls amino 84 2.8

157 H 2-hydroxymethyl-piperidyls 60 3.8

The amino sweet shape 3.4 of 158 H N-methyl-methoxyethyl

159 H 2-methoxymethyl piperidyls 123 4.5

160 H 2-hydroxymethyl-pyrrolidine bases 74 3.3

161 H 4-hydroxy piperidine bases 166 2.2

162 H 4-oxo group piperidyls 148 3.0

163 H 2-methoxymethyl pyrrolidyls 60 3.9

164 H 3-hydroxy piperidine bases 90 3.1

165 H 4-methoxyl group piperidyls 139 2.8

166 H 3-methoxyl group piperidyls 60 3.8

167 F N-methylethyls amino 103 3.8

168 F 2, the 6-thebaine is for 134 4.4

The amino sweet shape 3.6 of 169 F N-methyl methoxy base ethoxies

170 F two (dimethoxy ethyl) amino 99 3.9

Example 171-184:2-chloro-3 ', 4 '-dimethoxy-5-nitro-benzophenone [is the intermediate of preparation formula II product, wherein K ₁₁₀Be O, S or W(R ₁₁₀)].

In a round-bottomed flask, add the 11g(0.05 mole in succession) 2-chloro-5-nitro-Benzoyl chloride, 20ml(0.15 restrains mole) 1,2-dimethoxy benzene and 0.5g Anhydrous Ferric Chloride.Reaction mixture is heated to 150 ℃ gradually, keeps 1 hour.After cooling, reaction mixture is poured among the 200ml l NHCl, use 3 * 200ml dichloromethane extraction then.After the sodium bicarbonate washing, organic phase is at Mg SO ₄Last dry, concentrating under reduced pressure obtains brown oil then.Separable with 300ml pentane development back to 12.5g(yield 78%) 2-chloro-3 ', 4 '-dimethoxy-5-nitro-benzophenone, be beige solid, fusing point is 138 ℃ (compound n ° 171).

Other compounds can obtain under conditions of similarity: during their structures and physico-chemical property institute show afterwards.These compounds are formula (XII ') product, wherein R ₁₅Be H, R ₁₄Be methoxyl group, and A ₁, R ₁₃, R ₁₆, R ₁₇, R ₁₈And R ₁₉Have and the indicated implication of following table (III).

* example 201-253 relates to the subclass derivative of formula III.

Example 201:2-(3, the 4-dimethoxy phenyl)-the 4-(4-fluorophenyl)-1-morpholino carbonyl benzene:

In the 100ml round-bottomed flask, add the 1.6g(0.00454 mole) 2-(3, the 4-dimethoxy phenyl)-the 4-(4-fluorophenyl) phenylformic acid (compound 204), 50ml tetrahydrofuran (THF) and 0.92g(0.0057 mole) diimidazole base phosphinylidyne.Stirred 2 hours at 20 ℃, add the 1ml(0.013 mole then) morpholine, stir maintenance down 6 hours.To 150ml distilled water, will separate out solid filtering, use the 100ml water washing, then dry air to reaction mixture.So obtain 1.3g(yield 68.4%) 2-(3, the 4-dimethoxy phenyl)-the 4-(4-fluorophenyl)-1-morpholino carbonyl benzene, be white solid, 153 ℃ of fusing points (compound 201).

With obtain compound 201-231 with quadrat method.These compounds are formula III structure, wherein R ₂₃And R ₂₄Be methoxyl group, R ₂₅, R ₂₈And R ₂₉Be hydrogen atom, R ₂₆, R ₂₇And Z ₂Have with the implication of showing (IV), (IV ') expression later on.

Other subclass products have formula III structure, wherein R ₂₃And R ₂₄The common methylene-dioxy of forming a divalence, R ₂₅, R ₂₆, R ₂₈And R ₂₉Be hydrogen atom, and R ₂₇And Z ₂Have with showing the implication that (V) provides later on.

The table III

Compound R ₁₆R ₁₃A ₁R ₁₇R ₁₈R ₁₉Fusing point ℃

N°

171 H CH ₃O Cl NO ₂H H 138

172 H CH ₃O Cl H NO ₂H 140

173 H CH ₃O F H H H 84

174 H CH ₃O F F H H 125

175 H CH ₃O Cl H H NO ₂139.5

176 H CH ₃O F H H F 189

177 H CH ₃O F H H Cl 167

178 H CH ₃O F H Cl H 134

179 H CH ₃O F H NO ₂H 140

180 H CH ₃O F H H CH ₃110

181 F CH ₃O F H H H 102

182 H CH ₃O F CF ₃H H 79

183 H H Cl H NO ₂H 103

184 F CH ₃O F F F F 77

The table IV

N ° of Z ₂R ₂₇Fusing point ℃ log P

201 morpholino 4-fluorophenyls 153 4.1

202 morpholino phenyl 130 4.0

203 morpholino 4-aminomethyl phenyls 129 4.6

204 N(CH ₃) CH ₂CH ₂OCH ₃Br honey shape 3.2

205 N（C ₂H ₅） ₂Br 82 4.0

206 N（CH ₃）C ₂H ₅Br 85 3.4

207 pyrrolidyl Br 76 3.5

208 morpholino Cl 108 2.9

209 N（CH ₃）C ₂H ₅Cl 68 3.3

210 N(CH ₃) CH ₂CH ₂OCH ₃Cl honey shape 3.1

211 N（C ₂H ₅） ₂Cl 54 3.8

212

Propylene-2-base 98 3.6

213 N(CH ₃) CH ₂CH ₂OCH ₃Propylene-2-base 78 3.4

214 N(C ₂H ₅) ₂Propylene-2-base 68 4.1

215 N(CH ₃) C ₂H ₅Right-tolyl 130 5.0

216 N(CH ₃) CH ₂CH ₂OH is right-tolyl 130 4.2

217 N(CH ₃) ₂Right-tolyl 109 4.5

218 N（CH ₃）C ₂H ₅CH ₃110 3.2

219 N（C ₂H ₅） ₂CH ₃73 3.7

220 morpholino CH ₃132 2.8

221 N（CH ₃）CH ₂CH ₂OCH ₃CH ₃63 3.0

222 morpholino Br 123 3.0

Table (IV ')

N ° of Z ₂R ₁₆Fusing point ℃ log P

223 morpholino Br 55 3.0

Table (V)

N ° of Z ₂R fusing point ℃ log P

145 ℃ 2.9 of 224 morpholino Br

225 N(CH ₃) C ₂H ₅Br honey shape 3.4

226 N(CH ₃) CH ₂CH ₂OCH ₃Br honey shape 3.2

227 N(C ₂H ₅) ₂Br honey shape 3.9

228 N(CH ₃) C ₂H ₅98 ℃ 4.5 of 4-fluorophenyl

170 ℃ 4.0 of 229 morpholino 4-fluorophenyl

230 N(CH ₃) C ₂H ₅Right-148 ℃ 5.0 of tolyl

231 morpholinoes are right-137 ℃ 4.5 of tolyl

Example 232:2-(3, the 4-dimethoxy phenyl)-the 4-(4-fluorophenyl)-phenylformic acid (compound 232):

In a 100ml round-bottomed flask, add the 2.8g(0.074 mole) 2-(3, the 4-dimethoxy phenyl)-the 4-(4-fluorophenyl) ethyl benzoate, 50ml dehydrated alcohol and 2ml 10N soda.Mixture refluxed 2 hours, poured into then in the 150ml 1N hydrochloric acid.To separate out solid and filter by sand core funnel, and wash with water, then dry air can obtain 2.1g(yield 80%) 2-(3, the 4-dimethoxy phenyl)-the 4-(4-fluorophenyl) phenylformic acid, be white solid, 210 ℃ of fusing points.

Example 233:2-(3, the 4-dimethoxy phenyl)-the 4-(4-fluorophenyl) ethyl benzoate (compound 233):

In the 250ml three-necked flask, add 30ml 1 of argon-degassed, the 2-glycol dimethyl ether, add the 3.65g(0.010 mole again) 4-bromo-2-(3, the 4-dimethoxy phenyl)-ethyl benzoate (compound 209), 0.1g four [triphenyl phosphines] close palladium, the 1.7g(0.012 mole) 4-fluorophenyl-boric acid and 20ml 2M yellow soda ash.After refluxing in 8 hours, reaction mixture is poured in the 100ml distilled water.Use 2 * 100ml dichloromethane extraction then, with the 100ml water washing once, dry on sal epsom, and by the separation of silicic acid layer, boil off solvent, obtain 3.4g (yield 89.5%) 2-(3, the 4-dimethoxy phenyl)-the 4-(4-fluorophenyl) ethyl benzoate, 127 ℃ of fusing points (compound 233).With with quadrat method preparation formula (III) compound, wherein R ₂₃And R ₂₄Be methoxyl group, and R ₂₅, R ₂₆, R ₂₈, R ₂₉It is hydrogen atom; R ₂₇And Z ₂Has the implication that shows as later table (VI).

The table VI

* synthetic intermediate

Can make formula III compound, wherein R equally ₂₃And R ₂₄A common divalent group methylene-dioxy, the R of forming ₂₅, R ₂₆, R ₂₈And R ₂₉Be hydrogen atom, and R ₂₇And Z ₂Has the implication that shows as the following table VII.

The table VII

Example 250:4-bromo-2-(3,4-dimethoxy phenyl) ethyl benzoate (compound n ° 250):

In the 100ml three-necked flask, add the 20.0g(0.066 mole) 4-amino-2-(3, the 4-dimethoxy phenyl)-ethyl benzoate (compound 252) and 200ml acetate.After dissolving, add 60ml 47% bromine hydracid, be cooled to 0 ℃, add 150ml distilled water then.Slowly adding 10.066 moles of 4.6g) Sodium Nitrite is dissolved in the solution of 30ml water.Stirred 1 hour at 0-5 ℃ again, then mixture is poured into a kind of cuprous bromide (0.066 mole, the 9.5g) solution in 100ml 47% bromine hydracid.Reaction mixture is heated to 65 ℃, lasts 1 hour, is poured in the water then.The precipitation that leaching generates washes with water, and then dry air can obtain 18.4g(yield 76.3%) 4-bromo-2-(3, the 4-dimethoxy phenyl) ethyl benzoate, 53 ℃ of fusing points (compound 350).

Availablely be equipped with formula III compound, wherein R with the quadrat method manufacturing ₂₃, R ₂₄Be methoxyl group, R ₂₅, R ₂₆, R ₂₈, R ₂₉It is hydrogen atom; Z ₂Has implication described later, R ₂₇It is bromine atoms.

Compound N ° Z ₂R ₂₇Fusing point ℃

250 OC ₂H ₅Br 53

251????????OH????????Br????????181.5

Example 252:4-amino-2-(3, the 4-dimethoxy phenyl) ethyl benzoate (compound 252):

In the 500ml round-bottomed flask, add 200ml 1,2-dimethoxy-1,2-ethane, 17g(0.07 mole) 4-amino-2-bromo-ethyl benzoate (compound 218), 0.3g four [triphenyl phosphines] closes palladium and 100ml 2M yellow soda ash.After refluxing boiling in 8 hours, reaction mixture is poured in the 600ml water.Filter, wash with water, dry air obtains solid, again with obtaining 20.0g(yield 95% after the washing of 50ml pentane) 4-amino-2-(3, the 4-dimethoxy phenyl) ethyl benzoate, fusing point is 127 ℃ (compounds 252).

With obtaining (III) product, wherein R with quadrat method ₂₃, R ₂₄Be methoxyl group, R ₂₅, R ₂₈And R ₂₉It is hydrogen atom; Z ₂, R ₂₇And R ₂₆Have implication as shown in the table:

Compound N ° Z ₂R ₂₇R ₂₆Fusing point ℃

252 OC ₂H ₅NH ₂H 127

253 OH H NO ₂182

Example 254:4-amino-2-bromo-ethyl benzoate (compound 254):

In the 1000ml round-bottomed flask, add the 46g(0.17 mole in succession) 2-bromo-4-nitro-ethyl benzoate, 250ml ethanol, 28g(0.5 mole) iron powder and 20ml concentrated hydrochloric acid.This mixture refluxed 4 hours.After cooling, the Sodium bicarbonate saturated solution of reaction mixture 500ml is handled, and with 5 * 300ml ethyl acetate extraction.After drying on the sal epsom, filter and boil off solvent, separable to 35.2g(yield 86%) 4-amino-2-bromo-ethyl benzoate, 93 ℃ of fusing points (compound n ° 254).

Example 301-399 and 3100-3119 specify the preparation of formula IV compound.

Example 301:N-(2-(3, the 4-dimethoxy phenyl)-6-phenyl nicotinoyl)-morpholine (compound 301) (method b):

At 25-30 ℃, dropwise with the 1.8g(0.002 mole) morpholine is added to a kind of 0.9g(0.005 mole) 2-(3, the 4-dimethoxy phenyl)-solution of 6-phenyl-nicotinoyl chlorine (compound 2) in 60mlTHF.When dripping at the beginning, promptly separate out hydrochloride.After adding, restir 10 minutes is with 200ml vinyl acetic monomer dilute reaction solution.With this reaction solution of 2 * 100ml water washing.This solution is dry on anhydrous magnesium sulfate, under reduced pressure concentrates then, obtains a kind of oil, and it separates out crystallization in ether.After filtration and drying, obtain 1.9g cream-coloured powder (yield 95%), 185.5 ℃ of fusing points.

Example 304-308:2-(3, the 4-dimethoxy phenyl)-6-phenyl-nicotinoyl chlorine (compound 302):

With the 1.8g(0.0054 mole) 2-(3, the 4-dimethoxy phenyl)-the mixture heating up boiling reflux of 6-phenyl-nicotinic acid (compound 303) and 20ml thionyl chloride 1 hour.Concentrating under reduced pressure obtains 1.9g(yield 100%) yellow sweet shape thing.

So operation can obtain the nicotinoyl chlorine derivative of formula (IV " '), wherein Z ₃Be the chlorine atom, R ₂₇₁Has the following implication that shows.

Compound N ° R ₃₇₁PF ℃

304 H honey shape

305????????Cl????????114

306????????F????????114

307????????Br????????106

308????????CN????????160

Example 303 and 310-313:2-(3,4-dimethoxy phenyl)-6-phenyl-nicotinic acid (compound n ° 303).

2ml 30% soda is added to a kind of 3.6g(0.01 mole) 2-(3, the 4-dimethoxy phenyl)-solution of 6-phenyl-Nikithan (compound 309) in 100ml 95% ethanol.This medium was heated 2 hours at 60-70 ℃.Behind the concentrating under reduced pressure residue is dissolved in the 100ml water.With this medium of 2ml concentrated hydrochloric acid acidifying: jelly is separated out.Use the 100ml ethyl acetate extraction.This solution is with 2 * 100ml water washing, and dry on anhydrous magnesium sulfate, the dope that reduces pressure then can obtain a kind of meringue shape thing, can separate out crystallization with the development of 50ml ether.After filtration, drying can get 2.5g(yield 75%) cream-coloured powdered product, 178 ℃ of fusing points.With with the quadrat method operation, can get formula (IV ' ") compound, wherein Z ₃Be hydroxyl, R ₃₆₁Has the following implication that shows.

Compound N ° R ₃₇₁Fusing point ℃

303????????H????????178

310????????Cl????????145

311????????F????????170

312????????Br????????162

313????????CN????????163

Example 309 and 315-317:2-(3, the 4-dimethoxy phenyl)-6-phenyl-Nikithan (compound 309): method a ':

With a kind of 7.7g(0.02 mole) 2-(3,4-dimethoxy benzoyl)-5-oxo group-5-phenyl-pentanoic acid ethyl ester (compound 314), 3.1g(0.04 mole) mixture heating up of ammonium acetate and 30ml acetic acid refluxed 4 hours.Reaction solution is poured in the 300ml water: a kind of oil becomes granular solids.This thing 200ml ethyl acetate extraction.Organic solution is with 3 * 100ml water washing, and dry on anhydrous magnesium sulfate then, concentrating under reduced pressure obtains 4.5g shallow brown oil (yield 62%), is 2-(3, the 4-dimethoxy phenyl)-6-phenyl-Nikithan.

With getting formula (IV ' " with the quadrat method operation) compound, wherein Z ₃Be oxyethyl group, and R ₃₇₁Have following implication:

Compound N ° R ₃₇₁Physical property

315 phenyl honey shape

316 4-chloro-phenyl-s honey shape

317 4-fluorophenyls honey shape refractive index 1.611

Example 318-320:

Operate according to as above routine method,, can obtain with following formula (IV " ') compound, wherein Z by means of the corresponding intermediate of suitable replacement ₃=oxyethyl group:

Compound N ° R physical property

318 4-bromophenyls honey shape

118 ℃ of 319 4-hydrogen base phenyl fusing points

320 4-thienyls honey shape

Example 321-344:2-(3,4-dimethoxy benzoyl)-5-oxo group-5-phenyl-pentanoic acid ethyl ester (compound 314):

The 8.4g(0.05 mole) 3-chloro-phenyl ethyl ketone is added to a kind of 13.7g(0.05 mole) in the sodium salt of (3,4-dimethoxy benzoyl)-vinyl acetic monomer: reaction is heat release, and medium temperature slowly is elevated to 35 ℃ from 24 ℃.Under agitation react 3/4 hour (about room temperature).Reaction solution is poured in the 400ml water; Product is separated out agglutination, this thing 300ml chloroform extraction.

Chloroformic solution is with 5 * 200ml water washing, and is dry on anhydrous magnesium sulfate then, concentrates under the decompression, obtains the brown sweet shape thing of 19.5g.After in being dissolved in 100ml ether, product is separated out crystallization.After throw out filtration and filtration cakes torrefaction, obtain 15g(yield 77%) cream-coloured powdered product, 70 ℃ of fusing points are 2-(3,4-dimethoxy benzoyl)-5-oxo group-5-phenyl-pentanoic acid ethyl ester.

With with the quadrat method operation, can obtain similar compound: (3, the 4-dimethoxy phenyl) as structural formula in the following table

Embodiment 345:N-[5-(4-chlorophenyl)-and 2-(3,4-dimethoxy benzoyl)-the 5-nicotinoyl] morpholine (for compound 345) (method a):

With the 46g(0.1 mole) the N-[5-(4-chlorophenyl)-2-(3,4-dimethoxy benzoyl)-5-oxo group-pentanoyl] morpholine (compound 346) and 15.4g(0.2 mole) ammonium acetate is dissolved in the 150ml acetic acid.Ebuillition of heated refluxed 4 hours, simultaneously bubbling bubbling air stream in reaction solution.Cool to room temperature, reaction solution is poured in 0.5 premium on currency: a kind of colloid is separated out.Use the 200ml dichloromethane extraction, wash this dichloromethane solution with water, use this solution of activated carbon treatment then.Obtain a kind of brown sweet shape thing after concentrating, development makes it separate out crystallization in the 200ml ether, filters, and washs this filter cake with ether, and drying under reduced pressure can get the 21.2g cream-coloured powder then, 152 ℃ of yields 48% of fusing point).

Example 345-394:

With with example 345(method a) and 301(method b) one of the working method of method, initial from suitable replacement intermediate, can obtain formula (IV " ") derivative, its substituting group is shown in method therefor and physical constant can see the following form.

The morpholino group that replaces is by the Sauerstoffatom Base Serial Number, free valency chain azine atom.Asterisk represents that this compound is a kind of synthetic intermediate.

Compounds X n R ₃₈Side LopP

N ° of NR ₃₁R ₃₂Method fusing point ℃

301-H morpholino a 185.5 3.3

345 4-Cl H morpholino b 148 4.0

347 4-Cl H NCH ₃（C ₂H ₅） b 156 4.4

348 4-Cl H (CHO ₃CH ₂CH ₂) ₂N b honey shape 4.6

349 4-F H morpholino b 180 3.5

350 4-F H NCH ₃（C ₂H ₅） b 117 4.4

351 4-F H (CH ₃OCH ₂CH ₂) ₂N b refractive index

1.587????????4.0

Its biological result will be the product that can not use.

Example 3110-3119:

According to the working method of example 345 (method a), initial by the intermediate of suitable replacement, can obtain formula (IV ') derivative, wherein NR ₃₁R ₃₂Be a morpholino, R ₃₁Implication with and the normal thing of physics of product all see the following form:

Example 401-458 is the preparation of Ming Dynasty style (V) compound and derivative thereof specifically.

Example 401:3-(3, the 4-dimethoxy phenyl)-3-bridging oxygen-2-(dimethylamino methylene)-ethyl propionate (compound 401):

In reactor, add 20g3,4-dimethoxy benzoyl-ethyl acetate, 80ml toluene and 20g dimethyl formamide-dimethylacetal.Reflux 2 hours, room temperature are placed and are spent the night.Boil off solvent and excessive reagent.Product is by purification by silica gel column chromatography (eluent: vinyl acetic monomer), obtain the yellow sweet shape thing of 74% yield.

Example 402:1-(3, the 4-dimethoxy phenyl)-3-dimethylamino-2-morpholino carbonyl-acrylketone (compound 402):

In reactor, put into 20g3,4-dimethoxy benzoyl-acetyl morphine, 28g dimethyl formamide-dimethylacetal and 20ml dimethyl formamide.60 ℃ of heating 7 hours, room temperature was placed and is spent the night.Reaction solution to water, is filtered the solid of being separated out and can obtain a kind of yellow solid, 156.8 ℃ of fusing points, yield 84%.

Example 403: with method in the example 401 and 402, but initial, can obtain the derivative of formula (X V '), wherein Ar with the centre of suitable replacement ₄Have as aforementioned implication, and R wherein ₄₃And R ₄₄Be methoxyl group, R ₄₅And R ₄₉Be hydrogen atom, X ₄And Z ₄As shown in the table:

Compound N ° X ₄Z ₄Feature

403 NMe ₂NMe honey shape

404 NMe ₂NEt ₂The honey shape

Example 405:5-ethoxycarbonyl-2(4-chloro-phenyl)-and 4-(3, the 4-dimethoxy phenyl)-pyrimidine (compound 405):

In reactor, put into 20ml dehydrated alcohol and 0.3g sodium.After dissolving, add the iodine hydrohalogenic acid salt of 3.7g4-chloro-benzenyl amidine, reflux 1 hour adds synthetic enamine ketone 4.06g in the example 401 again, and reheat refluxed 2.5 hours.Boil off solvent, wash the precipitation of gained with water, drying can get the 4.2g white solid, 115.4 ℃ of fusing points.

Example 406:5-carboxyl-2-(4-chlorophenyl)-and 2-(3, the 4-dimethoxy phenyl) pyrimidine (compound N ° 406):

Product (3.3g) by example 404 gained is dissolved in the 100ml ethanol, handles with the 2ml10N soda again, heats these mixtures 1 hour at 80 ℃, boils off solvent, and the water dissolved residue is used the HCl acidifying again.Obtain yellow mercury oxide, filter, wash yield 95%, 258.1 ℃ of fusing points with water.

Example 407:2-(4-chloro-phenyl-)-and 4-(3, the 4-dimethoxy phenyl)-5-morpholino carbonyl-pyrimidine (compound N ° 407):

The acid and the 35ml thionyl chloride of 1.5g gained in example 406 were heated 1.5 hours in 75 ℃.Concentrate, add methylene dichloride again, and boil off solvent again and (, so can obtain orange solids to remove excess reagent fully.

Above-mentioned acyl chlorides is dissolved in the 100ml ether, is cooled to 0 ℃, drip 0.9g morpholine and the solution of 0.4g pyridine in the 40ml ether.After adding, at room temperature stirred 1.5 hours.Reaction solution to water, is used ether extraction, dry on sal epsom, concentrate.After with the ether recrystallization, can get the 1g solid, 168 ℃ of fusing points (yield 48%).

Example 408:2-(3, the 4-dichlorophenyl)-4-(3, the 4-dimethoxy phenyl)-5-morpholino carbonyl-pyrimidine (compound 408):

In reactor, put into 10ml dehydrated alcohol and 0.1g sodium, be stirred to dissolving, add 1.35g3 again, the benzene sulfonate of 4-two chloro-benzenyl amidines.60 ℃ of heating 30 minutes, be added in the enamine ketone and the 15ml dehydrated alcohol of preparation in the example 402 again.Reflux 5 hours.Filter, wash the gained solid with cold ethanol with pentane, drying can get the solid (83% yield) of 181 ℃ of a kind of fusing points.

Press the operation of example 405-408 respectively, but initial by the suitable replacement intermediate of difference, can get formula (V) derivative, wherein R ₄₃-R ₄₄Be methoxyl group, R ₄₅And R ₄₉It is hydrogen atom; Z ₄And R ₄₇Has implication as shown in the table.

Examples of compounds N ° of R ₄₇Z ₄Feature LogP

Method in N °

409 405 3-nitro-OC ₂H ₅Fusing point=141 ℃ *

Phenyl

410 406 3-nitro-OH fusing point=226 ℃ *

Phenyl

412 405 phenyl OC ₂H ₅Fusing point=98 ℃ *

413 406 phenyl OH fusing points=215 ℃ of *

414 407 phenylmorpholines are for fusing point=172 ℃ 2.3

415 407 phenyl N(CH ₃) fusing point=100 ℃ 2.7

（CH ₃）

416 407 phenyl N(CH ₃) orange oil 2.5

（CH ₃OC ₂H ₄）

405 405 4-chloro-OC ₂H ₅Fusing point-115 ℃ *

Phenyl

407 407 4-chloro-morpholino fusing points=168 ℃ 3.0

Phenyl

417 405 3,4-two OC ₂H ₅Fusing point=74 ℃ *

Chloro-phenyl-

418 406 3,4-two OH fusing point=267 ℃ *

Chloro-phenyl-

408 408 3,4-dimorpholino fusing point=181 ℃ 3.7

Chloro-phenyl-

420 407 3,4-two N(C ₂H ₅) ₂Fusing point=122 ℃ 3.6

Chloro-phenyl-

421 407 3,4-two N(CH ₃) fusing point=146 ℃ 4.1

Chloro-phenyl-(C ₂H ₅)

422 405ou methylthio group OC ₂H ₅Fusing point=81 ℃ *

423

423 407 methylthio group morpholino fusing points=151 ℃ of *

424 405 3-CF OC ₂H ₅Oil *

The base phenyl

425 408 3-CF morpholino fusing points=149 ℃ 3.2

The base phenyl

426 406 3-CF OH fusing points=162 ℃ of *

Phenyl

427 408 4-bromo-morpholinyl fusing point=169 ℃ 3.2

Phenyl

428 407 3-CF ₃-N(CH ₃) sweet shape 3.6

Phenyl (C ₂H ₅)

429 407 3-CF ₃N(C ₂H ₅) ₂Fusing point=98 ℃ 4.1

Phenyl

430 408 4-bromo-N(C ₂H ₅) ₂Honey shape 4.1

Phenyl

431 408 4-chloro-morpholino fusing points-116 ℃ 3.2

Benzyl

Example 423:4-(3, the 4-Dimethoxyphenyl)-2-methylthio group-5-morpholino carbonyl-pyrimidine (compound 423):

In reactor, get 6.6gKOH and be dissolved in 60ml water, add the vitriol of 16.3g S-methyl-isothiourea again, add 13.6g synthetic enamine ketone in example 402 then immediately.Refluxing after 1.5 hours forms precipitation, and leaching washes with water, and drying can get the solid of 58% yield, 151 ℃ of fusing points.

Example 432:4-(3, the 4-Dimethoxyphenyl)-2-methylsulfonyl-5-morpholino carbonyl-pyrimidine (compound 432):

In the 10ml methylene dichloride, dissolving 9.5g adds the 11g metachloroperbenzoic acid by the pyrimidine of example 432 gained in 0 ℃ of gradation.At room temperature stirred 2.5 hours.Destroy excessive peracid with hydrosulphite, again with the bicarbonate solution washing, detergent with dried over mgso after, boil off solvent, obtain the 9.9g white solid, 77 ℃ of fusing points.

Example 433:4-(3, the 4-Dimethoxyphenyl)-2-(4-methyl-phenoxy group)-5-morpholino carbonyl-pyrimidine (compound 433):

In reactor, put into the 10ml acetonitrile, 0.5g salt of wormwood, the pyrimidine of 2.7g p-cresol and 1g gained in example 432, and three TDA-1[three (3, the 6-dioxaheptyl) amine] as catalyzer.Heated 1 hour down at 65 ℃, boil off solvent.Again add water, extract with ether, dry on sal epsom, boil off solvent, can get white solid, yield 75%, 152 ℃ of fusing points.

Adopt the working method of example 423,432 and 433 respectively, but utilize the intermediate of suitable replacement, can make formula (V) derivative, wherein R ₄₃-R ₄₄Be methoxyl group, R ₄₅And R ₄₉Be hydrogen atom, Z ₁And R ₄₇Has implication such shown in the following table.

Examples of compounds N ° of R ₄₇Z ₄Fusing point log P

Method in N °

434 423 benzylthio-morpholinoes 53 2.9

435 423 4-benzyl chloride sulfenyl morpholinoes 134 3.9

436 423 4-chlorobenzene sulfenyl morpholinoes 147 3.7

437 422+432+433 4-chloryl morpholinoes 174 3.7

438 422+432+433 4-bromo-phenoxy group morpholinoes 170 3.9

439 422+432+433 4-fluoro-phenoxy group morpholinoes 189 3.1

440 422+432+433 2-methyl-phenoxy group morpholinoes 136 3.6

441 422+432+433 4-chloro-3-first morpholinoes 176 4.3

Base-phenoxy group

433 422+432+433 4-methyl-phenoxy group morpholinoes 152 3.6

442 422+432+433 4-CF-phenoxy group morpholinoes 54 3.9

444 422+432+433 2-chloro-thiophenyl morpholinoes 179 3.1

445 422+432+433 3-chloro-thiophenyl morpholinoes 58 3.6

446 422+432+433 2-bromo-thiophenyl morpholinoes 169 3.8

447 422+432+433 4-bromo-thiophenyl morpholinoes 158 3.8

448 422+432+433 3-fluoro-thiophenyl morpholinoes 67 3.1

449 422+432+433 4-fluoro-thiophenyl morpholinoes 116 3.1

450 42,2+4,32+,433 3,4-dichlorobenzene sulfenyl morpholino 135 3.1

451 42,2+4,32+,433 2,6-dichlorobenzene sulfenyl morpholino 187 3.2

453 422+432+432 anilino morpholinoes 210 3.2

454 422+432+432 4-chloro-anilino morpholinoes 184 3.3

455 42,2+4,32+,432 3,4-dichlorobenzene amido morpholino 152 4.6

456 422+432+432 2-chloro-4-bromine morpholinoes 122 4.8

-anilino

457 422+432+432 3-chloro-4-fluoro-morpholinoes 178 4.1

Anilino

458 422+432+432 piperazine purine base morpholinoes 150.6 2.6

Example 501:2-ethanoyl-3-(3,4-dimethoxy phenyl)-preparation of 5-phenyl-5-oxo group-Valeric acid ethylester (compound 501)

With the 26.8g(0.1 mole) 3,4-dimethoxy-phenyl styryl ketone (m, p-(CH ₃O) C ₆H ₃-CH=CHCO-C ₆H ₅) and the 13.09(0.1 mole) methyl aceto acetate is dissolved in the 300ml ethanol, adds 1g active oxidation barium, stirred 20 hours down at 20 ℃.Leaching oxidation valerate precipitation is used washing with alcohol, drying, can get 27g(receive 68%) compound 501,135 ℃ of fusing points.

Example 502:4-(3, the 4-dimethoxy phenyl)-2-methyl-6-phenyl-Nikithan (compound 502):

With the 20g(0.05 mole) compound 501, the 7.7g(0.1 mole) the mixture heating up boiling reflux 5 hours of ammonium acetate and 80ml acetic acid.Boil off solvent, residue is dissolved in the 200ml methylene dichloride again,, wash with water again with the sodium bicarbonate aqueous solution washing.Concentrate, drying is used the silica gel column chromatography purifying, can get the 8.5g beige solid, 82 ℃ of fusing points (yield 45%, compound 502).

Example 503:4-(3,4-dimethoxy phenyl)-preparation (compound 503) of 2-methyl-6-phenyl-nicotinic acid:

With the 10ml10N soda aqueous solution and a kind of 8.4g(0.022 mole) the mixture heating up boiling reflux 30 hours of the solution of n ° of 502 compounds in 100ml ethanol.Concentrate the back and use water dissolution, acidifying is extracted with ethyl acetate, and drying concentrates, and can get 4.7g(yield 61%) n ° 503 compounds, 208 ℃ of fusing points.

Example 504:4-(3,4-dimethoxy phenyl)-preparation of 2-methyl-6-phenyl-nicotinoyl chlorine (compound 504)

With the 3.5g(0.01 mole) n ° 503 compounds and 20ml thionyl chloride mixing post-heating boiling reflux 1 hour.Concentrate.N ° 504, product, be orange red crystallization, yield 100%, fusing point: 140 ℃.

Example 505:N-[4-(3, the 4-dimethoxy phenyl)-2-methyl-6-phenyl-nicotinoyl] morpholine (compound 505)

This relates to formula VI product, wherein R ₅₉=methyl, Z ₅=morpholino, R ₅₅=R ₅₄=methoxyl group, R ₅₅=R ₅₆=H, R ₅₇=C ₆H ₅

At a kind of 1.2g(0.033 mole) n ° 503 compounds put and add the 2ml morpholine in the solution in the 50ml chloroform.In 20 ℃ of stirrings 3 hours, wash with water, concentrate; Make it separate out crystallization with ether, heavy getting, drying can get 0.9gn ° of 505 compounds (white meal; Yield 65%), 176 ℃ of fusing points, logP=3.8

Example 506-507: compound 506 and 507 is to prepare by example 505, and just morpholine is respectively by CH ₃-NH-C ₂H ₅And CH ₃-NH-CH ₂-CH ₂-OCH ₃Replace.The fusing point of compound 506 is 76 ℃ (logP-4.2), and compound 507 is a kind of sweet shape things (logP=4.0).

Example 601:2-(3,4-dimethoxy phenyl)-preparation of 5-phenyl-3-furancarboxylic acid ethyl ester:

With the 10g(0.027 mole)-2(3,4-dimethylbenzoyl-4-phenyl)-4-oxo group-ethyl butyrate and 2.75g(0.027 mole) aceticanhydride, the mixture heating up of 2 vitriol oils and 50ml acetic acid refluxed 12 hours.Reaction solution is poured in the 500ml water, with 300ml ethyl acetate extraction product,, with the pure water washing, dry on anhydrous magnesium sulfate then with potassium-containing hydrogen salt solution washing organic phase.Concentrating under reduced pressure can get a jelly, can separate out crystallization when it is developed with the 50ml heptane.Leaching, drying can get 6.5g(yield 68%) the expection product, be cream-coloured powder.68 ℃ of fusing points (compound n ° 601).

Example 602:2-(3, the 4-dimethoxy phenyl)-6-phenyl-3-furancarboxylic acid:

To contain the 5g(0.0142 mole) compound of example 601,6ml 10N soda and 100ml alcoholic acid mixture heating up refluxed 1 hour.The concentrating under reduced pressure reaction solution is dissolved in residue in the 100ml water, is acidified to pH=4 with the concentrated hydrochloric acid adding and separates out white solid.The leaching precipitation washes with water, in decompression down, and at dewatering agent P ₂O ₅There is down dry this product.Obtain 4.3g(yield 93%) the expection product, be white powder, 177 ℃ of fusing points (compound n ° 602).

Example 603:2-(3, the 4-dimethoxy phenyl)-6-phenyl-3-furoyl chloride;

The mixture heating up of the product of 2.8g example 2 and 20ml thionyl chloride was refluxed the concentrating under reduced pressure reaction solution 45 minutes: green solid method crystallization, the 3g(quantitative yield) product, 14 ℃ of fusing points (compound n ° 603).

Example 604:2-(3, the 4-dimethoxy phenyl)-5-phenyl-N-ethyl-N-methyl-3-furoylamide:

With the 1.51g(4.4 mmole) example 603 gained acyl chlorides are dissolved among the 20mlTHF, stir to add the 0.59g(10 mmole down) methylethyl amine: the hydrochloride of separating out amine immediately.Stirred 1/4 hour down in normal temperature, this hydrochloride of leaching, filtrate concentrates.Sweet shape resistates 100ml chloroform extraction.Wash this chloroformic solution with water, make product crystallization in the mixed solvent of diisopropyl ether and heptane after concentrating.In the leaching crystallization, after the drying, can obtain 0.6g(yield 37%) expecting compound, be cream-coloured powder, 74 ℃ of fusing points (compound 604).

Example 605:N-[4-(3, the 4-dimethoxy phenyl)-the 6-(4-fluorophenyl)-the 3-furoyl] morpholine:

To contain the 1g(2.3 mmole) N-[2-(3, the 4-dimethylbenzoyl)-the 4-(4-fluorophenyl)-4-oxo group-butyryl radicals] morpholine, the mixture heating up of 20ml ethanol and 1ml concentrated hydrochloric acid refluxed 30 hours.Reaction solution is poured in the 200ml water, used the 150ml chloroform extraction, wash chloroform layer solution with water, concentrate chloroformic solution, make product separate out crystallization with 20ml ether development residue.After leaching and drying, can get 0.8g(yield 83%) the expection product, be white powder, 168 ℃ of fusing points (compound 605).

Example 606:2-(3,4-dimethoxy phenyl)-the 5-(4-fluorophenyl)-the 3-(morpholino carbonyl)-pyrroles's preparation:

With the 5g(11.6 mmole)-N-[2-(3; 4-dimethoxy benzoyl)-the 4(4-fluorophenyl)-4-oxo group-butyryl radicals] morpholine, 1.8g(23.2 mmole) mixture heating up of ammonium acetate and 30ml acetic acid refluxed 12 hours; reaction solution is poured in the 30ml water; with 200ml ethyl acetate extraction product; with potassium-containing hydrogen salt solution washing organic phase; the back is with the pure water washing, and is dry on anhydrous magnesium sulfate.Concentrate the back and residue (product) carried out recrystallization, can get 1.4g(yield 28% with 300ml toluene) the expection product, be yellow powder, 190 ℃ of fusing points (compound 606).

Example 607:5-(4-fluorophenyl)-and 2-(3, the 4-dimethoxy phenyl)-1-methyl-3-(morpholino carbonyl)-pyrroles:

With the 0.72g(0.023 mole) single methylamine; 5g(0.00115 N-[2-(3 mole); 4-dimethoxy benzoyl)-the 4-(4-phenyl)-4-oxo group-butyryl radicals] morpholine is dissolved in the 30ml acetate, and reaction solution reflux 10 hours is poured in the 300ml water then.Product 200ml ethyl acetate extraction.Organic solution earlier with supercarbonate, after wash with water.Dry on sal epsom then, reconcentration: can get a kind of maroon solid, in ether, behind the recrystallization, obtain 1.3g expection product (yield 26%), 148 ℃ of fusing points (compound 607).

Example 608:2-(4-chlorophenyl)-and 3(3, the 4-Dimethoxyphenyl)-4-(morpholino phenyl)-pyrazoles:

In reactor, add 2.5g1-(3, the 4-dimethoxy phenyl)-the 3-(dimethylamino)-2-morpholino carbonyl-acrylketone (example 402), 2.1g 4-chloro-phenyl-hydrazonium salt hydrochlorate, 1.2g triethylamine and 100ml ethanol, reflux 8 hours 30 minutes.Boil off solvent, residue is poured in the water, behind ethyl acetate extraction, dry on sodium sulfate, concentrate, in that (eluent is vinyl acetic monomer/heptane: 90/10) after filtered through silica gel, can obtain the 2.1g yellow solid, 125 ℃ of (yield 60%) (compounds 608) of fusing point:

Example 609:4-ethoxycarbonyl-2-(4-oxygen phenyl)-and 3-(3, the 4-dimethoxy phenyl)-pyrazoles:

In reactor, put into 2.5g3-(3, the 4-dimethoxy phenyl)-3-oxo group-2-(dimethylaminomethylene)-ethyl propionate (example 401), 1.49g4-chloro-phenyl-hydrazonium salt hydrochlorate, 0.82g triethylamine and 100ml ethanol, reflux 8 hours.After boiling off solvent residue is poured in the water, used ethyl acetate extraction again, boil off solvent after drying on the sodium sulfate, can get 3g maroon solid (yield 95%) (compound 609), it can be not purified directly by being used for the next step.

Example 610:4-carboxyl-2-(4-chloro-phenyl-)-and 3-(3, the 4-Dimethoxyphenyl)-pyrazoles:

The ester of gained is placed into and contains in the 150ml alcoholic acid reactor in example 609, handles with 1.01g86% particle potash, and reflux 4 hours boils off solvent, and residue is poured in the water, is acidified to pH=1 with the 1N hydrochloric acid soln.The precipitation of solvent is washed with water by leaching, uses heptane wash then, can get 2.6g maroon powder (93.5%) (compound 610), can not purifiedly be directly used in the next step.

Example 611:4-(N-methyl-N-ethyl-aminocarboxyl)-the 2-(4-chloro-phenyl-)-3-(3, the 4-dimethoxy phenyl)-pyrazoles:

Sour 2.6g and 50ml 75% thionyl chloride that example 610 is made heated 8 hours.Use dichloromethane extraction again, concentrate.Gained oil (1.4g) is dissolved in the 30ml methylene dichloride, is cooled to 3 ℃, adds 0.54g N-methyl-N-ethylamine and 0.3g pyridine, the 30ml methylene dichloride, and holding temperature is lower than 5 ℃.At room temperature stirred 6 hours 20 minutes.Reaction solution is poured in the water, used dichloromethane extraction, dry back concentrates on sodium sulfate, can get the orange throw out of 1.2g, 110 ℃ of (yield 82.2%) (compounds 611) of fusing point.

Example 612:4-(N, N-diethylamino carbonyl)-2-(4-chlorination phenyl)-3-(3, the 4-Dimethoxyphenyl) pyrazoles:

The working method of utilizing example 611 to introduce, and utilize diethylamine and get.Yield 80% gets a kind of orange sweet shape thing (compound 612).

Example 613:1-benzyl 3-(3, the 4-dimethoxy phenyl)-the 4-morpholino carbonyl)-pyrazoles:

Utilize same operation method in the example 608, adopt the benzyl hydrazine hydrochloride to prepare, obtain the yellow oil (compound n ° 613) of 22.8% yield, obtain normal desired isomer (45.7%) in addition.

Example 614:1-(4-bromobenzyl)-and 3-(3, the 4-dimethoxy phenyl)-the 4-(morpholino carbonyl)-pyrazoles:

In reactor, put into 0.9g3-(3, the 4-dimethoxy phenyl)-the 4-(morpholino carbonyl)-pyrazoles (utilize the working method of example 608, adopt hydrazine hydrate to make), 0.7g4-bromobenzyl 0.4g salt of wormwood and 70mlDMF(dimethyl formamide), this mixture was heated 5.5 hours in 75 ℃, reaction solution is poured in the water, uses ethyl acetate extraction, drying, concentrate, after silicic acid filters, separable to 0.6g(yield 43.5%) throw out, 122 ℃ of fusing points (compound 614).

Utilize example 601-614 to operate like that respectively, but initial, can obtain the derivative of formula (VII), wherein R by the intermediate of suitable replacement ₆₁₀Be-CH=R ₆₃And R ₆₄Be methoxyl group, R ₆₅Be hydrogen atom, NR ₆₁R ₆₂, K ₆₆And K ₆₇Have as the indicated implication of following table.

Compound is at example K ₆₆K ₆₇NR ₆₁R ₆₂Fusing point log P

N ° of N ° of intermediary ℃

Method continues

615 604 O-C(4-chloro-phenyl-)=NCH) CH 102 4.7

616 605 O-C(4-chloro-phenyl-)=morpholino 139 4.3

617 605 O-C(phenyl)=morpholino 177 3.6

604 604 O-C(phenyl)=NCH) CH 74 4.0

605 605 O-C(4-fluorophenyl)=morpholino 168 3.7

606 606-NH--C(4-fluorophenyl)=morpholino 190 3.1

607 607-N(CH ₃The C(4-of)--fluorophenyl)=morpholino 148 3.9

618 606-NH--C(4-chloro-phenyl-)=morpholino 225 3.7

619 607-N(CH ₃The C(4-of)--chloro-phenyl-)=morpholino 155 4.5

620 606-N(H)--the C(phenyl)=morpholino 160 3.0

621 607-N(CH ₃The C(of)--phenyl)=morpholino 173 3.8

622 606-N(H)--uncle's C(4-morpholino 156 4.9

Butyl phenyl)=

623 608-N(C ₆H ₅The N=of)--morpholino 110 2.5

624 611-N(C ₆H ₅The N=NCH of)--) CH honey shape 2.9

625 612 -N（C ₆H ₅）- -N＝ -NCH） 111 3.4

608 608-N(4-chloro-phenyl-)-N=morpholino 125 3.2

611 611-N(4-chloro-phenyl-)-CH 110 3.6 of N=-NCH)

612 612-N(4-chloro-phenyl-)-the sweet shape 4.0 of N=-NCH)

626 608-N-benzyl-N=morpholino honey shape 2.5

The CH 105 2.9 of 627 611-N-benzyl-N=-NCH)

628 612-N-benzyl-N=-NCH)-sweet shape 3.3

619 613-N=-N-(benzyl) morpholino honey shape 2.5

614 614-N=-N(4-bromobenzyl) morpholino 122 3.4

Biological Examples

The following example has shown the character of the good mycocide of The compounds of this invention.

Embodiment B 1: the processing of tomato mildew (phytophthora infestans):

With tomato (Lyeopersicon esculentum) plant culture of Marmande kind in alms bowl.(5 to 6 blade periods when these plant grow to a monthly age, height is 12 to 15 centimetres), by with the sprinkling of the suspension of test material or the aqueous solution plant being handled, this suspension or the aqueous solution have required concentration and contain the tensio-active agent of the condenses of dehydration sorb (sugar) alcohol-oleic acid and 20 moles of ethylene oxide.This surfactant concentrations equals half concentration of active substance.Each tomato plant obtains 5 ml solns or dispersion approximately.Use the various concentration of test material that two plant are handled.With the plant that compares with not containing active substance but the solution that contains the similar face promoting agent of same concentrations handle.

After dry 24 hours, aq suspension with phytophthora infestans (Phytophthora infestans) spore sprays, making each plant be infected (the phytophthora infestans spore can cause the tomato mildew) sprays with the consumption of about 5 milliliters/plant (promptly about 50,000 spores of each plant).

After infecting specifically, tomato plant saturated atmosphere press and about 15 ℃ down hatching cultivated one day, under about 17 ℃ and 70% to 90% relative humidity, cultivated five days then.

Infected back seven days, will compare with the result who uses gained in the plant that compares with the result who was handled gained in the plant by the test active substance.

In these cases, can be observed, dosage is 1, the 000ppm(1 grams per liter) compound 104,110,111,112,113,117,118,129,133,148,149,150,164,166,167,169,201 to 203,205,206,208,209,211,212,214,222,223,235,236,237,238,301,345,347,349,350,353,356,359,364,369,370,379,381,382,384 to 386,388,391 and 393,396,3113,3118,3119,407,414 to 416,433,434,435,440,445,458,505 to 507,607,619,621,608 and 6081 cause can suppressing 80% at least to the mould growth.

Embodiment B 2: the processing of downy mildew of garpe (it is mould that grape is given birth to single shaft):

Vine shoot (the Vit is vinifera) cutting of Chardonnay kind is cultivated in alms bowl.(8 to 10 blade period, height is 20 to 30 centimetres) are used with Embodiment B 1 similar methods they are handled when these plant grow to 2 monthly ages.

After dry 24 hours, grape is given birth to single shaft mould (Flasmopara vcticola) aqueous spore suspension to be sprayed to and to make it be infected that (grape is given birth to the mould spore of single shaft can cause downy mildew of garpe on each plant, with about 5 milliliters/plant (being about 100,000 spores of each plant) when consumption sprays.

After infecting specifically, depress 18 ℃ and saturated atmosphere grapevine seedling was cultivated two days, cultivation five days under about 20-22 ℃ and 90-100 ℃ of relative temperature then.

Infected back eight days, and will compare with the result who uses gained in the plant that compares with the result of gained in the plant of being handled by the test active substance.

Under these property conditions, can be observed the 330ppm(0.33 grams per liter) compound 101,104,105,107,110 to 118 of dosage, 121 to 125,127 to 134,136,137,141,148 to 150,152 to 160,162 to 164,166 to 170,201 to 203,204,205,206,208,209,210,211,212,213,214,215,217,222,223,229,234 to 239,301,345,347,349 to 351,353 to 356,358,359,361 to 370,373 to 380,382 to 391,393 to 394,396,397,399,3100,3112 to 3119,407,414 to 416,420,421,433 to 442,445,450,458,505 to 507,616,607,608,612,613,619,621,623, reach 626 and cause can suppressing 80% at least the mould growth.

Embodiment B 3: to the effect of the soil fungi of phytopathogen:

Compound of the present invention has effect to following fungi:

Phytophthora brown rot of citrus (Phylophthora citrophthora), the parasite of the citrus fruit root of expressing by the distortion of mycosis and gas first portion.

Carry out each experiment with following method: make based on nutrition base and adding to one group of Petri dish (20 milliliters of processes of every ware are sterilized) under the supercooled state in 120 ℃ of following autoclave sterilizers with agar solidified potato extract.

In the filling ware, the acetone soln of active substance is injected in the supercooled substratum to obtain required ultimate density.

In contrast, adopt Petri dish similar to the above, to the nutrition base of wherein pouring the equal amts that does not contain active substance into.

After the curing, the mycelial fragment that inoculation goes into to obtain from the identical fungal cultures in front in each ware.

These wares were preserved 5 days down at 22 ℃, and the series that will contain fungi in the ware of underproof active substance then compares with usefulness that the series of identical fungi compares in the ware.

In these cases, 30ppm(ppm be 1,000,000/) following compounds of dosage can suppress 80%:101,102,104,105,107 at least to the growth of fungi, 110 to 118,121 to 129,131 to 137,141,149 to 150,153 to 158,162 to 164,166,167,169,201 to 203,204,205,206,208,209,210,211,212,213,214,215,216,217,222,223,224,228,229,230,231,234 to 239,301,345,347,349,350,353,354,355,356,358 to 360,363 to 370,373,376 to 386,388 to 397,310 to 3119,407,414 to 416,420,425 to 430,433 to 443,445,447,449,450,458,505 to 507,607,608,619 and 621.

The purposes of The compounds of this invention:

The compounds of this invention can be used as active fungicidal substance, especially can resist the fungal disease of plant, particularly by the oomycetes kind of pathomycete especially phytophthora (Phytophthora sp) type, phytophthora infestans (Phytophthora infestans) (potato or tomato mildew) for example, phytophthora brown rot of citrus (Phytophthora citropthora,) Phytophthora capsici (Phytophthora capsici), Phytophthora cactorum (Phytophthora cactorum), palm mould (Phytophthora palmivora), camphor tree epidemic disease mould (Phytophthora cinnamoni), big male epidemic disease mould (Phytophthora meqasperma), phytophthora parasitica Phytophthora parasitica), Peronospora (Phytophthora sp, (especially to the tobacco mildew), Plasmopara (Plasmopara sp.) particularly grape is given birth to single shaft mould (Plasmopara viticola) (downy mildew of garpe) and this single shaft of Hall mould (Plasmopara halstedei) (heronsbill mildew), false Peronospora (Pseudoperonospora sp.) (particularly cucurbit mildew and hops mildew), Bremia (Bremia lactucae) (lettuce mildew) and soil fungi, caused plant mycosis.

It is 0.01 to 5 kilogram/hectare that these compounds use effective dosage, and 0.02 to 1.5 kilogram/hectare more preferred.Use for reality, compound of the present invention uses seldom separately.They mostly are the part of composition greatly.These compositions can protect vegetables to resist mycosis; these compositions or in the composition of plant growth regulating; contain at least a above-mentioned The compounds of this invention, be aided with that agricultural goes up acceptable solid or liquid inertia Zhi Zaiti and/or compatible and also be that agricultural goes up acceptable surfactant with active substance as active substance.Specifically, can adopt common inert support and common tensio-active agent.

In this patent, term " carrier " refers in particular to a kind of crude substance or synthetic of organic or inorganic: it can combine with active substance is convenient to it and uses on plant, seed or soil.This carrier thereby often be inert, and must be acceptable on agricultural, be acceptable especially in plant treatment.Carrier can be solid (clay, natural or synthetic silicate, silica gel, resin, wax, solid fertilizer or the like) or for liquid (water, alcohol, ketone, petroleum fractions, aromatic hydrocarbons or paraffinic hydrocarbons or hydrochloric ether) or be a kind of gas.

The present composition (selling or directly use under diluted state with enrichment stage) generally includes 0.0001 to 95%, better contains 0.0005 to 90% active substance, and 0 to 20%, be preferably 0.5 to 15% tensio-active agent.The spissated composition of planning to sell contains 0.1 to 95% usually, is preferably 0.5 to 90% active substance.

Tensio-active agent can be emulsifying agent, dispersion agent or is ionic or non-ionic wetting agent.For example, can mention polyacrylate, Sulfite lignin, phenolsulfonate or naphthalenesulfonate, oxyethane and Fatty Alcohol(C12-C14 and C12-C18) or with lipid acid or with salt, taurine derivatives (particularly taurine alkyl salt) and the phosphoric acid ester of polyoxyethylenated alcohol or the phosphoric acid ester of phenol of the bunching thing of aliphatic amide, substituted phenol (particularly alkylphenol or aryl phenol), esters of sulfosuccinic acids.When active substance and/or inert support is water insoluble and water is to use carrier, must there be at least a tensio-active agent usually.

The composition of Shi Yonging can be different forms in the present invention: fluid, liquid or solid.

Form as fluid composition or liquid composition, can mention emulsifiable concentrate, emulsion, spissated water suspending agent, paste, the solution of containing especially, especially water-soluble enriched material, spissated solution in organic medium (the ultralow volume solution of ULV=) and aerosol.

Emulsible or soluble enriched material often contains 10 to 80% active substance.Emulsion or the solution preparing to use contain 0.001 to 20% active substance.Except active substance and solvent, when needing, the emulsifiable concentrate suitable additive that also comprises suitable solubility promoter and 2 to 20% is such as stablizer, permeate agent, corrosion inhibitor, tinting material and tackiness agent.

From these enriched materials, can obtain the emulsion of any desired concn by dilute with water, this is particularly suitable for the use in ploughing.For example, be the composition of some emulsifiable concentrates here.

Embodiment C El

-active substance (compound No. 101 or No. 202 or No. 301) 250 grams per liters

-epoxidized vegetable oil 25 grams per liters

-alkyl aryl sulfonate and poly-second two

Mixture 100 grams per liters of alcohol ether and Fatty Alcohol(C12-C14 and C12-C18)

-dimethyl formamide 50 grams per liters

-dimethylbenzene 575 grams per liters

Embodiment C E2

-active substance (No. 105, compound or No. 206 or No. 345 400 grams per liters

-Witco 1298 Soft Acid an alkali metal salt 24 grams per liters

-with nonylphenol 16 grams per liters of 10 moles of ethylene oxide polycondensations

-pimelinketone 200 grams per liters

1 liter of-aromatic solvent

Can obtain the emulsion of any desired concn by dilute with water from these enriched materials, it especially is fit to leaf is used.

Spissated suspension agent also can spray use, it is a kind of stable fluid product that obtains through the preparation result, it does not precipitate and separates out, usually contain 10 to 74% active substance, 0.5 to 15% tensio-active agent, 0.1 to 10% thixotropic agent and 0 to 10% suitable additive, such as antifoams, erosion inhibitor, stablizer, permeate agent and tackiness agent, and as water or a kind of organic liquid of carrier, active substance is slightly soluble or insoluble therein; Some solid organic matter or inorganic salt can be dissolved in carrier separates out to stop precipitation, or helps the water anti-freeze.

For example, be according to spissated compositions that contain water suspending agent more of the present invention here:

Embodiment SACl:

-active substance (compound No. 106 or No. 206 or No. 350) 100 grams per liters

-wetting agent oxyethane is with polycondensate 5 grams/thousand of alkylphenol

-dispersion agent (sodium naphthasulfonate) 10 grams per liters

-frostproofer (propylene glycol) 100 grams per liters

-thickening material (glycan) 3 grams per liters

-biocide (formaldehyde) 1 grams per liter

-water adds to 1 liter

Embodiment SAC2:

Prepare a kind of water suspending agent that contains, comprising:

-active substance (compound No. 108 or No. 208 or No. 301) 250 grams per liters

-wetting agent (polycondensate of oxyethane and CB synthol) 10 grams per liters

-dispersion agent (lignosulfonic acid acid sodium) 15 grams per liters

-frostproofer (urea) 50 grams per liters

-thickening material (glycan) 2.5 grams per liters

-biocide (formaldehyde) 1 grams per liter

-water adds to 1 liter

Embodiment SAC3:

Prepare a kind of water suspending agent that contains, comprising:

-active substance (compound No. 109 or No. 209 or No. 345) 500 grams per liters

-wetting agent (polycondensate of oxyethane and C synthol) 10 grams per liters

-dispersion agent (the salify condenses of oxyethane and poly-aryl phenol phosphoric acid ester)

50 grams per liters

-antifreeze (propylene glycol) 100 grams per liters

-thickening material (glycan) 1.6 grams per liters

-biocide (4-methyl hydroxy-benzoic acid sodium) 3.3 grams per liters

-water adds to 1 liter

Form as solids composition; can mention pulvis (content of active substance can reach 100%) and the granule used as dusting, particularly by extruding, by compress, dipping by the granulating carrier or from powder resulting these the particle systems (content of formula I compound these granules is between 0.5 and 80% for these examples of back) of granulating.

It is that they contain 10 to 95% active substance that wettable powder (or as the pulvis that sprays) usually makes like this, they are usually except that containing solid carrier in addition, also contain 0 to 5% wetting agent, 3 to 10% dispersion agent and, when needing, contain 0 to 10% one or more stablizer and/or other additive, such as permeate agent, tackiness agent or anti-caking agent, tinting material or the like.

For example be the composition of some wettable powders here.

Embodiment PM1

-active substance (compound No. 111 or No. 211 or No. 350) 10%

-branched chain type synthetic C ₁₃Contain oxygen alcohol with 8 to 10

The condenses of individual oxyethane (wetting agent) 0.75%

-neutral Calcium Lignosulphonate 99.99 min (dispersion agent) 12%

-lime carbonate (inertia weighting material) adds to 100%

Embodiment PM2:

-active substance (compound of the present invention No. 102 or No. 202 or No. 301) 50%

The condenses of-oxyethane and Fatty Alcohol(C12-C14 and C12-C18) (wetting agent) 2.5%

The condenses of-oxyethane and styryl phenol (dispersion agent) 5%

-chalk (inert support) 42.5%

Embodiment PM3: contain the composition identical, have following proportioning with front embodiment

-active substance (compound No. 105 or No. 206 or No. 345) 75%

-wetting agent 1.5%

-dispersion agent 8%

-lime carbonate (inert filler) adds to 100%

Embodiment PM4:

-active substance (compound No. 106 or No. 206 or No. 350) 90%

The condenses of-oxyethane and Fatty Alcohol(C12-C14 and C12-C18) (wetting agent) 4%

-oxyethane and styryl phenol condenses (dispersion agent) 6%

Spray pulvis or wettable powder in order to obtain these, active substance is closely mixed with substance in suitable mixing tank, mixture grinds with mill mortar or other suitable shredder.Can obtain the pulvis that can spray with method now, its wetting properties and suspension property are good; They can be suspended in the water by any desired concn, and this suspension agent can be used effectively, can be applied to effectively on the leaf of plant especially.

The formula I compound can use for dusting powder with powder type in addition; Also can use the composition that contains active substance (50 gram) and talcum powder (950 gram); Also can use and contain active substance (20 gram), segment broken silica (10 gram) and talcum powder (970 gram); These components are mixed and grinding, and mixture can be used by removing the powder method.

Its size of granule of using for dusting can prepare by cohesion or dipping between 0.1 and 2 millimeter.Usually, granule contains 0.5 to 25% active substance, and 0 to 10% such as additives such as stablizer, slowly-releasing properties-correcting agent, binding agent and solvents.

Here be the embodiment of two kinds of granule composites:

Embodiment G1 and G2

-active substance (compound No. 108 or No. 208 or No. 301) 50 grams 200 grams

-propylene glycol 50 grams 50 grams

-n-Hexadecane and polyglycol ether 2.5 grams 2.5 grams

-polyoxyethylene glycol 35 grams 35 grams

-kaolin

(granular size: 0.3 to 0.8 millimeter) 910 grams 760 grams

Compound of the present invention can be mixed with the granule form that can be dispersed in the water effectively, and these are included in the scope of the present invention.

These dispersible granules agent, its apparent density are usually about 0.3 to 0.6, and its globule size is usually between about 150 and 2,000 microns, preferably between 300 and 1500 microns.

The content of active substance of these granules between about 1% and 90%, is between 25% and 90% usually preferably.

The lingering section of granule mainly comprises a kind of solid weighting agent, and at random the also comprises surfactant additive makes particle have dispersiveness in water.Whether water-soluble according to filler, these material agent can be divided into two kinds.For water soluble filler, it can be inorganic, but is organic filler preferably.Can obtain excellent results with urea.For the water-insoluble filler, it is inorganic preferably, such as, kaolin or wilkinite.Be accompanied by then and add tensio-active agent (accounting for 2 to 20% ratio of granule weight), surfactant additive must surpass half of at least a dispersion agent, this dispersion agent is necessary for anionic, such as a kind of poly-(naphthene sulfonic acid) an alkali metal salt or poly-(naphthene sulfonic acid) alkaline earth salt or a kind of lignosulfonic acid an alkali metal salt or lignosulfonic acid alkaline earth salt.Remaining part comprises such as the nonionic of alkyl naphthalene sulfonic acid an alkali metal salt or alkaline earth salt or anionic wetting agent.

In addition, though dispensable, also can add other assistant agent such as antifoaming agent.

By essential composition is mixed, adopt original more known technology (spherical granulator, fluidized-bed, atomizer, extrusion machine or the like) granulation to prepare then according to granule of the present invention.Pulverize the back by sieving the particle of selecting globule size in the above-mentioned limit, this process promptly comes to an end.

Preferably, granule of the present invention can obtain by extruding.But shown following dispersible granule preparation of compositions in the following example.

Embodiment GD1:

Place mixing tank to mix active substance [No. 111, compound or No. 211 90%(weight)] and urea pearl (10%).Mixture is pulverized in toothed roll crusher.The wet powder that obtains is extruded in porous roll-type forcing machine.Obtain particle after the drying, broken then and sieve, the result has only kept the particle of granular size between 150 and 2000 microns respectively time.

Embodiment GD2:

Place mixing tank to mix following composition

-active substance (compound No. 105 or No. 202 or No. 345) 75%

-wetting agent (sodium alkyl naphthalene sulfonate) 2%

-dispersion agent (poly-sodium naphthalene sulfonate) 8%

-water-insoluble inert filler (kaolin) 15%

Embodiment GD3:

-active substance (compound No. 105 or No. 206 or No. 350) 20%

-sodium alkyl naphthalene sulfonate 2%

-methylene radical-two-sodium naphthalene sulfonate 8%

-kaolin 70%

The granulation in fluidized-bed in the presence of water of this mixture, dry then, the broken and result that sieves obtains the particle of size between 0.16 and 0.40 millimeter.

These granules can be used separately with in solution or a kind of like this method that is dispersed in the water obtain required dosage.They also can be used for preparation and other active substance, and especially with back dose of mycocide, these latter are in wettable powder form or granule form or contain the water suspending agent form.

Compound of the present invention also can be mixed with organic solution agent form, and they can be formed the polymer wall film, for example based on polymeric amide, polyureas or polymeric amide urea by special in interfacial polymerization in the encapsulate.These capsules are spissated water dispersion state, and it can dilutedly obtain a kind of soup compound in use and be used for spraying.

As having addressed, contain water dispersant and emulsion,, be in the total size of the spendable composition of the present invention for example by dilute with water wettable powder of the present invention or missible oil resultant composition.Emulsion can be water-in-oil-type or oil-in-water-type, and they have the thick denseness that resembles " mayonnaise ".

The present invention relates in addition improvement by the caused disease of fungi of plant pathogenic bacteria, particularly to by phytophora sp, the oomycetes section of (phytophthora) type, phytophthora infestans (potato or tomato mildew) for example, phytophthora brown rot of citrus, Phytophthora capsici, Phytophthora cactorum, palm mould, the camphor tree epidemic disease is mould, big male epidemic disease is mould, phytophthora parasitica, Peronospora (especially tobacco mildew), Plasmopara, particularly grape is given birth to Plasmopara (grape mildew) and this single shaft of Hall mould (heronsbill mildew), false Peronospora (particularly cucurbit mildew and hops mildew), the improvement of the fungal disease of dish stalk mould (lettuce mildew) and the caused plant pathogenic bacteria of soil fungi.

Present method comprises the composition of these plants being used significant quantity, and composition contains the formula I compound of the present invention as active substance." significant quantity " means is enough to control and eliminate the fungi that is present in these plants.But the compound of the fungi that the dosage of use then can be killed according to need, kind, weather condition and the use of crop is different and change in broad range.

The actual dosage that uses from 1 gram/hectolitre to 500 restrain/hectolitre do not wait, the approximate dosage that is equivalent to active substance to 5000 gram/hectares, can obtain good result at 10 gram/hectares.

As the example of spendable treatment process, can mention that the fusion that leaf or soil are sprayed, remove powder, immersion, granule, pulvis or paste goes in soil pouring, the injection in-tree, brushes and to seed treatment.

Claims (51)

1, a kind of amide derivatives is characterized in that it is the formula I compound:

Wherein " CYCLE " mark that is centered on by semi-ring is represented to have 4 to 7 grades and is contained carbocyclic ring or heterocycle, and this semi-ring is connected with two carbon atoms, is often having At least one unsaturated link(age) that contains alkene type or aromatics type between two carbon atoms of base and phenyl, said ring can be optionally replaced by the organic group of 30 carbon atoms at the most,

Y is a Sauerstoffatom or sulphur atom,

Z is a NR ₁R ₂Base,

R ₁And R ₂Can be identical or different, represent that a low alkyl group or lower alkoxy are (at least and R ₁And R ₂One of be not alkoxyl group simultaneously), or have a cycloalkyl of 3 to 7 carbon atoms, these groups can be arbitrarily by at least one halogen atom and/or hydroxyl or lower alkoxy replaces or (rudimentary) alkoxyl group-(rudimentary) alkyl or (rudimentary) acyloxy or phenyl or contain that 1 or 2 heteroatoms (O, N or S) has the heterocyclic groups of 4 to 6 joints or for to be replaced or a disubstituted amino by the low alkyl group list;

The alkenyl or alkynyl that 3 to 7 carbon atoms are arranged,

* or even R ₁And R ₂Be joined together to form heterocycle by nitrogen-atoms, it can be saturated or unsaturated, contain 4 to 7 joint (be preferably 5 to 6 joint) and 1,2 or 3 heteroatoms (O, N or S), this heterocycle can be replaced by low alkyl group or lower alkoxy or hydroxyl or oxo group or one or more halogen atom or (rudimentary) alkyl-(rudimentary) alkoxyl group;

* R ₃, R ₄And R ₅Can be identical or different, expression:

* hydrogen atom or halogen atom, these R ₃, R ₄And R ₅In have one at least simultaneously for hydrogen atom or halogen atom;

* an amino that can be replaced by one or two low alkyl group arbitrarily;

* low alkyl group or lower alkoxy or (rudimentary) alkyl-(rudimentary) alkoxyl group or lower alkoxy sulfo-, these groups can be arbitrarily by halo or hydroxylation;

* R ₃And R ₄(being in 3-position and 4-position) and non-conterminous 1 or 2 Sauerstoffatoms are formed with single divalent groups of 3 or 4 joints.

2, compound according to claim 1, the ring that it is characterized in that CYCLE representative have 5 joint rings or 6 joint rings and can be at random replaced R by the organic group of maximum 30 carbon atoms altogether ₁And R ₂Being connected together by nitrogen-atoms, the heterocycle of representative is 5 joint rings or 6 joint rings.

3, compound according to claim 1 is characterized in that wherein their logarithms of partition ratio in octanol/water are between 2 and 5.

4, compound according to claim 3 is characterized in that wherein their logarithms of partition ratio in octanol/water are between 2.5 and 4.5.

5, according to claim 1,2,3 or 4 described compounds, it is characterized in that it be formula (I a) or the compound of formula (I b):

R wherein ₁And R ₂Represent a low alkyl group; Cycloalkyl with 3 to 7 carbon atoms; Alkenyl or alkynyl with 3 to 7 carbon atoms; Alkoxyalkyl with 3 to 8 carbon atoms;

* or R ₁And R ₂Form the saturation type unsaturated heterocycle that contains 4 to 7 joints and 1 or 2 heteroatoms (O, N, S) following of the connection of nitrogen-atoms, this heterocycle can be had 1 to 3 carbon atom or have the alkoxyalkyl institute of 2 to 4 carbon atoms to replace arbitrarily;

* R ₃, R ₄And R ₅Can be identical or different, represent hydrogen atom or halogen atom (having one in 3 groups at least is not hydrogen atom or halogen atom) separately; Or low alkyl group or lower alkoxy; Perhaps for having an alkoxyalkyl of 2 to 4 carbon atoms; Or be an alkylthio, or be a hydroxyl, or for being replaced by the low alkyl group list arbitrarily or a disubstituted amino, even perhaps

* R ₃And R ₄Can form together in (3-position and 4-position) and to have 3 or 4 joints and include the divalent group of 1 or 2 non-conterminous Sauerstoffatom;

Represented a divalent group-K by " CYCLE " mark that semi-ring centers on ₆-K ₇-K ₈-K ₉-or-K ₆-K ₇-K ₁₀, with two carbon atom results that are connected form one 5 joint ring or 6 joint rings (by formula (I a) and formula (I b) represented K ₆, K ₇, K ₈, K ₉And K ₁₀Group is such, that:

K ₆Expression-N=-C(R ₆)-

K ₇Expression-N=-C(R ₇)-

K ₈Expression-N=-C(R ₈)-

K ₉Expression-N=-C(R ₉)-

K ₁₀Expression-N=-C(R ₁₀)-

In addition, if the CYCLE mark that is centered on by semi-ring represents-K6-K7-K10 that these K, K and K are also such:

K ₆Expression-N(R ₆)-or-C(R ₆) ₂-or-O-or-S(O) n

K ₇Expression-N(R ₇)-or-C(R ₇) ₂-or-O-or-S(O) n

K ₁₀Expression-N(R ₁₀)-or-C(R ₁₀) ₂-or-O or-S(O) n or-CO-

N is 0,1 or 2 integer;

Group K ₆And K ₇Has a representative-C(R at least ₇)=or-C(R ₇) ₂-or-C(R ₆)=or-C(R ₆) ₂-and, these-K ₆-K ₇-K ₈-K ₉-and-K ₆-K ₇-K ₁₀On its major key, only contain 0,1 or 2 heteroatoms (N, O or S) and nothing-O-O or-sequence of S-S-;

-R ₆, R ₇, R ₈, R ₉Or R ₁₀Can be identical or different, expression:

* Sauerstoffatom or halogen atom, R ₆Or R ₇Have at least one not to be hydrogen atom simultaneously in the group, cyano group, nitro, thiocyano, hydroxyl or carboxyl, the n(0 of alkyl, cycloalkyl, thiazolinyl, alkynyl, alkyl-S(O), 1 or 2), alkoxyl group, have cycloalkyloxy, alkene oxygen base, the alkynyloxy group of 3 to 8 carbon atoms; These groups have 1 to 8 carbon atom preferably and can optionally be replaced by one or more halogen atom,

* the n(n=0 of phenyl, naphthyl, phenyl-S(O), 1 or 2), phenoxy group, phenylalkyl (low alkyl group), the n(low alkyl group of phenylalkyl-S(O); N=0,1 or 2), phenyl alkoxyl group (lower alkoxy) or saturated or undersaturated 5 yuan or 6 yuan of heterocyclic radicals that contain any replacement of 1 to 3 Sauerstoffatom, sulphur atom or nitrogen-atoms, phenyl or heterocycle can not be substituted or be substituted base and replace, and substituting group is selected from-organizes and comprises: halogen; Nitro, cyano group, carboxyl, hydroxyl, sulfenyl, thiocyano, (rudimentary) alkoxyl group-carbonyl ,-CO-NR ' R " ,-NR ' R " ,-N(R ')-CO-R " ,-O-CO-R ' or-O-CO-NR '-R ";

* the n(n=0 of low alkyl group, lower alkoxy, (rudimentary) alkyl-S(O), 1 or 2), cycloalkyl (has the n(n=0 of 3 to 7 carbon atoms, phenyl, phenoxy group or phenyl-S(O), 1 or 2), phenylalkyl, phenyl alkoxyl group or phenylalkyl-S(O) _n(n=0,1 or 2) these groups can at random be had 1 to 4 carbon atom by halo and moieties,

* (rudimentary) alkoxyl group-carbonyl, CO-NR ' R ", NR ' R ", N(R ')-CO-R ", O-CO-R ' or O-CO-NR ' R " group,

* R ' and R " can be identical or different, the hydrogen atom of respectively doing for oneself; A low alkyl group; Cycloalkyl with 3 to 7 carbon atoms; Can any halogenated phenyl; Can any halogenated phenylalkyl (low alkyl group); Alkenyl or alkynyl with 3 to 7 carbon atoms; Alkoxyalkyl with 3 to 8 carbon atoms;

* work as K ₆And K ₇Expression-C(R ₆)=or-C(R ₆) ₂-or-C(R ₇)=or-C(R ₇) ₂-time, and R ₆And R ₇Perhaps R ₆In one and R ₇An energy in the base is loaded with R with two ₆And R ₇Carbon atom form together and contain carbocyclic ring or heterocycle, they can be saturated or unsaturated, contain 5 or 6 joint and 0,1 or 2 non-conterminous heteroatoms (O, N or S)

* work as K ₆Or K ₇Or K ₈, K ₉Or K ₁₀Mean-N(R ₆)-,-N(R ₇)-,-N(R ₈)-,-N(R ₉)-and-N(R ₁₀)-in a radicals R then ₆, R ₇, R ₈, R ₉Or R ₁₀Representative: hydrogen atom, have an alkyl of 1 to 6 carbon atom; Arbitrarily (condition is R for phenyl that is replaced by one or more halogen atoms or cyano group or nitro or low alkyl group or low utmost point alkoxyl group or phenylalkyl (low alkyl group) ₆And R ₇Be not hydrogen atom simultaneously)

6, compound according to claim 5 is characterized in that wherein R ₆, R ₇, R ₈, R ₉Or R ₁₀Represent wherein n=0 of the n-(of alkyl, cycloalkyl, thiazolinyl, alkynyl, alkyl-S(O), 1 or 2), alkoxyl group, cycloalkyloxy, alkene oxygen base or alkynyloxy group, these groups contain 8 carbon atoms at most and can at random be replaced by one or more halogen atoms.

7,, it is characterized in that it is that (I is compound a) for formula according to claim 5 or 6 described compounds.

8,, it is characterized in that it is formula (I b) compound according to claim 5 or 6 described compounds.

9,, it is characterized in that it is the compound of formula II according to claim 1,2,3 or 4 described compounds

K wherein ₁₁₀Be a Sauerstoffatom, S(O) n(wherein n be .1 or 2), NR ₁₁₀, C(R ₁₁₀) ₂Or oxo group;

* Z ₁Be NR ₁₁R ₁₂, R wherein ₁₁And R ₁₂Can identical or differently have R in the claim 1 respectively ₁And R ₂One of all implications;

* R ₁₃To R ₁₅Can be identical or different, have R in the claim 1 ₃, R ₄And R ₅One of implication;

* R ₁₆To R ₁₉Can be identical or different, have R in the claim 5 ₆To R ₉One of implication;

* work as K ₁₁₀For-C(R ₁₁₀) ₂-time, R ₁₁₀Represent hydrogen atom, low alkyl group, phenmethyl, hydroxyl, low-grade alkane acidyl oxygen base or lower alkoxy,

* work as K ₁₁₀For-N(R ₁₁₀)-time, R then ₁₁₀Represent hydrogen atom, low alkyl group or phenmethyl.Wherein Z is morpholino, thiomorpholine generation, N-methylethyl amino or N-diethylamino

10, compound according to claim 9 is characterized in that wherein:

* R ₁₃And R ₁₄Can form methylene radical dioxy base or ethylidene dioxy base together, their carbon atom can at random be replaced by low alkyl group or halogen.

11, according to claim 9 or 10 described compounds, it is characterized in that wherein:

* K ₁₁₀Be Sauerstoffatom, sulphur atom ,-N(R ₁₁₀)-or-C(R ₁₁₀) ₂-,

* Z is-NR ₁₁R ₁₂R wherein ₁₁And R ₁₂Be that low alkyl group and they have 6 carbon atoms at most, or R ₁₁And R ₁₂The connection of nitrogen-atoms forms a morpholino base or thiomorpholine down for base.

12, according to claim 9 or 10 described compounds, it is characterized in that wherein:

* Z ₁Be that morpholino base, thiomorpholine are for base, N-methyl-N-ethylamino or N, the NR of N-diethylamino ₁₁R ₁₂Group;

R ₁₃To R ₁₅Can be identical or different, be hydrogen atom, halogen atom, low alkyl group, lower alkoxy or rudimentary alkylthio,

R ₁₆, R ₁₈And R ₁₉Be hydrogen atom or fluorine atom;

* R ₁₇Be hydrogen atom or halogen atom; Low alkyl group, lower alkoxy, rudimentary alkylthio, low-grade halogenated alkyl, elementary halogenated alkoxy or lower halogenated alkylthio; Nitro or cyano group; Low-grade alkenyl, low-grade alkynyl or (rudimentary) alkoxyl group-carbonyl.

13, it is characterized in that according to claim 1,2,3 or 4 described compounds it is the compound of formula III,

Wherein: * Z ₂Represent NR ₂₁R ₂₂Group, wherein R ₂₁And R ₂₂Can be identical or different, have R in the claim 1 respectively ₁And R ₂One of implication;

* R ₂₃To R ₂₅Can be identical or different, have R in the claim 1 respectively ₃, R ₄And R ₅One of implication;

* R ₂₆And R ₂₇Can be identical or different, have R in the claim 5 respectively ₆And R ₇One of implication, condition is R ₂₆And R ₂₇Be not hydrogen atom simultaneously;

* R ₂₈And R ₂₉Can be identical or different, represent hydrogen atom or halogen atom separately, hydroxyl; Low alkyl group; Lower alkoxy; (rudimentary) alkoxyl group-(rudimentary) alkyl; Or (rudimentary) alkoxy carbonyl.

14, compound according to claim 13 is characterized in that:

Z wherein ₂Be morpholino, thiomorpholine generation, N-methyl-N-ethylamino or N, N-diethylamino;

R ₂₃To R ₂₅Can be identical or different, be a hydrogen atom or halogen atom, low alkyl group, lower alkoxy or rudimentary alkylthio.

* R ₂₆To R ₂₇Can be identical or different, be a hydrogen atom or halogen atom, low alkyl group, low-grade alkenyl, lower alkoxy, low alkyl group sulfo-, low-grade halogenated alkyl, elementary halogenated alkoxy or low-grade halogenated alkyl sulfo-;

R ₂₈And R ₂₉Can be identical or different, be a hydrogen atom or fluorine atom.

15, compound according to claim 13, base is characterised in that wherein R ₂₄And R ₂₄Can form methylene radical dioxy base or ethylidene dioxy base together, can be replaced by low alkyl group or halogen arbitrarily on its carbon atom.

16, according to claim 1,2,3 or 4 described compounds, it is characterized in that it being the formula IV compound,

Z wherein ₃Expression NR ₃₁R ₃₂Base, R wherein ₃₁And R ₃₂Can be identical or different, they have respectively with claim 1 in give R ₁And R ₂One of implication;

* R ₃₃To R ₃₅Can be identical or different, they have respectively with claim 1 in R ₃, R ₄And R ₅One of implication;

R ₃₇With R in the claim 5 ₇Definition identical, condition is R ₇It or not hydrogen atom;

R ₃₈And R ₃₉Can be identical or different, can be a hydrogen atom or halogen atom or low alkyl group, lower alkoxy, (rudimentary) alkoxyl group-(rudimentary) alkyl or a lower alkoxycarbonyl or a cyano group; In addition, work as R ₃₇During for phenyl, R ₃₈Can with R ₃₇Carbon atom on the ortho position of pyridine ring bonding forms Y together ₃-(CH ₂) n ₃Key, wherein Y ₃Be a Sauerstoffatom or sulphur atom or a methylene radical, and n ₃Equal 0,1 or 2.

17, compound according to claim 16 is characterized in that R wherein ₃₃To R ₃₅Can be identical or different, be a hydrogen atom or halogen atom (have one in these three groups at least and be not hydrogen atom or halogen atom) or low alkyl group, lower alkoxy or a rudimentary alkylthio.

18, compound according to claim 16 is characterized in that R ₃₃And R ₃₄Can form methylene radical dioxy base or ethylidene dioxy base together, can at random be replaced on the carbon atom by low alkyl group or halogen.

19,, it is characterized in that it has the structure of formula (V) according to claim 1,2,3 or 4 described compounds:

Z wherein ₄Represent NR ₄₁R ₄₂Group, wherein R ₄₁And R ₄₂Can be identical or different, they have respectively with claim 1 in R ₁And R ₂One of implication;

* R ₄₃, R ₄₄And R ₄₅Can be identical or different, they have respectively with claim 1 in R ₃, R ₄And R ₅One of implication;

* R ₄₇Have with claim 5 in R ₇One of implication, but be not hydrogen atom;

* R ₄₉Can be hydrogen atom or low alkyl group.

20, compound according to claim 19 is characterized in that wherein Z is NR ₄₁R ₄₂Group, R wherein ₄₁And R ₄₂Be low alkyl group, as a result R ₄₁And R ₄₂Contain 6 carbon atoms at most altogether, or they form morpholino or thiomorpholine generation together;

* R ₄₃To R ₄₅Can be identical or different, be hydrogen atom or halogen atom or low alkyl group, lower alkoxy or low alkyl group sulfo-;

* R ₄₉Be hydrogen atom.

21,, it is characterized in that they have the structure of formula VI according to claim 1,2,3 or 4 described compounds:

* Z wherein ₅Represent NR ₅₁R ₅₂Group, R wherein ₅₁And R ₅₂Can be identical or different, they have respectively with claim 1 in give R ₁And R ₂One of implication;

* R ₅₃, R ₅₄And R ₅₅Can be identical or different, they have respectively with claim 1 in give R ₃, R ₄And R ₅One of implication;

* R ₅₆And R ₅₇Have with claim 5 in the R that provides ₆And R ₇One of implication, condition is R ₆And R ₇Be not hydrogen atom simultaneously;

* R ₅₉Can be a hydrogen atom or halogen atom, hydroxyl, low alkyl group, lower alkoxy, low-grade alkoxy alkyl, these groups can be by halo.

22, compound according to claim 21 is characterized in that wherein R ₅₃And R ₅₅Can be identical or different, be a hydrogen atom or halogen atom or low alkyl group, lower alkoxy or low alkyl group sulfo-;

R ₅₉Be hydrogen atom or low alkyl group.

23, compound according to claim 21 is characterized in that wherein R and R can form methylene radical dioxy base or ethylidene dioxy base together, can at random be replaced by low alkyl group or halogen on its carbon atom.

24,, it is characterized in that it has the structure of formula (VII) according to claim 1,2,3 or 4 described compounds

* Z wherein ₆Represent NR ₆₁R ₆₂Group, wherein R ₆₁And R ₆₂Can be identical or different, have respectively with claim 1 in give R ₁And R ₂One of implication;

* K ₆₆Be the nitrogen-atoms-N(R that replaces ₆₆)-or-N=, or be the carbon atom=C(R of a sulphur atom or Sauerstoffatom or replacement ₆₆) ₂-;

* K ₆₇Be a sulphur atom or Sauerstoffatom or nitrogen-atoms-N(R for replacing ₆₇)-or-N=, or the carbon atom=C(R for replacing ₆₇) ₂-, certain K ₆₆With K ₆₇Can not be simultaneously-N(R ₆₆)-and-N(R ₆₇)-;

* K ₁₁₀Be the nitrogen-atoms-N(R that replaces ₆₆) or-N=, or be sulphur atom or Sauerstoffatom, or the carbon atom=C(R for replacing ₆₁₀)-certainly, K ₆₁₀And K ₆₇Can not be N(R simultaneously ₆₁₀) or N(R ₆₇)-;

* R ₆₃, R ₆₄And R ₆₅Can be identical or different, they have respectively with claim 5 in give R ₃, R ₄And R ₅One of implication;

* R ₆₆, R ₆₇And R ₆₁₀Can be identical or different, they have respectively with claim 5 in give R ₆, R ₇And R ₁₀One of implication.

25, compound according to claim 24 is characterized in that wherein Z ₆Be NR ₆₁R ₆₂Group, R wherein ₆₁And R ₆₂Contain 6 carbon atoms at most altogether, or even form morpholino or thiomorpholine generation together;

* K ₆₆Be substituted nitrogen-atoms-N(R ₆₆)-;

* K ₆₇Carbon atom=C(R for nitrogen-atoms-N=or replacement ₆₇)-;

* K ₆₁₀Be carbon atom=CH-;

* R ₆₃, R ₆₄And R ₆₅Can identical or differently be hydrogen atom or halogen atom or for low alkyl group, lower alkoxy or low alkyl group sulfo-;

* R ₆₆And R ₆₇Can be identical or different, be a hydrogen atom or alkyl, can be arbitrarily by phenyl or phenylalkyl that halogen or haloalkyl replaced, certainly, R ₆₆And R ₆₇Can not be hydrogen atom simultaneously.

26, a kind of method for preparing the described amide derivatives of one of claim 1 to 25 is characterized in that it comprises the active substance that carries out according to following a certain characteristics.

A) the formula II compound is produced, wherein K ₁₁₀For-O-,-S-or NHR ₁₁₀, initial compounds is hexichol (first) ketone of formula (XII '), R in the formula ₁₃To R ₁₉Identical with the implication in the claim 9, A is commutable halogen atom or nitro, and this hexichol (first) ketone and formula are H-K ₁₁₀-CH ₂-CO-Z ₁Derivatives reaction, K wherein ₁₁₀And Z ₁Identical with the definition in the claim 9;

B) by the formula I compound and the HNR of hydroxyl or lower alkoxy replacement ₁R ₂Amine reaction can make the corresponding formula I compound that Z is NRR;

C) comprise the preparation of the formula I compound of an amino, can be with amino by the corresponding formula I compound reduction of nitro alternate;

D) comprise the preparation of the formula I compound of an acylated amino, can carry out acylation reaction comprising amino respective compound;

E) comprise the preparation of the formula I compound of chlorine atom, bromine atoms or iodine atom or hydroxyl or sulfydryl on phenyl ring, it comprises with corresponding aminocompound diazotization and with known method the diazonium groups of gained is transformed into required atom or group;

F) in order to make the formula I compound that has substituting group (heterocyclic radical, phenyl or thiazolinyl) on the phenyl ring, can be with formula Q ₂B(OH ₂) boric acid (wherein Q represents heterocyclic radical, phenyl or thiazolinyl) and corresponding formula I compound (wherein heterocyclic radical, phenyl or thiazolinyl place are not have another bromine substituent or iodine substituting group on the phenyl ring by condition that bromine or iodine substitutes); Carry out the aryl coupled reaction;

G) a not preparation of the formula I compound of the position of substitution is arranged on the phenyl ring, it comprises at high temperature reacts having amino respective compound and nitrous acid lower alkyl ester on this position, makes the hydrogen atom substituted-amino;

H) K in the preparation of formula II compound, the formula II ₁₁₀Be C(R ₁₁₀) ₂Group and R ₁₃To R ₁₉Identical with the definition in the claim 9, it comprises benzophenone and thionyl chloride (SOCl with formula (X XII ') ₂), phosphoryl chloride (POCl ₃), phosphorus trichloride or phosphorus pentachloride (PCl ₃Or PCl ₅) reaction, and will react the compound and the propanedioic acid lower alkyl ester that obtain like this and in the presence of alkali, react, then 100 ℃ under 200 ℃, under any pressure, in solvent or when solvent-free with excessive amine HN ₁₁R ₁₂R handles can obtain the formula II compound, K in the formula II ₁₁₀Be oxo group, R ₁₃To R ₁₉Identical with the definition in the claim 9, Z ₁Be defined NR in the claim 1 ₁₁R ₁₂Base, and the formula II compound optionally can be reduced.

Z wherein ₁₁Be OH, R ₁₃To R ₁₉Identical with the definition of claim 9;

ⅰ) with the compound (Z in the formula of formula (XX XII ') ₁Be NR ₁₁R ₁₂Group) with the formula (benzyl halogenide (R in the formula of XX XII ") ₁₆To R ₁₉And R ₁₁₀Identical with the definition in the claim 9, Hal represents halogen atom) react, under 0 ℃ to 150 ℃ temperature, handle the product of gained then in solvent or when solvent-free with organic or organic acid, can make the compound of formula II, K in the formula II ₁₁₀Be C(R ₁₁₀) ₂, R ₁₃To R ₁₉Identical with the definition in the claim 9;

J) with the compound (Z in the formula of formula (XX XII ') ₁Be NR ₁₁R ₁₂) with the reaction of the phenyl aldehyde of following formula:

(R in the formula ₁₆, R ₁₇, R ₁₈With R ₁₉Identical with the definition in the claim 9), product reduction with gained obtains vinyl carbinol then, in solvent or when solvent-free under 0 ℃ to 150 ℃ temperature, make the vinylcarbinol cyclisation with catalytic amount or more than the organic acid or the mineral acid treatment of stoichiometric quantity, can make the formula II compound like this, K in the formula II ₁₁₀Be C(R ₁₁₀) ₂Base, R ₁₃To R ₁₉And R ₁₁₀Definition and claim 9 in identical;

K) in the presence of the ammonium donor, in acidic medium, at high temperature make the compound cyclisation of formula (X IV '), can make the formula IV compound,

Ar wherein ₃For formula (group of X IV "),

R wherein ₃₃, R ₃₄And R ₃₅And Z ₃And R ₃₆To R ₃₉Identical with the definition in the claim 14;

L) with the enol of formula (X V ') with or formula be Amidine or its salt

Negatively charged ion ^-(R wherein ₄₇Definition identical with claim 19), in alkaline media, in solvent, react the compound of the formula that can make (V),

Ar wherein ₄Be formula (X V "), R ₄₃, R ₄₄, R ₄₅, R ₄₉And Z ₄Identical with the definition in the claim 19, X ₄Be (rudimentary) dialkyl-7-amino or (rudimentary) alkoxyl group,

M) compound and the formula with formula (XX V ') is R ₄₇Compound (the R of H ₄₇With R ₇Implication identical, condition is that the valence link that is connected with hydrogen atom also is R ₄₇The key that is connected with heteroatoms) reaction can make formula (V) compound, (R wherein ₄₇Not alkyl or benzyl-alkylsulfonyl or alkylsulfonyl)

R in the formula (XX V ') ₄₃To R ₄₅, R ₄₉And Z ₄Identical with the definition in the claim 19, A ₄Be (rudimentary) alkyl sulphonyl or basic alkylsulfonyl;

N) with the α-ethylidene phenyl ketone and the formula R of formula (X VI ') ₅₉-CO-CH ₂-COZ ₅Ester or beta-keto acyl amine (R wherein ₅₃To R ₅₉Definition and claim 21 in identical) in the presence of organic bases or mineral alkali, in low-grade alkane alcohol 0 ℃ react to the temperature between the boiling point of solvent for use the formula of obtaining (X VI ") compound:

(R wherein ₅₃To R ₅₉And Z ₅Definition and claim 21 in identical), by heating under the reflux temperature from 40 ℃ to solvent in the carboxylic acid medium, (cyclisation of X VI ") compound makes the formula VI compound and make formula.

O) from the beta, gamma-ketone ester or the acid amides of formula (X VII '), the simple heating carries out the compound that cyclization can make formula (VII), wherein K in the presence of the catalytic amount strong acid by having at alcohol or in such as the carboxylic acid of acetate ₆₆Be O, K ₆₇For-C(R ₆₇)=and R ₁₁₀For-C(R ₆₁₀)=;

R in (formula X VII ') ₆₃, R ₆₄, R ₆₅, R ₆₇And R ₆₁₀Identical with the definition in the claim 24);

P) at formula NHR ₆₆Amine (R wherein ₆₆Identical with aforementioned implication) existence under in acid medium, make the β of formula (X VII '), -two ketone esters or acid amides carry out the compound that thermal cyclization makes formula (VII), wherein K ₆₆Be NR ₆₆, K ₆₇For-C(R ₆₇)=, K ₆₁₀For-C(R ₆₁₀)=

Q) ketenes of formula (XX VII ')

Ar in the formula (XX VII ') ₆Be formula (R in the group of X VII "), formula (X VII) ₆₃, R ₆₄, R ₆₅, R ₆₆, R ₆₇And R ₆₁₀And Z ₆Identical with the definition of claim 24, X ₆(rudimentary) dialkyl amido or alkoxyl group, make formula (ketenes of XX VII ") with can be at random at most by a R ₆₆The hydrazine that replaces reaches the compound (K in the formula that makes formula (VII) in the presence of mineral alkali or the organic bases in alcohol ₆₆For-N-or-N(R ₆₆)-, K ₆₇For-N-or-N(R ₆₇), condition is K ₆₆And K ₆₇Can not be simultaneously-N(R ₆₆)-and-N(R ₆₇)-); And at random the formula I compound is transformed by known method itself and to obtain another kind of formula I compound.

27, the preparation method of the described compound of a kind of claim 1 is characterized in that it consists essentially of abovementioned steps.

28,, it is characterized in that it can make the described compound of claim 1 according to claim 26 or 27 described methods.

29, a kind of fungicide composition is characterized in that it comprises a kind of compound of one of a kind of active ingredient, the described compound of claim 1 to 25 and is aided with agricultural upward acceptable diluent or carrier.

30, composition according to claim 29 is characterized in that it further comprises tensio-active agent.

31,, it is characterized in that it contains 0.0001 to 95% active substance and 0 to 20% tensio-active agent according to claim 29 or 30 described compositions.

32,, it is characterized in that it is included in active substance between 0.0005 and 90% according to the described composition of claim 29,30 or 31.

33,, it is characterized in that it is included in active substance between 0.1 and 95% according to the described composition of claim 29,30 or 31.

34,, it is characterized in that it is included in active substance between 0.5 and 90% according to the described composition of claim 29,30 or 31.

35, according to claim 29,30,31,32,33 or 34 described compositions is characterized in that it comprises tensio-active agent between 0.5 and 15%.

36, according to claim 29,30,31,32,33,34 or 35 described compositions is characterized in that it is the state of emulsifiable concentrate, comprises 10 to 80% active substance.

37, according to claim 29,30,31,32,33,34 or 35 described compositions is characterized in that it is the spissated water suspending agent form that contains, and comprises 10 to 75% active substance.

38, according to claim 29,30,31,32,33,34 or 35 described compositions is characterized in that it is spissated wettable powder form, comprises 10 to 95% active substance.

39, according to claim 29,30,31,32,33,34 or 35 described compositions is characterized in that it is the granule form, comprises 0.5 to 25% active substance.

40, according to claim 29,30,31,32,33,34 or 35 described compositions, but it is characterized in that it is the dispersible granule form, comprises 1 to 90% active substance.

41, composition according to claim 29 is characterized in that it basically as previously mentioned.

42, a kind of method of resisting fungi to the plant invasion and attack is characterized in that using according to the described active substance of one of claim 1 to 28.

43,, it is characterized in that it can administer by crop mildew fungi infestation or that be easy to infect according to the described method of claim 42.

44,, it is characterized in that active substance uses with 0.01 to 5 kilogram of/hectare consumption according to claim 42 or 43 described methods.

45,, it is characterized in that active substance uses with 0.02 to 1.5 kilogram of/hectare consumption according to the described method of claim 44.

46,, it is characterized in that it basically as previously mentioned according to the described method of claim 40.

47, a kind of amide derivatives of formula I is characterized in that wherein:

What the CYCLE mark that is centered on by semi-ring represented that this semi-ring has 4 to 7 joints (being preferably 5 or 6 joints) contains carbocyclic ring or heterocycle, is connected with two carbon atoms, is having At least one unsaturated link(age) that contains alkene type or aromatics type between two carbon atoms of base and phenyl, said ring can be at random replaced by the organic group of 30 carbon atoms at the most;

* Y is a Sauerstoffatom or sulphur atom;

* Z is a chlorine atom or OW ' base, NHR ₁Base or NR ₁R ₂Base;

* W ' is a hydrogen atom or low alkyl group or basic metal or alkaline-earth metal;

R ₁And R ₂Can be identical or different, expression:

Low alkyl group or lower alkoxy (R ₁And R ₂In at least one is not an alkoxyl group), or has a cycloalkyl of 3 to 7 carbon atoms, these groups can be at random contained the heterocyclic group of 1 or 2 heteroatomss (O, N or S) by at least one halogen atom and/or hydroxyl or (rudimentary) alkoxyl group or (rudimentary) alkoxyl group-(rudimentary) alkyl or (rudimentary) acetoxyl group or phenyl or 4 to 6 joints or are replaced by the low alkyl group list or disubstituted amino replaces

Alkenyl or alkynyl with 3 to 7 carbon atoms,

* or even R ₁And R ₂Under connecting, nitrogen-atoms forms heterocycle together, it comprises 4 to 7 joints (being preferably 5 to 6 joints) and 1,2 or 3 heteroatoms (O, N or S), can be saturated or unsaturated ring, this heterocycle can be replaced by low alkyl group or lower alkoxy or hydroxyl or oxo group or a halogen atom or (rudimentary) alkyl-(rudimentary) alkoxyl group

* R ₃, R ₄And R ₅Can be identical or different, expression:

* hydrogen atom or halogen atom, these R ₃, R ₄And R ₅Have at least one not to be hydrogen atom or halogen atom in the group,

* the amino that can at random be replaced by one or two low alkyl group,

* can be at random by halogenation or hydroxylated low alkyl group or lower alkoxy or (rudimentary) alkyl-(rudimentary) alkoxyl group or low alkyl group sulfo-,

* R ₃And R ₄(in 3-position and 4-position) can form the single divalent group that has 3 or 4 joints (comprising 1 or 2 non-conterminous Sauerstoffatom) together.

48,, it is characterized in that group Z is a chlorine atom or OW ' base or NHR according to the described compound of claim 47 ₁

49,, it is characterized in that the implication that provides in group implication and the claim 5 to 25 except Z is identical according to claim 47 or 48 described compounds.

50,, it is characterized in that it does not comprise that (I compound a), (I a) middle Y is a Sauerstoffatom to formula to formula, simultaneously K according to the described compound of one of claim 1 to 25 ₈And K ₉Or be-CH K for-CH=or for-N=and another ₆And K ₇Form a undersaturated carbocyclic ring that contains together, this ring with contain K ₁₀5 joint rings link to each other; And the compound that does not comprise formula (I b), Y is a Sauerstoffatom in the formula, simultaneously K ₁₀Be O, S, SO, SO ₂,-NR ₁₆(R ₁₀Definition the same), CH ₂Or CO, and while K ₆And K ₇Form a unsaturated carbocyclic ring that contains together, this ring with contain K ₁₀5 joint rings link to each other.

51,, it is characterized in that it does not comprise that (I compound a), (I a) middle Y is a Sauerstoffatom to formula to formula, simultaneously K according to claim 47,48 or 49 described compounds ₈And K ₉Or be-CH K for-CH=or for-N=and another ₆And K ₇Form a undersaturated carbocyclic ring that contains together, this ring with contain K ₁₀5 joint rings link to each other; And the compound that does not comprise formula (I b), Y is a Sauerstoffatom in the formula, simultaneously K ₁₀Be O, S, SO, SO ₂,-NR ₁₀(R ₁₀Definition the same), CH ₂Or CO, and while K ₆And K ₇Form a unsaturated carbocyclic ring that contains together, this ring with contain K ₁₀5 joint rings link to each other.