CN1077110C - 13-substituted milbemycin 5-oxime derivatives their preparation and their use against insects and other pests - Google Patents
13-substituted milbemycin 5-oxime derivatives their preparation and their use against insects and other pests Download PDFInfo
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Abstract
Compounds of formula (I): in which: R<1> is methyl, ethyl, isopropyl or sec-butyl; X is carbonyl or methylene; Z is =C=(R<2>)2 or =C=(CH2)m (in which R<2> is alkyl, and m is integer of from 2 to 5); n is 0 or 1; R<3> is nitro, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, or a group (iii), (iv), (v), (vi), (vii), (viii) or (ix).
Description
The present invention relates to the milbemycin 5-9 oxime derivate that a series of new 13-replace, this compound has mite, desinsection and the anthelmintic activity of killing.The present invention also provides the method and composition that uses these compounds and prepares their method.
Have now found that multiple known compound with 16 Yuans macrolide structures, these compounds are chemically derived semi-synthetic the getting by fermentation of various microorganisms or natural fermented product, and this compounds has mite, desinsection, anthelmintic and parasite activity extremely.The doubly mould and avermectins of Mil is exactly two examples of these known compounds, also exist other compound and usually with prior art in different name or the compound of code be identical.The name of the Macrocyclic lactone compounds that these are different is normally named with the title of natural each quasi-microorganism of generation or code, and this name order extends to the chemical derivative of similar compound, and this compounds never has the systematic naming method of standard as a result.
For fear of obscuring, here will be with the systematic naming method of a standard, this name is abided by and is patrolled international pure chemistry and applied chemistry federation (I UP AC), the general naming rule of the organic compound that organic chemistry NK of organic chemistry branch is recommended, the parent compound of the hypothesis of this " milbemycin " represented based on formula (A) compound with definition here:
R wherein
aAnd R
bBoth are hydrogen atom.
For fear of query, following formula (A) compound is being understood Position Number at macrolide ring system subscript with those positions of the related compound of the present invention.
Natural milbemycin is a series of known Macrocyclic lactone compounds that anthelmintic kills acarid and insecticidal activity that have.Milbemycin D is at United States Patent (USP) 4,346, and is open with " compd B-41D " in 171, and milbemycin A3 and A4 are open in United States Patent (USP) 3950,360.These compounds can be used following formula (A) expression, wherein the R on 13
aBe hydrogen atom, the R on 25
bBe methyl, ethyl or sec.-propyl, these compounds are defined as milbemycin A3, milbemycin A4 and milbemycin D.13 is hydrogen atom, and 25 milbemycin analogues that are substituted in to sec-butyl are disclosed in United States Patent (USP) 4,173, and in 571, this compound is " 13-deoxidation-22,23-dihydro avermectins B
1aAglycon ".
In addition, prepared deriving and having studied their activity of many original milbemycins and avermectins.For example, 5 bit esterified milbemycins are disclosed in United States Patent (USP) 4,201,861,4,206,205,4,173,571,4,171,314,4,203,976,4,289,760,4,457,920,5,579,864,4,547,491, European patent discloses 8184,102,721,115,930,180,539 and 184,989 and Japanese Patent Laid open (promptly open) 57-120589 and 59-16849 to the public.
13-hydroxyl-5-ketone milbemycin derivatives is at United States Patent (USP) 4,423, and is open in 209, and milbemycin 5-9 oxime derivate is also at United States Patent (USP) 4,547,520 and European patent disclose in 203,832 and disclose.
13 milbemycins with ester bond and many 13 hydroxyl esterified formulas (A) compound relevant especially with the present invention discloses among the clear 61-180787 open in Japanese Patent Laid, wherein disclose the ester of various carboxylic acids such as paraffinic acid.Other 13 milbemycin derivatives with ester bond disclose among the flat 1-104078 open in Japan's special permission.The carboxylic moiety of disclosed compound has a side chain on the α position of carboxylic acid in this piece document, as alkyl.
Disclose a series of 13 ester group derivatives though we think with the immediate prior art United States Patent (USP) 4,963,582 of the present invention (being equivalent to European patent 246,739), the group in this and the The compounds of this invention on 13 is essentially different.
Above-mentioned various relevant milbemycin class Macrocyclic lactone compounds all has one or more antibiotic, and expelling parasite is killed epizoon, killed mite or insecticidal activity.But, also need continue to seek this class and have the active preparation that kills one or more agriculturals and gardening pest insect of improvement.
Have now found that the activity, particularly 13 substituting group that to improve the milbemycin compounds by the suitable selection of big ring propyl ester being fastened the substituting group combination.Especially, have now found that and to improve the activity of imitating compounds by suitably selecting 13 ester groups (as described below) of going up some high specific.Usually, The compounds of this invention has than compound of the prior art better murders the worm activity, and the chemical compound lot among the present invention has very excellent activity.The compounds of this invention comprises United States Patent (USP) 4,963 than prior art, and 582 have excellent especially activity, especially kills flea.
Therefore, the purpose of this invention is to provide to have and improve active this class Macrocyclic lactone compounds.
Another object of the present invention provides the method for these compounds of preparation.
Further object of the present invention provides insect-killing composition that contains described compound and the method for using these compounds.
In description subsequently, will see other purpose and advantage significantly.
The invention provides formula (I) compound and salt thereof:
Wherein: R
1Be methyl, ethyl, sec.-propyl or sec-butyl: X are that carbonyl or methylene radical: Z is formula (i) or (ii) group:
＝C＝(R
2)
2 (i)
＝C＝(CH
2)
m (ii)
R wherein
2Be the alkyl that contains 1 to 3 carbon atom, m is 2 to 5 integer; N is 0 or 1; R
3Be nitro, amino, (C
1-C
4Alkyl) amino ,=(C
1-C
4Alkyl) amino contains the alkoxyl group of 1 to 4 carbon atom, (C
1-C
3Alkoxyl group)-(C
2-C
3Alkoxyl group), or formula is (iii), (iv), (v), (vi), (vii), (viii), or (ix) group:
R wherein
4It is the alkyl that contains 1 to 6 carbon atom; The substituted alkyl that contains 1-6 carbon atom, this substituted alkyl are replaced by a substituents alpha that defines below at least; The cycloalkyl that contains 3-6 carbon atom; The cycloalkyl that contains 3-10 carbon atom and replaced by a substituting group β who defines below at least; The alkenyl that contains a carbon atom of 2-; The alkynyl that contains 2-6 carbon atom; The isocyclic aryl that does not replace or replaced by a substituting group γ who defines below at least that contains 6-14 ring carbon atom; Or contain the heterocyclic radical of 3-6 carbon atom, and it is nitrogen-atoms and/or Sauerstoffatom and/or sulphur atom that this heterocyclic radical has a heteroatoms at least, described heterocyclic radical does not replace or is replaced by a substituting group γ who defines below and Sauerstoffatom (forming the oxygen base) at least; R
5Be hydrogen atom or the alkyl that contains 1-4 carbon atom; R
6Be: hydrogen atom; The alkyl that contains 1-6 carbon atom; Or contain the cycloalkyl of 3 to 6 carbon atoms; R
7Be: the alkyl that contains 1 to 6 carbon atom; The cycloalkyl that contains 3 to 6 carbon atoms; The isocyclic aryl that does not replace or replaced by the substituting group γ that defines below at least that contains 6 to 14 ring carbon atoms; Or aralkyl, wherein aryl moiety is to contain the carbocyclic ring of 6 to 10 ring carbon atoms and moieties contains 1 to 4 carbon atom; Or R
6And R
7With the nitrogen-atoms that links to each other with them common thick and the heterocycle that becomes to contain 3 to 6 annular atomses; Y is Sauerstoffatom or sulphur atom; R is 1,2 or 3; Q is methylene radical or carbonyl; R
8Be: the isocyclic aryl that contains the alkyl of 1 to 4 carbon atom or contain 6 to 10 ring carbon atoms and do not replace or replaced by the substituting group γ that defines below at least; R
9Be: the alkyl that contains 1 to 6 carbon atom; The cycloalkyl that contains 3 to 6 carbon atoms; The isocyclic aryl that contains 6 to 10 ring carbon atoms and do not replace or replaced by the substituting group γ that defines below at least; Or aralkyl, wherein aryl moiety is to contain the carbocyclic ring of 6 to 10 carbon atoms and moieties contains 1 to 4 carbon atom; R
10Be the heterocyclic radical that contains 3 to 6 annular atomses, wherein have a nitrogen-atoms at least, Sauerstoffatom and sulphur atom are heteroatoms, and described heterocyclic radical does not replace or replaced by a substituting group δ who defines below or Sauerstoffatom (forming the oxygen base) at least; R
11It is the alkyl that contains 1 to 3 carbon atom; Substituents alpha is selected from: halogen atom; Cyano group; The alkoxyl group that contains 1 to 4 carbon atom; The alkylthio that contains 1 to 4 carbon atom; The alkyl sulphonyl that contains 1 to 4 carbon atom; The alkanoyloxy that contains 2 to 5 carbon atoms; The carbalkoxy that contains 2 to 5 carbon atoms; The carbocyclic ring aryloxy that contains 6 to 10 ring carbon atoms; The carbocyclic ring arylthio that contains 6 to 10 carbon atoms; Contain 6-10 carbon atom carbocyclic ring arylsulfonyl; Amino; The alkanoyl amido that contains 2 to 5 carbon atoms; N-((C
2-C
5Alkanoyl)-N-(C
1-C
3Alkyl) amino; The halogenated alkane amido that contains 2 to 5 carbon atoms; The alkoxycarbonyl amido that contains 2 to 5 carbon atoms; N-((C
2-C
5Carbalkoxy)-N-(C
1-C
3Alkyl) amino; The haloalkoxy carbonylamino that contains 2 to 5 carbon atoms; The isocyclic aryl carbonylamino, wherein aryl moiety contains 6 to 10 ring carbon atoms; Aromatic alkyl carbonyl amino, aromatic alkyl carbonyl amino, wherein aryl moiety is to contain the carbocyclic ring of 6-10 ring carbon atom and moieties contains 1 to 4 carbon atom; The isocyclic aryl that does not replace or replaced by a substituting group r at least that contains 6-10 ring carbon atom; Radicals R
h, and R
hBe the heterocyclic radical that contains 3 to 6 carbon atoms, this heterocyclic radical has a heteroatomic nitrogen-atoms Sauerstoffatom and sulphur atom at least, and this heterocyclic radical does not replace or replaced by a substituting group r who defines below and Sauerstoffatom at least; Radicals R
h-S-, wherein R
hDefinition as above; The alkanoyl that contains 2-5 carbon atom; Aromatic alkoxy carbonyl amino, wherein aryl moiety is to contain the carbocyclic ring of 6 to 10 ring carbon atoms and moieties contains 1 to 4 carbon atom; Substituting group β is selected from halogen atom, contains the alkoxyl group of 1 to 4 carbon atom, contains the alkanoyloxy of 2 to 5 carbon atoms; Substituting group γ is selected from: halogen atom; Hydroxyl; Cyano group; Nitro; The alkyl that contains 1 to 4 carbon atom; The alkoxyl group that contains 1 to 4 carbon atom; The carbalkoxy that contains 2 to 5 carbon atoms; Substituting group δ is selected from amino, contains the alkanoyl amido of 2 to 5 carbon atoms, contains the halogenated alkane amido of 2 to 5 carbon atoms, contains the alkoxycarbonyl amino of 2 to 6 carbon atoms;
The present invention also further provides and contains expelling parasite, kill that mite and insecticidal active compound and agricultural go up and Horticulture on expelling parasite, the mite and the insect-killing composition extremely of acceptable carrier or thinner, wherein said compound is selected from formula (I) compound and salt thereof.
The present invention also further provides and prevents plant and comprise that human and inhuman animal is comprised the method for the pest damage of acarid, parasite and insect etc., this method comprise active compound is used for described plant or animal be used for plant propagation thing part (as seed) or be used to comprise as described in the disease position of plant, animal or plant part or plant propagation thing, wherein active compound is selected from formula (I) compound and salt thereof.
In The compounds of this invention, R
1Be methyl, ethyl, sec.-propyl or the second month in a season-butyl.Certainly, preferable methyl and ethyl, more preferably ethyl.
X is methylene radical or carbonyl; Preferred carbonyl.
Z is formula＞C=(R
2)
2And R
2Being the alkyl that contains 1 to 3 carbon atom, can be the straight or branched alkyl of 1-3 carbon atom, as methyl, and ethyl, propyl group and sec.-propyl, preferable methyl.
Z is formula=C=(CH
2)
m, m is 2 to 5 integer, promptly 2,3,4 or 5, and in this case, Z is a spiro cycloalkyl group, particularly cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.Certainly, preferred especially cyclopropyl and cyclobutyl.
R
3Be (C
1-C
4Alkyl) amino, moieties can be the straight or branched alkyl, for example comprise methylamino-, ethylamino, and amino, isopropylamino, fourth amino, isobutyl amino, the second month in a season-Ding amino and uncle's fourth amino, preferred methylamino-, ethylamino, third amino and fourth amino, more preferably methylamino-.
R
3Be=(C
1-C
4Alkyl) amino, two alkyl can be the same or different and is the straight or branched alkyl that contains 1 to 4 carbon atom.These groups for example can be dimethylaminos, diethylin, dipropyl amino, diisopropylaminoethyl, dibutylamino, two isobutyl amino, two-second month in a season-Ding amino, two-uncle-Ding amino, N-methyl-N-ethylamino, N-methyl-N-third amino, N-methyl-N-isopropyl third amino, N-methyl-N-fourth amino, N-methyl-N-isopropyl fourth amino, N-methyl-N-second month in a season-Ding amino, N-methyl-uncle N--Ding amino, N-ethyl-N-third amino, N-ethyl-N-isopropylamino, N-ethyl-N-fourth amino, N-ethyl-N-isobutyl amino, N-ethyl-N-second month in a season-Ding amino, N-ethyl-uncle N--Ding amino, N-propyl group-N-isopropylamino, N-propyl group-N-fourth amino, N-propyl group-N-isobutyl amino, N-propyl group-N-second month in a season-Ding amino, N-propyl group-uncle N--Ding amino, N-sec.-propyl-N-fourth amino, N-sec.-propyl-N-isobutyl amino, N-sec.-propyl-N-second month in a season-Ding amino, N-sec.-propyl-uncle N--Ding amino, N-butyl-N-isobutyl amino, N-butyl-N-second month in a season-Ding amino, N-butyl-uncle N--Ding amino, N-isobutyl--N-second month in a season-Ding amino, the amino and N-second month in a season-butyl-uncle's N-fourth amino of N-isobutyl--uncle's N-fourth, wherein preferred two groups that alkyl is identical, dimethylamino particularly, diethylin, dipropyl amino, dibutylamino, most preferably dimethylamino and diethylin.
R
3Being the alkoxyl group that contains 1 to 4 carbon atom, can be 1 to 4 carbon alkoxyl group, i.e. methoxyl group straight chain or side chain, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, the second month in a season-butoxy and tert.-butoxy, preferred methoxyl group, oxyethyl group, propoxy-and butoxy, more preferably methoxyl group and oxyethyl group, most preferably methoxyl group.
R
3Be (C
1-C
3Alkoxyl group)-(C
2-C
3Alkoxyl group) group, each alkoxyl group can be to contain 1 to 3, or the straight or branched alkoxyl group of 2 to 3 carbon atoms, also can be to be selected from above-mentioned alkoxyl group.The example of alkoxyl group alkoxyl group has the 1-methoxy ethoxy, the 1-ethoxy ethoxy, 1-propoxy-oxyethyl group, 1-isopropoxy oxyethyl group, 1-butoxy oxyethyl group, 1-isobutoxy oxyethyl group, 1-second month in a season-butoxy oxyethyl group, uncle 1--butoxy oxyethyl group, 2-methoxy ethoxy, the 2-ethoxy ethoxy, 2-propoxy-oxyethyl group, 2-isopropoxy oxyethyl group, 2-butoxy oxyethyl group, 2-isobutoxy oxyethyl group, 2-second month in a season-butoxy oxyethyl group, uncle 2--butoxy oxyethyl group, 1-methoxy propoxy, 1-oxyethyl group propoxy-, 1-propoxy-propoxy-, 1-isopropoxy propoxy-, 1-butoxy propoxy-, 1-isobutoxy propoxy-, 1-second month in a season-butoxy propoxy-, uncle 1--butoxy propoxy-, 2-methoxy propoxy, 2-oxyethyl group propoxy-, 2-propoxy-propoxy-, 2-isopropoxy propoxy-, 2-butoxy propoxy-, 2-isobutoxy propoxy-, 2-second month in a season-butoxy propoxy-, uncle 2--butoxy propoxy-, 3-methoxy propoxy, 3-oxyethyl group propoxy-, 3-propoxy-propoxy-, 3-isopropoxy propoxy-, 3-butoxy propoxy-, 3-isobutoxy propoxy-, 3-second month in a season-butoxy propoxy-and uncle 3--butoxy propoxy-, preferred 2-methoxy ethoxy, 2-ethoxy ethoxy, 2-propoxy-oxyethyl group, 2-isopropoxy oxyethyl group, 2-butoxy oxyethyl group, 2-isobutoxy oxyethyl group, 2-second month in a season-butoxy oxyethyl group and uncle 2--butoxy oxyethyl group, more preferably 2-methoxy ethoxy.R
3Be (iii) group of formula:
And R
4Being the alkyl that contains 1 to 6 carbon atom, can be the straight or branched alkyl of 1 to 6 carbon atom, for example is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the second month in a season-butyl, tert-butyl, amyl group, isopentyl, neo-pentyl, 2-methyl butyl, 1-ethyl propyl, 4-methyl amyl, the 3-methyl amyl, 2-methyl-amyl group, 1-methyl amyl, 3,3-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 1-dimethylbutyl, 1,2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, the 2-ethyl-butyl, hexyl, isohexyl.The alkyl that wherein preferably contains 1-4 carbon atoms, preferable methyl, ethyl, propyl group, sec.-propyl, butyl and isobutyl-, more preferably methyl and ethyl, most preferable.By formula (iii) and contain 2 to 7, the alkanoyl amino of preferred 2 or 3 carbon atoms, and those formulas (iii) group wherein, R for example
4Be respectively the kharophen and the propionamido of methyl or ethyl.
R
3Be (iii) group of formula, wherein R
4It is the substituted alkyl that contains 1 to 6 carbon atom, this substituted alkyl is contained previously defined α substituting group replacement by a kind of being selected from least, alkyl can be the straight or branched alkyl of 1 to 6 carbon atom, for example comprise the not substituted alkyl that provides above, below the example that is included in group in the α substituting group and atom is listed in.As what explain above, gained formula (iii) group is the alkanoyl amido that contains 2 to 7 carbon atoms, in this case, is selected from by one at least and contains the substituent group replacement of α.R
3The object lesson of these alkanoyl amidos that comprise has:
The halogenated alkane acyl group group of containing 2 to 7 carbon atoms, halo kharophen (chloro acetylamino for example particularly, dichloro acetamino, tribromo-acetyl amino, acetobrom amino, acetyl fluoride amino, difluoro kharophen and trifluoroacetamido), halo propionamido (for example 3-chlorine propionamido, 3-dichloro propionamido, 3-chlorine propionamido and 3-fluorine propionamido), halo butyrylamino (4-neoprene amido for example, 4-dichloro butyrylamino, 4-trichlorine butyrylamino and 4-trifluoro butyrylamino), halo valeryl amino is (as 5-chlorine valeryl amino, 5-dichloro valeryl amino, amino and the 5-trifluoro valeryl amino of 5-trichlorine valeryl), and the halo hexanamido (as 6-fluorine hexanamido, 6-dichloro hexanamido, 6-trichlorine hexanamido and 6-trifluoro hexanamido), with halo heptanamido (as 7-chlorine heptanamido, 7-dichloro heptanamido, 7-trichlorine heptanamido and 7-trifluoro heptanamido); Wherein, preferred halo kharophen, particularly chloro acetylamino, acetobrom amino, difluoro kharophen and trifluoroacetamido; The alkanoyl amino that contains the cyano group replacement of 2 to 7 carbon atoms, the particularly kharophen of cyano group replacement, for example cyanoacetamide base, the propionamido that cyano group replaces, 3-cyano group propionamido for example, the butyrylamino that cyano group replaces, for example 4-cyano group butyrylamino, the valeryl amino that cyano group replaces, 5-cyano group valeryl amino for example, the caproyl amino that cyano group replaces, for example 6-cyano group hexanamido, with the heptanamido of cyano group replacement, as 7-cyano group heptanamido; Kharophen, particularly cyanoacetamide base that wherein preferred cyano group replaces; The alkanoyl amino that contains the alkylthio replacement of 2 to 7 carbon atoms, the kharophen that replaces of alkylthio [methylmercaptan ethyl amido for example particularly, two (methylthio group) kharophen, three (methylthio group) kharophen, rosickyite base kharophen, the ethylmercapto group kharophen, two (ethylmercapto group) kharophens and three (ethylmercapto group) kharophen], the propionamido [for example 3-methylthio group propionamido and 3-two (methylthio group) propionamido] that alkylthio replaces, the butyrylamino [for example 4-methylthio group butyrylamino and 4-two (methylthio group) butyrylamino] that alkylthio replaces, the valeryl amino that alkylthio replaces [for example 5-methylthio group valeryl is amino and 5-two (methylthio group) valeryl amino], the heptanamido [for example 7-methylthio group heptanamido and 7-two (methylthio group) heptanamido] that hexanamido [for example 6-methylthio group hexanamido and 6-two (methylthio group) hexanamido] that alkylthio replaces and alkylthio replace; Wherein, kharophen, particularly methylmercaptan ethyl amido that preferred sulfenyl replaces, rosickyite base kharophen and two (ethylmercapto group) kharophen; The alkanoyl amido that contains the alkyl sulphonyl replacement of 2 to 7 carbon atoms, the kharophen that replaces of alkyl sulphonyl [methylsulfonyl kharophen for example particularly, two (methylsulfonyl) kharophen, three (methylsulfonyl) kharophen, the third sulphonyl kharophen, second sulphonyl kharophen, two (second sulphonyl) kharophen and three (second sulphonyl) kharophen], the propionamido that alkyl sulphonyl replaces [for example 3-methylsulfonyl propionamido and 3-two (methylsulfonyl propionamido], the butyrylamino that alkyl sulphonyl replaces [for example 4-methylsulfonyl butyrylamino and 4-two (methylsulfonyl) amido] mutually, the valeryl amino that alkyl sulphonyl replaces [for example 5-methylsulfonyl valeryl is amino and 5-two (methylsulfonyl) valeryl amino], the hexanamido [for example 6-methylsulfonyl hexanamido and 6-two (methylsulfonyl) hexanamido] that alkyl sulphonyl replaces, the heptanamido [for example 7-methylsulfonyl heptanamido and 7-two (methylsulfonyl) heptanamido] that alkyl sulphonyl replaces; Wherein, kharophen, particularly methylsulfonyl kharophen that the preferred alkyl alkylsulfonyl replaces, the third sulphonyl kharophen and two (second sulphonyl) kharophen; The alkanoyl amido that contains the alkanoyloxy replacement of 2 to 7 carbon atoms, the kharophen that replaces of alkanoyloxy (acetoxyl kharophen for example particularly, propionyloxy kharophen and butyric acid base kharophen), the propionamido (for example 3-acetoxyl propionamido) that alkanoyloxy replaces, the butyrylamino (for example 4-acetoxyl butyrylamino) that alkanoyloxy replaces, the valeryl amino (for example 5-acetoxyl valeryl amino) that alkanoyloxy replaces, the hexylyloxy (for example 6-acetoxyl hexanamido) that alkanoyloxy replaces, the heptanamido (for example 7-acetoxyl heptanamido) that alkanoyloxy replaces; Wherein, kharophen, particularly acetoxyl kharophen that the preference chain alkanoyloxy replaces, propionyloxy kharophen and 3-acetoxyl propionamido; The alkanoyl amido that contains the carbalkoxy replacement of 2 to 7 carbon atoms, the kharophen that replaces of carbalkoxy [methoxycarbonyl kharophen for example particularly, the third oxygen carbonyl kharophen and ethoxycarbonyl kharophen], the propionamido [for example 3-methoxycarbonyl propionamido] that carbalkoxy replaces, the butyrylamino [for example 4-methoxycarbonyl butyrylamino] that carbalkoxy replaces, the valeryl amino [for example 5-methoxycarbonyl valeryl amino] that carbalkoxy replaces, the amido [for example 6-methoxycarbonyl hexanamido] that carbalkoxy replaces and the heptanamido [for example 7-methoxycarbonyl heptanamido] of oxygen carbonyl substituted; Wherein, the propionamido, particularly methoxycarbonyl propionamido of preferred alkoxy carbonyl replacement; Contain the kharophen that alkanoyl amido, particularly aryloxy that the aryloxy of 2 to 7 carbon atoms replaces replace, phenoxy group kharophen for example, the propionamido that aryloxy replaces.
The alkanoyl amido that the haloalkoxy carbonylamino replaces, wherein the haloalkoxy carbonyl moiety contains 2 to 5 carbon atoms, alkanoyl amido partly contains 2 to 7 carbon atoms, the preferred chlorine of halogen atom, bromine, fluorine or iodine, more preferably chlorine and fluorine, the kharophen that replaces of haloalkoxy carbonylamino (chloromethane oxygen carbonylamino kharophen for example particularly, trichlorine methoxycarbonyl glycyl amino, 2,2,2-trifluoro ethoxycarbonyl glycyl amino, 3-bromine third oxygen carbonylamino kharophen and 4-neoprene oxygen carbonylamino kharophen], the propionamido that the haloalkoxy carbonylamino replaces [2-chloromethane oxygen carbonylamino propionamido for example, the amino propionamido of 2-trichlorine methoxycarbonyl, 3-chloromethane oxygen carbonylamino propionamido, the amino propionamido of 3-trichlorine methoxycarbonyl, 2-(2,2,2-trifluoro ethoxycarbonyl amino) propionamido, 3-(2,2,2-trifluoro ethoxycarbonyl base) propionamido, 2-(the 3-bromine third oxygen carbonylamino) propionamido, 3-(the 3-bromine third oxygen carbonylamino) propionamido, 2-(4-neoprene oxygen carbonylamino) propionamido and 3-(4-neoprene oxygen carbonylamino) propionamido], [for example 2-chloromethane oxygen carbonyl ammonia is at butyrylamino for the butyrylamino that the haloalkoxy carbonylamino replaces, 4-chloromethane oxygen carbonylamino butyrylamino, 2-(2,2,2-trifluoro ethoxycarbonyl amino) butyrylamino and 4-(2,2,2-trifluoro ethoxycarbonyl amino) butyrylamino], the isobutyryl amino that the haloalkoxy carbonylamino replaces [2-chloromethane oxygen carbonylamino-2-methyl-prop amido for example, 2-(2,2,2-trifluoro ethoxycarbonyl amino)-2-methyl-prop amido, 2-(the 3-bromine third oxygen carbonylamino)-2-methyl-prop amido and 2-(4-neoprene oxygen carbonylamino)-2-methyl-prop amido], [for example 5-chloromethane oxygen carbonylamino valeryl is amino and 5-(2 for the valeryl amino that the haloalkoxy carbonylamino replaces, 2,2-trifluoro ethoxycarbonyl amino)-valeryl amino], the 4-methylpent amido that the haloalkoxy carbonylamino replaces [for example 2-chloromethane oxygen carbonylamino-4-methylpent amido and 2-(2,2,2-trifluoro ethoxycarbonyl amino)-4-methylpent amido], [for example 2-chloromethane oxygen carbonylamino-3-methylbutyryl is amino and 2-(2 for the isovaleryl amino that the haloalkoxy carbonylamino replaces, 2,2-trifluoro ethoxycarbonyl amino)-3-methylbutyryl amino], the hexanamido [for example 6-chloromethane oxygen carbonylamino-hexanamido] that the haloalkoxy carbonylamino replaces, 3 of haloalkoxy carbonylamino replacement, 3-dimethyl butyrate amido [2-chloromethane oxygen carbonylamino-3 for example, 3-dimethyl butyrate amido and 2-(2,2,2-trifluoro ethoxycarbonyl amino)-3,3-dimethyl butyrate amido] and the heptanamido [for example 7-chloromethane oxygen carbonylamino-heptanamido] that replaces of haloalkoxy carbonylamino; Wherein, the kharophen that preferred haloalkoxy carbonylamino replaces, propionamido, butyrylamino, isobutyryl amino, isovaleryl amino, 4-methyl pentanamide and 3,3-dimethyl butyrate amido; Chloromethane oxygen carbonylamino kharophen particularly, 2,2,2-trifluoro ethoxycarbonyl glycyl amino, 2-chloromethane oxygen carbonylamino propionamido, 3-chloromethane oxygen carbonylamino propionamido, 2-chloromethane oxygen carbonylamino butyrylamino, 2-chloromethane oxygen carbonylamino-2-methyl-prop amido, 2-chloromethane oxygen carbonylamino-3-methylbutyryl amino, 2-chloromethane oxygen carbonylamino-4-methylpent amido and 2-chloromethane oxygen carbonylamino-3,3-dimethyl butyrate amido; The alkanoyl amido that the isocyclic aryl carbonylamino replaces wherein alkanoyl amido portion contains 2 to 7 carbon atoms, aryl moiety contains 6 to 10 ring carbon atoms, and (this class aryl comprises phenyl, 1-naphthyl and 2-naphthyl), hippuryl amino for example, 3-benzamido propionamido, 4-benzamido butyrylamino, 5-benzamido valeryl amino, 6-benzamido hexanamido, 7-benzamido heptanamido and naphthoyl glycyl amino; The amino alkanoyl amido that replaces of carbocyclic ring aromatic alkyl carbonyl, wherein alkanoyl amido partly contains 2 to 7 carbon atoms, aryl moiety is 6 to 10 ring carbon atoms and moieties contains 1 to 4 carbon atom that (this class aralkyl comprises benzyl, styroyl, 3-phenyl propionyl and 4-phenyl butyryl radicals), phenylacetyl glycyl amino for example, 3-phenyl propionamido kharophen, the amino kharophen of 4-phenyl butyrylamino butyrylamino and 5-phenyl valeryl; The alkanoyl amido that isocyclic aryl replaces, wherein alkanoyl amido partly contains 2 to 7 carbon atoms and aryl moiety contains 6 to 10 ring carbon atoms and do not replace or be selected from the substituent group of γ by at least one replaces, phenylacetylamino for example, 4-oil of mirbane kharophen, 4-fluorophenethyl amido, 4-fluorophenethyl amido, 4-methylbenzene kharophen, 4-ethylbenzene kharophen, 4-trifluoromethyl phenylacetylamino, 4-amino methyl phenylacetylamino, 3-oil of mirbane kharophen, 3-fluorophenethyl amido, 3-chlorobenzene kharophen, 3-methylbenzene kharophen, 3-ethylbenzene kharophen, 3-trifluoromethyl phenylacetylamino, 3-amino methyl phenylacetylamino and 1-naphthyl kharophen; By radicals R
hThe alkanoyl amido that replaces, wherein R
hIt is the heterocyclic radical that contains 3 to 6 annular atomses, wherein have at least a heteroatoms to be selected from nitrogen-atoms Sauerstoffatom and sulphur atom, described heterocyclic radical does not replace or can be selected from the γ substituting group by at least one, and the group of Sauerstoffatom (forming an oxygen base) replaces, 2-oxygen-1-azetidinyl kharophen for example, 2-oxygen-piperidino kharophen, 2,6-dioxy-piperidino kharophen, the pyrimidyl kharophen, pyridyl kharophen, 2-oxygen-1-pyrrolidyl kharophen, 2,5-dioxy-1-pyrrolidyl kharophen, thiazolidyl kharophen, thienyl kharophen, thiazolyl kharophen and 2-oxygen-1,3-oxazoles quinoline-3-base kharophen; By radicals R
hThe alkanoyl amido that-S-replaces, wherein R
hDefinition as above, 2-pyrimidyl kharophen for example, 2-pyridyl kharophen, 2-thiazolidyl kharophen; The alkanoyl amido that is replaced by the alkanoyl of 2-5 carbon atom, acetyl acetamide for example, propionyl kharophen, the butyryl kharophen, the valeryl kharophen, 3-levulinic acyl group kharophen, 3-propionyl propionamido, 3-butyryl radicals propionamido, 3-valeryl propionamido, 4-ethanoyl butyrylamino, 4-ethanoyl butyrylamino, 4-propionyl butyrylamino, 4-butyryl radicals butyrylamino and 4-valeryl butyrylamino; And by the amino alkanoyl amido that replaces of aromatic alkoxy carbonyl, wherein aryl moiety is the carbocyclic ring that contains 6 to 10 ring carbon atoms, moieties contains 1 to 4 carbon atom, benzyloxycarbonyl amino kharophen for example, benzene ethoxycarbonyl glycyl amino, 3-phenylpropyl alcohol oxygen carbonyl ammonia kharophen, amino kharophen of 4-benzene butoxy carbonyl and 5-benzene penta oxygen carbonylamino kharophen.
Work as R
3Be (iii) base of formula, R
4Be the cycloalkyl that contains 3 to 6 carbon atoms, this group is a cycloalkyl amino carbonyl.For example this class group comprises cyclopropane carbonyl amino, the tetramethylene carbonylamino, the pentamethylene carbonylamino, the hexanaphthene carbonylamino, N-methyl-N-cyclopropane carbonyl amino, N-methyl-N-tetramethylene carbonylamino, N-methyl-N-pentamethylene carbonylamino, N-methyl-N-hexanaphthene carbonylamino, N-ethyl-N-cyclopropane carbonyl amino, N-ethyl-N-tetramethylene carbonylamino, N-ethyl-N-pentamethylene carbonylamino, N-ethyl-N-hexanaphthene carbonylamino, N-propyl group-N-cyclopropane carbonyl amino, N-propyl group-N-tetramethylene carbonylamino, N-propyl group-N-pentamethylene carbonylamino and N-propyl group-N-hexanaphthene carbonylamino.
Work as R
3Be (iii) base R of formula
4When being selected from the substituent group of previously defined β and replacing for the cycloalkyl that contains 3 to 10 carbon atoms and by at least one, unsubstituted cycloalkyl can be monocycle or many rings, as bicyclic ring system, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, norborneol alkyl, norpinanyl, bornyl or Gai Ji.Formula example (iii) comprises the amino tetramethylene of 1--1-carbonyl, 1-Aminocyclopentane-1-carbonyl, 1-aminocyclohexane-1-carbonyl, 2-chlorine tetramethylene-1-carbonyl, 2-chlorine pentamethylene-1-carbonyl, 2-chlorine hexanaphthene-1-carbonyl, 2-fluorine tetramethylene-1-carbonyl, 2-fluorine pentamethylene-1-carbonyl, 2-fluorine hexanaphthene-1-carbonyl, 2-methoxyl group tetramethylene-1-carbonyl, 2-methoxyl group pentamethylene-1-carbonyl, 2-methoxyl group hexanaphthene-1-carbonyl, 2-oxyethyl group tetramethylene-1-carbonyl, 2-oxyethyl group pentamethylene-1-carbonyl, 2-oxyethyl group hexanaphthene-1-carbonyl, 2-acetoxyl group tetramethylene-1-carbonyl, 2-acetoxyl group pentamethylene-1-carbonyl, 2-acetoxyl group hexanaphthene-1-carbonyl, 2-propionyloxy tetramethylene-1-carbonyl, 2-propionyloxy pentamethylene-1-carbonyl and 2-propionyloxy hexanaphthene-1-carbonyl.
Work as R
3Be (iii) base and R of formula
4Be when containing the alkenyl of 2 to 6 carbon atoms, alkenyl can contain 2 to 6 carbon atoms, the straight or branched alkenyl of preferred or 4 carbon atoms, and the example of this class thiazolinyl comprises vinyl, allyl group, methylallyl, 1-propenyl, pseudoallyl, the 1-butylene base, crotyl, 3-butenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, wherein, preferred vinyl, allyl group, methylallyl, 1-propenyl, pseudoallyl and butenyl.By R
3The preferred formula of representative (iii) group comprises acrylamido, crotonoyl amino, different crotonoyl amino, 3-crotonoyl amino, 2-amylene amido, 4-amylene amido, the amino and 5-hexenoyl amino of 2-hexenoyl, wherein, more preferably acrylamido, the amino and different crotonoyl amino of crotonoyl.
Work as R
3Be (iii) base R of formula
4When containing the alkynyl of 2 to 6 carbon atoms, alkynyl can be to contain 2 to 6, the straight or branched alkynyl of preferred 3 or 4 carbon atoms, the example of alkynyl comprises ethynyl, and alkynyl (2-propynyl), the 1-proyl, the ethyl acetylene base, 2-butyne base, 3-butynyl, the 1-pentynyl, the valerylene base, 3-pentynyl and 4-pentynyl, wherein, preferred ethynyl, proyl and butynyl.By R
3The formula of the representative (iii) preferred embodiment of group comprises propionyl, the 3-butyrylamino, and 2-valeryl amino, 4-valeryl amino, 2-hexanamido and 5-hexanamido, wherein, preferred propionyl.
Work as R
3Be (iii) group R of formula
4For containing 6 to 14 ring carbon atoms and replacement or being selected from the isocyclic aryl that the substituent group of previously defined r replaces by at least one, the γ substituting group will illustrate separately below.Formula example (iii) comprises benzamido, 1-naphthoyl amino, 2-naphthoyl amino, 1-fluorenes carbonyl amino, the luxuriant and rich with fragrance carbonyl amino of 1-, 1-anthracene carbonyl amino, 2-fluorobenzoyl amino, 3-fluorobenzoyl amino, 4-fluorobenzoyl amino, 2-chlorobenzoyl amino, 3-chlorobenzoyl amino, 4-chlorobenzoyl amino, 2-toluyl amino, 3-toluyl amino, 4-ethylamino benzonitrile amido, 2-propylbenzene formamido group, 3-propylbenzene formamido group, 4-propylbenzene formamido group, 2-isopropyl benzene formamido group, 3-isopropyl benzene formamido group, 4-isopropyl benzene formamido group, 2-butylbenzene formamido group, 3-butylbenzene formamido group, 4-butylbenzene formamido group, 2-tert-butyl benzamido, 3-tert-butyl benzamido, 4-tert-butyl benzamido, 2-methoxybenzoyl amino, 3-methoxybenzoyl amino, 4-methoxybenzoyl amino, 3,4-dimethoxy benzamido, 2-phenetole formamido group, 3-phenetole formamido group, 4-phenetole formamido group, 2-propoxy-benzamido, 3-propoxy-benzamido, 4-propoxy-benzamido, 2-isopropoxy benzamido, 3-isopropoxy benzamido, 4-isopropoxy benzamido, 2-butyl phenyl ether formamido group, 3-butyl phenyl ether formamido group, 4-butyl phenyl ether formamido group, uncle 2--butyl phenyl ether formamido group, uncle 3--butyl phenyl ether formamido group, uncle 4--butyl phenyl ether formamido group, 2-nitrobenzoyl amido, 3-nitrobenzoyl amido, 4-nitrobenzoyl amido, 2-aminobenzoic amido, 3-aminobenzoic amido and 4-aminobenzoic amido, wherein, preferred benzamido, 2-fluorobenzoyl amino, 4-fluorobenzoyl amino, 3-chlorobenzoyl amino, 4-chlorobenzoyl amino, 3-methoxybenzoyl amino, 4-methoxybenzoyl amino, 3,4-dimethoxy benzamido, 4-tert-butyl benzamido, 3-nitrobenzoyl amido and 4-nitrobenzoyl amido.
Work as R
3Be (iii) group R of formula
4When being the heterocyclic radical of nitrogen, oxygen and sulphur atom for containing 3 to 6 annular atomses and at least one heteroatoms, this heterocyclic radical is for replacing or be selected from the substituent group of previously defined γ by at least one, and Sauerstoffatom (forming the oxygen base) replaces.The example of heterocyclic radical comprises and replacing or unsubstituted furyl, lactam group, piperidyl, pyrimidyl, pyrrolidyl, thiazolidyl, thienyl and thiazolyl.The formula (iii) specific examples of base comprises 2-furoyl amino, 3-furoyl amino, 5-γ-Nei acyl aminocarbonyl amino, 2-piperidinyl carbonyl amino, 3-piperidinyl carbonyl amino, 4-piperidinyl carbonyl amino, 1-methoxycarbonyl-4-piperidinyl carbonyl amino, 1-ethoxycarbonyl-4-piperidinyl carbonyl amino, 2-pyrimidine carbonylamino, 3-pyrimidine carbonylamino, 3-pyridine carbonylamino, 4-pyridine carbonylamino, 3-tetramethyleneimine carbonylamino, 1-methoxycarbonyl-2-tetramethyleneimine carbonylamino, 1-ethoxycarbonyl-2-tetramethyleneimine carbonylamino, 3-thiazolidine carbonylamino, 4-thiazolidine carbonylamino, 3-methoxycarbonyl-4-thiazolidine carbonylamino, 3-ethoxycarbonyl-4-thiazolidine carbonylamino, 2-thienyl and 3-thienyl, wherein, preferred especially 2-furoyl amino, gamma-lactam carbonylamino, 1-methoxycarbonyl-4-piperidinyl carbonyl amino, 3-pyridine carbonylamino, 4-pyridine carbonylamino, 1-methoxycarbonyl-2-tetramethyleneimine carbonylamino, 1-ethoxycarbonyl-2-tetramethyleneimine carbonylamino, 3-methoxycarbonyl-4-thiazolidine carbonylamino and 2-thienyl.
Work as R
3For formula (iii), (iv), (vii), (viii) or (ix), and R
5When representing alkyl, this group is for containing 1 to 4, and the straight or branched alkyl of preferred 1 or 2 carbon atom for example comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-and tert-butyl.Wherein, preferable methyl.
Work as R
3Be (iv) R of formula
6When representing alkyl, this group is for containing 1 to 6, and the straight or branched alkyl of preferred 1 to 5 carbon atom for example comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the second month in a season-butyl, tert-butyl, amyl group, isopentyl, neo-pentyl, 2-methyl butyl, 1-ethyl propyl, the 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, the 1-methyl amyl, 3, the 3-dimethylbutyl, 2,2-dimethylbutyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1,3-dimethylbutyl, 2, the 3-dimethylbutyl, 2-ethyl-butyl, hexyl and isohexyl.Wherein, preferably contain the alkyl of 1 to 4 carbon atom, preferably methyl, ethyl, propyl group, sec.-propyl, butyl and isobutyl-, more preferably methyl.
Work as R
3Be formula (iv) and R
6During representation ring alkyl, this group is the cycloalkyl that contains 3 to 6 carbon atoms, and the example comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
Work as R
3Be formula (iv) and R
7When being alkyl or cycloalkyl, these groups can be give an example above and R
6Relevant group.
Work as R
3Be formula (iv) and R
7When being aryl, this aryl be contain 6 to 14 ring carbon atoms and do not replace or be selected from by at least one above the isocyclic aryl that replaces of the substituent substituting group of γ of giving an example.The example of this class aryl comprises it being phenyl, 1-naphthyl, 2-naphthyl, 1-fluorenyl, 1-phenanthryl, 1-anthryl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl; The 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, the 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-propyl group phenyl, 3-propyl group phenyl, 4-propyl group phenyl, the 2-isopropyl phenyl, 3-isopropyl phenyl, 4-isopropyl phenyl, the 2-butyl phenyl, 3-butyl phenyl, 4-butyl phenyl, 2-tert-butyl phenyl, 3-tert-butyl phenyl, 4-tert-butyl phenyl, the 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 3,4-Dimethoxyphenyl, 2-ethoxyl phenenyl, the 3-ethoxyl phenenyl, 4-ethoxyl phenenyl, 2-propoxy-phenyl, 3-propoxy-phenyl, 4-propoxy-phenyl, 2-isopropyl phenyl, the 3-isopropyl phenyl, the 4-isopropyl phenyl, 2-butoxy phenyl, 3-butoxy phenyl, the 4-butoxy phenyl, uncle 2--butoxy phenyl, uncle 3--butoxy phenyl, 4-tert.-butoxy phenyl, the 2-nitrophenyl, the 3-nitrophenyl, 4-nitrophenyl, 2-aminophenyl, 3-aminophenyl and 4-aminophenyl, wherein, preferred phenyl, 2-fluorophenyl, the 3-fluorophenyl, the 4-fluorophenyl, 3-chloro-phenyl-, 4-chloro-phenyl-, the 3-p-methoxy-phenyl, the 4-p-methoxy-phenyl, 3, the 4-Dimethoxyphenyl, 4-tert-butyl phenyl, 3-nitrophenyl and 4-nitrophenyl.
Work as R
3Be (iv) gene and R of formula
6And R
7Common thick when becoming to contain the heterocycle of 3 to 6 annular atomses with the nitrogen-atoms that links to each other with them, these groups can be any nitrogen heterocycles, comprise the R that gives an example above
4, preferred 1-pyrrolidyl.
Work as R
3Be formula (vii), (viii) or (ix), and R
8When representing alkyl, this group is for containing 1 to 4, and the straight or branched alkyl of preferred 1 or 2 carbon atom for example comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, tert-butyl.Wherein, preferable methyl.
Work as R
3Be formula (vii), (viii) or (ix), and R
8When being aryl, this aryl be contain 6 to 10 ring carbon atoms and do not replace or be selected from by at least one above the substituent substituting group of γ of giving an example replace isocyclic aryl.This class aryl example comprises phenyl, 1-naphthyl, 2-naphthyl, the 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, the 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, the 2-tolyl, 3-tolyl, 4-tolyl, 2-ethylbenzene base, 3-ethylbenzene base, 4-ethylbenzene base, the 2-propyl phenyl, 3-propyl phenyl, 4-propyl phenyl, the 2-cumyl, 3-cumyl, 4-cumyl, 2-butylbenzene base, 3-butylbenzene base, 4-butylbenzene base, uncle 2--butylbenzene base, uncle 3--butylbenzene base, uncle 4--butylbenzene base, the 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 3,4-Dimethoxyphenyl, 2-ethoxyl phenenyl, the 3-ethoxyl phenenyl, 4-ethoxyl phenenyl, 2-propoxy-phenyl, 3-propoxy-phenyl, 4-propoxy-phenyl, 2-isopropyl phenyl, the 3-isopropyl phenyl, 4-isopropyl phenyl, 2-butoxy phenyl, the 3-butoxy phenyl, 4-butoxy phenyl, uncle 2--butoxy phenyl, 3-tert.-butoxy phenyl, uncle 4--butoxy phenyl, 2-nitrophenyl, the 3-nitrophenyl, 4-nitrophenyl, 2-aminophenyl, 3-aminophenyl and 4-aminophenyl, wherein, preferred phenyl, 2-fluorophenyl, the 3-fluorophenyl, the 4-fluorophenyl, 3-chloro-phenyl-, 4-chloro-phenyl-, the 3-p-methoxy-phenyl, the 4-p-methoxy-phenyl, 3, the 4-Dimethoxyphenyl, 4-tert-butyl phenyl, 3-nitrophenyl and 4-nitrophenyl.
Work as R
3Be formula (viii) group, and R
9When being alkyl or aryl, this group can be the definition of any front and give an example and R
8Relevant group.
R
3Be formula (viii) group, and R
9When being cycloalkyl, this group can be the definition of any front and give an example and R
6Relevant group.
Work as R
3Be formula (viii) group, and R
9Be aralkyl, aryl moiety is the carbocyclic ring moieties that contains 6 to 10 ring carbon atoms when then containing 1 to 4 carbon atom, alkyl and aryl moiety independently of one another for the front definition and give an example and R
8Relevant group.The specific examples of this aralkyl comprises benzyl, the 1-styroyl, 2-styroyl (styroyl), 3-hydrocinnamyl, 2-hydrocinnamyl, 4-benzene butyl, 2-benzene butyl, 1-menaphthyl and 2-menaphthyl, these groups can be replacements or unsubstituted, if replace, then substituting group is maybe to be selected from the γ substituting group of giving an example below.Substituent example comprises the 2-luorobenzyl, 3-luorobenzyl, 4-luorobenzyl, 2-benzyl chloride base, 3-benzyl chloride base, 4-benzyl chloride base, the 2-methyl-benzyl, 3-methyl-benzyl, 4-methyl-benzyl, the 2-Ethylbenzyl, 3-Ethylbenzyl, 4-Ethylbenzyl, 2-propyl group benzyl, 3-propyl group benzyl, 4-propyl group benzyl, the 2-isopropyl benzyl, 3-isopropyl benzyl, 4-isopropyl benzyl, the 2-butyl benzyl, 3-butyl benzyl, 4-butyl benzyl, 2-tert-butyl benzyl, 3-tert-butyl benzyl, 4-tert-butyl benzyl, the 2-methoxy-benzyl, the 3-methoxy-benzyl, 4-methoxy-benzyl, 3, the 4-dimethoxy-benzyl, the 2-ethoxy benzyl, 3-ethoxy benzyl, 4-ethoxy benzyl, 2-propoxy-benzyl, 3-propoxy-benzyl, 2-isopropoxide benzyl, 3-and propoxy-benzyl, the 4-isopropoxide benzyl, 2-butoxy benzyl, 3-butoxy benzyl, 4-butoxy benzyl, uncle 2--butoxy benzyl, uncle 3--butoxy benzyl, uncle 4--butoxy benzyl, 2-nitrobenzyl, the 3-nitrobenzyl, 4-nitrobenzyl, 2-aminobenzyl, 3-nitrobenzyl and 4-aminobenzyl.
Work as R
3Be formula (ix) group, and R
10When being heterocyclic radical, this heterocyclic radical can be any comprise previous exemplary and R
4Relevant heterocyclic radical, preferred 2-chloro acetylamino-4-thiazolyl, 2-methoxycarbonyl amino-3-thiazolyl or 2-thienyl.
R
3Be formula (ix) group, and R
10When being alkyl, this alkyl can be the straight or branched alkyl that contains 1 to 3 carbon atom, and the example comprises methyl, ethyl, and propyl group and sec.-propyl, wherein, preferable methyl.
Substituents alpha comprises:
Halogen atom, as fluorine, chlorine, bromine or iodine atom, wherein preferred fluorine and chlorine atom;
Cyano group;
The alkoxyl group that contains 1 to 4 carbon atom, methoxyl group for example, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, the second month in a season-butoxy and uncle-butoxy, more preferably methoxyl group;
The alkylthio that contains 1 to 4 carbon atom, methylthio group for example, ethylmercapto group, rosickyite base, iprotiazem base, butylthio, isobutyl sulfenyl, the second month in a season-butylthio and uncle-butylthio, more preferably methylthio group;
The alkyl sulphonyl that contains 1 to 4 carbon atom, methylsulfonyl for example, ethylsulfonyl, third alkylsulfonyl, different third alkylsulfonyl, the fourth alkylsulfonyl, the isobutyl alkylsulfonyl, the second month in a season-Ding alkylsulfonyl and uncle-Ding alkylsulfonyl, more preferably methylsulfonyl;
The alkanoyloxy that contains 2 to 5 carbon atoms, acetoxyl group for example, propionyloxy, butyryl acyloxy, isobutyl acyloxy, penta acyloxy, isoamyl acyloxy and new pentane acyloxy, wherein preferred acetoxyl group;
The carbalkoxy that contains 2 to 5 carbon atoms, methoxycarbonyl for example, ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl, isobutyl boc, the second month in a season-butoxy carbonyl and uncle-butoxy carbonyl, more preferably methoxycarbonyl;
Contain 6 to 10 ring carbon atoms and carbocyclic ring aryloxy, phenoxy group for example, 1-naphthyloxy and 2-naphthyloxy, wherein preferred oxygen base;
The carbocyclic ring arylthio that contains 6 to 10 ring carbon atoms, thiophenyl for example, 1-naphthalene sulfenyl and 2-naphthalene sulfenyl, wherein preferred thiophenyl;
The carbocyclic ring arylsulfonyl that contains 6 to 10 ring carbon atoms, benzenesulfonyl for example, 1-naphthalene sulfonyl base and 2-naphthalene sulfonyl base, wherein preferred benzenesulfonyl;
Amino;
The alkanoyl amido that contains 2 to 5 carbon atoms, kharophen for example, propionamido, butyrylamino, isobutyryl amino, valeryl amino, the amino and pivalyl amino of isovaleryl, wherein preferred acetate amino;
N-(C
2-C
5Alkanoyl)-N-(C
1-C
3Alkyl) amino, for example, N-ethanoyl-N-methylamino, N-propionyl-N-methylamino-, N-butyryl radicals-N-methylamino, N-isobutyryl-N-methylamino, N-pentanoyl-N-methylamino, N-isovaleryl-N-methylamino, N-valeryl-N-methylamino, N-ethanoyl-N-ethylamino, N-propionyl-N-ethylamino, N-butyryl radicals-N-ethylamino, N-isobutyryl-N-ethylamino, N-pentanoyl-N-ethylamino, N-isovaleryl-N-ethylamino, N-valeryl-N-ethylamino, N-ethanoyl-N-third amino, N-propionyl-N-third amino, N-butyryl radicals-N-third amino, N-isobutyryl-N-third amino, N-pentanoyl-N-third amino, N-isovaleryl-N-third amino, N-valeryl-N-third amino, N-ethanoyl-N-isopropylamino, N-propionyl-N-isopropylamino, the N-butyryl radicals-and third amino, N-isobutyryl-N-isopropylamino, N-pentanoyl-N-isopropylamino, N-isovaleryl-N-isopropylamino and N-valeryl-N-isopropylamino, its its preferred N-methyl-N-kharophen;
The halogenated alkane amido that contains 2 to 5 carbon atoms, chloro acetylamino for example, dichloro acetamino, tribromo-acetyl amino, acetyl fluoride amino, difluoro kharophen, trifluoroacetamido, acetobrom amino, iodacetyl amino, 4-neoprene amido, 4-fluorine butyrylamino and 5-fluorine valeryl amino, wherein, preferred chloro acetylamino;
The alkoxycarbonyl amido that contains 2 to 5 carbon atoms, methoxycarbonyl amino for example, ethoxycarbonyl amino, the third oxygen carbonylamino, the different third oxygen carbonylamino, butoxy carbonyl amino, isobutyl boc amino, the second month in a season-butoxy carbonyl amino and uncle-butoxy carbonyl amino, more preferably methoxycarbonyl amino;
N-(C
2-C
5Carbalkoxy)-N-(C
1-C
3Alkyl) amino, N-methoxycarbonyl-N-methylamino-for example, N-ethoxycarbonyl-N-methylamino-, N-third oxygen carbonyl-N-methylamino-, different third oxygen carbonyl of N--N-methylamino-, N-butoxy carbonyl-N-methylamino-, N-isobutoxy-N-methylamino-, the N-second month in a season-butoxy carbonyl-N-methylamino-, uncle N--butoxy carbonyl-N-methylamino-, N-methoxycarbonyl-N-ethylamino, N-ethoxycarbonyl-N-ethylamino, N-third oxygen carbonyl-N-ethylamino, different third oxygen carbonyl of N--N-ethylamino, N-butoxy carbonyl-N-ethylamino, N-isobutyl boc-N-ethylamino, the N-second month in a season-butoxy carbonyl-N-ethylamino, uncle N--butoxy carbonyl-N-ethylamino, N-methoxycarbonyl-N-third amino, N-ethoxycarbonyl-N-third amino, N-third oxygen carbonyl-N-third amino, the different third oxygen carbonyl-N-of N-third amino, N-butoxy carbonyl-N-third amino, N-isobutyl boc-N-third amino, the N-second month in a season-butoxy carbonyl-N-third amino, uncle N--butoxy carbonyl-N-third amino, N-methoxycarbonyl-N-isopropylamino, N-ethoxycarbonyl-N-isopropylamino, different third oxygen carbonyl of N--N-isopropylamino, N-butoxy carbonyl-N-isopropylamino, N-isobutyl boc-N-isopropylamino, the N-second month in a season-butoxy carbonyl-N-isopropylamino and uncle N--butoxy carbonyl-N-isopropylamino, more preferably N-methoxyl group-N-methylamino-;
Contain 2 to 5 carbon atom haloalkoxy carbonylaminos, chloromethane oxygen carbonylamino for example, dichloro methoxy carbonylamino, trichlorine methoxycarbonyl amino, fluorine methoxycarbonyl amino, difluoro methoxycarbonyl amino, trifluoro methoxy carbonylamino, fluorine methoxycarbonyl amino, difluoro methoxycarbonyl amino, trifluoro methoxy carbonylamino, trifluoro methoxy carbonylamino, bromine methoxycarbonyl amino, iodine methoxycarbonyl amino, 2-fluorine ethoxycarbonyl amino, 2-fluorine ethoxycarbonyl amino, 2-bromine ethoxycarbonyl amino, 2-iodine ethoxycarbonyl amino, 2,2,2-trifluoro ethoxycarbonyl amino, 2,2,2-trichloro-ethoxycarbonyl amino, the 3-fluorine third oxygen carbonylamino, the 3-chlorine third oxygen carbonylamino, the 3-bromine third oxygen carbonylamino, the 3-iodine third oxygen carbonylamino, 4-neoprene oxygen carbonylamino and 5-chlorine penta oxygen carbonylamino, wherein preferred chloromethane oxygen carbonylamino, 2,2,2-trifluoro ethoxycarbonyl amino;
Aryl moiety contains the isocyclic aryl carbonylamino of 6 to 10 ring carbon atoms, benzamido for example, and the amino and 2-naphthoyl amino of 1-naphthoyl, wherein, preferred benzamido;
Aromatic alkyl carbonyl amino, wherein aromatic ring partly is to contain the carbocyclic ring of 6 to 10 ring carbon atoms and moieties contains 1 to 4 carbon atom, phenylacetylamino for example, 2-phenylpropyl alcohol amido, 3-phenylpropyl alcohol amido, 4-benzene butyrylamino, 3-benzene butyrylamino, 4-benzene valeryl amino, 2-benzene valeryl amino, 1-naphthalene kharophen and 2-naphthalene kharophen, wherein preferred phenylacetylamino;
Contain 6 to 10 ring carbon atoms and do not replace or be selected from the isocyclic aryl that the substituent substituting group of γ replaces, phenyl for example, 1-naphthyl by at least one, the 2-naphthyl, 2-fluorophenyl, 3-fluorophenyl, the 4-fluorophenyl, 2-chloro-phenyl-, 3-chloro-phenyl-, the 4-chloro-phenyl-, 2-tolyl, 4-tolyl, 2-ethylbenzene base, 3-ethylbenzene base, 4-ethylbenzene base, the 2-propyl phenyl, 3-propyl phenyl, 4-propyl phenyl, the 2-cumyl, 3-cumyl, 4-cumyl, 2-butylbenzene base, 3-butylbenzene base, 4-butylbenzene base, uncle 2--butylbenzene base, uncle 3--butylbenzene base, 4-trimethylphenylmethane base, the 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 3,4-Dimethoxyphenyl, 2-ethoxyl phenenyl, the 3-ethoxyl phenenyl, 4-ethoxyl phenenyl, 2-propoxy-phenyl, 3-propoxy-phenyl, 4-propoxy-phenyl, 2-isopropyl phenyl, the 3-isopropyl phenyl, 4-isopropyl phenyl, 2-butoxy phenyl, the 3-butoxy phenyl, 4-butoxy phenyl, uncle 2--butoxy phenyl, uncle 3--butoxy phenyl, uncle 4--butoxy phenyl, 2-nitrophenyl, the 3-nitrophenyl, the 4-nitrophenyl, 2-aminophenyl, 3-aminophenyl and 4-aminophenyl, wherein preferred phenyl, the 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, the 3-chloro-phenyl-, the 4-chloro-phenyl-, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 3, the 4-Dimethoxyphenyl, uncle 4--butoxy phenyl, 3-nitrophenyl and 4-nitrophenyl;
Radicals R
h, R
hFor contain 3 to 6 annular atomses wherein at least one heteroatoms be the heterocyclic radical of nitrogen, oxygen and sulphur atom, this heterocyclic radical is not for replacing or being selected from the substituent substituting group of γ by at least one, Sauerstoffatom (forming an oxygen groups) replaces, 3-oxa--1-azetidinyl for example, 2-oxa--piperidino, 2,6-two oxa-s-piperidino, pyrimidyl, pyridyl, 2-oxa--1-pyrrolidyl, 2,5-two oxa-s-1-pyrrolidyl, thiazolidyl, thienyl, thiazolyl and 2-oxa--1,3-oxazoline-3-base;
Formula R
h-S-group, R
hDefine as above, as 2-oxa--1-tetramethylene sulfenyl, 2-oxa--1-piperidines sulfenyl, 2,6-two oxa-s-1-piperidines sulfenyl, pyrimidine sulfenyl, the pyridine sulfenyl, 2-oxa--1-tetramethyleneimine sulfenyl, 2,5-two oxa-s-1-tetramethyleneimine sulfenyl, the thiazolidine sulfenyl, thiotetrole sulfenyl and 2-oxa--1,3-oxazoline-3-base sulfenyl, wherein preferred 2-pyrimidine sulfenyl, 2-pyridine sulfenyl and 2-thiazolidine sulfenyl;
The alkanoyl that contains 2 to 5 carbon atoms, ethanoyl for example, propionyl, butyryl radicals, isobutyryl, pentanoyl, isovaleryl and valeryl, wherein preferred ethanoyl;
With aralkoxycarbonyl amino, wherein aryl moiety is to contain the carbocyclic ring of 6 to 10 ring carbon atoms and moieties contains 1 to 4 carbon atom, benzyloxycarbonyl amino for example, benzene ethoxycarbonyl amino, 3-phenylpropyl alcohol oxygen carbonylamino, the amino and 5-benzene penta oxygen carbonylamino of 4-benzene butoxy carbonyl.
The substituent example of β comprises:
Halogen atom, for example fluorine, chlorine, bromine or iodine atom, wherein preferred fluorine and chlorine atom;
Alkoxyl group with 1 to 4 carbon atom, methoxyl group for example, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, the second month in a season-butoxy and uncle-butoxy, more preferably methoxyl group; And
The alkanoyloxy that contains 2 to 5 carbon atoms, as acetoxyl group, propionyloxy, butyryl acyloxy, isobutyl acyloxy, penta acyloxy, isoamyl acyloxy and new pentane acyloxy, wherein preferred acetoxyl group.
The substituent example of γ comprises:
Halogen atom, fluorine for example, chlorine, bromine or iodine atom, wherein preferred fluorine and chlorine atom;
Hydroxyl;
Cyano group;
Nitro;
The alkyl that contains 1 to 4 carbon atom, methyl for example, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the second month in a season-butyl and tert-butyl, more preferably methyl;
The alkoxyl group that contains 1 to 4 carbon atom, methoxyl group for example, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, the second month in a season-butoxy and uncle-butoxy, more preferably methoxyl group;
Contain and add up to 2 to 5 carbon atoms and alkoxy carbonyl (being that alkoxyl group partly contains 1 to 4 carbon atom), methoxycarbonyl for example, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, the second month in a season-butoxy carbonyl and uncle-butoxy carbonyl, more preferably methoxycarbonyl.
The substituent example of δ comprises:
Amino;
The alkanoyl amido that contains 2 to 5 carbon atoms, kharophen for example, propionamido, butyrylamino, isobutyryl amino, valeryl amino, the amino and pivalyl amino of isovaleryl, wherein preferred kharophen;
The halogenated alkane amido that contains 2 to 5 carbon atoms, chloro acetylamino for example, dichloro acetamino, tribromo-acetyl amino, acetyl fluoride amino, difluoro kharophen, trifluoroacetamido, acetobrom amino, iodacetyl amino, 4-neoprene amido, 4-fluorine butyrylamino and 5-fluorine valeryl amino, wherein, preferred chloro acetylamino; And
The alkoxycarbonyl amino that contains 2 to 6 carbon atoms, methoxycarbonyl amino for example, ethoxycarbonyl amino, the third oxygen carbonylamino, the different third oxygen carbonylamino, butoxy carbonyl amino, isobutyl boc amino, the second month in a season-butoxy carbonyl amino, uncle-butoxy carbonyl amino and penta oxygen carbonylamino, more preferably methoxycarbonyl amino.
Usually, above mentioned substituting group does not limit its quantity especially, unless this quantity is subjected to commutable position and three-dimensional restriction.And usually, this group is substituted base and replaces, preferred 1 to 3 substituting group, and more preferably 0,1 or 2 substituting group, 0 or 1 substituting group is more preferred.
Contain a plurality of unsymmetrical carbons in the molecule of The compounds of this invention, therefore can form optical isomer.Though these compounds only represent with the individual molecule formula that at this present invention had both comprised independent isolating isomer, mixture also comprises its racemic modification.The present invention includes three-dimensional synthetic technology or the starting raw material selected is Photoactive compounds and directly prepare independent isomer; On the other hand, if prepared be mixture of isomers, then can obtain independent isomer by the disassemble technique of routine.Especially, there is α-or beta configuration in The compounds of this invention on 13 stereochemistry of milbemycin skeleton.Though all isomer and its mixture have constituted a part of the present invention, preferred beta configuration.
Preferred The compounds of this invention be formula (I) compound wherein: (A), (Z) be formula (i) group and R
2Be methyl or ethyl.
Or (A '), Z are (ii) groups and m is 2,3 or 4 of formula.(B), n is 0.(C), R
3Be amino, (C
1-C
3Alkyl) amino, two (C
1-C
3Alkyl) amino contain the alkoxyl group of 1 to 3 carbon atom, or formula is (iii), (iv), (v), (vi) or (group vii):
R wherein
4Be: contain the alkyl of 1 to 4 carbon atom, contain the substituted alkyl of 1 to 3 carbon atom and be selected from by at least one below the α that defines
1Substituting group replaces; The cycloalkyl that contains 3 to 6 carbon atoms; The alkenyl that contains 3 to 4 carbon atoms; The alkynyl that contains 3 to 4 carbon atoms; The isocyclic aryl that contains 6 to 10 ring carbon atoms, this isocyclic aryl do not replace or are selected from the γ that defines below by at least one
1Substituting group; It is nitrogen, oxygen and sulphur atom that the heterocyclic radical that contains 3 to 6 annular atomses, this heterocyclic radical have a heteroatoms at least, and described heterocycle does not replace or is selected from the γ that defines below by at least one
1Substituent substituting group and Sauerstoffatom replace; R
5Be hydrogen atom or the alkyl that contains 1 to 3 carbon atom; R
6Be: hydrogen atom; The alkyl that contains 1 to 4 carbon atom; R
7Be: the alkyl that contains 1 to 6 carbon atom; Contain 6 to 10 ring carbon atoms and do not replace or be selected from by at least one below the γ that defines
1The isocyclic aryl that substituent substituting group replaced; Perhaps be aralkyl, wherein aryl moiety is to contain the carbocyclic ring of 6 to 10 ring carbon atoms and 1 to 2 carbon atom of moieties;
Or R
6And R
7With the nitrogen-atoms that links to each other with them common thick with become 5 or 6 element heterocycles; Y is that Sauerstoffatom or sulphur atom γ are 1,2 or 3; Q is methylene radical or carbonyl; R
8Be: contain the alkyl of 1 to 4 carbon atom or contain 6 to 10 1 to 2 carbon atoms; Contain the isocyclic aryl of 6 to 10 ring carbon atoms, this aryl does not replace or is selected from γ by at least one
1Substituent substituting group replaces; R
hGroup, R
hBe the heterocyclic radical that contains 3 to 6 annular atomses, wherein have at least a heteroatoms to be selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, this heterocyclic radical is not for replacing or being selected from the γ that defines below by at least one
1Substituent substituting group and Sauerstoffatom replace; R
h-S-group, R
hDefinition as above; The alkanoyl that contains 2 to 5 carbon atoms; Substituting group γ
1Be selected from: halogen atom; Cyano group; Nitro; The alkyl that contains 1 to 4 carbon atom; The alkoxyl group that contains 1 to 4 carbon atom; The carbalkoxy that contains 2 to 5 carbon atoms.
Wherein, particularly preferred formula (I) compound and salt thereof, wherein definition among Z such as top (A) and (A '), R
3As defining R among definition, particularly Z such as top (A) in top (C) and (A ')
3As definition in top (C), and n is definition in top (B).
More preferably formula (2) compound is wherein for The compounds of this invention: (D), R
1Be methyl or ethyl.(E), Z is formula (i) base and R
2It is methyl.(E '), Z are (ii) bases and m is 2 or 4 of formula.(F), R
3Be amino, methylamino-, ethylamino contains the alkoxyl group of 1 to 3 carbon atom, or formula (iii) (v) or (vi) group:
Wherein: R
4It is the alkyl that contains 1 to 4 carbon atom; Contain 1 to 3 carbon atom and be selected from by at least one below the α that defines
2The alkyl that substituting group in the substituting group replaces; Contain the ring carbon atom of 3 to 6 carbon atoms and do not replace or be selected from by at least one below the γ that defines
1The isocyclic aryl that substituent substituting group replaced; Substituents alpha
1Be selected from: halogen atom; Cyano group; The alkoxyl group that contains 1 to 3 carbon atom; The alkylthio that contains 1 to 3 carbon atom; The alkanoyloxy that contains 2 to 5 carbon atoms; The carbalkoxy that contains 2 to 4 carbon atoms; The carbocyclic ring aryloxy that contains 6 to 10 ring carbon atoms; The carbocyclic ring arylthio that contains 6 to 10 ring carbon atoms; The alkanoyl amido that contains 2 to 5 carbon atoms; N-(C
2-C
5Alkanoyl)-N-(C
1-C
3Alkyl) amino; The halogenated alkane amido that contains 2 to 4 carbon atoms; The alkoxycarbonyl amido that contains 2 to 4 carbon atoms; N-(C
2-C
5Carbalkoxy)-N-(C
1-C
3Alkyl) amino; The haloalkoxy carbonylamino that contains 2 to 5 carbon atoms; The isocyclic aryl carbonylamino, wherein aryl moiety contains 6 to 10 ring carbon atoms; Aromatic alkyl carbonyl amino, wherein aryl moiety contains the carbocyclic ring of 6 to 10 ring carbon atoms and moieties contains cycloalkyl; The alkenyl that contains 3 to 4 carbon atoms; The alkynyl that contains 3 to 4 carbon atoms; Contain 6 to 10 ring carbon atoms do not replace or at least by a γ who defines below being selected from
1The isocyclic aryl that substituting group replaced in the substituting group; Or contain the heterocyclic radical of 3 to 6 annular atomses, and wherein have at least a heteroatoms to be selected from nitrogen, oxygen and sulphur atom, this heterocycle does not replace or is selected from the γ that defines below by at least one
1Substituting group in the substituting group, and Sauerstoffatom replaces; γ is 1,2 or 3; Q is methylene radical or carbonyl; Substituents alpha
2Be selected from: halogen atom; Cyano group; Methoxyl group; Oxyethyl group; Methylthio group; Ethylmercapto group; The alkanoyloxy that contains 2 or 3 carbon atoms; The carbalkoxy that contains 2 or 3 carbon atoms; Phenoxy group; Thiophenyl; Amino; The alkanoyl amido that contains 2 to 5 carbon atoms; N-(C
2-C
5Alkanoyl)-N-(C
1-C
3Alkyl) amino; The halogenated alkane amido that contains 2 to 4 carbon atoms; The alkoxycarbonyl amido that contains 2 to 4 carbon atoms; N-(C
2-C
5Carbalkoxy)-N-(C
1-C
3Alkyl) amino; The halo alkoxy carbonyl amino that contains 2 to 5 carbon atoms; The isocyclic aryl carbonylamino, wherein aryl moiety contains 6 to 10 ring carbon atoms; Aromatic alkyl carbonyl amino, wherein aryl moiety is to contain the carbocyclic ring of 6 to 10 ring carbon atoms and moieties contains 1 or 2 carbon atom; Replace or be selected from γ by at least one
2The phenyl that substituent substituting group replaces; R
hGroup, R
hBe the heterocyclic radical that contains 3 to 6 annular atomses, wherein have at least a heteroatoms to be selected from nitrogen, oxygen and sulphur atom, this heterocycle do not replace or are selected from the γ that defines below by at least one
2Substituent substituting group, and Sauerstoffatom replaces; And R
h-S-group, R
hDefinition as above; Substituting group γ
2Be selected from: halogen atom; Cyano group; Nitro; Methyl; Ethyl; Methoxyl group; The carbalkoxy that contains 2 or 3 carbon atoms.
Wherein, special preferred formula (I) compound and salt, wherein R
1As definition in top (D), definition among Z such as top (E) or (E '), R
3As definition in top (F), and R wherein particularly
1As definition in top (D), definition among Z such as top (E) or (E '), R
3Those compounds as definition among definition and n such as top (B) in top (F).
The further preferred compound of the present invention be formula (I) compound wherein: (G), R
1Be ethyl.(H), R
3Be amino, methylamino-, ethylamino, or formula (iii) or (vi) group:
Wherein: R
4Be: the alkyl that contains 1 to 4 carbon atom; Contain 1 to 3 carbon atom and be selected from by at least one below the substituents alpha that defines
3The substituted alkyl that substituting group replaced; 5 or 6 Yuans cycloalkyl; Replace or be selected from the substituting group γ that defines below by at least one
3The phenyl that substituting group replaced; 5 or 6 element heterocycle bases wherein have at least a heteroatoms to be selected from nitrogen, oxygen or sulphur atom, and this heterocycle does not replace or is selected from the substituting group γ that defines below by at least one
3Substituting group replace; γ is 2; Q is methylene radical or carbonyl; Substituents alpha
3Be selected from: halogen atom; Cyano group; Methoxyl group; Oxyethyl group; The alkanoyloxy that contains 2 or 3 carbon atoms; The carbalkoxy that contains 2 or 3 carbon atoms; Phenoxy group; Amino; The alkanoyl amido that contains 2 or 3 carbon atoms; The alkoxycarbonyl amido that contains 2 to 4 carbon atoms; Benzyloxycarbonyl amino; Substituting group γ
2Be selected from: halogen atom; Cyano group; Nitro; Methyl; Ethyl; Methoxyl group; And oxyethyl group;
Wherein, special preferred formula (I) compound and salt, wherein R
1As definition in top (G), definition among Z such as top (E) or (E '), R
3As definition, especially wherein R in top (H)
1As definition in top (G), definition among Z such as top (E) or (E '), R
3Those compounds as definition among definition and n such as top (B) in top (H).
Some example of The compounds of this invention is following formula (I) compound:
Wherein substituting group is defined in the table 1.In table 1, use following abbreviation:
The Ac ethanoyl
The Azt azetidinyl
The Bu butyl
The cBu cyclobutyl
The iBu isobutyl-
The sBu sec-butyl
The tBu tertiary butyl
The Bz benzyl
The Et ethyl
The Fur furyl
The Hx hexyl
The cHx cyclohexyl
The Isox isoxazolyl
The Lac lactam group, promptly 5-γ-Lac is
The Me methyl
The Ph phenyl
The Pip piperidyl
The Pn amyl group
The cPn cyclopentyl
The Pr propyl group
The cPr cyclopropyl
The iPr sec.-propyl
The Pym pyrimidyl
The Pyr pyridyl
The Pyrd pyrrolidyl
The Thdn thiazolidyl
The Thi thienyl
The Thiz thiazolyl
Table 1
| Compound number | R 1 | Z | n | X | R 3 |
| 1 | Et | ＝C(Me) 2 | 1 | C＝0 | 4-NO 2 |
| 2 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NO 2 |
| 3 | Et | ＝C(Me) 2 | 0 | C＝0 | 3-NO 2 |
| 4 | Et | ＝C(Me) 2 | 0 | C＝0 | 2-NO 2 |
| 5 | Et | ＝C(Me) 2 | 1 | C＝0 | 4-NH 2 |
| 6 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NH 2 |
| 7 | Et | ＝C(Me) 2 | 0 | C＝0 | 3-NH 2 |
| 8 | Et | ＝C(Me) 2 | 0 | C＝0 | 2-NH 2 |
| 9 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHMe |
| 10 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHEt |
| 11 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHPr |
| 12 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHBu |
| 13 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NMe 2 |
| 14 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NEt 2 |
| 15 | Et | ＝C(Me) 2 | 1 | C＝0 | 4-MeO |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 16 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-MeO |
| 17 | Et | ＝C(Me) 2 | 0 | C＝0 | 3-MeO |
| 18 | Et | ＝C(Me) 2 | 0 | C＝0 | 2-MeO |
| 19 | Et | ＝C(Mc) 2 | 0 | C＝0 | 4-OEt |
| 20 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-OPr |
| 21 | Et | ＝C(Me) 2 | 0 | C＝0 | 2-OiPr |
| 22 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-OBu |
| 23 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-OiBu |
| 24 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-OCH 2CH 2OCH 3 |
| 25 | Et | ＝C(Me) 2 | 1 | C＝0 | 4-NHAc |
| 26 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHAc |
| 27 | Mc | ＝C(Me) 2 | 0 | C＝0 | 4-NHAc |
| 28 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-N(Me)Ac |
| 29 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-N(Et)Ac |
| 30 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-N(Pr)Ac |
| 31 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-N(Bu)Ac |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 32 | Et | ＝C(Me) 2 | 0 | C＝0 | 3-NHAc |
| 33 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOEt |
| 34 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOPr |
| 35 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOiPr |
| 36 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOBu |
| 37 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOiBu |
| 38 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOtBu |
| 39 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOcPr |
| 40 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOcBu |
| 41 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOcPn |
| 42 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOcHx |
| 43 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2Br |
| 44 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCF 3 |
| 45 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCHF 2 |
| 46 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2CN |
| 47 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2OMe |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 48 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2OEt |
| 49 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2OAc |
| 50 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2OCOPr |
| 51 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2SMe |
| 52 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2SO 2Me |
| 53 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2SPh |
| 54 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2S(2-Pym) |
| 55 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2S(2-Pyr) |
| 56 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2S(2-Thdn) |
| 57 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2CH 2COMe |
| 58 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2CH 2COOMe |
| 59 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH＝CHMe |
| 60 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOC≡CH |
| 61 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2(4-NO 2Ph) |
| 62 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2(4-MeOPh) |
| 63 | Et | ＝C(Me) 2 | 0 | C＝O | 4-NHCOPh |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 64 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(2-FPh) |
| 65 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(3-FPh) |
| 66 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(4-FPh) |
| 67 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(4-ClPh) |
| 68 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(3-ClPh) |
| 69 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(4-MeOPh) |
| 70 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(3-MeOPh) |
| 71 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(3，4-di-MeOPh) |
| 72 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(4-tBuPh) |
| 73 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(4-NO 2Ph) |
| 74 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(3-NO 2Ph) |
| 75 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(3-Pyr) |
| 76 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(4-Pyr) |
| 77 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(2-Fur) |
| 78 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(2-Thi) |
| 79 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2NH 2 |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 80 | Et | ＝C(Me) 2 | 1 | C＝0 | 4-NHCOCH 2NHCOOMe |
| 81 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2NHCOOMe |
| 82 | Et | ＝C(Me) 2 | 0 | C＝0 | 3-NHCOCH 2NHCOOMe |
| 83 | Et | ＝C(Me) 2 | 0 | C＝0 | 2-NHCOCH 2NHCOOMe |
| 84 | Me | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2NHCOOMe |
| 85 | iPr | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2NHCOOMe |
| 86 | sBu | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2NHCOOMe |
| 87 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2NHCOOEt |
| 88 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2NHCOOCH 2CCl 3 |
| 89 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2NHCOOtBu |
| 90 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2NHCOOBz |
| 91 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2NHAc |
| 92 | Me | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2NHAc |
| 93 | Et | ＝C(Me) 2 | 0 | C＝0 | 3-NHCOCH 2NHAc |
| 94 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2NHCOPh |
| 95 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2N(Me)COOMe |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 96 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-N(Me)COCH 2NHCOOMe |
| 97 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH(Me)NHCOOMe |
| 98 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2NHCOEt |
| 99 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH(Me)NHCOOEt |
| 100 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH(Et)NHCOOMe |
| 101 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH(iPr)NHCOOMe |
| 102 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH(iBu)NHCOOMe |
| 103 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH(tBu)NHCOOMe |
| 104 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH(CH 2CH 2SMe)NHCOOMe |
| 105 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH(CH 2SMe)NHCOOMe |
| 106 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH(CH 2SEt)NHCOOMe |
| 107 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOC(Me) 2NHCOOMe |
| 108 | Me | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOC(Me) 2NHCOOMe |
| 109 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2CH 2NH 2 |
| 110 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOCH 2CH 2NHCOOMe |
| 111 | Et | ＝C(Me) 2 | 1 | C＝0 | 4-NHCO(1-COOMe-2-Pyrd) |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 112 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(1-COOMe-2-Pyrd) |
| 113 | Me | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(1-COOMe-2-Pyrd) |
| 114 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(1-COOEt-2-Pyrd) |
| 115 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(1-COOMe-4-Pip) |
| 116 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(3-COOEt-4-Thdn) |
| 117 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(5-γ-Lac) |
| 118 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOC(＝NOMe)(2-NHCOCH 2Cl- 4-Thiz) |
| 119 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOC(＝NOMe)(2-NHCOOMe- 4-Thiz) |
| 120 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOC(＝NOMe)(2-Thi) |
| 121 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOOMe |
| 122 | Me | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOOMe |
| 123 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-N(Me)COOMe |
| 124 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOOEt |
| 125 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOOPr |
| 126 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOOiPr |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 127 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOOBu |
| 128 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOOiBu |
| 129 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOOcPr |
| 130 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOOBz |
| 131 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCOOPh |
| 132 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCONHMe |
| 133 | Me | ＝C(Me) 2 | 0 | C＝0 | 4-NHCONHMe |
| 134 | Et | ＝C(Me) 2 | 0 | C＝0 | 3-NHCONHMe |
| 135 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCONHEt |
| 136 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCONHPr |
| 137 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCONHiPr |
| 138 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCONHBu |
| 139 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCONHtBu |
| 140 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCONHcHx |
| 141 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCONHBz |
| 142 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCONMe 2 |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 143 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCO(1-Pyrd) |
| 144 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCONHPh |
| 145 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCSNHMe |
| 146 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHCSNHEt |
| 147 | Et | ＝C(Me) 2 | 1 | C＝0 | 4-NHSO 2Me |
| 148 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHSO 2Me |
| 149 | Me | ＝C(Me) 2 | 0 | C＝0 | 4-NHSO 2Me |
| 150 | Et | ＝C(Me) 2 | 0 | C＝0 | 3-NHSO 2Me |
| 151 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-N(Me)SO 2Me |
| 152 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-N(Et)SO 2Me |
| 153 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-N(Pr)SO 2Me |
| 154 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-N(Bu)SO 2Me |
| 155 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHSO 2Et |
| 156 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHSO 2Pr |
| 157 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHSO 2Bu |
| 158 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHSO 2Ph |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 159 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NHSO 2(4-MePh) |
| 160 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-(2-oxo-1-Azt) |
| 161 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-(2-oxo-1-Pip) |
| 162 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-(2，6-dioxo-1-Pip) |
| 163 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-(2-oxo-1-Pyrd) |
| 164 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-(2, the 5-dioxy-1-Pyrd) |
| 165 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-(2-oxa--1,3-oxazoline) |
| 166 | Et | ＝C(CH 2) 4 | 1 | C＝0 | 4-NO 2 |
| 167 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NO 2 |
| 168 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 3-NO 2 |
| 169 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 2-NO 2 |
| 170 | Et | ＝C(CH 2) 4 | 1 | C＝0 | 4-NH 2 |
| 17l | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NH 2 |
| 172 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 3-NH 2 |
| 173 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 2-NH 2 |
| 174 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHMe |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 175 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHEt |
| 176 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHPr |
| 177 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHBu |
| 178 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NMe 2 |
| 179 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHt 2 |
| 180 | Et | ＝C(CH 2) 4 | 1 | C＝0 | 4-MeO |
| 181 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-MeO |
| 182 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 3-MeO |
| 183 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 2-MeO |
| 184 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-OEt |
| 185 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-OPr |
| 186 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 2-OiPr |
| 187 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-OBu |
| 188 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-OiBu |
| 189 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-OCH 2CH 2OCH 3 |
| 190 | Et | ＝C(CH 2) 4 | 1 | C＝0 | 4-NHAc |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 191 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHAc |
| 192 | Me | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHAc |
| 193 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-N(Me)Ac |
| 194 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-N(Et)Ac |
| 195 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-N(Pr)Ac |
| 196 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-N(Bu)Ac |
| 197 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 3-NHAc |
| 198 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOEt |
| 199 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOPr |
| 200 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOiPr |
| 201 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOBu |
| 202 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOiBu |
| 203 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-HCOtBu |
| 204 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOcPr |
| 205 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOcBu |
| 206 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOcPn |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 207 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOcHx |
| 208 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2Br |
| 209 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCF 3 |
| 210 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCHF 2 |
| 211 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2CN |
| 212 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2OMe |
| 213 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2OEt |
| 214 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2OAc |
| 215 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2OCOPr |
| 216 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2SMe |
| 217 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2SO 2Ph |
| 218 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2SPh |
| 219 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2S(2-Pym) |
| 220 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2S(2-Pyr) |
| 221 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2S(2-Thdn) |
| 222 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2CH 2COMe |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 223 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2CH 2COOMe |
| 224 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH＝CHMe |
| 225 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOC＝CH |
| 226 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2Ph |
| 227 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2(4-NO 2Ph) |
| 228 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOPh |
| 229 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(2-FPh) |
| 230 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(3-FPh) |
| 231 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(4-FPh) |
| 232 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(4-ClPt) |
| 233 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(3-ClPh) |
| 234 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(4-MeOPh) |
| 235 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(3-MeOPh) |
| 236 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(3，4-di-MeOPh) |
| 237 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(4-rBuPh) |
| 238 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(4-NO 2Ph) |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 239 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(3-NO 2Ph) |
| 240 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(3-Pyr) |
| 241 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(4-Pyr) |
| 242 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(2-Fur) |
| 243 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(2-Thi) |
| 244 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2NH 2 |
| 245 | Et | ＝C(CH 2) 4 | 1 | C＝0 | 4-NHCOCH 2NHCOOMe |
| 246 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2NHCOOMe |
| 247 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 3-NHCOCH 2NHCOOMe |
| 248 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 2-NHCOCH 2NHCOOMe |
| 249 | Me | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2NHCOOMe |
| 250 | iPr | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2NHCOOMe |
| 251 | sBu | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2NHCOOMe |
| 252 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2NHCOOEt |
| 253 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2NHCOOCH 2CCl 3 |
| 254 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2NHCOOtBu |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 255 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2NHCOOBz |
| 256 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2NHAc |
| 257 | Me | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2NHAc |
| 258 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 3-NHCOCH 2NHAc |
| 259 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2NHCOPh |
| 260 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2N(Me)COOMe |
| 261 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-N(Me)COCH 2NHCOOMe |
| 262 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH(Me)NHCOOMe |
| 263 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2NHCOEt |
| 264 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH(Me)NHCOOEt |
| 265 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH(Et)NHCOOMe |
| 266 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH(iPr)NHCOOMe |
| 267 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH(iBu)NHCOOMe |
| 268 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH(tBu)NHCOOMe |
| 269 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH(CH 2CH 2SMe)NHCOOMe |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 270 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH(CH 2SMe)NHCOOMe |
| 271 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH(CH 2SEt)NHCOOMe |
| 272 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOC(Me) 2NHCOOMe |
| 273 | Me | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOC(Me) 2NHCOOMe |
| 274 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2CH 2NH 2 |
| 275 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOCH 2CH 2NHCOOMe |
| 276 | Et | ＝C(CH 2) 4 | 1 | C＝0 | 4-NHCO(1-COOMe-2-Pyrd) |
| 277 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(1-COOMe-2-Pyrd) |
| 278 | Me | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(1-COOMe-2-Pyrd) |
| 279 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(1-COOEt-2-Pyrd) |
| 280 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(1-COOMe-4-Pip) |
| 281 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(3-COOEt-4-Thdn) |
| 282 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(5-γ-Lac) |
| 283 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOC(＝NOMe)(2-NHCOCH 2Cl- 4-Thiz) |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 284 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOC(＝NOMe)(2-NHCOOMe- 4-Thiz) |
| 285 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOC(＝NOMe)(2-Thi) |
| 286 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOOMe |
| 287 | Me | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOOMe |
| 288 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 3-NHCOOMe |
| 289 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOOEt |
| 290 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOOPr |
| 291 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOOiPr |
| 292 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOOBu |
| 293 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOOiBu |
| 294 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOOcPr |
| 295 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOOBz |
| 296 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCOOPh |
| 297 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCONHMe |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 | |
| 298 | Me | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCONHMe | |
| 299 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 3-NHCONHMe | |
| 300 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCONHEt | |
| 301 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCONHPr | |
| 302 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCONHiPr | |
| 303 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCONHBu | |
| 304 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCONHiBu | |
| 305 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCONHcHx | |
| 306 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCONHBz | |
| 307 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCONMe 2 | |
| 308 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCO(1-Pyrd) | |
| 309 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCONHPh | |
| 310 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCSNHMe | |
| 311 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHCSNHEt | |
| 312 | Et | ＝C(CH 2) 4 | 1 | C＝0 | 4-NHSO 2Me | |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 313 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHSO 2Me |
| 314 | Me | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHSO 2Me |
| 315 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 3-NHSO 2Me |
| 316 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-N(Me)SO 2Me |
| 317 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-N(Et)SO 2Me |
| 318 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-N(Pr)SO 2Me |
| 319 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-N(Bu)SO 2Me |
| 320 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHSO 2Et |
| 321 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHSO 2Pr |
| 322 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHSO 2Bu |
| 323 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHSO 2Ph |
| 324 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-NHSO 2(4-MePh) |
| 325 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-(2-oxo-1-Azt) |
| 326 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-(2-oxo-1-Pip) |
| 327 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-(2，6-dioxo-1-Pip) |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 328 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-(2-oxygen-1-Pyrd) |
| 329 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-(2, the 5-dioxy-1-Pyrd) |
| 330 | Et | ＝C(CH 2) 4 | 0 | C＝0 | 4-(2-oxa--1, the 3-oxazoline-3-yl) |
| 331 | Et | ＝C(Me) 2 | 0 | C＝0 | 4-NO 2 |
| 332 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NH 2 |
| 333 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHMe |
| 334 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NMe 2 |
| 335 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-MeO |
| 336 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHAc |
| 337 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-N(Me)Ac |
| 338 | Et | ＝C(Et) 2 | 0 | C＝0 | 3-NHAc |
| 339 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOEt |
| 340 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOPr |
| 341 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOiPr |
| 342 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOBu |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 343 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOcPr |
| 344 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOcBu |
| 345 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOcHx |
| 346 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOCF 3 |
| 347 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOCH 2CN |
| 348 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOCH 2OMe |
| 349 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOCH 2OEt |
| 350 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOCH 2OAc |
| 351 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOCH 2SMe |
| 352 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOPh |
| 353 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCO(2-FPh) |
| 354 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCO(3-FPh) |
| 355 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCO(4-FPh) |
| 356 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCO(4-ClPh) |
| 357 | Et | ＝C(Et) 2 | 0 | C＝0 | (3,4-two-MeOPh) for 4-NHCO |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 358 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCO(3-Pyr) |
| 359 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCO(4-Pyr) |
| 360 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCO(2-Fur) |
| 361 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCO(2-Thi) |
| 362 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOCH 2NHCOOMe |
| 363 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOCH 2NHAc |
| 364 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-N(Me)COCH 2NHCOOMe |
| 365 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOCH 2N(Me)Ac |
| 366 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOC(Me) 2NHCOOMe |
| 367 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOCH 2CH 2NHCOOMe |
| 368 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCO(1-COOMe-2-Pyrd) |
| 369 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOOMe |
| 370 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOOEt |
| 371 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCOOiBu |
| 372 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCONHMe |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 373 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCONHEt |
| 374 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCONHPr |
| 375 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCONHBu |
| 376 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCONHtBu |
| 377 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCONHcHx |
| 378 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCONHPh |
| 379 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHCSNHMe |
| 380 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHSO 2Me |
| 381 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-N(Me)SO 2Me |
| 382 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-NHSO 2(4-MePh) |
| 383 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-(2-oxygen-1-Azt) |
| 384 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-(2-oxygen-1-Pip) |
| 385 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-(2-oxygen-1-Pyrd) |
| 386 | Et | ＝C(Et) 2 | 0 | C＝0 | 4-(2-oxa--1, the 3-oxazoline-3-yl) |
| 387 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NO 2 |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 388 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NH 2 |
| 389 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHMe |
| 390 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NMe 2 |
| 391 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-MeO |
| 392 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHAc |
| 393 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-N(Me)Ac |
| 394 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOEt |
| 395 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOPr |
| 396 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOtBu |
| 397 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOcPr |
| 398 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOcBu |
| 399 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOcHx |
| 400 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOCF 3 |
| 401 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOCH 2CN |
| 402 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOCH 2Br |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 403 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOCH 2OEt |
| 404 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOCH 2OAc |
| 405 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOCH 2SMe |
| 406 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOCH 2S(2-Pym) |
| 407 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOCH 2S(2-Pyr) |
| 408 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOCH 2S(2-Thdn) |
| 409 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOCH＝CHMe |
| 410 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOPh |
| 411 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCO(2-FPh) |
| 412 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCO(3-FPh) |
| 413 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCO(4-FPh) |
| 414 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCO(4-MeOPh) |
| 415 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCO(3，4-di-MeOPh) |
| 416 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCO(4-NO 2Ph) |
| 417 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCO(4-iBuPh) |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 418 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCO(3-Pyr) |
| 419 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCO(4-Pyr) |
| 420 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCO(2-Fur) |
| 421 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCO(2-Thi) |
| 422 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOCH 2NHCOOMe |
| 423 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOCH 2NHAc |
| 424 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-N(Me)COCH 2NHCOOMe |
| 425 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOCH 2N(Me)Ac |
| 426 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOC(Me) 2NHCOOMe |
| 427 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOCH 2CH 2NHCOOMe |
| 428 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCO(1-COOMe-2-Pyrd) |
| 429 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOOMe |
| 430 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOOEt |
| 431 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCOOiBu |
| 432 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCONHMe |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 433 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCONHEt |
| 434 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCONHPr |
| 435 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCONHBu |
| 436 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCONHcHx |
| 437 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCO(1-Pyrd) |
| 438 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCONHPh |
| 439 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHCSNHMe |
| 440 | Et | ＝C(CH 2) 2 | 1 | C＝0 | 4-NHSO 2Me |
| 441 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHSO 2Me |
| 442 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-N(Me)SO 2Me |
| 443 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-N(Bu)SO 2Me |
| 444 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-NHSO 2(4-MePh) |
| 445 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-(2-oxygen-1-Azt) |
| 446 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-(2-oxygen-1-Pip) |
| 447 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-(2, the 6-dioxy-1-Pip) |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 448 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-(2-oxygen-1-Pyrd) |
| 449 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-(2, the 5-dioxy-1-Pyrd) |
| 450 | Et | ＝C(CH 2) 2 | 0 | C＝0 | 4-(2-oxa--1, the 3-oxazoline-3-y1) |
| 451 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NO 2 |
| 452 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NH 2 |
| 453 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHMe |
| 454 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NMe 2 |
| 455 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-MeO |
| 456 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-OEt |
| 457 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHAc |
| 458 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-N(Me)Ac |
| 459 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOEt |
| 460 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOPr |
| 461 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOBu |
| 462 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOtBu |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 463 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOcBu |
| 464 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOcHx |
| 465 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOCF 3 |
| 466 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOCH 2CN |
| 467 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOCH 2OMe |
| 468 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOCH 2OEt |
| 469 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOCH 2OAc |
| 470 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOCH 2SMe |
| 471 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOCH＝CHMe |
| 472 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOPh |
| 473 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCO(2-FPh) |
| 474 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCO(3-FPh) |
| 475 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCO(4-FPh) |
| 476 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCO(4-MeOPh) |
| 477 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCO(4-ClPh) |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 478 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCO(4-NO 2Ph) |
| 479 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCO(4-tBuPh) |
| 480 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCO(3-Pyr) |
| 481 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCO(4-Pyr) |
| 482 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCO(2-Fur) |
| 483 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCO(2-Thi) |
| 484 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOCH 2NHCOOMe |
| 485 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOCH 2NHAc |
| 486 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-N(Me)COCH 2NHCOOMe |
| 487 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOCH 2N(Me)Ac |
| 488 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOC(Me) 2NHCOOMe |
| 489 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOCH 2CH 2NHCOOMe |
| 490 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCO(1-COOMe-2-Pyrd) |
| 491 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOOMe |
| 492 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOOEt |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 493 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCOOiBu |
| 494 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCONHMe |
| 495 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCONHEt |
| 496 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCONHPr |
| 497 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCONHBu |
| 498 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCONHcHx |
| 499 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCO(1-Pyrd) |
| 500 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCONHPh |
| 501 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHCSNHMe |
| 502 | Et | ＝C(CH 2) 3 | 1 | C＝0 | 4-NHSO 2Me |
| 503 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHSO 2Me |
| 504 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-N(Me)SO 2Me |
| 505 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-N(Bu)SO 2Me |
| 506 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-NHSO 2(4-MePh) |
| 507 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-(2-oxo-1-Azt) |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 508 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-(the 2-oxa--1-Pip) |
| 509 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-(2, the 6-dioxy-1-Pip) |
| 510 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-(the 2-oxa--1-Pyrd) |
| 511 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-(2, the 5-dioxy-1-Pyrd) |
| 512 | Et | ＝C(CH 2) 3 | 0 | C＝0 | 4-(2-oxa--1,3-oxazoline-3-yl |
| 513 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NO 2 |
| 514 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NH 2 |
| 515 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHMe |
| 516 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NMe 2 |
| 517 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-MeO |
| 518 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-OEt |
| 519 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHAc |
| 520 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-N(Me)Ac |
| 521 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOEt |
| 522 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOPr |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 523 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOcPr |
| 524 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOcBu |
| 525 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOcPn |
| 526 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOCF 3 |
| 527 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOCH 2CN |
| 528 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOCH 2OMe |
| 529 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOCH 2OEt |
| 530 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOCH 2OAc |
| 531 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOCH 2OCOPr |
| 532 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOCH 2SMe |
| 533 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOCH＝CHMe |
| 534 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOPh |
| 535 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCO(2-FPh) |
| 536 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCO(3-FPh) |
| 537 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCO(4-FPh) |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 538 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCO(4-MeOPh) |
| 539 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCO(3-MeOPh) |
| 540 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCO(3，4-di-MeOPh) |
| 541 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCO(4-NO 2Ph) |
| 542 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCO(3-NO 2Ph) |
| 543 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCO(3-Pyr) |
| 544 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCO(4-Pyr) |
| 545 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCO(2-Fyr) |
| 546 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCO(2-Thi) |
| 547 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOCH 2NHCOOMe |
| 548 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOCH 2NHAc |
| 549 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-N(Me)COCH 2NHCOOMe |
| 550 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOCH 2N(Me)COOMe |
| 551 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOC(Me) 2NHCOOMe |
| 552 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOCH 2CH 2NHCOOMe |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 553 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCO(1-COOMe-2-Pyrd) |
| 554 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOOMe |
| 555 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOOEt |
| 556 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOOiBu |
| 557 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCOOPh |
| 557 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCONHMe |
| 559 | Et | ＝C(Me) 2 | 0 | CH 2 | 3-NHCONHMe |
| 560 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCONHcHx |
| 561 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCO(1-Pyrd) |
| 562 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCONHPh |
| 563 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHCSNHMe |
| 564 | Et | ＝C(Me) 2 | 1 | CH 2 | 4-NHSO 2Me |
| 565 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHSO 2Me |
| 566 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-N(Me)SO 2Me |
| 567 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-N(Bu)SO 2Me |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 568 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-NHSO 2(4-MePh) |
| 569 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-(the 2-oxa--1-Azt) |
| 570 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-(the 2-oxa--1-Pip) |
| 571 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-(2, the 6-dioxy-1-Pip) |
| 572 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-(the 2-oxa--1-Pyrd) |
| 573 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-(2, the 5-dioxy-1-Pyrd) |
| 574 | Et | ＝C(Me) 2 | 0 | CH 2 | 4-(2-oxa--1, the 3-oxazoline-3-yl) |
| 575 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-NO 2 |
| 576 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-NH 2 |
| 577 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-NHMe |
| 578 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-MeO |
| 579 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-NHAc |
| 580 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-N(Me)Ac |
| 581 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-NHCOEt |
| 582 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-NHCOCF 3 |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 | |
| 583 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-NHCOCH 2CN | |
| 584 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-NHCOCH 2OMe | |
| 585 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-NHCOCH 2OAc | |
| 586 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-NHCO(4-FPh) | |
| 587 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-NHCOCH 2NHCOOMe | |
| 588 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-NHCO(1-COOMe-2-Pyrd) | |
| 589 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-NHCOOMe | |
| 590 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-NHCONHMe | |
| 591 | Et | ＝C(CH 2) 2 | 0 | CH 2 | 4-NHSO 2Me | |
| 592 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-NO 2 | |
| 593 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-NH 2 | |
| 594 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-NHMe | |
| 595 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-MeO | |
| 596 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-NHAc | |
| 597 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-N(Me)Ac | |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 598 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-NHCOEt |
| 599 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-NHCOCF 3 |
| 600 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-NHCOCH 2CN |
| 601 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-NHCOCH 2OMe |
| 602 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-NHCOCH 2OAc |
| 603 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-NHCO(4-FPh) |
| 604 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-NHCOCH 2NHCOOMe |
| 605 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-NHCO(1-COOMe-2-Pyrd) |
| 606 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-NHCOOMe |
| 607 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-NHCONHMe |
| 608 | Et | ＝C(CH 2) 3 | 0 | CH 2 | 4-NHSO 2Me |
| 609 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-NO 2 |
| 610 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-NH 2 |
| 611 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-NHMe |
| 612 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-MeO |
Table 1 (continuing)
| Compound number | R 1 | Z | n | X | R 3 |
| 613 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-NHAc |
| 614 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-N(Me)Ac |
| 615 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-NHCOEt |
| 616 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-NHCOCF 3 |
| 617 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-NHCOCH 2CN |
| 618 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-NHCOCH 2OMe |
| 619 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-NHCOCH 2OAc |
| 620 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-NHCO(4-FPh) |
| 621 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-NHCOCH 2NHCOOMe |
| 622 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-NHCO(1-COOMe-2-Pyrd) |
| 623 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-NHCOOMe |
| 624 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-NHCONHMe |
| 625 | Et | ＝C(CH 2) 4 | 0 | CH 2 | 4-NHSO 2Me |
| 626 | Et | ＝C(CH 2) 4 | 0 | C＝O | 4-NHCOCH 2(3-OH-4-Isox) |
| 627 | Et | ＝C(Me) 2 | 0 | C＝O | 4-NHCOCH 2(3-OH-4-Isox) |
In above-mentioned listed compound, preferred compound is as follows, and promptly its compound number is:
9，16，26，28，33，34，35，36，37，38，39，40，41，42，43，44，
46，47，48，49，51，63，64，65，66，69，74，75，76，77，78，81，89，91，95，96，107，
110，112，121，132，138，139，140，144，145，148，151，160，161，164，165，171，
174，181，191，193，198，199，200，201，202，205，209，211，212，213，214，218，
228，229，230，231，234，240，241，242，243，246，256，272，277，286，289，297，
309，310，313，316，320，325，326，329，330，332，333，335，336，337，339，346，
347，348，349，350，351，352，353，354，355，362，363，366，367，369，372，380，
381，392，399，429，431，452，453，455，457，458，461，465，466，467，468，469，
470，472，473，474，475，476，484，485，488，489，490，491，494，500，501，503，
504，547，548，551，552，and 553.
Preferred compound is as follows, and promptly its compound number is: 9,26,42,46,63,64,65,91,96,121,144,165,171,191,209,213,214,313,320,336,457,547,548 and 553.
Most preferred is: 46.13-[2-(4-cyano group acetylamino phenyl)-2-methyl-prop acyloxy]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R ｀ 4NHCOCH
2CN, n=0]; (91.13-{2-[4-N-ethanoyl glycyl) aminophenyl]-2-methyl-prop acyloxy }-5-oximido-milbemycin A
4{ (I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOCH
2NHAc, n=0]; (96.13-{2-[4-N-methoxycarbonyl glycyl) methylamino phenyl]-2-methyl-prop acyloxy }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Mc)
2, R ' 4N (Mc) COCH
2NHCOOMe, n=0]; (121.13-[2-4-methoxycarbonyl aminophenyl)-2-methyl-prop acyloxy]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOOMe, n=0]; (144.13-{2-[4-N-phenyl amino formyl radical amino) phenyl]-2-methyl-prop acyloxy }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＜C (Me)
2, R
3=4-NHCOCHPh, n=0]; (165.13-{2-[4-2-oxa-azoles quinoline-3-yl) phenyl]-2-methyl-prop acyloxy }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＜C (Me)
2, R
3=4-(2-oxa-1,3-azoles quinoline-3-base, n=0]; (171.13-[1-4-aminophenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NH
2, n=0]; (191.13-[1-4-acetylamino phenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHAc, n=0]; (214.13-[1-4-acetoxyl group acetylamino phenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOCH
2Ac, n=0]; (313.13-[1-4-methanesulfonamido phenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHSO
2Me, n=0]; (336.13-[1-4-acetylamino phenyl)-1-ethyl butyryl acyloxy]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Et)
2, R
3=4-NHAc, n=0]; And 457.13-[1-(4-acetylamino phenyl) tetramethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
3, R
3=4-NHAc, n=0];
The compounds of this invention can prepare with the currently known methods of conventional this compounds of preparation, and is for example, as described below.For example, The compounds of this invention can be by following reaction process A and B preparation.Reaction process A:
Reaction process B:
In above-mentioned formula: R
1, X, the Me of Z as above defines; R
3aRepresent the R of arbitrary definition
3Group is except amino amino or that replace; Formula (Ia) compound is included in formula (I) compound, but has radicals R on its phenyl ring
3aRather than radicals R
3Formula (Ia ') compound is included in formula (I) compound, but nitro rather than radicals R are arranged on its phenyl ring
3Formula (Ib) compound is included in formula (I) compound, but amino rather than radicals R are arranged on its phenyl ring
3R
3cRepresentative is included in R
3The amino of the replacement in the definition; Formula (Ic) compound is included in formula (I) compound, but on its phenyl ring radicals R is arranged
3cRather than R
3
Formula (III) 15-hydroxyl milbemycin derivatives as starting raw material is disclosed known compound in the method, for example, openly applies among clear-60-18191 at Japanese Patent.Steps A 1
In this step, preparation through type (III) compound of formula (IV) compound and the carboxylic acid or the alcohol of formula V:
In the presence of organic acid such as trifluoromethanesulfonic acid, react.
Organic acid such as trifluoromethanesulfonic acid be as catalyzer, the no more than in principle catalytic amount of its consumption.Yet aequum can change in wide region according to the reactive behavior of used formula V carboxylic acid or alcohol.Usually, the consumption of trifluoromethanesulfonic acid is the no more than mole that waits with respect to the formula V compound.
In some cases, adding powdered inorganic compound may accelerated reaction in the reaction mixture.Example with suitable mineral compound of this character comprises metal-salt, as copper trifluoromethanesulfcomposite, and cuprous iodide, Tin tetraiodide, cobaltous iodide or nickelous iodide; Celite (mark merchant) flocculating aids; Silica gel or aluminum oxide.Wherein, preferred mantoquita is as copper trifluoromethanesulfcomposite or cuprous iodide, most preferably cuprous iodide.
This reaction usually and preferably carry out in the presence of solvent.Character for solvent for use has no particular limits, as long as this solvent does not have disadvantageous effect and at least to a certain extent can solubilising reagent to reaction or reagent.The The suitable solvent example comprises aromatic hydrocarbon, as benzene, and toluene or dimethylbenzene; Halohydrocarbon, as methylene dichloride, 1,2-ethylene dichloride or chloroform; Ester is as ethyl acetate or propyl acetate; Ether, as ether, tetrahydrofuran (THF), dioxan or glycol dimethyl ether; Acid amides, as dimethyl formamide, N,N-DIMETHYLACETAMIDE or HMPA; Sulfoxide is as methyl-sulphoxide; And nitrile, as acetonitrile.
This reaction can be carried out in wide temperature range, the unqualified accurate temperature of reaction of the present invention.Preferable reaction temperature will depend on all multifactor as solvent, the character of starting raw material or agents useful for same.Yet usually, we find ℃-100 ℃ preferred 0 ℃-50 ℃ can to carry out this reaction easily in temperature-10.The required reaction times also can change in wide scope, and this depends on the characteristic of many factors, particularly temperature of reaction and agents useful for same and solvent.Yet above being reflected at, summarize when carrying out under the optimum condition, reacted 5 minutes to 6 hours, more preferably 10 minutes to 2 hours just enough.Steps A 2
In this step, preparation through type (IV) compound of formula (Ia) compound and azanol or its reactant salt make that carbonyl is converted into oximido on the 5-position.
In this reaction, can use various hydroxylammonium salt.The example of operable this salt comprises salt example hydrochloric acid salt or the vitriol that forms with mineral acid; Salt such as acetate or oxalate with organic acid formation.Wherein, preferably salt hydrochlorate.
This reaction usually and preferably carry out in the presence of solvent.The present invention has no particular limits the character of solvent for use, as long as reaction or agents useful for same are not had disadvantageous effect and solubilized reagent at least to a certain extent.The example of suitable solvent comprises: any and miscible lower alcohol of water, and as methyl alcohol, acetate or propyl alcohol; Or the mixture of ether, as tetrahydrofuran (THF) Huo diox and water.
This reaction can be carried out in wide temperature range, the unqualified accurate temperature of reaction of the present invention.Preferable reaction temperature will depend on all multifactor as solvent, the character of used starting raw material or reagent.Yet usually, temperature can be reacted between 0 ℃-50 ℃ easily.The required reaction times also can change in wide region, and this depends on the character of many factors, particularly temperature of reaction and agents useful for same and solvent.Yet, carry out if be reflected under the top generalized optimum condition, react 1 hour to 10 hours just enough.Step B1
Before step B1, compound (Ia
1) in hydroxylamino protected by acid stable protecting group such as t-butyldimethylsilyl.The available ordinary method of the introducing of protecting group is carried out, for example, and at " Protective Group in Organic Systhesis ", Znd, edition, T.W.Green﹠amp; P.G.M.Wut; John Wiley and Sons Inc., New York (1991), described in method, the document is hereby incorporated by reference.
At step B1, contain the preparation through type (Ia of amino formula (Ib) compound
1) compound [i.e. R wherein
3aRepresent formula (Ia) compound of nitro] in the reduction of nitro.
The available ordinary method of the reduction of nitro is advanced.The example noble metal catalyst of suitable method of reducing, as palladium-charcoal, the catalytic reduction of palladium-barium sulfate or platinum oxide.
This reaction usually and preferably carry out in the presence of solvent.The present invention has no particular limits the character of solvent for use, as long as it does not have disadvantageous effect to reaction or agents useful for same, and at least to a certain extent can solubilising reagent.The example of The suitable solvent comprises: alcohol, as methyl alcohol or ethanol; Ether is as tetrahydrofuran (THF) or dioxan; And ester, as ethyl acetate.
This reaction can be carried out in wide temperature range, the accurate without limits temperature of reaction of the present invention.Preferable reaction temperature will depend on all multifactor as solvent, the character of used starting raw material or reagent.Yet usually, we find that temperature can react easily from 10 ℃ to 80 ℃.The required reaction times also can change in wide region, and this depends on the character of many factors, particularly temperature of reaction and agents useful for same and solvent.Yet, when above being reflected at, carrying out under the generalized optimum condition, react 10 minutes to 5 hours just enough.
Another preferred method of reducing is with the reduction of zinc powder in acetic acid solvent.
This reaction can carried out in the wide temperature range very much, the accurate without limits temperature of reaction of the present invention.Preferable reaction temperature will depend on all multifactor as solvent, the character of used starting raw material or reagent.Yet usually, we find can to react easily in 0 ℃ of temperature to room temperature.The required reaction times also can be depended on the character of many factors, particularly temperature of reaction and agents useful for same and solvent changing this in wide region.Yet, carry out if be reflected under the above-mentioned summary optimum condition, react 30 minutes to 12 hours just enough.
Preferred method of reducing is with the reduction of sodium borohydride in the presence of nickel catalyzator.Suitable nickel catalyzator comprises: nickel salt, as nickelous chloride or nickelous bromide; The triphenyl phosphine mixture of these nickel salts.The triphenyl phosphine mixture is preferred.
Reaction usually and preferably advance in the presence of solvent.Character to solvent for use has no particular limits, as long as it does not have disadvantageous effect to reaction or agents useful for same, and at least to a certain extent can solubilising reagent.The example of suitable solvent comprises: alcohol, as methyl alcohol or ethanol; Ether such as tetrahydrofuran (THF) or dioxan.
This reaction can be carried out in wide temperature range, the unqualified accurate temperature of reaction of the present invention.Preferable reaction temperature will depend on all multifactor as solvent, the character of used starting raw material and reagent.Yet usually, we find can to react easily in 0 ℃ of temperature to room temperature.The required reaction times also can change in wide scope, and this depends on the character of many factors, particularly temperature of reaction and agents useful for same and solvent.Yet, carry out if be reflected under the top generalized optimum condition, react 10 minutes to 120 minutes just enough.Step B2
In this step, contain amino and acid or its reactive derivative or isocyanate or isothiocyanic acid reactant salt in the preparation through type (Ib) of formula (Ic) compound of substituted-amino (ANH) with formula A-OH (A is as giving a definition).
A represents the following formula group:
R
4-CO- (x)
R
6R
7N-C(＝Y)-(R
6≠H) (xi)
R
8SO
2- (xii)
R
9OC(＝O)- (xiii)
R
10C(＝NOR
11)C(＝0)- (xiv)
Above-mentioned isocyanate and isothiocyanic acid are following formula:
R
7N＝C＝Y (xv)
In the following formula, R
4, R
6, R
7, R
8, R
9, R
10, R
11And the Y definition as above.
Here without limits, the reactive derivative of used acid all can here use usually and in this class condensation reaction to the character of the reactive derivative of used acid.The example of the reactive derivative of this acid comprises: carboxylic acid halides, as acyl chlorides or acylbromide; Acid anhydrides, mixed acid anhydride, active ester or active amide.
When the formula of use A-OH acid itself, should use dewatering agent, as dicyclohexyl carbodiimide (DCC), 2-chloro-1-methyl iodate pyridine, right-toluenesulphonic acids or sulfuric acid, preferred 2-chloro-1-methyl iodate pyridine.The preferred every equimolar acid of the consumption of dewatering agent (A-OH) is used the 1-5 mole, more preferably the 1-2 mole.
This reaction usually and preferably carry out in the presence of solvent.Character to solvent for use has no particular limits, as long as it does not have disadvantageous effect to reaction and agents useful for same, and at least to a certain extent can solubilising reagent.The example of suitable solvent comprises: hydrocarbon, and as hexane, sherwood oil, benzene or toluene; Halohydrocarbon, as chloroform, methylene dichloride or 1,2-ethylene dichloride; Acid amides, as dimethyl formamide, sulfoxide is as methyl-sulphoxide; Nitrile is as acetonitrile; Or its two or more mixtures; More preferably methylene dichloride or 1, the 2-ethylene dichloride.
This reaction can be carried out in wide temperature range, the accurate without limits temperature of reaction of the present invention.Preferable reaction temperature will depend on all multifactor as solvent for use, the character of starting raw material or reagent.Yet usually, we find that in temperature-70 ℃ to 90 ℃, preferred 0 ℃ to 60 ℃ can be reacted easily.The required reaction times also can change in wide region, and this depends on the character of many factors, particularly temperature of reaction and agents useful for same and solvent.Yet, carry out if this is reflected under the top generalized optimum condition, reacted 15 minutes to 24 hours, more preferably 30 minutes to 6 hours just enough.
When the formula of use A-OH carboxylic acid halides, this reaction is preferably carried out in the presence of alkali.Character to used alkali has no particular limits.Any alkali that is generally used in this class reaction here all can use.The example of this alkali comprises: organic bases, and as triethylamine, xylidine, pyridine, 4-Dimethylamino pyridine, 1,5-diazabicyclo ([4.3.0] nonene (DBN) and 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU).
The consumption of the carboxylic acid halides of formula A-OH is preferably every mole of formula (Ib) compound 1-10 mole, and the consumption of alkali is preferably every mole of formula (Ib) compound 2-8 mole.
Preferred solvent is identical when using corresponding carboxylic acid.
This reaction can be carried out in wide temperature range, the unqualified accurate temperature of reaction of the present invention.Preferable reaction temperature will depend on all multifactor and solvent for use, the character of starting raw material or reagent.Yet usually, we find can react easily for 0 ℃ to 50 ℃ in temperature.The required reaction times also can change in wide region, and this depends on many factors, particularly temperature of reaction and agents useful for same and solvent.Yet, usually, carry out if be reflected under the above-mentioned generalized optimum condition, react 5 minutes to 2 hours just enough.
When using isocyanate and isothiocyanate, reaction should be carried out in solvent.Preferred solvent is identical during with above-mentioned use carboxylic acid.Reaction conditions is for example temperature of reaction and reaction times, identical during also with above-mentioned use carboxylic acid.
R
3The representative formula (v) or formula (compound vi) can make under the condition of not using formula A-OH compound or isocyanate or different sulfuric acid cyanate.
If oximido is protected by silyl, can remove protecting group by in solvent, handling in the step in the end so with acid.
Character to used acid catalyst has no particular limits, and any acid catalyst that is generally used in this class reaction all can here use.The example of this acid catalyst comprises: hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, methylsulfonic acid or toluenesulphonic acids.
This reaction can be carried out in wide temperature range.Preferable reaction temperature will depend on all multifactor as solvent for use, the character of starting raw material or reagent.Yet usually, we find that in temperature-100 ℃ to 100 ℃, more preferably 0 ℃ to 50 ℃ can be reacted easily.The required reaction times also can change in wide scope, and this depends on the character of many factors, particularly temperature of reaction and agents useful for same and solvent.Yet, carry out if this is reflected under the top generalized optimum condition, reacted 5 minutes to 6 hours, more preferably 10 minutes to 2 hours just enough.
This reaction usually and preferably carry out in the presence of solvent.Character to solvent for use has no particular limits, as long as reaction or agents useful for same are not had disadvantageous effect, and at least to a certain extent can solubilising reagent.The example of suitable solvent comprises: any and miscible lower alcohol of water, and as methyl alcohol, ethanol or propyl alcohol; Or the mixture of ether, as tetrahydrofuran (THF) Huo diox and water.
Be used for synthesis type (III) compound starting raw material milbemycin and similarly natural product is obtained as mixture with the various ratios of related compound usually, they can be used to reaction or be formed in the above-mentioned reaction with mixture (no matter being the natural mixture or the mixture of synthetic) after being separated into various flow points.Therefore, each the step compound used therefor in above-mentioned reaction promptly can be that the simplification compound also can be the mixture of multiple compound.So, formula (I) compound can the simplification compound or the mixture of multiple compound be produced, and, if be produced, can directly use or be separated into before use the simplification compound with the form of mixtures of multiple compound.
After per step finishes, can be with each target compound, formula (IV), (Ia), (Ia
1), (Ib) or (Ic) compound separates from reaction mixture with ordinary method, and, if desired, with any currently known methods such as column chromatography purifying.
The formula V compound, other starting raw material exists with all cpds form in this method, promptly in these compounds, connect the group Z of phenyl ring and the different in kind of X through any Sauerstoffatom, and these compounds can (Vb), (Vc) and (Vd) be represented by following formula (Va):
In these formulas, X and Z as above define; M ' represents 0 or integer 1-3.
This compound can prepare with several ordinary methods, and commodity in use reagent, sketches as following (1) and (2).(1) when n=1
Alpha-alkyl-α-halogen alkanoates (commodity or undertaken alpha-alkylization by corresponding commodity alkanoates and alkali and alkyl halide, α-halogenation subsequently prepares) reacts in the presence of alkali with phenol and obtains α-(phenoxy group)-alpha-alkyl-alkanoates.These esters of hydrolysis obtain the carboxylic acid by formula (Va) representative.When using saturated dihalide, as glycol dibromide, 1,3-dibromopropane or 1,4-dibromo pentane can obtain the cycloalkanes carboxylic acid by formula (Vc) representative during as alkyl halide.With metal hydride such as lithium aluminium hydride reduction gained carboxylic acid obtain by formula (Vb) or (Vd) representative alcohol.(2) during n=0
With α-phenyl-α, α ,-dialkyl group acetic ester (by commodity phenylacetate and corresponding alkali and the acquisition of alkyl halide alpha-alkyl) hydrolysis obtains the carboxylic acid by formula (VIIa) representative.When using saturated dihalide, as glycol dibromide, 1,3-dibromopropane or 1 when the 4-dibromo pentane is made alkyl halide, can obtain the cycloalkanes carboxylic acid by formula (Vc) representative.With metal hydride such as lithium aluminium hydride reduction gained carboxylic acid obtain by (Vb) or (Vd) representative alcohol.
The compounds of this invention has strong acaricidal activity.Therefore, they have anti-mite class activity, and these mites are restive and occasion a great deal of trouble recently with known miticide.
The compounds of this invention also has strong insecticidal activity with respect to other milbemycin compound, particularly to flea, therefore, can be used as sterilant.Active compound of the present invention has prophylactic effect and does not have phytotoxicity insect, so these compounds never cause damage to farm crop.The compounds of this invention can be used to kill various insects, comprises by inhaling or eat the insect that damages plant, phytotrophy insect, the insect of damage grain in the storage, insect of hygienic reason or the like.These compounds also are effective for the nematode that various influence agriculturals go up important animal.
When The compounds of this invention is used as animal (no matter people or inhuman) anthelmintic agent, can the liquid drink form by oral administration.This beverage comprises solution, the suitable innoxious solvent of suspension or active compound or the dispersion of water and with its blended suspension agent, as the soap clay, wetting agent or other vehicle.This beverage generally also can contain defoamer.Usually the amount of the active compound that exists in beverage is about 0.01-0.5%, preferred 0.01-0.1% (weight).
In addition, composition can contain the dried solid form of the active compound of aequum, preferred unit dosage form such as capsule, pill or tablet oral administration.These preparation of compositions are with active compound and suitable powdery thinner, weighting agent, dispersion agent and/or binding agent such as starch, lactose, talcum, Magnesium Stearate and vegetable jelly thorough mixing.The weight of preparation and content can change in wide region, and this will depend on the character that will treat animal, gradient of infection, parasitic character and the body weight that will treat animal.
The compounds of this invention also can add to and carry out administration in the animal-feed, at this moment it can be evenly spread in the feed, forms as upper strata dressing or with pill and uses.For the content that obtains active compound in the required anthelmintic activated feed preferably from 0.0001 to 0.02%.
When The compounds of this invention dissolves or is dispersed in the liquid vehicle, can pass through glandular stomach, parenterai administration is carried out in muscle or tracheae injection or subcutaneous injection.For parenterai administration, active compound preferably with suitable vegetables oil, as peanut oil or cottonseed oil mixture.The content of active compound is generally 0.05 to 50% (weight) in the preparation.
The compounds of this invention also can with appropriate carriers, as the mixture of dimethyl sulfoxide (DMSO) or hydrocarbon solvent and topical.This preparation can by spraying or dipping be direct or treated in vitro.
The dosage of active compound can infect parasitic nature and extent and change according to the character that will treat animal.Yet, for oral, obtain best result, its dosage is about every 1kg the weight of animals 0.01-100mg, preferred 0.5-50mg.The compounds of this invention can single dose or is carried out administration as 1-5 days divided doses in a short time.
When the present composition was used by agricultural or gardening in advance, various forms and preparation all were possible.For example, can be made into dust agent, thick dust agent, soluble powder, microgranules, precise and tiny granula, wettable powder, rare emulsion, but emulsion concentrate, water-based or oiliness suspension agent or oily solution (can directly spray or be used for dilution), aerosol or the capsule in polymkeric substance.Used carrier can be natural or synthetic and organic or inorganic material.Usually using carrier is for active compound arrives the matrix that will treat, and active compound is stored easily, transportation or processing.According to the type of using composition, can from the known carrier of prior art, select solid, the liquids and gases carrier.
Available ordinary method prepares this preparation, for example, thorough mixing and/or grind activeconstituents and carrier or thinner (solvent) or, tensio-active agent arbitrarily; if desired, after the mixing, it is passed through further step as pulverizing; granulation, in flakes, dressing or absorption.
The example of available support comprises, powder for example, and meal, soluble powder, particulate, particulate, wettable powder and dispersion agent comprise kaolin families or pyrophyllite class clay; Talcum; Lime carbonate; Illiteracy is taken off class clay such as bentonite or Japanese sour soil; The powder of natural mineral or grain, as attapulgite, sepiolite, diatomite, frivolous stone or silica sand, the fine powder of mineral compound such as moisture or anhydrous synthetic amorphous silica, Calucium Silicate powder or magnesiumcarbonate: sugar, as sucrose, lactose worker glucose; Organism, as starch, dextrin, fine crystallization Mierocrystalline cellulose, wood powder, coffee bean powder, chaff powder, whole meal flour or thumb powder; Or inorganic salt, as sodium sulfate, yellow soda ash, sodium bicarbonate, sodium phosphate, calcium sulfate or Tai-Ace S 150; Or urea.
The example of suitable solvent comprises: have high boiling aromatic hydrocarbon solvent, and as dimethylbenzene, methylnaphthalene, alkylbenzene or phenyl xylyl ethane; Have high boiling paraffinic hydrocarbons or naphthalene kind solvent; Various carboxylicesterss, as oleic acid, hexanodioic acid, lauric acid, coco-nut oil fatty acid, toxilic acid and phthalic acid, various phosphoric acid ester; Ketone is as pimelinketone or methyl iso-butyl ketone (MIBK); Polar solvent is as N-alkyl pyrrolidone or methyl-sulphoxide; Glycols, as ethylene glycol, propylene glycol, butyleneglycol or hexylene glycol, its polymkeric substance, other class or its ester; Alcohol, as methyl alcohol, ethanol, propyl alcohol, butanols, hexanol, octanol or lauryl alcohol, its ester or its ether; Any epoxidized vegetable oil is as Oleum Cocois or soybean oil; Or water.
Tensio-active agent can be to have a well emulsify, the positively charged ion of dispersed and wetting property, and negatively charged ion or non-ionic compound are used in tensio-active agent in this based composition as routine.Also can use single tensio-active agent or two or more this class surfactant mixtures.
Operable suitable ionic surfactant pack is drawn together: Voranol EP 2001; Polyxyethylated ester; Polyoxyethylene alkylaryl ether; Polyoxyethylene aryl aryl ester; The polyoxyethylene sorbitol alkyl ester; The sorbyl alcohol alkyl ester; The sugar fatty acid alkyl ester; Glycerine or pentaerythritol fatty ester; Pluronic type tensio-active agent; Acetylene alcohol or acetylenic glycol or its ethylene oxide additive; Silicon class or alkyl glycoside class tensio-active agent.
The suitable anion surfactant of available comprises: the salt of alkyl benzene sulphonate (ABS); Dialkyl benzene sulfonate; The salt of alkyl sulfuric ester; The salt of alkyl methyl taurine ester (tauride); Anion surfactant (its preparation is by the esterification of nonionogenic tenside and the sulfuric acid or the phosphoric acid of above-mentioned diepoxide for example addition, subsequently if desired with suitable alkali neutralization); Sulfite lignin; Sulfonated alkyl naphathalene or its condenses; Phenolsulfonate or its condenses; By for example vinylformic acid, toxilic acid, poly carboxylic acid or poly-sulfonic acid type polysoap that the salt of styrene sulfonic acid or vinyl condensation product is formed; By starch additive or have 1-(2-octene acyl group) sodium succinate, the starch-type tensio-active agent that the dextrin of Xylo-Mucine is formed; The soap class is as sodium long-chain fatty acid salts or sylvite; Alpha-alefinically sulfonate.
The suitable cats product of available comprises: amine salt type or quaternary ammonium salt cationic surfactant, the diepoxide for example affixture of long-chain fat amine or lipid acid.
The suitable amphoterics of available comprises amino acid pattern or betaine type amphoteric surfactant, or Yelkin TTS.
In the molecule of each above-mentioned tensio-active agent, one of them or all hydrogen atoms are shown the strong low influence of surface tension by the deutero-tensio-active agent that fluorine atom replaces, and these tensio-active agents can be used effectively.
Composition also can contain one or more and be selected from stablizer, defoamer, and consistency modifiers, the additive of binding agent and tackiness agent or its arbitrary binding substances, and fertilizer or other reach the active substance of special-effect in advance.
Desinsection has 0.01-99% usually with killing in the acarid composition, more preferably the active compound of 0.1-95%; 1-99.99% solid or fluid additive; 0-25%, more preferably 0.1-25% tensio-active agent.Usually, when concentrate composition during as commodity selling, will be finally be concentration 0.001-0.0001% weight (from 10 to 1ppm) by the user with its dilution.
Hereinbefore, all per-cents all are weight percentage.
The compounds of this invention can other active compound be mixed and made into preparation or other compound uses together, for example, and sterilant, poisonous food, sterilant, miticide, nematocides, mycocide, plant-growth regulator or weedicide.The example of described sterilant comprises: organic phosphates chemical, carbonates chemical, carboxylic acid esters chemical, chlorinated hydrocarbons chemical and by the insect killing substance of microorganisms.
The compounds of this invention also can be mixed and made into preparation or uses with synergistic agent with synergistic agent.The preparation of this class chemical substance be need and also this type of service commercial be useful.Synergistic agent has independently active, and itself can improve the effect of active compound its compound.
Biological activity
Following biological test embodiment will further specify the effect of The compounds of this invention.
In following table 2, comparative compound 1 is 5-oximido milbemycin A
4(CGA-179246), it has been disclosed among the embodiment that Japanese Patent Laid discloses clear 60-142991; Comparative compound 2 is to be disclosed in Japanese Patent Laid to disclose one of compound of implementing among the flat 5-255343, comparative compound 3 is to be disclosed in Japanese Patent Laid to disclose one of embodiment compound among the clear 63-10791, its structure [in these formulas, Me means methyl] as follows;
Comparative compound 1:
Comparative compound 2:
Comparative compound 3
Experimental example
To the cat flea insect killing effect test
With container of Parafilm preparation (wherein the living space of flea is this common artificial skin that is used as of separating from bovine serum).Test compound is added in the bovine serum of capacity so that its concentration is 1ppm, at 37 ℃ flea is drawn onto in the bovine serum sample through Parafilm.Every group contains 20 fleas.After 48 hours, the dead flea number of number is estimated the insecticidal effect of drug sample to flea with it.By counting the dead flea number of the control group that does not have drug sample, calculate mortality ratio.The result is as shown in table 2.
Table 2
| Embodiment number | Mortality ratio (%) |
| 3 | 97.5 |
| 14 | 97.5 |
| 15 | 92.6 |
| 16 | 100.0 |
| 17 | 90.2 |
| 19 | 90.0 |
| 20 | 94.6 |
| 21 | 92.7 |
| 24 | 92.5 |
| 25 | 97.5 |
Table 2 (continuing)
| Embodiment number | Mortality ratio (%) |
| 26 | 90.0 |
| 27 | 97.6 |
| 28 | 94.7 |
| 30 | 97.5 |
| 39 | 92.7 |
| 40 | 97.5 |
| 42 | 90.2 |
| 43 | 95.3 |
| 44 | 90.5 |
| 46 | 97.5 |
| 47 | 97.4 |
| 49 | 97.5 |
| 50 | 92.3 |
| 55 | 92.1 |
| 57 | 97.5 |
| 58 | 95.0 |
| 59 | 100.0 |
Table 2 (continuing)
| Embodiment number | Mortality ratio (%) |
| 115 | 92.3 |
| 116 | 97.3 |
| 118 | 95.1 |
| 123 | 95.0 |
| 124 | 97.3 |
| 130 | 100.0 |
| 137 | 97.4 |
| Comparative compound 1 | 20.9 |
| Comparative compound 2 | 31.4 |
| Comparative compound 3 | 26.8 |
Table 2 (continuing)
Embodiment 113-[2-(4-nitrophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NO
2, n=0 (compound 2)] and 1 (a) 13-[2-(4-nitrophenyl)-2-methylpropionyl]-5-oxygen-milbemycin A4[(IV): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NO
2, n=0]
| Embodiment number | Mortality ratio (%) |
| 60 | 100.0 |
| 64 | 90.2 |
| 66 | 95.0 |
| 67 | 90.0 |
| 68 | 95.0 |
| 70 | 97.5 |
| 74 | 90.0 |
| 85 | 100.0 |
| 91 | 97.5 |
| 93 | 90.0 |
| 101 | 97.5 |
| 105 | 95.2 |
| 109 | 100.0 |
| 110 | 100.0 |
| 111 | 91.1 |
| 112 | 95.5 |
| 114 | 94.7 |
Under ice-cooled and argon gas stream, 212mg (1.01mmol) 2-(4-nitrophenyl)-2 methylpropanoic acids and 15 μ l trifluoromethanesulfonic acids are added in the 8ml dichloromethane solution of 188mg (0.34mmol) 15-hydroxyl-5-oxygen-milbemycin A4, then with mixture stirring at room 30 minutes.Pour into reaction soln in the water during end and use ethyl acetate extraction.Extraction liquid is successively with 5%w/v sodium bicarbonate aqueous solution and saturated aqueous sodium chloride washing.The solution anhydrous magnesium sulfate drying, underpressure distillation removes and desolvates.Residuum carries out the column chromatography purifying by silicon amine, is that 4: 6 the ethyl acetate and the mixture of hexane are made eluent with volume ratio, obtains 502mg (productive rate 58%) title compound.
Nuclear magnetic resonance spectrum (270MHz) δ ppm:
8.16 (2H, doublet, J=9.8Hz);
6.54 (1H, triplet, J=1.8Hz);
(5.92-5.69 2H, multiplet);
(5.47-5.29 3H, multiplet);
4.91 (1H, doublet, J=10.5Hz);
(4.70 2H, wide unimodal);
(3.84 1H, unimodal);
(1.63 6H, unimodal).1 (b) 13-[2-(4-nitrophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A4
Will be according to 186mg (0.25mmol) 13-[2-(4-the nitrophenyl)-2-methylpropionyl of above-mentioned steps (a) preparation]-5-oxygen-milbemycin A4 is dissolved in the 1.5ml dioxan.In gained solution, add 0.75ml water, 1.5ml methyl alcohol and 165mg hydroxylamine hydrochloride, and mixture stirred 3 hours at 40 ℃.During end, reaction soln washes with water 3 times with the dilution of 20ml ethyl acetate.With the solution anhydrous magnesium sulfate drying, underpressure distillation removes and desolvates then.Residuum carries out the column chromatography purifying by silica gel, is that 5: 5 the ethyl acetate and the mixture of hexane are made eluent with volume ratio, obtains 170mg (productive rate 89.2%) title compound.Nuclear magnetic resonance spectrum (270MHz) δ ppm:
8.17 (2H, doublet, J=8.7Hz);
(8.00 1H, wide unimodal);
7.47 (2H, doublet, J=8.7Hz);
(5.90-5.71 3H, multiplet);
(5.48-5.27 3H, multiplet);
4.91 (1H, doublet, J=10.6Hz);
4.70﹠amp; 4.68 (2H, the AB-quartet, J=15.0Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=2.3﹠amp; 9.3Hz);
(1.93 3H, unimodal);
(1.63 3H, unimodal);
(1.60 3H, unimodal);
(1.29 3H, unimodal);
0.99 (3H, triplet, J=7.3Hz);
0.82 (6H, doublet, J=6.5Hz).Embodiment 2-8
According to being similar to the synthetic embodiment 2-8 compound of the described method of embodiment.To productive rate be with step (a) and (b) polymerization of productive rate calculate.Embodiment 213-[2-(3-nitrophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=3-NO
2, n=0 (compound 3)] and productive rate: 64.3% nuclear magnetic resonance spectrum (270MHz) δ ppm:
8.19 (1H, dual doublet, J=1.9﹠amp; 1.9Hz);
8.12 (1H, dual doublet, J=1.9﹠amp; 7.9Hz);
7.63 (1H, dual doublet, J=1.9﹠amp; 7.9Hz);
7.49 (1H, dual doublet, J=7.9﹠amp; 7.9Hz);
(5.90-5.70 3H, multiplet);
(5.47-5.29 3H, multiplet);
4.92 (1H, doublet, J=10.6Hz);
4.73﹠amp; 4.68 (2H, the AB-quartet, J=14.4Hz);
(4.66 1H, unimodal);
(3.97 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=2.1﹠amp; 9.1Hz);
(1.93 3H, unimodal);
(1.66 3H, unimodal);
(1.61 3H, unimodal);
(1.29 3H, unimodal);
0.96 (3H, triplet, J=7.3Hz);
0.84 (3H, doublet, J=6.5Hz);
0.83 (3H, doublet, J=6.4Hz).Embodiment 313-[2-(4-p-methoxy-phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-MeO, n=0 (compound 16)] mass spectrum (FAB-MS) m/z:748 (M+H+, M=C
43H
57NO
10).(FAB-MS is a fast atom bombardment mass spectroscopy(FABMS))
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(7.95 1H, wide unimodal);
7.22 (2H, doublet, J=8.8Hz);
6.83 (2H, doublet, J=8.8Hz);
4.86 (1H, doublet, J=10.5Hz);
4.73﹠amp; 4.68 (2H, dual AB-quartet, J=1.8﹠amp; 14.4Hz);
(4.65 1H, unimodal);
(3.96 1H, unimodal);
(3.79 3H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual doublet, J=2.2﹠amp; 9.2Hz);
(1.93 3H, unimodal);
(1.56 3H, unimodal);
(1.53 3H, unimodal);
(1.30 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (3H, doublet, J=6.4Hz);
0.82 (3H, doublet, J=6.4Hz).Embodiment 413-[1-(4-p-methoxy-phenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-MeO, n=0 (compound 181)] mass spectrum (FAB-MS) m/z:774 (M+H
+, M=C
45H
59NO
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
7.25 (2H, doublet, J=8.6Hz);
6.81 (2H, doublet, J=8.6Hz);
4.80 (1H, doublet, J=10.6Hz);
4.72﹠amp; 4.70 (2H, the AB-quartet, J=14.4Hz);
(4.65 1H, unimodal);
(3.96 1H, unimodal);
(3.78 3H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
3.02 (1H, dual doublet, J=2.2﹠amp; 9.2Hz);
(2.66-2.54 2H, multiplet);
(1.93 3H, unimodal);
(1.29 3H, unimodal);
0.97 (3H, triplet, J=7.3Hz);
0.82 (3H, doublet, J=6.6Hz);
0.77 (3H, doublet, J=5.9Hz).Embodiment 513-[2-(4-isobutoxy phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-OiBu, n=0 (compound 23)] mass spectrum (FAB-MS) m/z:790 (M+H
+, M=C
46H
60NO
10).
Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(7.85 1H, wide unimodal);
7.20 (2H, doublet, J=8.6Hz);
6.81 (2H, doublet, J=8.6Hz);
4.86 (1H, doublet, J=10.0Hz);
4.75﹠amp; 4.66 (2H, the AB-quartet, J=14.5Hz);
(4.65 1H, unimodal);
(3.96 1H, unimodal);
(3.71 3H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.93 3H, unimodal);
(1.55 3H, unimodal);
(1.53 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
(0.88-0.80 6H, multiplet).Embodiment 613-[1-(4-nitrophenyl) cyclopropanecarbonyl-oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
2, R
3=4-NO
2, n=0 (compound 387)]
Nuclear magnetic resonance spectrum (270MHz) δ ppm:
8.18 (2H, doublet, J=8.7Hz);
7.51 (2H, doublet, J=8.7Hz);
(5.82 1H, unimodal);
(5.90-5.71 3H, multiplet);
(5.46-5.27 3H, multiplet);
4.91 (1H, doublet, J=10.6Hz);
4.72﹠amp; 4.66 (2H, the AB-quartet, J=14.4Hz);
(4.65 1H, unimodal);
(3.93 1H, unimodal);
(3.55 1H, multiplet);
(3.35 1H, multiplet);
3.03 (1H, dual triplet, J=2.2﹠amp; 9.2Hz);
(1.93 3H, unimodal);
(1.36 3H, unimodal);
0.97 (3H, triplet, J=7.3Hz);
0.91 (3H, doublet, J=6.5Hz);
0.82 (3H, doublet, J=6.5Hz).Embodiment 713-[1-(4-nitrophenyl) tetramethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
3, R
3=4-NO
2, n=0 (compound 451)] and productive rate: 66.1%
Nuclear magnetic resonance spectrum (270MHz) δ ppm:
8.18 (2H, doublet, J=8.9Hz);
7.42 (2H, doublet, J=8.9Hz);
(5.89-5.72 3H, multiplet);
(5.46-5.27 3H, multiplet);
4.88 (1H, doublet, J=10.5Hz);
4.73﹠amp; 4.67 (2H, the AB-quartet, J=14.4Hz);
(4.66 1H, unimodal);
(3.95 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
3.03 (1H, dual triplet, J=2.3﹠amp; 9.2Hz);
(1.93 3H, unimodal);
(1.35 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.82 (3H, doublet, J=6.4Hz);
0.78 (3H, doublet, J=6.6Hz).Embodiment 813-[2-(4-nitrophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CH
2, Z=＞C (Me)
2, R
3=4-NO
2, n=0 (compound 513)] and productive rate: 65.3%
Nuclear magnetic resonance spectrum (270MHz) δ ppm:
8.14 (2H, doublet, J=8.9Hz);
7.51 (2H, doublet, J=8.9Hz);
(5.90-5.71 3H, multiplet);
(5.46-5.27 3H, multiplet);
(4.65 1H, unimodal);
(3.94 1H, unimodal);
3.31 (1H, doublet, J=9.0Hz);
3.13 (2H, doublet, J=9.0Hz);
(1.87 6H, unimodal).Embodiment 913-[2-(4-aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NH
2, n=0 (compound 6)]
Will be according to 1.0g (1.31mmol) 13-[2-(4-the nitrophenyl)-2 Methylpropionic acid base of the described method preparation of embodiment 1]-5-oximido-milbemycin A
4Be dissolved in 13ml methyl alcohol and the 7ml tetrahydrofuran compound, and in ice-cooled, in solution, add 85mg (0.13mmol) nickelous chloride (II) triphenylphosphine complex and 100mg (2.6mmol) sodium borohydride.Reaction mixture was stirred 30 minutes, with the ethyl acetate dilution, wash 3 times with water, and use anhydrous sodium sulfate drying afterwards.Underpressure distillation removes and desolvates.Residuum carries out the column chromatography purifying by silica gel, is that 5: 5 the ethyl acetate and the mixture of hexane are made eluent with volume ratio, obtains 802mg (productive rate 83.8%) title compound.
Nuclear magnetic resonance spectrum (270MHz) δ ppm:
(8.00 1H, wide unimodal);
7.09 (2H, doublet, J=8.5Hz);
6.62 (2H, doublet, J=8.5Hz);
(5.95-5.71 3H, multiplet);
(5.50-5.25 3H, multiplet);
4.86 (1H, doublet, J=10.5Hz);
4.75﹠amp; 4.68 (2H, the AB-quartet, J=15.0Hz);
(4.66 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=2.1﹠amp; 9.0Hz);
(1.93 3H, unimodal);
(1.54 3H, unimodal);
(1.51 3H, unimodal);
(1.32 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
0.82 (6H, doublet, J=6.4Hz).Embodiment 10-13
According to being similar to the synthetic embodiment 10-13 compound of embodiment 9 described methods.Embodiment 1013-[2-(3-aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=3-NH
2, n=0 (compound 7)]
Nuclear magnetic resonance spectrum (270MHz) δ ppm:
(7.42 1H, multiplet);
(7.21 1H, multiplet);
(6.90 1H, multiplet);
(5.90-5.70 3H, multiplet);
(5.48-5.29 3H, multiplet);
4.89 (1H, doublet, J=10.6Hz);
4.73﹠amp; 4.68 (2H, the AB-quartet, J=14.4Hz);
(4.65 1H, unimodal);
(3.97 1H, wide unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.93 3H, unimodal);
(1.65 3H, unimodal);
(1.62 3H, unimodal);
(1.29 3H, unimodal);
0.97 (3H, triplet, J=7.3Hz);
0.84 (3H, doublet, J=6.5Hz);
0.83 (3H, doublet, J=6.4Hz).Embodiment 1113-[1-(4-aminophenyl) cyclopropanecarbonyl-oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
2, R
3=4-NH
2, n=0 (compound 388)] and mass spectrum (FAB-MS) m/z:731 (M+H
+, M=C
42H
54N
209).
Nuclear magnetic resonance spectrum (270MHz) δ ppm:
7.11 (2H, doublet, J=8.2Hz);
6.63 (2H, doublet, J=8.2Hz);
4.85 (1H, doublet, J=10.6Hz);
4.74﹠amp; 4.67 (2H, the AB-quartet, J=14.8Hz);
(4.65 1H, unimodal);
(3.92 1H, unimodal);
(3.68 2H, wide unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
3.03 (1H, dual triplet, J=2.3﹠amp; 9.2Hz);
(1.93 3H, unimodal);
(1.39 3H, unimodal);
(1.12 2H, multiplet);
0.97 (3H, triplet, J=7.3Hz);
0.91 (3H, doublet, J=6.5Hz);
0.83 (3H, doublet, J=6.4Hz).Embodiment 1213-[1-(4-aminophenyl) tetramethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
3, R
3=4-NH
2, n=0 (compound 452)]
Nuclear magnetic resonance spectrum (270MHz) δ ppm:
7.19 (2H, doublet, J=8.1Hz);
7.01 (2H, doublet, J=8.1Hz);
(5.96-5.71 3H, multiplet);
(5.50-5.25 3H, multiplet);
4.82 (1H, doublet, J=10.5Hz);
(4.66 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
3.03 (1H, dual triplet, J=2.2﹠amp; 9.2Hz);
(1.96 3H, unimodal);
(1.40 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
0.89 (3H, doublet, J=6.5Hz);
0.82 (3H, doublet, J=6.5Hz).Embodiment 1313-[2-(4-oxygen base phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CH
2, Z=＞C (Me)
2, R
3=4-NH
2, n=0 (compound 514)]
Nuclear magnetic resonance spectrum (270MHz) δ ppm:
7.14 (2H, doublet, J=8.5Hz);
6.63 (2H, doublet, J=8.5Hz);
(5.90-5.71 3H, multiplet);
(5.46-5.27 3H, multiplet);
(4.65 1H, unimodal);
(3.94 1H, unimodal);
3.22 (1H, doublet, J=8.9Hz).Embodiment 1413-[2-(4-methoxycarbonyl glycyl aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOCH
2NHCOOMe, n=0 (compound 81)]
With 3.61g (5.0mmol) 13-[2-(4-aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
41.012g (10.0mmol) triethylamine and 2.56g (10.0mmol) 2-chloro-1-iodine formylpyridine (methylpyridinium iodide) is added in the 20ml dichloromethane solution of 2.0g (15.0mmol) N-methoxycarbonyl glycine successively, then in stirring at room mixture 1.5 hours.During end, reaction mixture is poured in the water, and used ethyl acetate extraction.Extraction liquid concentrates with anhydrous magnesium sulfate drying and reduction vaporization.Residuum carries out the column chromatography purifying by silica gel, is that 6: 4 the ethyl acetate and the mixture of hexane are made eluent with volume ratio, obtains 3.53g (productive rate 84.4%) title compound.
Nuclear magnetic resonance spectrum (270MHz) δ ppm:
(8.30 1H, wide unimodal);
(7.96 1H, wide unimodal);
7.45 (2H, doublet, J=8.5Hz);
7.24 (2H, doublet, J=8.5Hz);
(5.89-5.71 3H, multiplet);
(5.51-5.26 4H, multiplet);
4.86 (1H, doublet, J=10.8Hz);
4.73﹠amp; 4.65 (2H, the AB-quartet, J=15.0Hz);
3.99 (1H, doublet, J=5.6Hz);
(3.97 3H, unimodal);
(3.36 1H, multiplet);
(3.75 3H, unimodal).Embodiment 15 and 16
According to being similar to embodiment 9 described methods, with 13-[2-(4-aminophenyl)-2 Methylpropionic acid base of pressing embodiment 13 preparations]-5-oximido-milbemycin A
4Make synthetic embodiment 15 of starting raw material and 16 compounds.Embodiment 1513-[2-(4-methoxycarbonyl glycyl aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CH
2, Z=＞C (Me)
2, R
3=4-NHCOCH
2NHCOOMe, n=0 (compound 547)] mass spectrum (FAB-MS) m/z:983 (M+H
++ trolamine=833+1+149).
Nuclear magnetic resonance spectrum (270MHz) δ ppm:
(7.88 1H, wide unimodal);
(7.80 1H, wide unimodal);
7.42 (2H, doublet, J=8.9Hz);
7.31 (2H, doublet, J=8.9Hz);
(5.85-5.69 3H, multiplet);
(5.45-5.26 3H, multiplet);
(5.12 1H, multiplet);
(4.70 2H, multiplet);
(4.66 1H, unimodal);
3.98 (2H, doublet, J=5.9Hz);
(3.90 1H, unimodal);
(3.74 3H, unimodal);
(3.57 1H, wide unimodal);
3.36 (1H, triplet, J=2.4Hz);
3.25 (1H, doublet, J=8.9Hz);
(3.13-3.04 3H, multiplet).Embodiment 1613-{2-[4-(1-methoxycarbonyl tetramethyleneimine-2-carbonylamino) phenyl]-2-methyl propoxy-}-5-oxyimino-milbemycin A
4[(I): R
1=Et, X=CH
2, Z=＞C (Me)
2, R
3=4-NHCO (1-COOMe-2-pyrd), n=0 (compound 553)] mass spectrum (FAB-MS) m/z:1023 (M+H
++ trolamine=873+1+149).
Nuclear magnetic resonance spectrum (270MHz) δ ppm:
(7.89 1H, wide unimodal);
7.44 (2H, doublet, J=8.5Hz);
7.30 (2H, doublet, J=8.5Hz);
(5.85-5.69 3H, multiplet);
(5.44-5.27 3H, multiplet);
(5.14 1H, multiplet);
(4.75 2H, multiplet);
(4.66 1H, unimodal);
(4.47 1H, wide unimodal);
(3.91 1H, unimodal);
(3.77 3H, unimodal);
(3.73-3.38 5H, multiplet);
3.37 (1H, triplet, J=2.4Hz);
3.25 (1H, doublet, J=8.7Hz);
(3.14-3.04 3H, multiplet).Embodiment 1713-[1-(4-acetylamino phenyl) cyclopropanecarbonyl-oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
2, R
3=4-NHAc, n=0 (compound 392)] the 1.0ml dichloromethane solution of 0.0121ml (0.15mmol) pyridine and the 1.0ml dichloromethane solution of 0.0142ml (0.15mmol) acetic anhydride are added to 98.0g 13-[1-(4-aminophenyl) the cyclopropanecarbonyl-oxygen base for preparing by embodiment 11]-5-oximido-milbemycin A
4The 1.0ml dichloromethane solution in.Mixture was stirred 30 minutes in this temperature, then stirring at room 10 minutes.During end, reaction soln washes with water 3 times with the dilution of 15ml ethyl acetate, uses anhydrous sodium sulfate drying then.Underpressure distillation removes and desolvates.Residuum carries out the column chromatography purifying by silica gel, is that 6: 4 the ethyl acetate and the mixture of hexane are made eluent with volume ratio, obtains 70.0mg (productive rate 67.6%) title compound.Mass spectrum (FAB-MS) m/z:773 (M+H
+, M=C
44H
56N
2010).
Nuclear magnetic resonance spectrum (270MHz) δ ppm:
(8.26 1H, unimodal);
7.43 (2H, doublet, J=8.4Hz);
7.28 (2H, doublet, J=8.4Hz);
(5.90-5.73 3H, multiplet);
(5.44-5.27 3H, multiplet);
4.87 (1H, doublet, J=10.6Hz);
4.73﹠amp; 4.67 (2H, the AB-quartet, J=14.4Hz);
(4.65 1H, unimodal);
(3.93 1H, unimodal);
(3.56 1H, multiplet);
(3.35 1H, multiplet);
3.04 (1H, dual doublet, J=2.2﹠amp; 9.2Hz);
(2.18 3H, unimodal);
(1.93 3H, unimodal);
(1.37 3H, unimodal);
0.97 (1H, triplet, J=7.3Hz);
0.91 (3H, doublet, J=6.5Hz);
0.83 (3H, doublet, J=6.5Hz).Embodiment 1813-[2-(4-methylsulfonyl aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHSO
2Me, n=0 (compound 148)] 18 (a) 13-[2-(4-nitrophenyl)-2 Methylpropionic acid base]-5-t-butyldimethylsilyloxy base imino--milbemycin A
4Mg (3.6mmol) imidazoles, 543mg (3.6mmol) tert-butyldimethylsilyl chloride and 20mg 4-Dimethylamino pyridine are added to 13-[2-(4-nitrophenyl)-2 Methylpropionic acid base that 2.289g (3.0mmol) presses embodiment 1 preparation]-5-oximido-milbemycin A
4The 25ml dichloromethane solution in, and mixture stirred 2 hours at 40 ℃.During end, reaction mixture is used the 0.2M aqueous citric acid solution successively with the dilution of 100ml ethyl acetate, water, and anhydrous sodium sulfate drying is used in 4%w/v sodium bicarbonate aqueous solution and water washing then.Solvent removed by evaporation at reduced pressure.Residuum carries out the column chromatography purifying by silica gel, is that 1: 9 the ethyl acetate and the mixture of hexane are made eluent with volume ratio, and obtaining 2.542g (productive rate 96.6%) title compound is amorphous solid.18 (b) 13-[2-(4-aminophenyl)-2 Methylpropionic acid base]-5-t-butyldimethylsilyloxy base imino--milbemycin A
45g (2.71mmol) is by 13-[2-(4-the nitrophenyl)-2 Methylpropionic acid base of above-mentioned steps (a) preparation]-5-t-butyldimethylsilyloxy base imino--milbemycin A4 is dissolved in 15ml methyl alcohol, and two (triphenylphosphine)-nickel (II) muriates of 253mg is added in the gained solution.In said mixture, add the 170mg sodium borohydride with 10 fens clock times when stirring, and continue to stir 7 minutes.Reaction mixture is poured in the 200ml 1%w/v acetic acid aqueous solution, used 200ml and 50ml ethyl acetate extraction successively.Extraction liquid is water successively, and anhydrous sodium sulfate drying is used in 4%w/v sodium bicarbonate aqueous solution and water washing then.Solvent removed by evaporation at reduced pressure.Residuum carries out the column chromatography purifying by silica gel, is that 3: 7 the ethyl acetate and the mixture of hexane are made eluent with volume ratio, and obtaining 2.101g (productive rate 91.5%) title compound is amorphous solid.18 (c) 13-[2-(4-methylsulfonyl aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
477ml (2.20mmol) pyridine and 252mg (2.20mmol) methylsulfonyl chloride are added to 13-[2-(4-the aminophenyl)-2 Methylpropionic acid base of 169mg (0.20mmol) by above-mentioned steps (b) preparation]-the 2.0ml dichloromethane solution of 5-t-butyldimethylsilyloxy base imino--milbemycin A4 in, and with mixture stirring at room 2 hours.During end, reaction mixture is used the 0.2M aqueous citric acid solution successively with the dilution of 20ml ethyl acetate, water, and anhydrous sodium sulfate drying is used in 4%w/v sodium bicarbonate aqueous solution and water washing then.Solvent removed by evaporation at reduced pressure.Residuum is dissolved in the 3.0ml methyl alcohol, and adds 0.3ml 1M aqueous hydrochloric acid.Mixture was stirring at room 20 minutes.During end, reaction mixture is with the dilution of 20ml ethyl acetate, water successively, and anhydrous sodium sulfate drying is used in 4%w/v sodium bicarbonate aqueous solution and water washing then.Solvent removed by evaporation at reduced pressure.Residuum carries out the column chromatography purifying by silica gel, is that 6: 4 the ethyl acetate and the mixture of hexane are made eluent with volume ratio, and obtaining 717mg (productive rate 94.5%) title compound is amorphous solid.
Mass spectrum (FAB-MS) m/z:811 (M+H
+, M=C
43H
58N
2O
11S).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.14 1H, wide unimodal);
7.26 (2H, doublet, J=8.6Hz);
7.20 (2H, doublet, J=8.6Hz);
(6.35 1H, wide unimodal);
4.87 (1H, doublet, J=9.9Hz);
4.71﹠amp; 4.69 (2H, the AB-quartet, J=14.5Hz);
(4.65 1H, unimodal);
(3.95 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(2.98 3H, unimodal);
(1.93 3H, unimodal);
(1.58 3H, unimodal);
(1.55 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
(0.84-0.80 6H, multiplet).Embodiment 19-56
Prepare embodiment 19-56 compound according to being similar to embodiment 18 described methods.Embodiment 1913-[2-(4-benzamido phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOPh, n=0 (compound 63)] mass spectrum (FAB-MS) m/z:837 (M+H
+, M=C
49H
60N
2O
10).
Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(7.89-7.31 2H, multiplet);
(7.77 1H, wide unimodal);
(7.60-7.47 5H, multiplet);
7.31 (2H, doublet, J=8.6HZ);
4.89 (1H, doublet, J=10.6Hz);
4.71﹠amp; 4.69 (2H, the AB-quartet, J=15.2Hz);
(4.65 1H, unimodal);
(3.95 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.93 3H, unimodal);
(1.59 3H, unimodal);
(1.56 3H, unimodal);
(1.33 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
(0.85-0.82 6H, multiplet).Embodiment 2013-[2-(4-methoxycarbonyl aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOOMe, n=0 (compound 121)] mass spectrum (FAB-MS) m/z:791 (M+H
+, M=C
44H
58N
2O
11).
Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(7.82 1H, wide unimodal);
7.31 (2H, doublet, J=8.6HZ);
7.23 (2H, doublet, J=8.6HZ);
(6.56 1H, wide unimodal);
4.87 (1H, doublet, J=10.6Hz);
4.71﹠amp; 4.69 (2H, the AB-quartet, J=14.5Hz);
(4.65 1H, unimodal);
(3.96 1H, unimodal);
(3.78 3H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=2.6﹠amp; 9.2Hz);
(1.93 3H, unimodal);
(1.56 3H, unimodal);
(1.53 3H, unimodal);
(1.30 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
(0.84-0.81 6H, multiplet).Embodiment 2113-[2-(4-acetylamino phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHAc, n=0 (compound 26)] mass spectrum (FAB-MS) m/z:775 (M+H
+, M=C
44H
58N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(7.83 1H, wide unimodal);
7.42 (2H, doublet, J=8.6HZ);
7.25 (2H, doublet, J=8.6HZ);
(7.11 1H, wide unimodal);
4.87 (1H, doublet, J=10.6Hz);
4.71﹠amp; 4.69 (2H, the AB-quartet, J=14.5Hz);
(4.65 1H, unimodal);
(3.95 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=2.3﹠amp; 9.2Hz);
(2.18 3H, unimodal);
(1.93 3H, unimodal);
(1.57 3H, unimodal);
(1.53 3H, unimodal);
(1.30 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
(0.84-0.80 6H, multiplet).Embodiment 2213-[2-(4-phenyloxycarbonyl aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOOPh, n=0 (compound 131)] mass spectrum (FAB-MS) m/z:853 (M+H
+, M=C
49H
60N
2O
11).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(7.89 1H, wide unimodal);
(7.43-7.37 4H, multiplet);
(7.29-7.24 2H, multiplet);
7.19 (2H, doublet, J=7.3Hz);
(6.91 1H, wide unimodal);
4.88 (1H, doublet, J=10.6Hz);
4.72﹠amp; 4.69 (2H, the AB-quartet, J=14.5Hz);
(4.65 1H, unimodal);
(3.96 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.93 3H, unimodal);
(1.57 3H, unimodal);
(1.55 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (6H, doublet, J=6.6Hz).Embodiment 2313-[2-(the amino phenyl of 4-crotonoyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOCH=CHMe (instead), n=0 (compound 59)] mass spectrum (FAB-MS) m/z:801 (M+H
+, M=C
46H
60N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.16 1H, unimodal);
7.48 (2H, doublet, J=8.5HZ);
7.26 (2H, doublet, J=8.5HZ);
(7.11 1H, unimodal);
(7.00 1H, multiplet);
5.93 (1H, dual doublet, J=1.4﹠amp; 15.2Hz);
5.84 (1H, two dual doublets, J=2.0,2.0﹠amp; 11.5Hz);
4.87 (1H, doublet, J=10.6Hz);
4.73﹠amp; 4.66 (2H, dual AB-quartet, J=1.9Hz﹠amp; 14.6Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=2.0﹠amp; 9.4Hz);
(1.93 3H, unimodal);
(1.57 3H, unimodal);
(1.54 3H, unimodal);
(1.30 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (3H, doublet, J=6.3Hz);
0.81 (3H, doublet, J=6.3Hz).Embodiment 2413-[2-(4-pivalyl aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOtBu, n=0 (compound 38)] mass spectrum (FAB-MS) m/z:817 (M+H
+, M=C
47H
64N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(7.81 1H, unimodal);
4.88 (1H, doublet, J=10.6Hz);
4.72﹠amp; 4.69 (2H, the AB-quartet, J=13.9Hz);
(4.65 1H, unimodal);
(3.96 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=2.6﹠amp; 9.2Hz);
(1.93 3H, unimodal);
(1.57 3H, unimodal);
(1.53 3H, unimodal);
(1.32 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (6H, doublet, J=6.3Hz).
Embodiment 2513-[2-(4-valeryl aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOBu, n=0 (compound 36)] mass spectrum (FAB-MS) m/z:817 (M+H
+, M=C
47H
64N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(7.90 1H, wide unimodal);
7.44 (2H, doublet, J=8.6Hz);
7.24 (2H, doublet, J=8.6Hz);
(7.08 1H, unimodal);
4.87 (1H, doublet, J=10.6Hz);
4.72﹠amp; 4.69 (2H, the AB-quartet, J=15.8Hz);
(4.65 1H, unimodal);
(3.96 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.93 3H, unimodal);
(1.57 3H, unimodal);
(1.53 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.95 (3H, triplet, J=7.6Hz);
(0.84-0.81 6H, multiplet).Embodiment 2613-{2-[4-(3-fluoro benzoyl) aminophenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCO (3-FPh), n=0 (compound 65)] mass spectrum (FAB-MS) m/z:855 (M+H
+, M=C
49H
59FN
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(9.05 1H, wide unimodal);
(7.97 1H, unimodal);
(7.65-7.56 2H, multiplet);
7.57 (2H, doublet, J=8.6Hz);
(7.32-7.20 1H, multiplet);
7.29 (2H, doublet, J=8.6Hz);
4.88 (1H, doublet, J=10.5Hz);
4.70﹠amp; 4.68 (2H, the AB-quartet, J=15.2Hz);
(4.65 1H, unimodal);
(4.00 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
(3.05 1H, multiplet);
(1.91 3H, unimodal);
(1.58 3H, unimodal);
(1.56 3H, unimodal);
(1.33 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
0.83 (6H, doublet, J=6.6Hz).Embodiment 2713-[2-(4-methylmercaptan ethyl amido phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOCH
2SMe, n=0 (compound 51)] mass spectrum (FAB-MS) m/z:821 (M+H
+, M=C
45H
60N
2O
10S).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.67 1H, unimodal);
(8.30 1H, wide unimodal);
7.50 (2H, doublet, J=8.6Hz);
7.28 (2H, doublet, J=8.6Hz);
4.88 (1H, doublet, J=10.5Hz);
4.72﹠amp; 4.69 (2H, the AB-quartet, J=14.6Hz);
(4.66 1H, unimodal);
(3.97 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
(3.35 2H, unimodal);
(3.04 1H, multiplet);
(2.05 3H, unimodal);
(1.93 3H, unimodal);
(1.57 3H, unimodal);
(1.55 3H, unimodal);
(1.32 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
0.83 (6H, doublet, J=6.4Hz).Embodiment 2813-[2-(4-methoxyl group acetylamino phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOCH
2OMe, n=0 (compound 47)] mass spectrum (FAB-MS) m/z:805 (M+H
+, M=C
45H
60N
2O
11).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(9.01 1H, wide unimodal);
(8.24 1H, unimodal);
7.51 (2H, doublet, J=8.6Hz);
7.28 (2H, doublet, J=8.6Hz);
4.87 (1H, doublet, J=10.5Hz);
4.71﹠amp; 4.68 (2H, the AB-quartet, J=15.2Hz);
(4.66 1H, unimodal);
(3.97 3H, unimodal);
(3.58 1H, multiplet);
(3.51 3H, unimodal);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.92 3H, unimodal);
(1.57 3H, unimodal);
(1.54 3H, unimodal);
(1.30 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
0.83 (3H, doublet, J=6.4Hz);
0.82 (3H, doublet, J=6.4Hz).Embodiment 2913-[2-(4-cyclopropyl carbonyl aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOcPr, n=0 (compound 39)] mass spectrum (FAB-MS) m/z:801 (M+H
+, M=C
46H
60N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.80 1H, wide unimodal);
(7.49 1H, unimodal);
7.44 (2H, doublet, J=8.6Hz);
7.24 (2H, doublet, J=8.6Hz);
4.87 (1H, doublet, J=10.6Hz);
4.72﹠amp; 4.69 (2H, the AB-quartet, J=14.8Hz);
(4.66 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.92 3H, unimodal);
(1.56 3H, unimodal);
(1.53 3H, unimodal);
(1.30 3H, unimodal);
(1.09 2H, multiplet);
0.98 (3H, triplet, J=7.3Hz);
0.83 (3H, doublet, J=6.3Hz);
0.82 (3H, doublet, J=6.5Hz).Embodiment 3013-[2-(4-hexanaphthene carbonylamino phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=
CO, Z=＞C (Me)
2, R
3=4-NHCOcHx, n=0 (compound 42)] mass spectrum (FAB-MS) m/z:843 (M+H
+, M=C
49H
66N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(7.99 1H, wide unimodal);
7.45 (2H, doublet, J=8.6Hz);
7.24 (2H, doublet, J=8.6Hz);
(7.10 1H, wide unimodal);
4.87 (1H, doublet, J=10.6Hz);
4.72﹠amp; 4.70 (2H, the AB-quartet, J=14.5Hz);
(4.65 1H, unimodal);
(3.96 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.93 3H, unimodal);
(1.56 3H, unimodal);
(1.53 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (3H, doublet, J=6.3Hz);
0.82 (3H, doublet, J=6.5Hz).Embodiment 3113-{2-[4-(4-p-methoxy-phenyl) acetylamino phenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOCH
2(4-MeOPh), n=0 (compound 62)] mass spectrum (FAB-MS) m/z:881 (M+H
+, M=C
51H
64N
2O
11).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(7.91 1H, wide unimodal);
7.34 (2H, doublet, J=8.6Hz);
7.25 (2H, doublet, J=8.6Hz);
7.21 (2H, doublet, J=8.6Hz);
(7.01 1H, wide unimodal);
(6.94 2H, doublet, J=8.6 Hz);
4.86 (1H, doublet, J=10.5Hz);
4.72﹠amp; 4.70 (2H, the AB-quartet, J=14.3Hz);
(4.66 1H, unimodal);
(3.96 1H, unimodal);
(3.84 3H, unimodal);
(3.69 2H, unimodal);
(3.58 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.94 3H, unimodal);
(1.54 3H, unimodal);
(1.51 3H, unimodal);
(1.29 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
0.82 (6H, doublet, J=6.6Hz).Embodiment 3213-{2-[4-(4-nitro benzoyl) aminophenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCO (4-NO2Ph), n=0 (compound 73)] mass spectrum (FAB-MS) m/z:882 (M+H
+, M=C
49H
60N
2O
12).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(9.10 1H, wide unimodal);
8.35 (2H, doublet, J=8.6Hz);
8.05 (2H, doublet, J=8.6Hz);
(7.82 1H, unimodal);
7.58 (2H, doublet, J=8.6Hz);
7.34 (2H, doublet, J=8.6Hz);
4.89 (1H, doublet, J=10.6Hz);
4.74﹠amp; 4.66 (2H, the AB-quartet, J=15.0Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.57 1H, multiplet);
(3.35 1H, multiplet);
(3.04 1H, multiplet);
(1.93 3H, unimodal);
(1.60 3H, unimodal);
(1.57 3H, unimodal);
(1.33 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
(0.90-0.80 4H, multiplet).Embodiment 3313-{2-[4-(2-furoyl) aminophenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me) 2, R
3=4-NHCO (2-furyl), n=0 (compound 77)] mass spectrum (FAB-MS) m/z:827 (M+H
+, M=C
47H
58N
2O
11).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.08 1H, unimodal);
7.59 (2H, doublet, J=8.6Hz);
7.51 (1H, doublet, J=2.0Hz);
7.30 (2H, doublet, J=8.6Hz);
7.26 (1H, doublet, J=3.7Hz);
6.56 (1H, dual doublet, J=2.0﹠amp; 3.7Hz);
4.88 (1H, doublet, J=10.5Hz);
4.71﹠amp; 4.68 (2H, the AB-quartet, J=14.3Hz);
(4.66 1H, unimodal);
(3.97 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.92 3H, unimodal);
(1.58 3H, unimodal);
(1.56 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (6H, doublet, J=6.4Hz).Embodiment 3413-[2-(4-propiolyl aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOC (CH, n=0 (compound 60)] mass spectrum (FAB-MS) m/z:785 (M+H
+, M=C
45H
56N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(7.61 1H, wide unimodal);
(7.62 1H, unimodal);
7.45 (2H, doublet, J=8.6Hz);
7.27 (2H, doublet, J=8.6Hz);
4.87 (1H, doublet, J=10.5Hz);
4.71﹠amp; 4.69 (2H, the AB-quartet, J=14.4Hz);
(4.66 1H, unimodal);
(3.98 1H, wide unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(2.93 1H, unimodal);
(1.92 3H, unimodal);
(1.57 3H, unimodal);
(1.54 3H, unimodal);
(1.30 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.84 (3H, doublet, J=6.4Hz);
0.83 (3H, doublet, J=6.5Hz).Embodiment 3513-{2-[4-(4-nitrophenyl) acetylamino phenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me) 2, R
3=4-NHCOCH
2(4-NO2Ph), n=0 (compound 61)] mass spectrum (FAB-MS) m/z:896 (M+H
+, M=C
50H
61N
3O
12).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
8.25 (2H, doublet, J=8.6Hz);
(7.80 1H, wide unimodal);
7.54 (2H, doublet, J=8.6Hz);
7.39 (2H, doublet, J=8.6Hz);
7.24 (2H, doublet, J=8.6Hz);
(7.11 1H, wide unimodal);
4.87 (1H, doublet, J=10.6Hz);
4.71﹠amp; 4.69 (2H, the AB-quartet, J=14.1Hz);
(4.65 1H, unimodal);
(3.96 1H, unimodal);
(3.82 2H, unimodal);
(3.58 1H, multiplet);
(3.36 1H, multiplet);
3.03 (1H, dual triplet, J=2.2﹠amp; 7.1Hz);
(1.93 3H, unimodal);
(1.56 3H, unimodal);
(1.52 3H, unimodal);
(1.29 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
(0.84-0.80 6H, multiplet).Embodiment 3613-{2-[4-(4-methoxybenzoyl) aminophenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCO (4-MeOPh), n=0 (compound 69)] mass spectrum (FAB-MS) m/z:867 (M+H
+, M=C
50H
62N
2O
11).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
7.85 (2H, doublet, J=8.8Hz);
(7.70 1H, wide unimodal);
7.57 (2H, doublet, J=8.7Hz);
7.30 (2H, doublet, J=8.7Hz);
6.98 (2H, doublet, J=8.8Hz);
4.88 (1H, doublet, J=10.4Hz);
4.72﹠amp; 4.70 (2H, the AB-quartet, J=14.6Hz);
(4.65 1H, unimodal);
(3.96 1H, unimodal);
(3.88 3H, unimodal);
(3.57 1H, multiplet);
(3.35 1H, multiplet);
3.04 (1H, dual triplet, J=2.4﹠amp; 9.1Hz);
(1.93 3H, unimodal);
(1.59 3H, unimodal);
(1.56 3H, unimodal);
(1.32 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (6H, doublet, J=6.3Hz).Embodiment 3713-{2-[4-(4-tert.-butylbenzene formyl) aminophenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCO (4-tBuPh), n=0 (compound 72)] mass spectrum (FAB-MS) m/z:893 (M+H
+, M=C
53H
68N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
7.81 (2H, doublet, J=8.4Hz);
(7.76 1H, wide unimodal);
7.58 (2H, doublet, J=8.6Hz);
7.51 (2H, doublet, J=8.4Hz);
7.31 (2H, doublet, J=8.6Hz);
4.89 (1H, doublet, J=10.4Hz);
4.72﹠amp; 4.70 (2H, the AB-quartet, J=14.8Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.56 1H, multiplet);
(3.35 1H, multiplet);
(3.04 1H, multiplet);
(1.93 3H, unimodal);
(1.58 3H, unimodal);
(1.56 3H, unimodal);
(1.36 9H, unimodal);
(1.33 3H, unimodal);
0.99 (3H, triplet, J=7.2Hz);
0.78 (6H, doublet, J=6.3Hz).Embodiment 3813-{2-[4-(4-chlorobenzoyl) aminophenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCO (4-ClPh), n=0 (compound 67)] mass spectrum (FAB-MS) m/z:871 (M+H
+, M=C
49H
59ClN
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(7.94 1H, wide unimodal);
7.83 (2H, doublet, J=8.5Hz);
(7.74 1H, wide unimodal);
7.57 (2H, doublet, J=8.6Hz);
7.48 (2H, doublet, J=8.5Hz);
7.32 (2H, doublet, J=8.6Hz);
4.89 (1H, doublet, J=10.5Hz);
4.72﹠amp; 4.69 (2H, the AB-quartet, J=14.4Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.56 1H, multiplet);
(3.35 1H, multiplet);
(3.04 1H, multiplet);
(1.93 3H, unimodal);
(1.59 3H, unimodal);
(1.56 3H, unimodal);
(1.32 3H, unimodal);
0.99 (3H, triplet, J=7.3Hz);
0.83 (6H, doublet, J=6.4Hz).Embodiment 3913-[2-(4-tetramethylene carbonylamino phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOcBu, n=0 (compound 40)] mass spectrum (FAB-MS) m/z:815 (M+H
+, M=C
47H
62N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(9.24 1H, wide unimodal);
7.46 (2H, doublet, J=8.6Hz);
7.24 (2H, doublet, J=8.6Hz);
(7.20 1H, unimodal);
4.87 (1H, doublet, J=9.9Hz);
4.71﹠amp; 4.67 (2H, the AB-quartet, J=14.9Hz);
(4.66 1H, unimodal);
(3.99 1H, wide unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.15 1H, multiplet);
(3.04 1H, multiplet);
(1.91 3H, unimodal);
(1.56 3H, unimodal);
(1.53 3H, unimodal);
(1.30 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (3H, doublet, J=6.3Hz);
0.82 (3H, doublet, J=6.4Hz).Embodiment 4013-[2-(4-pentamethylene carbonylamino phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOcPn, n=0 (compound 41)] mass spectrum (FAB-MS) m/z:829 (M+H
+, M=C
48H
64N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
7.46 (2H, doublet, J=8.6Hz);
7.24 (2H, doublet, J=8.6Hz);
(7.21 1H, unimodal);
4.87 (1H, doublet, J=10.5Hz);
4.72﹠amp; 4.69 (2H, the AB-quartet, J=15.3Hz);
(4.66 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(2.67 1H, multiplet);
(1.92 3H, unimodal);
(1.56 3H, unimodal);
(1.53 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (3H, doublet, J=6.3Hz);
0.82 (3H, doublet, J=6.5Hz).Embodiment 4113-[2-(4-propionamido phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOEt, n=0 (compound 33)] mass spectrum (FAB-MS) m/z:789 (M+H
+, M=C
45H
60N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(9.09 1H, wide unimodal);
7.45 (2H, doublet, J=8.6Hz);
7.24 (2H, doublet, J=8.6Hz);
4.87 (1H, doublet, J=10.6Hz);
4.71﹠amp; 4.69 (2H, the AB-quartet, J=14.5Hz);
(4.66 1H, unimodal);
(3.98 1H, wide unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
2.38 (1H, quartet, J=7.6Hz);
(1.92 3H, unimodal);
(1.56 3H, unimodal);
(1.53 3H, unimodal);
(1.30 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (3H, doublet, J=6.4Hz);
0.82 (3H, doublet, J=6.5Hz).Embodiment 4213-[2-(4-isovaleryl aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOiBu, n=0 (compound 37)] mass spectrum (FAB-MS) m/z:817 (M+H
+, M=C
47H
64N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.70 1H, wide unimodal);
7.45 (2H, doublet, J=8.6Hz);
7.25 (2H, doublet, J=8.6Hz);
(7.16 1H, unimodal);
4.87 (1H, doublet, J=10.5Hz);
4.71﹠amp; 4.68 (2H, the AB-quartet, J=15.0Hz);
(4.66 1H, unimodal);
(3.88 1H, wide unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(2.21 1H, doublet);
(1.92 3H, unimodal);
(1.56 3H, unimodal);
(1.53 3H, unimodal);
(1.31 3H, unimodal);
(1.02-0.92 9H, multiplet);
0.83 (3H, doublet, J=6.6Hz);
0.82 (3H, doublet, J=6.3Hz).Embodiment 4313-[2-(4-isobutyryl aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOiPr, n=0 (compound 35)] mass spectrum (FAB-MS) m/z:803 (M+H
+, M=C
46H
62N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(9.20 1H, wide unimodal);
7.45 (2H, doublet, J=8.6Hz);
(7.31 1H, unimodal);
7.24 (2H, doublet, J=8.6Hz);
4.87 (1H, doublet, J=10.5Hz);
4.71﹠amp; 4.69 (2H, the AB-quartet, J=15.3Hz);
(4.66 1H, unimodal);
(4.01 1H, wide unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(2.33 1H, multiplet);
(1.92 3H, unimodal);
(1.56 3H, unimodal);
(1.53 3H, unimodal);
(1.31 3H, unimodal);
(1.03-0.95 9H, multiplet);
0.83 (3H, doublet, J=6.2Hz);
0.82 (3H, doublet, J=6.4Hz).Embodiment 4413-[2-(4-butyrylamino phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOPr, n=0 (compound 34)] mass spectrum (FAB-MS) m/z:803 (M+H
+, M=C
46H
62N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(9.35 1H, wide unimodal);
7.45 (2H, doublet, J=8.6Hz);
(7.35 1H, unimodal);
7.24 (2H, doublet, J=8.6Hz);
4.87 (1H, doublet, J=10.5Hz);
4.72﹠amp; 4.69 (2H, the AB-quartet, J=15.0Hz);
(4.66 1H, unimodal);
(3.99 1H, wide unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
2.51 (1H, triplet, J=6.8Hz);
(1.91 3H, unimodal);
(1.56 3H, unimodal);
(1.53 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
0.83 (3H, doublet, J=6.3Hz);
0.82 (3H, doublet, J=6.5Hz).Embodiment 4513-[2-(4-acetobrom aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOCH2Br, n=0 (compound 43)] mass spectrum (FAB-MS) m/z:853 (M+H
+, M=C
44H
57BrN
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.09 1H, wide unimodal);
7.47 (2H, doublet, J=8.6Hz);
7.30 (2H, doublet, J=8.6Hz);
4.88 (1H, doublet, J=10.7Hz);
4.72﹠amp; 4.69 (2H, the AB-quartet, J=14.6Hz);
(4.65 1H, unimodal);
(4.03 2H, unimodal);
(3.56 1H, multiplet);
(3.37 1H, multiplet);
3.04 (1H, dual triplet, J=2.0﹠amp; 8.9Hz);
(1.93 3H, unimodal);
(1.58 3H, unimodal);
(1.56 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
(0.83-0.74 6H, multiplet).Embodiment 4613-[2-(4-cyanoacetamide base phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOCH
2CN, n=0 (compound 46)] mass spectrum (FAB-MS) m/z:853 (M+H
+, M=C
45H
57N
3O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(7.69 1H, wide unimodal);
7.44 (2H, doublet, J=8.6Hz);
7.30 (2H, doublet, J=8.6Hz);
4.88 (1H, doublet, J=10.5Hz);
4.72﹠amp; 4.70 (2H, the AB-quartet, J=14.8Hz);
(4.66 1H, unimodal);
(3.57 1H, multiplet);
(3.56 2H, unimodal);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.93 3H, unimodal);
(1.58 3H, unimodal);
(1.55 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
(0.84-0.74 6H, multiplet).Embodiment 4713-{2-[4-(3-oil of mirbane formyl) aminophenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCO (3-NO2Ph), n=0 (compound 74)] mass spectrum (FAB-MS) m/z:871 (M+H
+, M=C
49H
59N
3O
12).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.71 1H, unimodal);
8.43 (1H, dual doublet, J=1.4﹠amp; 8.0Hz);
8.27 (1H, doublet, J=8.0Hz);
(7.88 1H, wide unimodal);
7.73 (1H, dual doublet, J=8.0﹠amp; 8.0Hz);
7.60 (2H, doublet, J=8.6Hz);
7.35 (2H, doublet, J=8.6Hz);
4.90 (1H, doublet, J=10.5Hz);
4.72﹠amp; 4.69 (2H, the AB-quartet, J=14.4Hz);
(4.65 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=2.2﹠amp; 9.7Hz);
(1.93 3H, unimodal);
(1.60 3H, unimodal);
(1.57 3H, unimodal);
(1.33 3H, unimodal);
0.99 (3H, triplet, J=7.2Hz);
(0.88-0.79 6H, multiplet).Embodiment 4813-{2-[4-(3-chlorobenzoyl) aminophenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCO (3-ClPh), n=0 (compound 68)] mass spectrum (FAB-MS) m/z:871 (M+H
+, M=C
49H
59ClN
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(7.87-7.85 1H, multiplet);
(7.76-7.70 2H, multiplet);
7.57 (2H, doublet, J=8.6Hz);
7.44 (1H, dual doublet, J=7.8﹠amp; 7.8Hz);
(7.32 2H, doublet, J=8.6 Hz);
4.89 (1H, doublet, J=10.5Hz);
4.71﹠amp; 4.69 (2H, the AB-quartet, J=14.2Hz);
(4.65 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.93 3H, unimodal);
(1.59 3H, unimodal);
(1.56 3H, unimodal);
(1.32 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
(0.84-0.77 6H, multiplet).Embodiment 4913-{2-[4-(4-fluorobenzoyl) aminophenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCO (4-FPh), n=0 (compound 66)] mass spectrum (FAB-MS) m/z:855 (M+H
+, M=C
49H
59FN
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
7.90 (2H, doublet, J=8.5Hz);
(7.72 1H, wide unimodal);
7.57 (2H, doublet, J=8.6Hz);
7.32 (1H, doublet, J=7.6Hz);
7.18 (2H, doublet, J=8.5Hz);
4.89 (1H, doublet, J=10.5Hz);
4.72﹠amp; 4.69 (2H, the AB-quartet, J=14.4Hz);
(4.65 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=1.9﹠amp; 8.9Hz);
(1.93 3H, unimodal);
(1.59 3H, unimodal);
(1.56 3H, unimodal);
(1.32 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
0.83 (6H, doublet, J=6.3Hz).Embodiment 5013-{2-[4-(2-fluorobenzoyl) aminophenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCO (2-FPh), n=0 (compound 64)] mass spectrum (FAB-MS) m/z:855 (M+H
+, M=C
49H
59FN
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
7.61 (2H, doublet, J=8.6Hz);
7.31 (1H, doublet, J=7.6Hz);
4.89 (1H, doublet, J=10.5Hz);
4.72﹠amp; 4.69 (2H, the AB-quartet, J=14.4Hz);
(4.65 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.93 3H, unimodal);
(1.59 3H, unimodal);
(1.56 3H, unimodal);
(1.32 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (6H, doublet, J=6.3Hz).Embodiment 5113-[2-(4-trifluoroacetamido phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOCF
3, n=0 (compound 44)] and mass spectrum (FAB-MS) m/z:829 (M+H
+, M=C
44H
55F
3N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.81 1H, wide unimodal);
(8.03 1H, unimodal);
7.51 (2H, doublet, J=8.7Hz);
7.33 (2H, doublet, J=8.7Hz);
4.88 (1H, doublet, J=10.5Hz);
4.71﹠amp; 4.68 (2H, the AB-quartet, J=14.2Hz);
(4.65 1H, unimodal);
(3.98 1H, wide unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.92 3H, unimodal);
(1.58 3H, unimodal);
(1.56 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (6H, doublet, J=6.4Hz).Embodiment 5213-[2-(4-difluoro acetylamino phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOCHF
2, n=0 (compound 45)] and mass spectrum (FAB-MS) m/z:811 (M+H
+, M=C
44H
56F
2N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.72 1H, wide unimodal);
(7.93 1H, unimodal);
7.52 (2H, doublet, J=8.7Hz);
7.31 (2H, doublet, J=8.7Hz);
6.02 (1H, triplet, J=54.6Hz);
4.88 (1H, doublet, J=10.5Hz);
4.71﹠amp; 4.69 (2H, the AB-quartet, J=15.2Hz);
(4.65 1H, unimodal);
(3.98 1H, wide unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.92 3H, unimodal);
(1.58 3H, unimodal);
(1.55 3H, unimodal);
(1.30 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (3H, doublet, J=6.4Hz);
0.82 (3H, doublet, J=6.5Hz).Embodiment 5313-{2-[4-(3-methoxybenzoyl) aminophenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCO (3-MeOPh), n=0 (compound 70)] mass spectrum (FAB-MS) m/z:867 (M+H
+, M=C
50H
62N
2O
11).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.05 1H, wide unimodal);
(7.78 1H, unimodal);
7.58 (2H, doublet, J=8.6Hz);
7.44 (1H, doublet, J=1.4Hz);
(7.34-7.41 2H, multiplet);
7.31 (2H, doublet, J=8.6Hz);
(7.09 1H, multiplet);
4.88 (1H, doublet, J=10.5Hz);
4.72﹠amp; 4.69 (2H, the AB-quartet, J=14.5Hz);
(4.65 1H, unimodal);
(3.96 1H, unimodal);
(3.88 3H, unimodal);
(3.57 1H, multiplet);
(3.35 1H, multiplet);
3.04 (1H, dual triplet, J=2.0﹠amp; 9.3Hz);
(1.93 3H, unimodal);
(1.59 3H, unimodal);
(1.56 3H, unimodal);
(1.32 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (6H, doublet, J=5.8Hz).Embodiment 5413-[2-(4-thenoyl aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCO (2-thienyl), n=0 (compound 78)] mass spectrum (FAB-MS) m/z:843 (M+H
+, M=C
47H
58N
2O
10S).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.09 1H, unimodal);
(7.66 1H, unimodal);
(7.62 1H, multiplet);
7.55 (2H, doublet, J=8.7Hz);
7.55 (1H, dual doublet, J=2.0﹠amp; 4.2Hz);
7.30 (2H, doublet, J=8.7Hz);
7.14 (1H, dual doublet, J=4.2﹠amp; 4.2Hz);
5.84 (1H, two dual doublets, J=2.1,2.1﹠amp; 11.5Hz);
(5.78 1H, multiplet);
4.88 (1H, doublet, J=10.4Hz);
4.73﹠amp; 4.67 (2H, dual AB-quartet, J=2.0﹠amp; 14.5Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=2.3﹠amp; 9.3Hz);
1.93 (3H, doublet, J=1.4Hz);
(1.59 3H, unimodal);
(1.56 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
0.83 (6H, doublet, J=6.5Hz).Embodiment 5513-[2-(4-nicotinoyl aminophenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCO (3-Pyr), n=0 (compound 75)] mass spectrum (FAB-MS) m/z:838 (M+H
+, M=C
48H
59N
3O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(9.09 1H, unimodal);
8.78 (1H, doublet, J=4.8Hz);
(8.61 1H, unimodal);
8.23 (1H, doublet, J=7.9Hz);
(7.91 1H, unimodal);
7.58 (2H, doublet, J=8.6Hz);
7.46 (1H, dual doublet, J=4.8﹠amp; 7.9Hz);
7.33 (2H, doublet, J=8.6Hz);
4.89 (1H, doublet, J=10.6Hz);
4.73﹠amp; 4.67 (2H, dual AB-quartet, J=2.0﹠amp; 14.7Hz);
(4.66 1H, unimodal);
(4.02 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=2.2﹠amp; 9.3Hz);
1.92 (3H, doublet, J=1.5Hz);
(1.59 3H, unimodal);
(1.56 3H, unimodal);
(1.33 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (6H, doublet, J=6.6Hz).Embodiment 5613-[2-(the different nicotinoyl aminophenyl of 4-)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCO (4-Pyr), n=0 (compound 76)] mass spectrum (FAB-MS) m/z:838 (M+H
+, M=C
48H
59N
3O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
8.81 (2H, doublet, J=5.7Hz);
(8.52 1H, unimodal);
(7.88 1H, unimodal);
7.72 (2H, doublet, J=5.7Hz);
7.58 (2H, doublet, J=8.6Hz);
7.33 (2H, doublet, J=8.6Hz);
4.89 (1H, doublet, J=10.5Hz);
4.73﹠amp; 4.67 (2H, dual AB-quartet, J=2.0﹠amp; 13.5Hz);
(4.66 1H, unimodal);
(3.99 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=2.2﹠amp; 9.3Hz);
(1.93 3H, unimodal);
(1.59 3H, unimodal);
(1.57 3H, unimodal);
(1.32 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (6H, doublet, J=6.5Hz).Embodiment 5713-[1-(4-aminophenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NH
2, n=0 (compound 171)] and 57 (a) 13-[1-(4-nitrophenyl) pentamethylene carbonyl oxygen base]-5-oxygen-milbemycin A
4
With 4.11g (17.5mmol) 1-(4-nitrophenyl) Cyclopentane carboxylic acid, 2.0g anhydrous cupric sulfate (II) and 8 trifluoromethanesulfonic acids are added to 1.95g (3.50mmol) 15-hydroxyl-5-oxygen-milbemycin A
4The 50ml dichloromethane solution in, and mixture stirred 20 minutes under room temperature and nitrogen atmosphere.During end, filter reaction mixture is to remove insoluble substance.Stir down filtrate is poured in the mixture of 4%w/v sodium bicarbonate aqueous solution and ethyl acetate.Isolate the ethyl acetate phase from mixture, water extracts with amount of ethyl acetate.Isolated ethyl acetate and acetic acid ethyl acetate extract are merged, use 4%w/v sodium bicarbonate aqueous solution and water washing then successively.Use anhydrous sodium sulfate drying, solvent removed by evaporation at reduced pressure.The gained residuum need not be further purified and promptly can be used for next step.57 (b) 13-[1-(4-nitrophenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4
13-[1-(4-nitrophenyl) pentamethylene carbonyl oxygen base with above-mentioned steps (a) preparation]-5-oxygen-milbemycin A
4Dissolving crude product is in the 20ml dioxan, and then with 10ml water, 20ml methyl alcohol and 3.0g azanol hydrochloric acid are added in the gained solution.Mixture was stirred 1 hour at 55 ℃,, and wash with water twice then with the ethyl acetate dilution.Solvent removed by evaporation at reduced pressure, gained residuum need not be further purified and promptly can be used for next step.57 (c) 13-[1-(4-nitrophenyl) pentamethylene carbonyl oxygen base]-5-t-butyldimethylsilyloxy base imino--milbemycin A
4
13-[1-(4-nitrophenyl) pentamethylene carbonyl oxygen base with above-mentioned steps (b) preparation]-5-oximido-milbemycin A
4Dissolving crude product and adds 286mg (4.2mmol) imidazoles, 634mg (4.2mmol) tert-butyldimethylsilyl chloride and 20mg 4-Dimethylamino pyridine therein in the 30ml dichloromethane solution.Mixture stirred 2 hours at 40 ℃.During end, reaction mixture dilutes with the 200ml ethyl acetate, and uses the 0.2M aqueous citric acid solution successively, water, and anhydrous sodium sulfate drying is used in 4%w/v sodium bicarbonate aqueous solution and water washing then.Solvent removed by evaporation at reduced pressure.Residuum carries out the column chromatography purifying by silica gel, is that 1: 9 the ethyl acetate and the mixture of hexane are made eluent with volume ratio, and obtaining 2.327g (productive rate 73.6%) title compound is that compound is an amorphous solid.57 (d) 13-[1-(4-aminophenyl) pentamethylene carbonyl oxygen base]-5-t-butyldimethylsilyloxy base imino--milbemycin A
4The bright haze street c of porcelain) 13-[1-(4-nitrophenyl) the pentamethylene carbonyl oxygen base of preparation]-5-t-butyldimethylsilyloxy base imino--milbemycin A
4Dissolving crude product is in 15ml methyl alcohol, and adds 327mg two (triphenylphosphine)-nickelous chloride (II) therein.When stirring, in mixture, add the 230mg sodium borohydride then, and continue to stir 7 minutes with 10 fens clock times.During end, reaction mixture is poured in the 200ml1%w/v acetic acid aqueous solution, and successively with 200ml and 50ml ethyl acetate extraction.Extraction liquid is water successively, and anhydrous sodium sulfate drying is used in 4%w/v sodium bicarbonate aqueous solution and water washing then.Solvent removed by evaporation at reduced pressure, the gained residuum carries out the column chromatography purifying by silica gel, is that 3: 7 the ethyl acetate and the mixture of hexane are made eluent with volume ratio, and obtaining 1.834g (productive rate 81.5%) title compound is amorphous solid.57 (e) 13-[1-(4-aminophenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4The bright haze street d of porcelain) 873mg (1.0mmol) 13-[1-(4-aminophenyl) the pentamethylene carbonyl oxygen base of preparation]-5-t-butyldimethylsilyloxy base imino--milbemycin A4 is dissolved in 20ml methyl alcohol, and adds 2.0ml 1M aqueous hydrochloric acid therein.Mixture was stirring at room 20 minutes.During end, reaction mixture dilutes with ethyl acetate, and water successively, and anhydrous sodium sulfate drying is used in 4%w/v sodium bicarbonate aqueous solution and water washing then.Solvent removed by evaporation at reduced pressure.Residuum carries out the column chromatography purifying by silica gel, is that 6: 4 the ethyl acetate and the mixture of hexane are made eluent with volume ratio, and obtaining 717mg (productive rate 94.5%) title compound is amorphous solid.Mass spectrum (FAB-MS) m/z:759 (M+H
+, M=C
44H
58N
2O
9).
Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.59 1H, wide unimodal);
7.11 (2H, doublet, J=8.5Hz);
6.60 (2H, doublet, J=8.5Hz);
4.80 (1H, doublet, J=10.5Hz);
(4.65 1H, unimodal);
(3.90 2H, wide unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
3.02 (1H, dual triplet, J=2.1﹠amp; 9.3Hz);
(2.60 2H, multiplet);
(1.93 3H, unimodal);
(1.31 3H, unimodal);
0.97 (3H, triplet, J=7.3Hz);
0.82 (3H, doublet, J=6.4Hz);
0.77 (3H, doublet, J=6.5Hz).Embodiment 5813-[2-(4-methylamino-phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHMe, n=0 (compound 9)]
With similar embodiment 57 described methods, just with 2-[4-(N-(4-nitro carbobenzoxy-(Cbz)) methylamino-phenyl]-2 Methylpropionic acid replaces 1-(4-nitrophenyl) Cyclopentane carboxylic acid, the preparation title compound.Mass spectrum (m/z:747 (the M+H of FAB-MS)
+, M=C
43H
58N
2O
9).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.13 1H, wide unimodal);
7.12 (2H, doublet, J=8.6Hz);
7.54 (2H, doublet, J=8.6Hz);
5.86 (1H, two dual doublets, J=2.1,2.1﹠amp; 11.2Hz);
(5.79 1H, multiplet);
5.77 (1H, dual doublet, J=11.2﹠amp; 14.0Hz);
4.86 (1H, doublet, J=10.4Hz);
4.74﹠amp; 4.71 (2H, dual AB-quartet, J=2.1﹠amp; 14.5Hz);
(4.65 1H, unimodal);
(3.97 1H, wide unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=2.3﹠amp; 9.4Hz);
(2.82 3H, unimodal);
1.93 (3H, doublet, J=1.4Hz);
(1.54 3H, unimodal);
(1.51 3H, unimodal);
(1.32 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
0.83 (6H, doublet, J=6.5Hz).Embodiment 5913-[1-(4-acetylamino phenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHAc, n=0 (compound 191)]
Will be by 1.31g (1.50mmol) 13-[1-(4-aminophenyl) the pentamethylene carbonyl oxygen base of the described preparation of embodiment 57 (c)]-5-t-butyldimethylsilyloxy base imino--milbemycin A4 is dissolved in the 15ml methylene dichloride, and adds 0.137ml (1.70mmol) pyridine and 0.161ml (1.70mmol) acetic anhydride therein.With mixture stirring at room 20 minutes.During end, reaction mixture dilutes with the 100ml ethyl acetate, and uses the 0.2M aqueous citric acid solution successively, water, and anhydrous sodium sulfate drying is used in 4%w/v sodium bicarbonate aqueous solution and water washing then.Solvent removed by evaporation at reduced pressure.The gained residuum is dissolved in 30ml methyl alcohol, and adds 3.0ml 1M aqueous hydrochloric acid therein.Reaction mixture is stirring at room 20 minutes, then with the ethyl acetate dilution, and water successively, 4%w/v sodium bicarbonate aqueous solution and water washing.Use anhydrous sodium sulfate drying, solvent removed by evaporation at reduced pressure.Residuum carries out the column chromatography purifying by silica gel, is that 6: 4 the ethyl acetate and the mixture of hexane are made eluent with volume ratio, and obtaining 717mg (productive rate 94.5%) title compound is amorphous solid.Mass spectrum (FAB-MS) m/z:801 (M+H
+, M=C
46H
60N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.34 1H, unimodal);
7.41 (2H, doublet, J=8.5Hz);
7.28 (2H, doublet, J=8.5Hz);
(7.17 1H, unimodal);
(5.83 1H, multiplet);
(5.78 1H, multiplet);
(5.77 1H, multiplet);
4.80 (1H, doublet, J=10.5Hz);
4.74﹠amp; 4.60 (2H, dual AB-quartet, J=1.9﹠amp; 14.6Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
3.02 (1H, dual triplet, J=2.2﹠amp; 9.3Hz);
(2.61 2H, multiplet);
(2.17 3H, unimodal);
(1.93 3H, unimodal);
(1.29 3H, unimodal);
0.97 (3H, triplet, J=7.3Hz);
0.82 (3H, doublet, J=6.5Hz);
0.76 (3H, doublet, J=6.5Hz).Embodiment 60-71
Embodiment 60-71 compound is with being same as embodiment 59 described method preparations.Embodiment 6013-[1-(4-methanesulfonamido phenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHSO
2Me, n=0 (compound 313)] mass spectrum (FAB-MS) m/z:837 (M+H
+, M=C
45H
60N
2O
11S).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.74 1H, wide unimodal);
7.32 (2H, doublet, J=8.6Hz);
7.14 (2H, doublet, J=8.6Hz);
(6.72 1H, wide unimodal);
4.80 (1H, doublet, J=10.6Hz);
4.73﹠amp; 4.60 (2H, the AB-quartet, J=14.5Hz);
(4.65 1H, unimodal);
(3.99 1H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
3.01 (1H, dual triplet, J=2.2﹠amp; 9.3Hz);
(2.96 3H, unimodal);
(2.61 2H, multiplet);
(1.91 3H, unimodal);
(1.28 3H, unimodal);
0.96 (3H, triplet, J=7.2Hz);
0.81 (3H, doublet, J=6.3Hz);
0.74 (3H, doublet, J=6.5Hz).Embodiment 6113-[1-(4-pivalyl aminophenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOtBu, n=0 (compound 203)] mass spectrum (FAB-MS) m/z:843 (M+H
+, M=C
49H
66N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.50 1H, wide unimodal);
7.44 (2H, doublet, J=8.7Hz);
(7.20-7.30 3H, multiplet);
4.81 (1H, doublet, J=10.5Hz);
4.75﹠amp; 4.67 (2H, the AB-quartet, J=14.5Hz);
(4.65 1H, unimodal);
(3.96 1H, wide unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(2.59 1H, multiplet);
(1.92 3H, unimodal);
(1.31 3H, unimodal);
1.14 (3H, doublet, J=5.9Hz);
1.02 (3H, doublet, J=6.4Hz);
0.82 (3H, doublet, J=6.4Hz).Embodiment 6213-[1-(4-hexanaphthene carbonylamino phenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCO-cHx, n=0 (compound 207)] mass spectrum (FAB-MS) m/z:869 (M+H
+, M=C
51H
68N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.75 1H, wide unimodal);
7.44 (2H, doublet, J=8.6Hz);
7.27 (2H, doublet, J=8.6Hz);
(7.17 1H, unimodal);
4.81 (1H, doublet, J=10.6Hz);
4.74﹠amp; 4.66 (2H, the AB-quartet, J=15.2Hz);
(4.66 1H, unimodal);
(4.00 1H, wide unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.02 1H, multiplet);
(2.59 2H, multiplet);
(1.92 3H, unimodal);
(1.30 3H, unimodal);
0.97 (3H, triplet, J=7.3Hz);
0.82 (3H, doublet, J=6.4Hz);
0.76 (3H, doublet, J=6.5Hz).Embodiment 6313-[1-(4-valeryl aminophenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOBu, n=0 (compound 201)] mass spectrum (FAB-MS) m/z:843 (M+H
+, M=C
49H
66N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.30 1H, wide unimodal);
7.43 (2H, doublet, J=8.5Hz);
7.27 (2H, doublet, J=8.5Hz);
(7.08 1H, unimodal);
4.81 (1H, doublet, J=10.6Hz);
4.75﹠amp; 4.67 (2H, the AB-quartet, J=15.0Hz);
(4.66 1H, unimodal);
(3.95 1H, wide unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.02 1H, multiplet);
(2.60 2H, multiplet);
(1.93 3H, unimodal);
(1.31 3H, unimodal);
(1.00-0.90 4H, multiplet);
0.82 (3H, doublet, J=6.4Hz);
0.76 (3H, doublet, J=6.5Hz).Embodiment 6413-[1-(4-propionamido phenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOEt, n=0 (compound 198)] mass spectrum (FAB-MS) m/z:815 (M+H
+, M=C
48H
62N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.50 1H, wide unimodal);
7.43 (2H, doublet, J=8.5Hz);
7.27 (2H, doublet, J=8.5Hz);
(7.12 1H, wide unimodal);
4.81 (1H, doublet, J=10.5Hz);
4.74﹠amp; 4.66 (2H, the AB-quartet, J=15.2Hz);
(4.65 1H, unimodal);
(3.95 1H, wide unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.02 1H, multiplet);
(2.60 2H, multiplet);
(1.92 3H, unimodal);
(1.30 3H, unimodal);
0.97 (3H, triplet, J=7.2Hz);
0.82 (3H, doublet, J=6.3Hz);
0.76 (3H, doublet, J=6.5Hz).Embodiment 6513-[1-(4-cyclopropane carbonyl aminophenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOcPr, n=0 (compound 204)] mass spectrum (FAB-MS) m/z:827 (M+H
+, M=C
48H
62N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.11 1H, wide unimodal);
(7.52-7.28 5H, multiplet);
4.80 (1H, doublet, J=10.4Hz);
4.75﹠amp; 4.68 (2H, dual AB-quartet, J=1.8﹠amp; 14.9Hz);
(4.65 1H, unimodal);
(3.97 1H, wide unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(2.62 2H, multiplet);
(1.93 3H, unimodal);
(1.29 3H, unimodal);
0.97 (3H, triplet, J=7.2Hz);
0.82 (3H, doublet, J=6.4Hz);
0.76 (3H, doublet, J=6.5Hz).Embodiment 66 13-{1-[4-(tetramethylene carbonylamino) phenyl] pentamethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOcBu, n=0 (compound 205)] mass spectrum (FAB-MS) m/z:843 (M+H
+, M=C
49H
64N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.13 1H, unimodal);
7.44 (2H, doublet, J=8.7Hz);
7.27 (2H, doublet, J=8.7Hz);
(6.97 1H, unimodal);
4.81 (1H, doublet, J=10.4Hz);
4.74﹠amp; 4.68 (2H, the AB-quartet, J=14.4Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.02 1H, multiplet);
(2.58 2H, multiplet);
(1.93 3H, unimodal);
(1.30 3H, unimodal);
0.97 (3H, triplet, J=7.2Hz);
0.82 (3H, doublet, J=6.4Hz);
0.76 (3H, doublet, J=6.5Hz).Embodiment 6713-[1-(4-cyanoacetamide base phenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOCH
2CN, n=0 (compound 211)] mass spectrum (FAB-MS) m/z:826 (M+H
+, M=C
47H
59N
3O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.07 1H, unimodal);
(7.70 1H, unimodal);
7.42 (2H, doublet, J=8.7Hz);
7.33 (2H, doublet, J=8.7Hz);
4.81 (1H, doublet, J=10.4Hz);
4.74﹠amp; 4.68 (2H, the AB-quartet, J=14.4Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.55 2H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
(3.02 1H, multiplet);
(2.61 2H, multiplet);
1.93 (3H, doublet, J=1.6Hz);
(1.30 3H, unimodal);
0.97 (3H, triplet, J=7.2Hz);
0.82 (3H, doublet, J=6.5Hz);
0.76 (3H, doublet, J=6.5Hz).Embodiment 6813-[1-(4-butyrylamino phenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOPr, n=0 (compound 199)] mass spectrum (FAB-MS) m/z:829 (M+H
+, M=C
48H
64N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.12 1H, unimodal);
7.43 (2H, doublet, J=8.6Hz);
7.28 (2H, doublet, J=8.6Hz);
(7.09 1H, unimodal);
4.81 (1H, doublet, J=10.4Hz);
4.74﹠amp; 4.67 (2H, dual AB-quartet, J=2.0﹠amp; 14.4Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
(3.02 1H, multiplet);
(2.61 2H, multiplet);
1.93 (3H, doublet, J=1.6Hz);
(1.30 3H, unimodal);
(1.03-0.95 6H, multiplet);
0.82 (3H, doublet, J=6.4Hz);
0.76 (3H, doublet, J=6.4Hz).Embodiment 6913-[1-(4-isobutyryl aminophenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOiPr, n=0 (compound 200)] mass spectrum (FAB-MS) m/z:829 (M+H
+, M=C
48H
64N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.11 1H, unimodal);
7.44 (2H, doublet, J=8.6Hz);
7.28 (2H, doublet, J=8.6Hz);
(7.10 1H, unimodal);
4.81 (1H, doublet, J=10.4Hz);
4.75﹠amp; 4.68 (2H, dual AB-quartet, J=2.0﹠amp; 14.4Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
(3.02 1H, multiplet);
(2.60 2H, multiplet);
1.93 (3H, doublet, J=1.6Hz);
(1.30 3H, unimodal);
1.26 (6H, doublet, J=6.8Hz);
0.97 (3H, triplet, J=7.2Hz);
0.82 (3H, doublet, J=6.4Hz);
0.77 (3H, doublet, J=6.4Hz).Embodiment 7013-[1-(4-isovaleryl aminophenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOiBu, n=0 (compound 202)] mass spectrum (FAB-MS) m/z:843 (M+H
+, M=C
49H
66N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.14 1H, wide unimodal);
7.43 (2H, doublet, J=8.6Hz);
7.28 (2H, doublet, J=8.6Hz);
(7.07 1H, unimodal);
4.81 (1H, doublet, J=10.4Hz);
4.74﹠amp; 4.68 (2H, dual AB-quartet, J=1.8﹠amp; 14.2Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
(3.02 1H, multiplet);
(2.60 2H, multiplet);
1.93 (3H, doublet, J=1.4Hz);
(1.30 3H, unimodal);
1.02 (6H, doublet, J=7.2Hz);
0.97 (3H, triplet, J=7.2Hz);
0.82 (3H, doublet, J=6.4Hz);
0.76 (3H, doublet, J=6.4Hz).Embodiment 7113-{1-[4-(pentamethylene carbonylamino) phenyl] pentamethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOcPn, n=0 (compound 206)] mass spectrum (FAB-MS) m/z:855 (M+H
+, M=C
50H
66N
2O
10).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.16 1H, wide unimodal);
7.44 (2H, doublet, J=8.4Hz);
7.27 (2H, doublet, J=8.4Hz);
(7.12 1H, unimodal);
4.81 (1H, doublet, J=10.8Hz);
4.74﹠amp; 4.68 (2H, dual AB-quartet, J=1.8﹠amp; 14.2Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(2.66 1H, multiplet);
(2.61 2H, multiplet);
1.93 (3H, doublet, J=1.4Hz);
(1.30 3H, unimodal);
0.97 (3H, triplet, J=7.3Hz);
0.82 (3H, doublet, J=6.4Hz);
0.76 (3H, doublet, J=6.4Hz).Embodiment 7213-{2-[4-(N-methyl methanesulfonamido) phenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-N (Me) SO
2Me, n=0 (compound 151)] mass spectrum (FAB-MS) m/z:825 (M+H
+, M=C
44H
60N
2O
11S).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.05 1H, unimodal);
(7.31 4H, unimodal);
4.87 (1H, doublet, J=10.7Hz);
4.73﹠amp; 4.67 (2H, dual AB-quartet, J=2.0﹠amp; 14.3Hz);
(4.65 1H, unimodal);
(3.96 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.30 3H, unimodal);
3.03 (1H, dual doublet, J=2.3﹠amp; 9.3Hz);
(2.81 3H, unimodal);
(1.93 3H, unimodal);
(1.59 3H, unimodal);
(1.56 3H, unimodal);
(1.29 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz); 0.83 (3H, doublet, J=6.6Hz); 0.81 (3H, doublet, J=6.6Hz).Embodiment 7313-{2-[4-(N-methyl methoxy base carbonylamino) phenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-N (Me) COOMe, n=0 (compound 123)] mass spectrum (FAB-MS) m/z:805 (M+H
+, M=C
45H
60N
2O
11).
Nuclear magnetic resonance spectrum (CDCl
3) δ ppm:
(8.10 1H, unimodal);
7.27 (2H, doublet, J=8.5Hz);
7.16 (2H, doublet, J=8.5Hz);
4.87 (1H, doublet, J=10.6Hz);
4.73﹠amp; 4.67 (2H, dual AB-quartet, J=2.0﹠amp; 14.5Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.71 3H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.27 3H, unimodal);
3.03 (1H, dual doublet, J=2.2﹠amp; 9.3Hz);
(1.93 3H, unimodal);
(1.59 3H, unimodal);
(1.56 3H, unimodal);
(1.29 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (3H, doublet, J=6.5Hz);
0.81 (3H, doublet, J=6.5Hz).Embodiment 74-83
With the method identical, from 13-[1-(4-nitrophenyl) tetramethylene carbonyl oxygen base with embodiment 18]-5-oximido-milbemycin A4 begins to prepare embodiment 74-83 compound.Embodiment 7413-[1-(4-acetylamino phenyl) tetramethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2) 3, R
3=4-NHAc, n=0 (compound 457)] mass spectrum (FAB-MS) m/z:787 (M+H
+, M=C
45H
58N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.34 1H, unimodal);
7.41 (2H, doublet, J=8.5Hz);
7.28 (2H, doublet, J=8.5Hz);
17 (1H, unimodal);
(5.83 1H, multiplet);
(5.78 1H, multiplet);
(5.77 1H, multiplet);
4.80 (1H, doublet, J=10.5Hz);
4.74﹠amp; 4.60 (2H, dual AB-quartet, J=1.9﹠amp; 14.6Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
3.02 (1H, dual triplet, J=2.2﹠amp; 9.3Hz);
(2.61 2H, multiplet);
(2.17 3H, unimodal);
(1.93 3H, unimodal);
(1.29 3H, unimodal);
0.97 (3H, triplet, J=7.3Hz);
0.82 (3H, doublet, J=6.5Hz);
0.76 (3H, doublet, J=6.5Hz).Embodiment 7513-[1-(4-methoxycarbonyl aminophenyl) tetramethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
3, R
3=4-NHCOOMe, n=0 (compound 491)] mass spectrum (FAB-MS) m/z:803 (M+H
+, M=C
45H
58N
2O
11).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(7.82 1H, wide unimodal);
7.32 (2H, doublet, J=8.6Hz);
7.21 (2H, doublet, J=8.6Hz);
(6.57 1H, wide unimodal);
4.84 (1H, doublet, J=10.6Hz);
4.72﹠amp; 4.70 (2H, the AB-quartet, J=14.5Hz);
(4.65 1H, unimodal);
(3.95 1H, unimodal);
(3.78 3H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
3.03 (1H, dual triplet, J=2.3﹠amp; 9.2Hz);
(2.86-2.70 2H, multiplet);
(2.52-2.41 3H, multiplet);
(1.93 3H, unimodal);
(1.34 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.82 (3H, doublet, J=6.6Hz);
0.76 (3H, doublet, J=6.6Hz).Embodiment 7613-[1-(4-methanesulfonamido phenyl) tetramethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
3, R
3=4-NHSO
2Me, n=0 (compound 503)] mass spectrum (FAB-MS) m/z:823 (M+H
+, M=C
44H
58N
2O
11S).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(7.85 1H, wide unimodal);
7.27 (2H, doublet, J=8.6Hz);
7.17 (2H, doublet, J=8.6Hz);
(6.35 1H, wide unimodal);
4.85 (1H, doublet, J=10.6Hz);
4.73﹠amp; 4.70 (2H, the AB-quartet, J=14.5Hz);
(4.66 1H, unimodal);
(3.96 1H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(2.98 3H, unimodal);
(2.88-2.73 2H, multiplet);
(2.53-2.42 3H, multiplet);
(1.93 3H, unimodal);
(1.34 3H, unimodal);
0.97 (3H, triple, J=7.3Hz);
0.82 (3H, doublet, J=6.4Hz);
0.76 (3H, doublet, J=6.6Hz).Embodiment 7713-{1-[4-(4-nitrobenzoyl amido) phenyl] tetramethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
3, R
3=4-NHCO (4-NO
2Ph), n=0 (compound 478)] mass spectrum (FAB-MS) m/z:894 (M+H
+, M=C
50H
59N
3O
12).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:.60 (1H, wide unimodal);
.35 (2H, doublet, J=8.8Hz);
.05 (2H, doublet, J=8.4Hz);
.85 (1H, unimodal);
.59 (2H, doublet, J=8.4Hz);
.31 (2H, doublet, J=8.8Hz);
.87 (1H, doublet, J=10.4Hz);
.74﹠amp; 4.68 (2H, dual AB-quartet, J=1.6﹠amp; 14.4Hz);
.65 (1H, unimodal);
.96 (1H, unimodal);
.54 (1H, multiplet);
.36 (1H, multiplet);
.03 (1H, multiplet);
.88-2.75 (2H, multiplet);
.93 (3H, unimodal);
.36 (3H, unimodal);
.98 (3H, triplet, J=7.3Hz);
.82 (3H, doublet, J=6.4Hz);
.79 (3H, doublet, J=6.4Hz).Embodiment 7813-{1-[4-(4-tert.-butylbenzene formamido group) phenyl] tetramethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
3, R
3=4-NHCO (4-tBuPh), n=0 (compound 479)] mass spectrum (FAB-MS) m/z:905 (M+H
+, M=C
54H
68N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.02 1H, wide unimodal);
7.81 (2H, doublet, J=8.4Hz);
(7.77 1H, unimodal);
7.59 (2H, doublet, J=8.4Hz);
7.50 (2H, doublet, J=8.4Hz);
(7.29 1H, unimodal);
4.86 (1H, doublet, J=10.4Hz);
4.75﹠amp; 4.68 (2H, the AB-quartet, J=14.7Hz);
(4.66 1H, unimodal);
(3.95 1H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(2.87-2.74 2H, multiplet);
(1.93 3H, unimodal);
(1.36 12H, multiplet);
0.98 (3H, triplet, J=7.4Hz);
0.82 (3H, doublet, J=6.4Hz);
0.78 (3H, doublet, J=6.8Hz).Embodiment 7913-{1-[4-(4-methoxybenzoyl amino) phenyl] tetramethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
3, R
3=4-NHCO (4-MeOPh), n=0 (compound 476)] mass spectrum (FAB-MS) m/z:867 (M+H
+, M=C
50H
62N
2O
11).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.23 1H, wide unimodal);
7.85 (2H, doublet, J=8.8Hz);
(7.73 1H, unimodal);
7.58 (2H, doublet, J=8.6Hz);
(7.28 1H, unimodal);
6.98 (2H, doublet, J=8.8Hz);
4.86 (1H, doublet, J=10.4Hz);
4.75﹠amp; 4.68 (2H, dual AB-quartet, J=1.8﹠amp; 14.6Hz);
(4.66 1H, unimodal);
(3.95 1H, unimodal);
(3.88 3H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(2.87-2.74 2H, multiplet);
(1.93 3H, unimodal);
(1.36 3H, unimodal);
0.98 (3H, triplet, J=7.4Hz);
0.82 (3H, doublet, J=6.6Hz);
0.78 (3H, doublet, J=6.4Hz).Embodiment 8013-{1-[4-(4-chlorobenzoyl amino) phenyl] tetramethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
3, R
3=4-NHCO (4-ClPh), n=0 (compound 477)] mass spectrum (FAB-MS) m/z:883 (M+H
+, M=C
50H
59N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.04 1H, wide unimodal);
7.82 (2H, doublet, J=8.8Hz);
(7.76 1H, unimodal);
7.57 (2H, doublet, J=8.4Hz);
7.47 (2H, doublet, J=8.4Hz);
7.28 (2H, doublet, J=8.8Hz);
4.86 (1H, doublet, J=10.4Hz);
4.75﹠amp; 4.68 (2H, dual AB-quartet, J=1.8﹠amp; 14.6Hz);
(4.66 1H, unimodal);
(3.96 1H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(2.87-2.74 2H, multiplet);
(1.93 3H, unimodal);
(1.36 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
0.82 (3H, doublet, J=6.4Hz);
0.78 (3H, doublet, J=6.4Hz).Embodiment 8113-[1-(4-valeryl aminophenyl) tetramethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
3, R
3=4-NHCOBu, n=0 (compound 461)] mass spectrum (FAB-MS) m/z:829 (M+H
+, M=C
48H
64N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.48 1H, wide unimodal);
7.46 (2H, doublet, J=8.6Hz);
7.22 (2H, doublet, J=8.6Hz);
(7.11 1H, unimodal);
4.85 (1H, doublet, J=10.4Hz);
4.75﹠amp; 4.68 (2H, dual AB-quartet, J=1.6﹠amp; 14.4Hz);
(4.66 1H, unimodal);
(3.96 1H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(2.84-2.72 2H, multiplet);
(1.93 3H, unimodal);
(1.34 3H, unimodal);
(0.99-0.93 6H, multiplet);
0.82 (3H, doublet, J=6.4Hz);
0.77 (3H, doublet, J=6.4Hz).Embodiment 8213-[1-(4-pivalyl aminophenyl) tetramethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
3, R
3=4-NHCOtBu, n=0 (compound 462)] mass spectrum (FAB-MS) m/z:829 (M+H
+, M=C
48H
64N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.09 1H, wide unimodal);
7.47 (2H, doublet, J=8.8Hz);
(7.29 1H, unimodal);
7.23 (2H, doublet, J=8.8Hz);
4.85 (1H, doublet, J=10.8Hz);
4.75﹠amp; 4.68 (2H, dual AB-quartet, J=1.8﹠amp; 14.2Hz);
(4.66 1H, unimodal);
(3.95 1H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(2.85-2.72 2H, multiplet);
(1.93 3H, unimodal);
(1.34 3H, unimodal);
(1.32 9H, unimodal);
0.98 (3H, triplet, J=7.4Hz);
0.82 (3H, doublet, J=6.8Hz);
0.78 (3H, doublet, J=6.4Hz).Embodiment 8313-{1-[4-(hexanaphthene carbonylamino) phenyl] tetramethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, x=CO, Z=＞C (CH
2)
3, R
3=4-NHCOcHx, n=0 (compound 464)] mass spectrum (FAB-MS) m/z:855 (M+H
+, M=C
50H
66N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.20 1H, wide unimodal);
7.47 (2H, doublet, J=8.6Hz);
7.22 (2H, doublet, J=8.6Hz);
(7.12 1H, unimodal);
4.85 (1H, doublet, J=10.4Hz);
4.75﹠amp; 4.68 (2H, dual AB-quartet, J=1.8﹠amp; 14.2Hz);
(4.66 1H, unimodal);
(3.95 1H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
(3.05 1H, multiplet);
(2.85-2.71 2H, multiplet);
(1.93 3H, unimodal);
(1.34 3H, unimodal);
0.97 (3H, triplet, J=7.2Hz);
0.82 (3H, doublet, J=6.4Hz);
0.77 (3H, doublet, J=6.4Hz).Embodiment 8413-[1-(4-aminophenyl)-1-ethyl butyryl acyloxy]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Et)
2, R
3=4-NH2, n=0 (compound 332)] 84 (a) 3-[1-(4-aminophenyl)-1-ethyl butyryl acyloxy]-5-t-butyldimethylsilyloxy base imino--milbemycin A
4
Under the described condition of embodiment 57 (a), handle 15-hydroxyl-5-oxygen-milbemycin with 1-(4-nitrophenyl)-1-ethyl butyric acid, products therefrom is pressed embodiment 57 (b), (c) and (d) described same way as is handled, and obtaining title compound (productive rate 46.9%) is amorphous solid.84 (b) 3-[1-(4-aminophenyl)-1-ethyl butyryl acyloxy]-5-oximido-milbemycin A
4
With the described same procedure of embodiment 57 (e), from 13-[1-(4-the aminophenyl)-1-ethyl butyryl acyloxy of top step (a) preparation]-5-t-butyldimethylsilyloxy base imino--milbemycin A
4Beginning, the preparation title compound.Mass spectrum (FAB-MS) m/z:761 (M+H
+, M=C
44H
60N
2O
9).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(7.84 1H, unimodal);
6.99 (2H, doublet, J=8.6Hz);
6.61 (2H, doublet, J=8.6Hz);
4.88 (1H, doublet, J=10.7Hz);
4.73﹠amp; 4.67 (2H, dual AB-quartet, J=2.2﹠amp; 14.4Hz);
(4.65 1H, unimodal);
(3.99 1H, unimodal);
(3.65-3.50 3H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual doublet, J=2.2﹠amp; 9.4Hz);
1.93 (3H, bimodal, J=1.8Hz);
(1.27 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (3H, doublet, J=6.1Hz);
0.82 (3H, doublet, J=6.4Hz);
0.72 (3H, triplet, J=7.4Hz);
0.67 (3H, triplet, J=7.4Hz).Embodiment 8513-[1-(4-acetylamino phenyl)-1-ethyl butyryl acyloxy]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Et)
2, R
3=4-NHAC, n=0 (compound 336)]
Will be by 172mg (0.20mmol) 13-[1-(4-the aminophenyl)-1-ethyl butyryl acyloxy of embodiment 84 (a) preparation]-5-t-butyldimethylsilyloxy base imino--milbemycin A4 is dissolved in the 2.0ml methylene dichloride, and adds 0.018ml (0.22mmol) pyridine and 0.021ml (0.22mmol) acetic anhydride therein.The gained mixture was stirring at room 20 minutes.During end, reaction mixture dilutes with the 20ml ethyl acetate, and uses the 0.2M aqueous citric acid solution successively, water, and anhydrous sodium sulfate drying is used in 4%w/v sodium bicarbonate aqueous solution and water washing then.Solvent removed by evaporation at reduced pressure.The gained residuum is dissolved in 4.0ml methyl alcohol, and adds 0.4ml 1M aqueous hydrochloric acid therein.Reaction mixture is stirring at room 20 minutes, then with the dilution of 20ml ethyl acetate, and water successively, 4%w/v sodium bicarbonate aqueous solution and water washing.Use anhydrous sodium sulfate drying, solvent removed by evaporation at reduced pressure.Residuum carries out the column chromatography purifying by silica gel, is that 6: 4 the ethyl acetate and the mixture of hexane are made eluent with volume ratio, and obtaining 149mg (productive rate 92.7%) title compound is amorphous solid.Mass spectrum (FAB-MS) m/z:803 (M+H
+, M=C
46H
62N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.30 1H, unimodal);
7.42 (2H, doublet, J=8.6Hz);
7.17 (2H, doublet, J=8.6Hz);
(7.15 1H, wide unimodal);
4.89 (1H, doublet, J=10.6Hz);
4.73﹠amp; 4.65 (2H, the AB-quartet, J=14.3Hz);
(4.65 1H, unimodal);
(3.99 1H, unimodal);
(3.58 1H, multiplet);
(3.37 1H, multiplet);
(3.03 1H, multiplet);
(2.17 3H, unimodal);
(1.93 3H, unimodal);
(1.25 3H, unimodal);
0.98 (3H, triplet, J=7.1Hz);
(0.84-0.79 6H, multiplet);
(0.72-0.65 6H, multiplet).Embodiment 86-89
Prepare embodiment 86-89 compound with embodiment 85 described same procedure.Embodiment 8613-[1-(4-methanesulfonamido phenyl)-1-ethyl butyryl acyloxy]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Et)
2, R
3=4-NHSO
2Me, n=0 (compound 380)] mass spectrum (FAB-MS) m/z:839 (M+H
+, M=C
45H
62N
2O
11S).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.15 1H, unimodal);
7.23 (2H, doublet, J=8.6Hz);
7.14 (2H, doublet, J=8.6Hz);
(6.43 1H, unimodal);
4.89 (1H, doublet, J=10.6Hz);
4.73﹠amp; 4.65 (2H, the AB-quartet, J=15.4Hz);
(4.65 1H, unimodal);
(4.00 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(2.98 3H, unimodal);
(1.93 3H, unimodal);
(1.27 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (3H, doublet, J=6.6Hz);
0.79 (3H, doublet, J=6.0Hz);
(0.75-0.66 6H, multiplet).Embodiment 8713-{1-[4-(4-chlorobenzoyl amino) phenyl]-1-ethyl butyryl acyloxy }-the doubly plain A of 5-oximido-Mil
4[(I): R
1=Et, X=CO, Z=＞C (Et)
2, R
3=4-NHCO (4-ClPh), n=0 (compound 356)] mass spectrum (FAB-MS) m/z:899 (M+H
+, M=C
51H
64ClN
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.65 1H, unimodal);
7.82 (2H, doublet, J=8.5Hz);
(7.73 1H, unimodal);
7.56 (2H, doublet, J=8.6Hz);
7.48 (2H, doublet, J=8.5Hz);
7.24 (2H, doublet, J=8.7Hz);
4.91 (1H, doublet, J=10.5Hz);
4.74﹠amp; 4.66 (2H, the AB-quartet, J=14.4Hz);
(4.65 1H, unimodal);
(4.00 1H, unimodal);
(3.58 1H, multiplet);
(3.35 1H, multiplet);
(3.05 1H, multiplet);
(1.93 3H, unimodal);
(1.28 3H, unimodal);
0.99 (3H, triplet, J=7.3Hz);
(0.81-0.84 6H, multiplet);
(0.76-0.66 6H, multiplet).Embodiment 8813-[1-(4-pentanamide base table base)-1-ethyl butyryl acyloxy]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Et)
2, R
3=4-NHCOBu, n=0 (compound 342)] mass spectrum (FAB-MS) m/z:845 (M+H
+, M=C
49H
68N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.34 1H, wide unimodal);
7.43 (2H, doublet, J=8.6Hz);
7.17 (2H, doublet, J=8.6Hz);
(7.09 1H, unimodal);
4.90 (1H, doublet, J=10.8Hz);
4.73﹠amp; 4.65 (2H, dual AB-quartet, J=2.2﹠amp; 14.6Hz);
(4.65 1H, unimodal);
(3.99 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
2.20 (1H, dual doublet, J=11.6﹠amp; 24.0Hz);
(1.93 3H, unimodal);
(1.26 3H, unimodal);
(1.00-0.88 6H, multiplet);
(0.86-0.77 6H, multiplet);
(0.73-0.66 6H, multiplet).Embodiment 8913-{1-[4-(hexanaphthene carbonylamino) phenyl]-1-ethyl butyryl acyloxy }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Et)
2, R
3=4-NHCOcHx, n=0 (compound 345)] mass spectrum (FAB-MS) m/z:871 (M+H
+, M=C
51H
70N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.05 1H, wide unimodal);
7.45 (2H, doublet, J=8.6Hz);
7.16 (2H, doublet, J=8.6Hz);
(7.11 1H, unimodal);
4.90 (1H, doublet, J=10.8Hz);
4.73﹠amp; 4.65 (2H, dual AB-quartet, J=2.0﹠amp; 14.4Hz);
(4.65 1H, unimodal);
(3.99 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.93 3H, unimodal);
(1.27 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
(0.84-0.80 6H, multiplet);
(0.73-0.67 6H, multiplet).Embodiment 90-97
With embodiment 18 described same procedure, from 13-[1-(4-nitrophenyl) the cyclopropanecarbonyl-oxygen base of embodiment 6 preparations]-5-oximido-milbemycin A4, preparation embodiment 90-97 compound.Embodiment 9013-[1-(4-methanesulfonamido phenyl) cyclopropanecarbonyl-oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
2, R
3=4-NHSO
2Me, n=0 (compound 441)] mass spectrum (FAB-MS) m/z:809 (M+H
+, M=C
43H
56N
2O
11S).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.13 1H, unimodal);
7.32 (2H, doublet, J=8.5Hz);
7.15 (2H, doublet, J=8.5Hz);
(6.50 1H, unimodal);
4.88 (1H, doublet, J=10.4Hz);
4.73﹠amp; 4.70 (2H, dual AB-quartet, J=2.0﹠amp; 14.5Hz);
(4.65 1H, unimodal);
(3.93 1H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(3.01 3H, unimodal);
1.93 (3H, doublet, J=1.4Hz);
(1.38 3H, unimodal);
(1.17 2H, multiplet);
0.97 (3H, triplet, J=7.3Hz);
0.92 (3H, doublet, J=6.5Hz);
0.82 (3H, doublet, J=6.5Hz).Embodiment 9113-[1-(4-methoxycarbonyl aminophenyl) cyclopropanecarbonyl-oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
2, R
3=4-NHCOOMe, n=0 (compound 429)] mass spectrum (FAB-MS) m/z:789 (M+H
+, M=C
44H
56N
2O
11).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.11 1H, unimodal);
7.31 (2H, doublet, J=8.4Hz);
7.26 (2H, doublet, J=8.4Hz);
6 61 (1H, unimodal);
4.86 (1H, doublet, J=10.4Hz);
4.73﹠amp; 4.65 (2H, dual AB-quartet, J=2.1﹠amp; 14.5Hz);
(4.65 1H, unimodal);
(3.92 1H, unimodal);
(3.78 3H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
3.03 (1H, dual triplet, J=2.2﹠amp; 9.3Hz)
(1.93 3H, unimodal);
(1.37 3H, unimodal);
(1.15 2H, multiplet);
0.97 (3H, triplet, J=7.3Hz);
0.91 (3H, doublet, J=6.5Hz);
0.82 (3H, doublet, J=6.5Hz).Embodiment 9213-[1-(4-acetobrom aminophenyl) cyclopropanecarbonyl-oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH2) 2, R
3=4-NHCOCH
2Br, n=0 (compound 402)] mass spectrum (FAB-MS) m/z:851 (M+H
+, M=C
44H
55N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.14 1H, unimodal);
(8.13 1H, unimodal);
7.47 (2H, doublet, J=8.4Hz);
7.32 (2H, doublet, J=8.4Hz);
4.87 (1H, doublet, J=10.5Hz);
4.73﹠amp; 4.66 (2H, dual AB-quartet, J=2.0﹠amp; 15.3Hz);
(4.65 1H, unimodal);
(4.04 2H, unimodal);
(3.93 1H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
3.03 (1H, dual triplet, J=2.2﹠amp; 9.4Hz);
1.93 (3H, dual doublet, J=1.5﹠amp; 1.5Hz);
(1.37 3H, unimodal);
(1.15 2H, multiplet);
0.97 (3H, triplet, J=7.3Hz);
0.91 (3H, doublet, J=6.5Hz);
0.83 (3H, doublet, J=6.5Hz).Embodiment 9313-[1-(4-isobutyl boc aminophenyl) cyclopropanecarbonyl-oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
2, R
3=4-NHCOOiBu, n=0 (compound 431)] mass spectrum (FAB-MS) m/z:831 (M+H
+, M=C
47H
62N
2O
11).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.01 1H, unimodal);
7.32 (2H, doublet, J=8.6Hz);
7.26 (2H, doublet, J=8.6Hz);
(6.60 1H, unimodal);
4.86 (1H, doublet, J=10.5Hz);
4.73﹠amp; 4.67 (2H, dual AB-quartet, J=2.0﹠amp; 14.6Hz);
(4.65 1H, unimodal);
3.96 (2H, doublet, J=6.7Hz);
(3.92 1H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
3.03 (1H, dual triplet, J=2.2﹠amp; 9.4Hz);
(1.93 3H, unimodal);
(1.37 3H, unimodal);
(1.15 2H, multiplet);
0.97 (6H, doublet, J=6.9Hz);
0.97 (3H, triplet, J=7.2Hz);
0.91 (3H, doublet, J=6.5Hz);
0.83 (3H, doublet, J=6.5Hz).Embodiment 9413-[1-(4-cyanoacetamide base phenyl) cyclopropanecarbonyl-oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
2, R
3=4-NHCOCH
2CN, n=0 (compound 401)] mass spectrum (FAB-MS) m/z:798 (M+H
+, M=C
45H
55N
3O
10).Nuclear magnetic resonance spectrum (CDC13) δ (ppm:
(8.24 1H, unimodal);
(7.80 1H, unimodal);
7.42 (2H, doublet, J=8.6Hz);
7.32 (2H, doublet, J=8.6Hz);
4.88 (1H, doublet, J=10.5Hz);
4.73﹠amp; 4.67 (2H, dual AB-quartet, J=1.9﹠amp; 14.6Hz);
(4.65 1H, unimodal);
(3.94 1H, unimodal);
(3.55 1H, multiplet);
(3.54 2H, unimodal);
(3.36 1H, multiplet);
3.03 (1H, dual triplet, J=2.1﹠amp; 9.5Hz);
1.93 (3H, doublet, J=1.5Hz);
(1.38 3H, unimodal);
(1.18 2H, multiplet);
0.97 (3H, triplet, J=7.3Hz);
0.92 (3H, doublet, J=6.6Hz);
0.83 (3H, doublet, J=6.5Hz).Embodiment 9513-{1-[4-(4-nitrobenzoyl amido) phenyl] cyclopropanecarbonyl-oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
2, R
3=4-NHCO (4-NO
2Ph), n=0 (compound 416)] mass spectrum (FAB-MS) m/z:880 (M+H
+, M=C
49H
58N
3O
12).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
8.35 (2H, doublet, J=8.8Hz);
(8.07 1H, unimodal);
8.05 (2H, doublet; J=8.8Hz);
(7.88 1H, unimodal);
7.58 (2H, doublet, J=8.4Hz);
7.37 (2H, doublet, J=8.4Hz);
4.90 (1H, doublet, J=10.4Hz);
4.73﹠amp; 4.66 (2H, dual AB-quartet, J=1.9﹠amp; 14.4Hz);
(4.64 1H, unimodal);
(3.94 1H, unimodal);
(3.55 1H, multiplet);
(3.54 2H, unimodal);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(1.93 3H, unimodal);
(1.39 3H, unimodal);
(1.18 2H, multiplet);
0.97 (3H, triplet, J=7.2Hz);
0.93 (3H, doublet, J=6.4Hz);
0.83 (3H, doublet, J=6.4Hz).Embodiment 9613-{1-[4-(4-tert.-butylbenzene formamido group) phenyl] cyclopropanecarbonyl-oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
2, R
3=4-NHCO (4-tBuPh), n=0 (compound 417)] mass spectrum (FAB-MS) m/z:913 (M+H
+, M=C
53H
67N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.08 1H, wide unimodal);
7.81 (2H, doublet, J=8.8Hz);
(7.79 1H, unimodal);
7.58 (2H, doublet, J=8.4Hz);
7.51 (2H, doublet, J=8.8Hz);
7.33 (2H, doublet, J=8.4Hz);
4.88 (1H, doublet, J=10.4Hz);
4.73﹠amp; 4.66 (2H, dual AB-quartet, J=1.9﹠amp; 14.6Hz);
(4.65 1H, unimodal);
(3.92 1H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(1.93 3H, unimodal);
(1.38 3H, unimodal);
(1.18 2H, multiplet);
0.97 (3H, triplet, J=7.2Hz);
0.92 (3H, doublet, J=6.4Hz);
0.83 (3H, doublet, J=6.4Hz).Embodiment 9713-{1-[4-(3,4-dimethoxy benzamido) phenyl] cyclopropanecarbonyl-oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
2, R
3=4-NHCO (3,4-two-MeOPh), n=0 (compound 415)] mass spectrum (FAB-MS) m/z:895 (M+H
+, M=C
51H
62N
2O
12).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
7.76 (1H, doublet, J=7.5Hz);
(7.59 1H, unimodal);
7.11 (2H, doublet, J=7.9Hz);
6.91 (1H, doublet, J=8.6Hz);
6.63 (2H, doublet, J=8.6Hz);
4.85 (1H, doublet, J=10.8Hz);
(4.78-4.64 2H, multiplet);
(4.68 1H, unimodal);
(3.96 3H, unimodal);
(3.95 3H, unimodal);
(3.55 1H, multiplet);
(3.37 1H, multiplet);
(3.03 1H, multiplet);
(1.95 3H, unimodal);
(1.39 3H, unimodal);
(1.18 2H, multiplet);
(1.00-0.92 6H, multiplet);
0.83 (3H, doublet, J=6.6Hz).Embodiment 9813-{2-[4-(the amino propionyl of 3-methoxycarbonyl) aminophenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOCH
2CH
2NHCOOMe, n=0 (compound 110)] 0.032ml (0.30mmol) triethylamine and 41mg (0.30mmol) isobutyl chlorocarbonate are added in the 2.0ml dichloromethane solution of 44mg (0.30mmol) 3-methoxycarbonyl alanine, and mixture was stirred 5 minutes.In mixture, add then and press embodiment 18 (a) and (b) 101mg of described preparation (0.12mmol) 13-[2-(4-aminophenyl)-2 Methylpropionic acid base]-5-t-butyldimethylsilyloxy base imino--milbemycin A4, and with mixture stirring at room 2 hours.During end, reaction mixture dilutes with the 20ml ethyl acetate, and uses the 0.2M aqueous citric acid solution successively, water, and anhydrous sodium sulfate drying is used in 4%w/v sodium bicarbonate aqueous solution and water washing then.Solvent removed by evaporation at reduced pressure.The gained residuum is dissolved in 2.0ml methyl alcohol, and adds 0.2ml 1M aqueous hydrochloric acid therein.Reaction mixture is stirring at room 20 minutes, then with the dilution of 20ml ethyl acetate, and water successively, 4%w/v sodium bicarbonate aqueous solution and water washing.Use anhydrous sodium sulfate drying, solvent removed by evaporation at reduced pressure.Residuum carries out the column chromatography purifying by silica gel, is that 6: 4 the ethyl acetate and the mixture of hexane are made eluent with volume ratio, and obtaining 96mg (productive rate 92.8%) title compound is amorphous solid.Mass spectrum (FAB-MS) m/z:862 (M+H
+, M=C
47H
63N
3O
12).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.39 1H, unimodal);
(7.50 1H, unimodal);
7.44 (2H, doublet, J=8.6Hz);
7.26 (2H, doublet, J=8.6Hz);
4.87 (1H, doublet, J=10.6Hz);
4.73﹠amp; 4.67 (2H, dual AB-quartet, J=2.0﹠amp; 14.7Hz);
(4.66 1H, unimodal);
(3.98 1H, unimodal);
(3.78 3H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=2.2﹠amp; 9.3Hz);
(1.93 3H, unimodal);
(1.56 3H, unimodal);
(1.54 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (3H, doublet, J=6.0Hz);
0.82 (3H, doublet, J=6.3Hz).Embodiment 99-109
Prepare embodiment 99-109 compound with embodiment 98 described same procedure.Embodiment 9913-{2-[4-(N-methyl-N-methoxycarbonyl glycyl) aminophenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOCH
2N (Me) COOMe, n=0 (compound 95)] mass spectrum (FAB-MS) m/z:862 (M+H
+, M=C
4754H
63N
3O
12).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.22 1H, unimodal);
7.45 (2H, doublet, J=8.6Hz);
7.26 (2H, doublet, J=8.6Hz);
4.87 (1H, doublet, J=10.4Hz);
4.74﹠amp; 4.67 (2H, dual AB-quartet, J=2.0﹠amp; 14.5Hz);
(4.66 1H, unimodal);
(4.03 2H, unimodal);
(3.97 1H, unimodal);
(3.78 3H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.06 3H, unimodal);
3.04 (1H, dual triplet, J=2.3﹠amp; 9.4Hz);
1.93 (3H, doublet, J=1.4Hz);
(1.56 3H, unimodal);
(1.53 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (3H, doublet, J=6.5Hz);
0.82 (3H, doublet, J=6.5Hz).Embodiment 10013-{2-[4-(N-methoxycarbonyl prolyl) aminophenyl]-the 2 Methylpropionic acid base }-5-that times mycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCO (1-COOMe-2-Pyrd), n=0 (compound 112)] mass spectrum (FAB-MS) m/z:888 (M+H
+, M=C
49H
65N
3O
12).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.13 1H, unimodal);
7.46 (2H, doublet, J=8.6Hz);
7.24 (2H, doublet, J=8.6Hz);
4.88 (1H, doublet, J=10.6Hz);
4.74﹠amp; 4.68 (2H, dual AB-quartet, J=2.0﹠amp; 14.4Hz);
(4.66 1H, unimodal);
(3.97 1H, unimodal);
(3.78 3H, unimodal);
(3.73 1H, multiplet);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=2.3﹠amp; 9.3Hz);
1.93 (3H, doublet, J=1.5Hz);
(1.56 3H, unimodal);
(1.53 3H, unimodal);
(1.32 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (6H, doublet, J=6.5Hz).Embodiment 10113-{2-[4-(N-methoxycarbonyl glycyl) methylamino-phenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-N (Me) COCH
2NHCOOMe, n=0 (compound 96)] mass spectrum (FAB-MS) m/z:862 (M+H
+, M=C
47H
63N
3O
12).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.12 1H, unimodal);
7.38 (2H, doublet, J=8.5Hz);
7.14 (2H, doublet, J=8.5Hz);
4.88 (1H, doublet, J=10.4Hz);
4.74﹠amp; 4.68 (2H, dual AB-quartet, J=1.9﹠amp; 14.7Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.64 3H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.23 3H, unimodal);
3.04 (1H, dual triplet, J=2.2﹠amp; 9.4Hz);
1.93 (3H, doublet, J=1.5Hz);
(1.61 3H, unimodal);
(1.58 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
0.83 (3H, doublet, J=6.4Hz);
0.82 (3H, doublet, J=6.3Hz).Embodiment 10213-{2-[4-(N-tertbutyloxycarbonyl glycyl) aminophenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOCH
2NHCOOtBu, n=0 (compound 89)] mass spectrum (FAB-MS) m/z:890 (M+H
+, M=C
49H
67N
3O
12).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.19 1H, unimodal);
(8.07 1H, wide unimodal);
7.36 (2H, doublet, J=8.4Hz);
7.26 (2H, doublet, J=8.4Hz);
4.87 (1H, doublet, J=10.4Hz);
4.74﹠amp; 4.67 (2H, dual AB-quartet, J=1.7﹠amp; 14.6Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
3.92 (2H, doublet, J=6.0Hz);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.93 3H, unimodal);
(1.60 3H, unimodal);
(1.56 3H, unimodal);
(1.53 3H, unimodal);
(1.48 9H, unimodal);
0.98 (3H, triplet, J=7.4Hz);
0.83 (6H, doublet, J=6.5Hz).Embodiment 10313-{2-[4-(N-methoxycarbonyl-2,2-dimethyl glycyl) aminophenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOC (Me)
2NHCOOMe, n=0 (compound 107)] mass spectrum (FAB-MS) m/z:874 (M+H
+, M=C
48H
62N
3O
12).Nuclear magnetic resonance spectrum (CDC13) δ ppm:
(8.67 1H, wide unimodal);
(8.17 1H, unimodal);
7.47 (2H, doublet, J=8.6Hz);
7.28 (2H, doublet, J=8.6Hz);
(5.13 1H, unimodal);
4.87 (1H, doublet, J=10.4Hz);
4.74﹠amp; 4.67 (2H, dual AB-quartet, J=1.8﹠amp; 14.6Hz);
(4.65 1H, unimodal);
(3.92 1H, unimodal);
(3.71 3H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.93 3H, unimodal);
(1.61 6H, unimodal);
(1.38 3H, unimodal);
0.98 (3H, triplet, J=7.4Hz);
0.83 (6H, doublet, J=6.5Hz).Embodiment 10413-{1-[4-(N-methoxycarbonyl glycyl) aminophenyl] cyclopropanecarbonyl-oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
2, R
3=4-NHCOCH
2NHCOOMe, n=0 (compound 422)] mass spectrum (FAB-MS) m/z:846 (M+H
+, M=C
46H
59N
3O
12).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.43 1H, unimodal);
(8.00 1H, wide unimodal);
7.46 (2H, doublet, J=8.5Hz);
7.29 (2H, doublet, J=8.5Hz);
4.87 (1H, doublet, J=10.4Hz);
4.73﹠amp; 4.67 (2H, dual AB-quartet, J=2.0﹠amp; 14.7Hz);
(4.66 1H, unimodal);
4.00 (2H, doublet, J=5.9Hz);
(3.94 1H, unimodal);
(3.75 3H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
3.03 (1H, dual triplet, J=2.0﹠amp; 9.3Hz);
1.93 (3H, doublet, J=1.6Hz);
(1.36 3H, unimodal);
(1.15 2H, multiplet);
0.97 (3H, triplet, J=7.2Hz);
0.91 (3H, doublet, J=6.5Hz);
0.83 (3H, doublet, J=6.4Hz).Embodiment 10513-{1-[4-(N-methoxycarbonyl glycyl) aminophenyl] tetramethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
3, R
3=4-NHCOCH
2NHCOOMe, n=0 (compound 484)] mass spectrum (FAB-MS) m/z:860 (M+H
+, M=C
47H
61N
3O
12).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.23 1H, unimodal);
(7.94 1H, wide unimodal);
7.46 (2H, doublet, J=8.4Hz);
7.23 (2H, doublet, J=8.4Hz);
(5.47 1H, multiplet);
4.84 (1H, doublet, J=10.4Hz);
4.75﹠amp; 4.68 (2H, dual AB-quartet, J=1.9﹠amp; 14.6Hz);
(4.66 1H, unimodal);
4.00 (2H, doublet, J=6.0Hz);
(3.96 1H, unimodal);
(3.75 3H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(2.84-2.73 2H, multiplet);
(1.93 3H, unimodal);
(1.33 3H, unimodal);
0.97 (3H, triplet, J=7.2Hz);
0.82 (3H, doublet, J=6.4Hz);
0.77 (3H, doublet, J=6.4Hz).Embodiment 10613-{1-[4-(N-methoxycarbonyl glycyl) aminophenyl] pentamethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOCH
2NHCOOMe, n=0 (compound 246)] mass spectrum (FAB-MS) m/z:874 (M+H
+, M=C
48H
63N
3O
12).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.34 1H, unimodal);
(7.96 1H, wide unimodal);
7.43 (2H, doublet, J=8.4Hz);
7.29 (2H, doublet, J=8.4Hz);
(5.50 1H, wide unimodal);
4.81 (1H, doublet, J=10.4Hz);
4.74﹠amp; 4.67 (2H, dual AB-quartet, J=1.8﹠amp; 14.4Hz);
(4.66 1H, unimodal);
3.99 (2H, doublet, J=6.0Hz);
(3.98 1H, unimodal);
(3.75 3H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(2.64-2.56 2H, multiplet);
2.17 (1H, dual doublet, J=11.6﹠amp; 24.0Hz);
(1.93 3H, unimodal);
(1.29 3H, unimodal);
0.97 (3H, triplet, J=7.2Hz);
0.82 (3H, doublet, J=6.4Hz);
0.76 (3H, doublet, J=6.4Hz).Embodiment 10713-{1-[4-(N-methoxycarbonyl-2,2-dimethyl glycyl) aminophenyl] pentamethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOC (Me)
2NHCOOMe, n=0 (compound 272)] mass spectrum (FAB-MS) m/z:902 (M+H
+, M=C
50H
67N
3O
12).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.64 1H, wide unimodal);
7.45 (2H, doublet, J=8.4Hz);
7.28 (2H, doublet, J=8.4Hz);
(5.20 1H, wide unimodal);
4.82 (1H, doublet, J=10.4Hz);
4.75﹠amp; 4.68 (2H, dual AB-quartet, J=1.8﹠amp; 14.2Hz);
(4.66 1H, unimodal);
(3.67 3H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(2.65-2.52 2H, multiplet);
2.18 (1H, dual doublet, J=11.6﹠amp; 24.0Hz);
(1.93 3H, unimodal);
(1.60 3H, unimodal);
(1.58 3H, unimodal);
(1.32 3H, unimodal);
0.97 (3H, triplet, J=7.2Hz);
0.82 (3H, doublet, J=6.4Hz);
0.78 (3H, doublet, J=6.4Hz).Embodiment 10813-{1-[4-(N-ethanoyl glycyl) aminophenyl] pentamethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOCH
2NHAC, n=0 (compound 256)] mass spectrum (FAB-MS) m/z:858 (M+H
+, M=C
48H
63N
3O
11).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.50 1H, unimodal);
(8.45 1H, wide unimodal);
7.45 (2H, doublet, J=8.6Hz);
7.28 (2H, doublet, J=8.6Hz);
(6.56 1H, multiplet);
4.80 (1H, doublet, J=10.4Hz);
4.74﹠amp; 4.67 (2H, dual AB-quartet, J=1.8﹠amp; 14.6Hz);
4.10 (2H, doublet, J=5.2Hz);
(4.00 1H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(2.64-2.56 2H, multiplet);
2.17 (1H, dual doublet, J=11.6﹠amp; 24.0Hz);
(2.09 3H, unimodal);
(1.93 3H, unimodal);
(1.29 3H, unimodal);
0.97 (3H, triplet, J=7.4Hz);
0.82 (3H, doublet, J=6.4Hz);
0.75 (3H, doublet, J=6.4Hz).Embodiment 10913-{2-[4-(N-ethanoyl glycyl) aminophenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCOCH
2NHAC, n=0 (compound 91)] mass spectrum (FAB-MS) m/z:832 (M+H
+, M=C
46H
61N
3O
11).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.34 1H, wide unimodal);
7.46 (2H, doublet, J=8.4Hz);
7.26 (2H, doublet, J=8.4Hz);
(6.48 1H, wide unimodal);
4.87 (1H, doublet, J=10.5Hz);
4.72﹠amp; 4.70 (2H, the AB-quartet, J=14.4Hz);
(4.66 1H, unimodal);
4.09 (2H, doublet, J=4.4Hz);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=2.1﹠amp; 8.9Hz);
(2.10 3H, unimodal);
(1.93 3H, unimodal);
(1.57 3H, unimodal);
(1.54 3H, unimodal);
(1.30 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
(0.84-0.76 6H, multiplet).Embodiment 11013-[1-(4-acetoxyl acetylamino phenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOCH
2OAC, n=0 (compound 214)]
With 47.2mg (0.40mmol) 3-acetoxyl ethyl, 0.028ml (0.20mmol) triethylamine and 51.1mg (0.20mmol) 2-chloro-1-picoline gold father-in-law iodide 7.3mg (0.10mmol) press 13-[2-(4-the aminophenyl)-2 Methylpropionic acid base of the described preparation of embodiment 57 (a)-(d)]-the 2.0ml methylene dichloride of 5-t-butyldimethylsilyloxy base imino--milbemycin A4 in, and with mixture stirring 1.5 hours.During end, reaction mixture dilutes with the 20ml ethyl acetate, and uses the 0.2M aqueous citric acid solution successively, water, and anhydrous sodium sulfate drying is used in 4%w/v sodium bicarbonate aqueous solution and water washing then.Solvent removed by evaporation at reduced pressure.The gained residuum is dissolved in 2.0ml methyl alcohol, and adds 0.2ml 1M aqueous hydrochloric acid therein.Reaction mixture is stirring at room 20 minutes, then with the dilution of 20ml ethyl acetate, and water successively, 4%w/v sodium bicarbonate aqueous solution and water washing.Use anhydrous sodium sulfate drying, solvent removed by evaporation at reduced pressure.Residuum carries out the column chromatography purifying by silica gel, is that 3: 97 the ethanol and the mixture of methylene dichloride are made eluent with volume ratio, and obtaining 66.4mg (productive rate 77.4%) title compound is amorphous solid.Mass spectrum (FAB-MS) m/z:859 (M+H
+, M=C
48H
62N
2O
12).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.00 1H, unimodal);
(7.74 1H, unimodal);
7.46 (2H, doublet, J=8.6Hz);
7.31 (2H, doublet, J=8.6Hz);
4.81 (1H, doublet, J=10.4Hz);
4.74﹠amp; 4.68 (2H, dual AB-quartet, J=1.9﹠amp; 14.6Hz);
(4.69 2H, unimodal);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet); 3.03 (1H, dual triplet, J=2.2﹠amp; 9.3Hz);
(2.62 2H, multiplet);
(2.25 3H, unimodal);
(1.93 3H, unimodal);
(1.29 3H, unimodal);
0.97 (3H, triplet, J=7.4Hz);
0.82 (3H, doublet, J=6.4Hz);
0.77 (3H, doublet, J=6.4Hz).Embodiment 111-113
Prepare embodiment 111-113 compound with embodiment 110 described same procedure.Embodiment 11113-[1-(4-oxyethyl group acetylamino phenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOCH
2OEt, n=0 (compound 213)] mass spectrum (FAB-MS) m/z:845 (M+H+, M=C
48H
64N
2O
11).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.27 1H, unimodal);
(8.13 1H, unimodal);
7.49 (2H, doublet, J=8.4Hz);
7.30 (2H, doublet, J=8.4Hz);
4.81 (1H, doublet, J=10.4Hz);
4.74﹠amp; 4.67 (2H, dual AB-quartet, J=1.8﹠amp; 14.6Hz);
(4.65 1H, unimodal);
(4.05 2H, unimodal);
(3.97 1H, unimodal);
3.66 (2H, quartet, J=7.2Hz);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
3.02 (1H, dual triplet, J=2.1﹠amp; 9.4Hz);
(2.61 2H, multiplet);
(1.93 3H, unimodal);
1.31 (3H, triplet, J=7.2Hz);
(1.29 3H, unimodal);
0.97 (3H, triplet, J=7.4Hz);
0.82 (3H, doublet, J=6.4Hz);
0.76 (3H, doublet, J=6.4Hz).Embodiment 11213-[1-(the amino phenyl of 4-benzene thioacetyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOCH
2SPh, n=0 (compound 218)] mass spectrum (FAB-MS) m/z:909 (M+H
+, M=C
52H
64N
2O
10S).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.54 1H, unimodal);
(8.09 1H, unimodal);
(7.40-7.21 9H, multiplet);
4.80 (1H, doublet, J=10.4Hz);
4.75﹠amp; 4.68 (2H, dual AB-quartet, J=1.8﹠amp; 14.6Hz);
(4.66 1H, unimodal);
(3.97 1H, unimodal);
(3.77 2H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
3.02 (1H, dual triplet, J=2.1﹠amp; 9.4Hz);
(2.60 2H, multiplet);
1.93 (3H, doublet, J=1.4Hz);
(1.29 3H, unimodal);
0.97 (3H, triplet, J=7.2Hz);
0.82 (3H, doublet, J=6.5Hz);
0.76 (3H, doublet, J=6.4Hz).Embodiment 11313-[1-(4-benzenesulfonyl acetylamino phenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCOCH
2SO
2Ph, n=0 (compound 217)] mass spectrum (FAB-MS) m/z:941 (M+H
+, M=C
52H
64N
2O
12S).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.46 1H, unimodal);
(8.06 1H, unimodal);
7.92 (2H, doublet, J=7.3Hz);
7.70 (1H, dual doublet, J=7.4﹠amp; 7.4Hz);
7.58 (2H, dual doublet, J=7.3﹠amp; 7.4Hz);
7.42 (2H, doublet, J=8.7Hz);
7.31 (2H, doublet, J=8.7Hz);
4.82 (1H, doublet, J=10.5Hz);
4.75﹠amp; 4.68 (2H, dual AB-quartet, J=1.8﹠amp; 14.5Hz);
(4.65 1H, unimodal);
(4.15 2H, unimodal);
(3.97 1H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
3.02 (1H, dual triplet, J=2.2﹠amp; 9.4Hz);
(2.62 2H, multiplet);
1.93 (3H, doublet, J=1.6Hz);
(1.31 3H, unimodal);
0.97 (3H, triplet, J=7.3Hz);
0.82 (3H, doublet, J=6.5Hz);
0.76 (3H, doublet, J=6.5Hz).Embodiment 11413-{2-[4-(N-methylamino formyl radical amino) phenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCONHMe, n=0 (compound 132)] 4mg (0.20mmol) methyl isocyanate is added to 101mg (0.12mmol) and presses the embodiment 18 (a) and (b) 13-[2-(4-the aminophenyl)-2 Methylpropionic acid base of preparation]-the 2.0ml methylene dichloride of 5-t-butyldimethylsilyloxy base imino--milbemycin A4 in, and with mixture stirring at room 5 hours.During end, solvent removed by evaporation at reduced pressure from reaction mixture.The gained residuum is dissolved in 2.0ml methyl alcohol, and adds 0.2ml 1M aqueous hydrochloric acid therein.Reaction mixture is stirring at room 20 minutes, then with the dilution of 20ml ethyl acetate, and water successively, 4%w/v sodium bicarbonate aqueous solution and water washing.Use anhydrous sodium sulfate drying, solvent removed by evaporation at reduced pressure.Residuum carries out the column chromatography purifying by silica gel, is that 6: 4 the ethyl acetate and the mixture of hexane are made eluent with volume ratio, and obtaining 87mg (productive rate 91%) title compound is amorphous solid.Mass spectrum (FAB-MS) m/z:790 (M+H
+, M=C
44H
59N
3O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.14 1H, wide unimodal);
7.26 (2H, doublet, J=8.6Hz);
7.20 (2H, doublet, J=8.6Hz);
(6.27 1H, wide unimodal);
4.87 (1H, doublet, J=10.6Hz);
4.72﹠amp; 4.69 (2H, the AB-quartet, J=15.2Hz);
(4.66 1H, unimodal);
(3.95 1H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
2.84 (3H, doublet, J=4.7Hz);
(1.93 3H, unimodal);
(1.58 3H, unimodal);
(1.54 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
(0.83-0.81 6H, multiplet).Embodiment 115-119
Prepare embodiment 115-119 compound with embodiment 114 described same procedure.Embodiment 11513-{2-[4-(N-phenyl amino formyl radical amino) phenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCONHPh, n=0 (compound 144)] mass spectrum (FAB-MS) m/z:852 (M+H
+, M=C
49H
61N
3O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.22 1H, wide unimodal);
(6.69 1H, wide unimodal);
(6.64 1H, wide unimodal);
4.87 (1H, doublet, J=10.6Hz);
4.72﹠amp; 4.70 (2H, the AB-quartet, J=14.5Hz);
(4.66 1H, unimodal);
(3.95 1H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(1.92 3H, unimodal);
(1.58 3H, unimodal);
(1.54 3H, unimodal);
(1.32 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (6H, doublet, J=6.6Hz).Embodiment 116 13-{2-[4-(N-methylthio group formamyl amino) phenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et.X=CO.Z=＞C (Me)
2, R
3=4-NHCSNHMe, n=0 (compound 145)] mass spectrum (FAB-MS) m/z:806 (M+H
+, M=C
44H
59N
3O
9S).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(7.94 1H, wide unimodal);
(7.61 1H, wide unimodal);
7.37 (2H, doublet, J=8.6Hz);
7.14 (2H, doublet, J=8.6Hz);
(5.97 1H, wide unimodal);
4.89 (1H, doublet, J=10.6Hz);
4.72﹠amp; 4.70 (2H, the AB-quartet, J=14.5Hz);
(4.66 1H, unimodal);
(3.96 1H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
3.14 (3H, doublet, J=4.6Hz);
3.03 (1H, dual doublet, J=2.0﹠amp; 9.2Hz);
(1.93 3H, unimodal);
(1.59 3H, unimodal);
(1.57 3H, unimodal);
(1.34 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (6H, doublet, J=6.5Hz).Embodiment 11713-{1-[4-(N-methylamino formyl radical amino) phenyl] tetramethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
3, R
3=4-NHCONHMe, n=0 (compound 494)] mass spectrum (FAB-MS) m/z:802 (M+H
+, M=C
45H
59N
3O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.30 1H, wide unimodal);
(7.22 1H, unimodal);
(6.31 1H, wide unimodal);
4.85 (1H, doublet, J=10.6Hz);
4.73﹠amp; 4.70 (2H, the AB-quartet, J=14.5Hz);
(4.66 1H, unimodal);
(3.95 1H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
3.03 (1H, dual doublet, J=2.3﹠amp; 9.2Hz);
2.84 (3H, doublet, J=4.6Hz);
(2.53-2.42 3H, multiplet);
(1.93 3H, unimodal);
(1.35 3H, unimodal);
0.97 (3H, triplet, J=7.3Hz);
0.82 (3H, doublet, J=6.6Hz);
0.77 (3H, doublet, J=6.3Hz).Embodiment 11813-{1-[4-(N-phenyl amino formyl radical amino) phenyl] tetramethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞HC (CH
2)
3, R
3=4-NHCONHPh, n=0 (compound 500)] mass spectrum (FAB-MS) m/z:864 (M+H
+, M=C
50H
61N
3O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.56 1H, wide unimodal);
(7.35-7.30 4H, multiplet);
(7.25-7.19 4H, multiplet);
(7.15-7.10 1H, multiplet);
(6.89 1H, unimodal);
(6.75 1H, unimodal);
4.86 (1H, doublet, J=10.4Hz);
4.75﹠amp; 4.68 (2H, dual AB-quartet, J=1.6﹠amp; 14.8Hz);
(4.67 1H, unimodal);
(3.95 1H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(2.84-2.72 2H, multiplet);
(1.91 3H, unimodal);
(1.36 3H, unimodal);
0.96 (3H, triplet, J=7.4Hz);
0.82 (3H, doublet, J=6.5Hz);
0.79 (3H, doublet, J=6.5Hz).Embodiment 11913-{1-[4-(N-phenyl amino formyl radical amino) phenyl] pentamethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-NHCONHPh, n=0 (compound 309)] mass spectrum (FAB-MS) m/z:878 (M+H
+, M=C
51H
63N
3O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.80 1H, unimodal);
(7.40-7.00 10H, multiplet);
4.86 (1H, doublet, J=10.3Hz);
4.74﹠amp; 4.66 (2H, the AB-quartet, J=15.5Hz);
(4.66 1H, unimodal);
(3.95 1H, unimodal);
(3.53 1H, multiplet);
(3.36 1H, multiplet);
(3.01 1H, multiplet);
(2.60 2H, multiplet);
(1.88 3H, unimodal);
(1.34 3H, unimodal);
0.95 (3H, triplet, J=7.2Hz);
0.81 (3H, doublet, J=6.3Hz);
0.76 (3H, doublet, J=6.4Hz).Embodiment 12013-{1-[4-(N-methylamino formyl radical amino) phenyl] cyclopropanecarbonyl-oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
2, R
3=4-NHCONHMe, n=0 (compound 432)] 120 (a) 3-{1-[4-(1,2,4-triazolo [4,3-a] pyridine-3-ketone-2-carbonyl) aminophenyl] cyclopropanecarbonyl-oxygen base }-5-t-butyldimethylsilyloxy base imino--milbemycin A
4
Described same procedure will be by 13-[1-(4-nitrophenyl) the cyclopropanecarbonyl-oxygen base of embodiment 6 preparation with embodiment 18 (a) with (b)]-5-oximido-milbemycin A4 changes into 13-[1-(4-aminophenyl) cyclopropanecarbonyl-oxygen base]-5-t-butyldimethylsilyloxy base imino--milbemycin A4.This aminoderivative of 845mg (1.0mmol) is dissolved in the 10ml methylene dichloride, and adds 0.081ml (1.0mmol) pyridine and 198mg (1.0mmol) 2-chloroformyl-1,2,4-triazolo [4,3-a] pyridine-3-ketone therein.Reaction mixture stirring at room 20 minutes, then with the dilution of 100ml ethyl acetate, and is used the 0.2M aqueous citric acid solution, water, 4%w/v sodium bicarbonate aqueous solution and water washing successively.Use anhydrous sodium sulfate drying, solvent removed by evaporation at reduced pressure.Residuum carries out the column chromatography purifying by silica gel, is that 1: 1 the ethyl acetate and the mixture of hexane are made eluent with volume ratio, and obtaining 995mg (productive rate 97.4%) title compound is amorphous solid.120 (b) 3-{1-[4-(N-methylamino formyl radical amino) phenyl] cyclopropanecarbonyl-oxygen base }-5-oximido-milbemycin A
4153mg (0.15mmol) 13-{1-[4-that Li street, tall building a) prepares (1,2,4-triazolo [4,3-a] pyridine-3-ketone-2-carbonyl) aminophenyl] cyclopropanecarbonyl-oxygen base }-5-t-butyldimethylsilyloxy base imino--milbemycin A
4Be dissolved in the 1.0ml N-Methyl pyrrolidone.The aqueous methylamine solution that in gained solution, adds 19.4mg (0.25mmol) 40%v/v then, and with mixture stirring at room 1 hour.Reaction mixture is with the dilution of 20ml ethyl acetate, and water successively, 0.2M aqueous citric acid solution, water, 4%w/v sodium bicarbonate aqueous solution and water washing.Use anhydrous sodium sulfate drying, solvent removed by evaporation at reduced pressure.The gained residuum is dissolved in 2.0ml methyl alcohol, and adds 0.2ml 1M aqueous hydrochloric acid therein.With reaction mixture stirring at room 20 minutes, afterwards with the dilution of 20ml ethyl acetate, and water successively, 4%w/v sodium bicarbonate aqueous solution and water washing.Use anhydrous sodium sulfate drying, solvent removed by evaporation at reduced pressure.Residuum carries out the column chromatography purifying by silica gel, is that 5: 95 the ethanol and the mixture of methylene dichloride are made eluent with volume ratio, and obtaining 109mg (productive rate 92.4%) title compound is amorphous solid.Mass spectrum (FAB-MS) m/z:788 (M+H
+, M=C
44H
57N
3O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.86 1H, unimodal);
7.27 (2H, doublet, J=8.4Hz);
7.21 (2H, doublet, J=8.4Hz);
(6.53 1H, unimodal);
(4.87 1H, doublet, J=10.4 Hz);
(4.81 1H, multiplet);
4.73﹠amp; 4.67 (2H, dual AB-quartet, J=1.8﹠amp; 14.6Hz);
(4.67 1H, unimodal);
(3.93 1H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
3.03 (1H, dual doublet, J=2.1﹠amp; 9.4Hz);
2.83 (3H, doublet, J=4.9Hz);
(1.93 3H, unimodal);
(1.38 3H, unimodal);
(1.16 2H, multiplet);
0.97 (3H, triplet, J=7.3Hz);
0.92 (3H, doublet, J=6.5Hz);
0.82 (3H, doublet, J=6.5Hz).Embodiment 121-124
Prepare embodiment 121-124 compound with embodiment 120 described same procedure.Embodiment 12113-{1-[4-(1-pyrrolidyl carbonylamino) phenyl] cyclopropanecarbonyl-oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
2, R
3=4-NHCO (1-Pyrd), n=0 (compound 437)] mass spectrum (FAB-MS) m/z:828 (M+H
+, M=C
47H
61N
3O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.37 1H, unimodal);
7.35 (2H, doublet, J=8.6Hz);
7.23 (2H, doublet, J=8.6Hz);
(6.15 1H, unimodal);
4.86 (1H, doublet, J=10.4Hz);
4.73﹠amp; 4.67 (2H, dual AB-quartet, J=1.9﹠amp; 14.7Hz);
(4.66 1H, unimodal);
(3.92 1H, unimodal);
(3.55 1H, multiplet);
(3.47 4H, multiplet);
(3.36 1H, multiplet);
3.03 (1H, dual doublet, J=2.2﹠amp; 9.4Hz);
(1.98 4H, multiplet);
1.93 (3H, doublet, J=1.5Hz);
(1.36 3H, unimodal);
(1.15 2H, multiplet);
0.97 (3H, triplet, J=7.3Hz);
0.90 (3H, doublet, J=6.5Hz);
0.83 (3H, doublet, J=6.5Hz).Embodiment 12213-{1-[4-(N-butyl formamyl amino) phenyl] cyclopropanecarbonyl-oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCONHBu, n=0 (compound 138)] mass spectrum (FAB-MS) m/z:832 (M+H
+, M=C
47H
65N
3O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.24 1H, unimodal);
7.25 (2H, doublet, J=8.6Hz);
7.20 (2H, doublet, J=8.6Hz);
(6.28 1H, wide unimodal);
4.87 (1H, doublet, J=10.6Hz);
4.72﹠amp; 4.69 (2H, dual AB-quartet, J=14.5Hz);
(4.66 1H, unimodal);
(3.95 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
3.25 (2H, quartet, J=6.6Hz);
(3.03 1H, multiplet);
(1.93 3H, unimodal);
(1.57 3H, unimodal);
(1.54 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
(0.84-0.81 6H, multiplet).Embodiment 12313-{1-[4-(N-tertiary butyl formamyl amino) phenyl] cyclopropanecarbonyl-oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCONHtBu, n=0 (compound 139)] mass spectrum (FAB-MS) m/z:832 (M+H
+, M=C
47H
65N
3O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.22 1H, wide unimodal);
7.23 (2H, doublet, J=8.6Hz);
7.17 (2H, doublet, J=8.6Hz);
(6.13 1H, wide unimodal);
4.87 (1H, doublet, J=10.6Hz);
4.72﹠amp; 4.69 (2H, the AB-quartet, J=14.5Hz);
(4.66 1H, unimodal);
(3.95 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
3.03 (1H, dual triplet, J=1.7﹠amp; 8.9Hz);
(1.93 3H, unimodal);
(1.56 3H, unimodal);
(1.53 3H, unimodal);
(1.37 9H, unimodal);
(1.32 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
(0.84-0.80 6H, multiplet).Embodiment 12413-{1-[4-(N-cyclohexyl carboxyamide base amino) phenyl] cyclopropanecarbonyl-oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-NHCONH-CHX, n=0 (compound 140)] mass spectrum (FAB-MS) m/z:858 (M+H
+, M=C
49H
67N
3O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.17 1H, wide unimodal);
7.25 (2H, doublet, J=8.6Hz);
7.19 (2H, doublet, J=8.6Hz);
(6.18 1H, wide unimodal);
4.87 (1H, doublet, J=10.5Hz);
4.72﹠amp; 4.69 (2H, the AB-quartet, J=14.5Hz);
(4.66 1H, unimodal);
(3.95 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual triplet, J=1.9﹠amp; 9.2Hz);
(1.93 3H, unimodal);
(1.57 3H, unimodal);
(1.54 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
(0.84-0.81 6H, multiplet).Embodiment 12513-{1-[4-(pyrimidine-2-base thioacetyl amino) phenyl] cyclopropanecarbonyl-oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
2, R
3=4-NHCOCH
2S-(2-pym), n=0 (compound 406)]
With 13-[1-(4-nitrophenyl) the cyclopropanecarbonyl-oxygen base of embodiment 18 described same procedure with embodiment 6 preparation]-5-oximido-milbemycin A4 changes into 13-[1-(4-acetobrom aminophenyl) cyclopropanecarbonyl-oxygen base]-5-t-butyldimethylsilyloxy base imino--milbemycin A4.
The above-mentioned acetobrom derivative of 115mg (0.12mmol) is dissolved in the 2.0ml N-Methyl pyrrolidone, and adds 22.4mg (0.20mmol) 2-mercaptopyrimidine and 6.5mg (0.15mmol) sodium hydride (55%w/v is suspended in mineral oil) therein.Reaction mixture stirring at room 30 minutes, then with the dilution of 20ml ethyl acetate, and is used the 0.2M aqueous citric acid solution, water, 4%w/v sodium bicarbonate aqueous solution and water washing successively.Use anhydrous sodium sulfate drying, solvent removed by evaporation at reduced pressure.The gained residuum is dissolved in 2.0ml methyl alcohol, and adds 0.2ml 1M aqueous hydrochloric acid therein.With reaction mixture stirring at room 20 minutes, afterwards with the dilution of 20ml ethyl acetate, and water successively, 4%w/v sodium bicarbonate aqueous solution and water washing.Use anhydrous sodium sulfate drying, solvent removed by evaporation at reduced pressure.Residuum carries out the column chromatography purifying by silica gel, is that 2.5: 97.5 the ethanol and the mixture of methylene dichloride are made eluent with volume ratio, and obtaining 105mg (productive rate 99.1%) title compound is amorphous solid.Mass spectrum (FAB-MS) m/z:883 (M+H
+, M=C
48H
58N
4O
10S).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(9.13 1H, unimodal);
8.63 (2H, doublet, J=5.1Hz);
(8.28 1H, unimodal);
7.40 (2H, doublet, J=8.4Hz);
7.25 (2H, doublet, J=8.4Hz);
7.13 (1H, triplet, J=5.1Hz);
4.85 (1H, doublet, J=10.5Hz);
4.73﹠amp; 4.66 (2H, dual AB-quartet, J=2.0﹠amp; 14.5Hz);
(4.65 1H, unimodal);
(3.93 1H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
3.02 (1H, dual doublet, J=2.2﹠amp; 9.4Hz);
1.93 (3H, doublet, J=1.5Hz);
(1.36 3H, unimodal);
(1.13 2H, multiplet);
0.97 (3H, triplet, J=7.3Hz);
0.89 (3H, doublet, J=6.5Hz);
0.82 (3H, doublet, J=6.5Hz).Embodiment 126-127
Prepare embodiment 126-127 compound with embodiment 125 described same procedure.Embodiment 12613-{1-[4-(thiazolidine-2-Ji thioacetyl amino) phenyl] cyclopropanecarbonyl-oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
2, R
3=4-NHCOCH
2S-(2-Thdn), n=0 (compound 408)] mass spectrum (FAB-MS) m/z:890 (M+H
+, M=C
47H
59N
3O
10S
2).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.21 1H, unimodal);
7.41 (2H, doublet, J=8.5Hz);
7.27 (2H, doublet, J=8.5Hz);
4.87 (1H, doublet, J=10.5Hz);
4.73﹠amp; 4.66 (2H, dual AB-quartet, J=2.0﹠amp; 14.5Hz);
(4.65 1H, unimodal);
4.31 (2H, triplet, J=8.0Hz);
(3.92 1H, unimodal);
(3.79 2H, unimodal);
(3.56 1H, multiplet);
3.54 (2H, triplet, J=8.0Hz);
(3.36 1H, multiplet);
3.03 (1H, dual doublet, J=2.2﹠amp; 9.4Hz);
1.93 (3H, doublet, J=1.4Hz);
(1.37 3H, unimodal);
(1.14 2H, multiplet);
0.97 (3H, triplet, J=7.3Hz);
0.91 (3H, doublet, J=6.5Hz);
0.82 (3H, doublet, J=6.5Hz).Embodiment 12713-{1-[4-(pyridine-2-base thioacetyl amino) phenyl] cyclopropanecarbonyl-oxygen base } 5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
2, R
3=4-NHCOCH
2S-(2-Pyr), n=0 (compound 407)] mass spectrum (FAB-MS) m/z:882 (M+H
+, M=C
49H
59N
3O
10S).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
8.55 (1H, doublet, J=5.2Hz);
(8.18 1H, unimodal);
(7.60 1H, multiplet);
7.42 (2H, doublet, J=8.6Hz);
7.32 (1H, doublet, J=8.0Hz);
7.25 (2H, doublet, J=8.6Hz);
7.16 (1H, dual doublet, J=5.2﹠amp; 7.2Hz);
4.85 (1H, doublet, J=10.5Hz);
4.73﹠amp; 4.66 (2H, dual AB-quartet, J=2.0﹠amp; 14.6Hz);
(4.65 1H, unimodal);
(3.92 1H, unimodal);
(3.89 2H, unimodal);
(3.54 1H, multiplet);
(3.36 1H, multiplet);
3.03 (1H, dual doublet, J=2.2﹠amp; 9.4Hz);
(1.93 3H, multiplet);
(1.36 3H, unimodal);
(1.13 2H, multiplet);
0.97 (3H, triplet, J=7.3Hz);
0.89 (3H, doublet, J=6.4Hz);
0.82 (3H, doublet, J=6.5Hz).Embodiment 128-137
Prepare embodiment 128-137 compound with embodiment 1 described same procedure.Embodiment 12813-{1-[4-(N-methyl kharophen) phenyl] pentamethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-N (Me) AC, n=0 (compound 193)] mass spectrum (FAB-MS) m/z:815 (M+H
+, M=C
47H
62N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.70 1H, wide unimodal);
7.38 (2H, doublet, J=8.3Hz);
7.11 (2H, doublet, J=8.3Hz);
4.81 (1H, doublet, J=10.5Hz);
4.74﹠amp; 4.66 (2H, the AB-quartet, J=14.9Hz);
(4.65 1H, unimodal);
(3.95 1H, wide unimodal);
(3.55 1H, multiplet);
(3.35 1H, multiplet);
(3.23 3H, unimodal);
(3.02 1H, multiplet);
(2.65 2H, multiplet);
(1.92 3H, unimodal);
(1.84 3H, unimodal);
(1.30 3H, unimodal);
0.97 (3H, triplet, J=7.2Hz);
0.82 (3H, doublet, J=6.3Hz);
0.76 (3H, doublet, J=6.5Hz).Embodiment 12913-{1-[4-(N-butyl kharophen) phenyl] pentamethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-N (Bu) AC, n=0 (compound 196)] mass spectrum (FAB-MS) m/z:857 (M+H
+, M=C
50H
68N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.11 1H, unimodal);
7.38 (2H, doublet, J=8.6Hz);
7.07 (2H, doublet, J=8.6Hz);
4.80 (1H, doublet, J=10.4Hz);
4.74﹠amp; 4.67 (2H, the AB-quartet, J=14.4Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
3.66 (2H, triplet, J=7.6Hz);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(2.65 2H, multiplet);
(1.93 3H, unimodal);
(1.78 3H, unimodal);
(1.28 3H, unimodal);
0.97 (3H, triplet, J=7.3Hz);
0.87 (3H, triplet, J=7.2Hz);
0.82 (3H, doublet, J=6.4Hz);
0.72 (3H, doublet, J=6.4Hz).Embodiment 13013-{1-[4-(N-methyl methanesulfonamido) phenyl] pentamethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4, R
3=4-N (Me) SO
2Me, n=0 (compound 316)] mass spectrum (FAB-MS) m/z:851 (M+H
+, M=C
46H
62N
2O
11S).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.13 1H, unimodal);
7.35 (2H, doublet, J=8.7Hz);
7.29 (2H, doublet, J=8.7Hz);
4.80 (1H, doublet, J=10.4Hz);
4.74﹠amp; 4.67 (2H, dual AB-quartet, J=1.8﹠amp; 14.2Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.29 3H, unimodal);
(3.02 1H, multiplet);
(2.80 3H, unimodal);
(2.62 2H, multiplet);
(1.93 3H, unimodal);
(1.27 3H, unimodal);
0.97 (3H, triplet, J=7.2Hz);
0.82 (3H, doublet, J=6.4Hz);
0.75 (3H, doublet, J=6.4Hz).Embodiment 13113-{-[4-(N-butyl methanesulfonamido) phenyl] pentamethylene carbonyl oxygen base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (CH
2)
4.R
3=4-N (Bu) SO
2Me, n=0 (compound 319)] mass spectrum (FAB-MS) m/z:893 (M+H
+, M=C
49H
68N
2O
11S).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.03 1H, unimodal);
7.36 (2H, doublet, J=8.7Hz);
7.25 (2H, doublet, J=8.7Hz);
4.79 (1H, doublet, J=10.8Hz);
4.74﹠amp; 4.67 (2H, dual AB-quartet, J=1.8﹠amp; 14.6Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
3.64 (2H, triplet, J=6.8Hz);
(3.55 1H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(2.83 3H, unimodal);
(2.65 2H, multiplet);
(1.93 3H, unimodal);
(1.27 3H, unimodal);
0.97 (3H, triplet, J=7.3Hz);
0.86 (3H, triplet, J=7.2Hz);
0.82 (3H, doublet, J=6.4Hz);
0.72 (3H, doublet, J=6.4Hz).Embodiment 13213-{2-[4-(2-Oxypertine subbase) phenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-(2-oxygen-Pip), n=0 (compound 161)] mass spectrum (FAB-MS) m/z:815 (M+H
+, M=C
47H
62N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.18 1H, unimodal);
7.31 (2H, doublet, J=8.5Hz);
7.18 (2H, doublet, J=8.5Hz);
4.87 (1H, doublet, J=10.8Hz);
4.73﹠amp; 4.66 (2H, dual AB-quartet, J=1.8﹠amp; 14.6Hz);
(4.65 1H, unimodal);
(3.96 1H, wide unimodal);
(3.62-3.52 3H, multiplet);
(3.36 1H, multiplet);
(3.03 1H, multiplet);
(2.57 2H, multiplet);
(1.92 3H, unimodal);
(1.58 3H, unimodal);
(1.55 3H, unimodal);
(1.29 3H, unimodal);
0.98 (3H, triplet, J=7.4Hz);
(0.84-0.82 6H, multiplet).Embodiment 13313-{2-[4-(2-oxygen-1-pyrrolidyl) phenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-(2-oxygen-1-Pyrd), n=0 (compound 163)] mass spectrum (FAB-MS) m/z:801 (M+H
+, M=C
46H
60N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.80 1H, wide unimodal);
7.55 (2H, doublet, J=8.6Hz);
7.30 (2H, doublet, J=8.6Hz);
4.88 (1H, doublet, J=10.6Hz);
4.74﹠amp; 4.65 (2H, the AB-quartet, J=14.5Hz);
(4.65 1H, unimodal);
(3.96 1H, unimodal);
(3.71 2H, unimodal);
(3.57 1H, multiplet);
(3.38 1H, multiplet);
(3.04 1H, multiplet);
2.62 (2H, triplet, J=8.2Hz);
2.17 (2H, triplet, J=7.5Hz);
(1.93 3H, unimodal);
(1.57 3H, unimodal);
(1.54 3H, unimodal);
(1.32 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
(0.85-0.82 6H, multiplet).Embodiment 134 13-{2-[4-(2-oxaza butane-1-yl) phenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-(2-oxygen-1-Azt), n=0 (compound 160)] mass spectrum (FAB-MS) m/z:787 (M+H
+, M=C
45H
58N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(7.99 1H, unimodal);
(7.28-7.26 4H, multiplet);
4.87 (1H, doublet, J=10.8Hz);
4.74﹠amp; 4.67 (2H, dual AB-quartet, J=2.0﹠amp; 14.4Hz);
(4.66 1H, unimodal);
(3.97 1H, unimodal);
(3.63-3.60 2H, multiplet);
(3.57 1H, multiplet);
(3.38 1H, multiplet);
(3.13-3.10 2H, multiplet);
(3.03 1H, multiplet);
(1.93 3H, unimodal);
(1.58 3H, unimodal);
(1.54 3H, unimodal);
(1.32 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
(0.84-0.81 6H, multiplet).Embodiment 13513-{2-[4-(2,6-dioxopiperidin subbase) phenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-(2, the 6-dioxy-Pip), and n=0 (compound 162)] mass spectrum (FAB-MS) m/z:829 (M+H
+, M=C
47H
60N
2O
11).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.12 1H, unimodal);
7.36 (2H, doublet, J=8.6Hz);
7.01 (2H, doublet, J=8.6Hz);
4.86 (1H, doublet, J=10.4Hz);
4.72﹠amp; 4.66 (2H, dual AB-quartet, J=2.1﹠amp; 14.5Hz);
(4.65 1H, unimodal);
(3.96 1H, unimodal);
(3.56 1H, multiplet);
(3.35 1H, multiplet);
(3.04 1H, multiplet);
2.81 (4H, triplet, J=6.6Hz);
(2.11 2H, multiplet);
(1.93 3H, unimodal);
(1.61 3H, unimodal);
(1.56 3H, unimodal);
(1.23 3H, unimodal);
0.98 (3H, triplet, J=7.2Hz);
0.84 (3H, doublet, J=6.5Hz);
0.83 (3H, doublet, J=6.4Hz).Embodiment 13613-{2-[4-(2,5-dioxy-1-pyrrolidyl) phenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-(2, the 5-dioxy-1-pyrd), and n=0 (compound 164)] mass spectrum (FAB-MS) m/z:815 (M+H
+, M=C
46H
58N
2O
11).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.25 1H, unimodal);
7.39 (2H, doublet, J=8.5Hz);
7.23 (2H, doublet, J=8.5Hz);
4.88 (1H, doublet, J=10.6Hz);
4.73﹠amp; 4.67 (2H, dual AB-quartet, J=2.0﹠amp; 14.5Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.56 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual doublet, J=2.2﹠amp; 9.5Hz);
(2.90 4H, unimodal);
1.93 (3H, doublet, J=1.5Hz);
(1.60 3H, unimodal);
(1.56 3H, unimodal);
(1.27 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.84 (3H, doublet, J=6.5Hz);
0.83 (3H, doublet, J=8.5Hz).Embodiment 13713-{2-[4-(2-Yang oxazoline-3-yl) phenyl]-the 2 Methylpropionic acid base }-5-oximido-milbemycin A
4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=4-(2-oxygen-3-oxazoline), n=0 (compound 165)] mass spectrum (FAB-MS) m/z:803 (M+H
+, M=C
45H
58N
2O
11).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.19 1H, wide unimodal);
7.48 (2H, doublet, J=9.0Hz);
7.30 (2H, doublet, J=9.0Hz);
4.88 (1H, doublet, J=10.5Hz);
4.74﹠amp; 4.66 (2H, dual AB-quartet, J=2.0﹠amp; 14.5Hz);
(4.65 1H, unimodal);
(4.49 2H, multiplet);
(4.05 2H, multiplet);
(3.97 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
3.04 (1H, dual doublet, J=2.2﹠amp; 9.4Hz);
1.93 (3H, doublet, J=1.4Hz);
(1.58 3H, unimodal);
(1.55 3H, unimodal);
(1.32 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
0.83 (3H, doublet, J=6.5Hz);
0.82 (3H, doublet, J=6.5Hz).Embodiment 138-139
With 13-[2-(3-the nitrophenyl)-2 Methylpropionic acid base of embodiment 18 described same procedure from embodiment 2 preparations]-5-oximido-milbemycin A
4Preparation embodiment 138-139 compound.Embodiment 138 13-[2-(3-acetylamino phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=3-NHAO, n=0 (compound 32)] mass spectrum (FAB-MS) m/z:775 (M+H
+, M=C
44H
58N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(7.87 1H, wide unimodal);
7.50 (1H, doublet, J=8.6Hz);
(7.39 1H, unimodal);
7.22 (1H, doublet, J=7.9Hz);
(7.10 1H, wide unimodal);
7.02 (1H, doublet, J=7.9Hz);
4.87 (1H, doublet, J=10.6Hz);
4.71﹠amp; 4.69 (2H, the AB-quartet, J=13.9Hz);
(4.65 1H, unimodal);
(3.95 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(2.18 3H, unimodal);
(1.93 3H, unimodal);
(1.57 3H, unimodal);
(1.54 3H, unimodal);
(1.28 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
(0.84-0.81 6H, multiplet).Embodiment 139 13-[2-(3-methanesulfonamido phenyl)-2 Methylpropionic acid base]-5-oximido-milbemycin A4[(I): R
1=Et, X=CO, Z=＞C (Me)
2, R
3=3-NHSO
2Me, n=0 (compound 150)] mass spectrum (FAB-MS) m/z:711 (M+H
+, M=C
43H
58N
2O
11S).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(7.76 1H, unimodal);
(7.50-7.10 24, multiplet);
(6.33 1H, wide unimodal);
4.88 (1H, doublet, J=10.6Hz);
4.71﹠amp; 4.70 (2H, the AB-quartet, J=14.5Hz);
(4.65 1H, unimodal);
(3.94 1H, unimodal);
(3.57 1H, multiplet);
(3.36 1H, multiplet);
(3.04 1H, multiplet);
(2.99 3H, unimodal);
(1.93 3H, unimodal);
(1.58 3H, unimodal);
(1.56 3H, unimodal);
(1.31 3H, unimodal);
0.98 (3H, triplet, J=7.3Hz);
(0.84-0.81 6H, multiplet).Embodiment 1401 3-[1-(4-acetylamino phenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
3[(I): R
1=Me, X=CO, Z=＞C (CH
2)
4, R
3=4-NHAC, n=0 (compound 192)]
Prepare title compound with embodiment 57 and 59 described same procedure people 15-hydroxyl-5-oxygen-milbemycin A3.Mass spectrum (FAB-MS) m/z:787 (M+H
+, M=C
45H
58N
2O
10).Nuclear magnetic resonance spectrum (CDCl3) δ ppm:
(8.11 1H, wide unimodal);
7.41 (2H, doublet, J=8.6Hz);
7.28 (2H, doublet, J=8.6Hz);
(7.13 1H, unimodal);
4.81 (1H, doublet, J=10.4Hz);
4.75﹠amp; 4.69 (2H, the AB-quartet, J=14.7Hz);
(4.65 1H, unimodal);
(3.97 1H, unimodal);
(3.52 1H, multiplet);
(3.36 1H, multiplet);
(3.21 1H, multiplet);
(2.61 3H, multiplet);
(2.17 3H, unimodal);
(1.93 3H, unimodal);
(1.29 3H, unimodal);
1.14 (3H, doublet, J=6.4Hz);
0.83 (3H, doublet, J=6.5Hz);
0.75 (3H, doublet, J=6.5Hz).Embodiment 141-142
Prepare embodiment 141-142 compound with the described same procedure of embodiment 57-110 from 15-hydroxyl-5-oxygen-milbemycin A4.Embodiment 14113-{2-[4-(1-methoxycarbonyl tetramethyleneimine-2-carbonylamino) phenoxy group] }-5-oximido-milbemycin A
4[(I): R
1=Et, X=C=O, Z=C (Me)
2, R
3=4-NHCO (1-COOMe-2-Pyrd), n=1 (compound 111)] mass spectrum (FAB-MS) m/z:1053 (M+H
++ trolamine=903+1+149).Nuclear magnetic resonance spectrum (270MHz) δ ppm:
(8.63 1H, wide unimodal);
7.34 (2H, doublet, J=8.8Hz);
6.74 (2H, doublet, J=8.8Hz);
(5.86-5.79 3H, multiplet);
(5.45-5.30 3H, multiplet);
5.02 (1H, doublet, J=10.9Hz);
4.79-4.68 (2H, the AB-quartet, J=14.5Hz)
(4.67 1H, unimodal);
(4.45 1H, wide unimodal);
(4.00 1H, unimodal);
(3.77 3H, unimodal);
(3.73-3.38 5H, multiplet);
(3.65-3.42 3H, multiplet);
(3.37 1H, multiplet);
(3.06 1H, multiplet).Embodiment 14213-{2-[4-(N-methoxycarbonyl glycyl amino)-2 Methylpropionic acid phenoxyl] }-5-oximido-milbemycin A
4[(I): R
1=Et, X=C=O, Z=C (Me)
2, R
3=4-NHCOCH
2NHCOOMe, n=1 (compound 80)] mass spectrum (FAB-MS) m/z:1013 (M+H
++ trolamine=863+1+149).Nuclear magnetic resonance spectrum (270MHz) δ ppm:
(8.27 1H, wide unimodal);
(7.83 1H, wide unimodal);
7.31 (2H, doublet, J=8.9Hz);
6.74 (2H, doublet, J=8.9Hz);
(5.90-5.82 3H, multiplet);
(5.50-5.31 4H, multiplet);
5.00 (1H, doublet, J=10.4Hz);
4.73-4.67 (2H, the AB-quartet, J=14.4Hz);
(4.66 1H, unimodal);
(3.98 2H, unimodal);
(3.97 1H, unimodal);
(3.74 3H, unimodal);
(3.66-3.55 1H, multiplet);
(3.37 1H, multiplet);
(3.05 1H, multiplet).
Claims (26)
1. formula (I) compound or its salt:
Wherein: R
1The expression methyl, ethyl, sec.-propyl or sec-butyl; X represents carbonyl or methylene radical; Z expression (i) or (ii) group:
＝C＝(R
2)
2 (i)
＝C＝(CH
2)
m (ii)
R wherein
2Be the alkyl that contains 1 to 3 carbon atom, m is 2 to 5 integer; N is 0 or 1; R
3The expression nitro, amino, (C
1-C
4Alkyl) amino, two (C
1-C
4Alkyl) amino contains the alkoxyl group of 1 to 4 carbon atom, (C
1-C
3Alkoxyl group)-(C
2-C
3Alkoxyl group), or formula is (iii), (iv), (v), (Vi), (vii) or (viii) group:
Wherein: R
4Expression contains the alkyl of 1 to 6 carbon atom; The substituted alkyl that contains 1-6 carbon atom and replaced by a substituents alpha that defines below at least; The cycloalkyl that contains 3-6 carbon atom; The alkenyl that contains 2-6 carbon atom; The alkynyl that contains 2-6 carbon atom; The isocyclic aryl that does not replace or replaced by a substituting group γ who defines below at least that contains 6-14 ring carbon atom; It is nitrogen-atoms and/or Sauerstoffatom and/or sulphur atom that the heterocyclic radical that perhaps contains 3-6 annular atoms, this heterocyclic radical have a heteroatoms at least, and described heterocyclic radical does not replace or replaced by a substituting group γ who defines below at least; R
5Expression hydrogen atom or contain the alkyl of 1-4 carbon atom; R
6The expression hydrogen atom; The alkyl that contains 1-6 carbon atom; R
7Expression contains the alkyl of 1 to 6 carbon atom; The cycloalkyl that contains 3 to 6 carbon atoms; Or contain the unsubstituted isocyclic aryl of 6 to 14 ring carbon atoms; Y is Sauerstoffatom or sulphur atom; R is 1,2 or 3; Q represents methylene radical or carbonyl; R
8Expression contains the alkyl of 1 to 4 carbon atom; R
9Expression contains the alkyl of 1 to 6 carbon atom; The cycloalkyl that contains 3 to 6 carbon atoms; Or contain 6 to 10 ring carbon atoms and unsubstituted isocyclic aryl; Substituents alpha is selected from: halogen atom; Cyano group; The alkoxyl group that contains 1 to 4 carbon atom; The alkylthio that contains 1 to 4 carbon atom; The alkyl sulphonyl that contains 1 to 4 carbon atom; The alkanoyloxy that contains 2 to 5 carbon atoms; The alkoxy carbonyl that contains 2 to 5 carbon atoms; The carbocyclic ring aryloxy that contains 6 to 10 ring carbon atoms; The carbocyclic ring arylthio that contains 6 to 10 ring carbon atoms; The carbocyclic ring arylsulfonyl that contains 6-10 ring carbon atom; Amino; The alkanoyl amido that contains 2 to 5 carbon atoms; The alkoxycarbonyl amino that contains 2 to 5 carbon atoms; N-(C
2-C
5Alkoxy carbonyl)-N-(C
1-C
3Alkyl) amino; The isocyclic aryl carbonylamino, wherein aryl moiety contains 6 to 10 ring carbon atoms; Aromatic alkyl carbonyl amino, wherein aryl moiety is to contain the carbocyclic ring of 6-10 ring carbon atom and moieties contains 1 to 4 carbon atom; The isocyclic aryl that does not replace or replaced by a substituting group γ at least that contains 6-10 ring carbon atom; R
h-S-group, wherein R
hExpression contains the heterocyclic radical of 3 to 6 annular atomses, and it is nitrogen-atoms and/or Sauerstoffatom and/or sulphur atom that this heterocyclic radical has a heteroatoms at least, and this heterocyclic radical is not substituted; The alkanoyl that contains 2-5 carbon atom; Aromatic alkoxy carbonyl amino, wherein aryl moiety is to contain the carbocyclic ring of 6 to 10 ring carbon atoms and moieties contains 1 to 4 carbon atom; Substituting group γ is selected from: halogen atom; Hydroxyl; Cyano group; Nitro; The alkyl that contains 1 to 4 carbon atom; The alkoxyl group that contains 1 to 4 carbon atom; With the alkoxy carbonyl that contains 2 to 5 carbon atoms.
2. according to the compound of claim 1, R wherein
1Be methyl or ethyl.
3. according to the compound of claim 2, R wherein
1It is ethyl.
4. according to each the compound of claim 1-3, wherein Z is formula (i) group and R
2Be methyl or ethyl.
5. according to the compound of claim 4, wherein Z is formula (i) group and R
2It is methyl.
6. according to each compound of claim 1 to 3, wherein Z is that (ii) group and m are 2,3 or 4 to formula.
7. according to the compound of claim 6, wherein Z is that (ii) group and m are 2 or 4 to formula.
8. according to each the compound of claim 1-3, R wherein
3Expression is amino, (C
1-C
3Alkyl) amino, two (C
1-C
3Alkyl) amino contain the alkoxyl group of 1 to 3 carbon atom, or formula is (iii), (iv), (v), (vi) or (vii) group:
Wherein: R
4Expression contains the alkyl of 1 to 4 carbon atom; Contain the substituted alkyl that substituents alpha 1 that 1 to 3 carbon atom defined below one at least replaces; The cycloalkyl that contains 3 to 6 carbon atoms; The alkenyl that contains 3 to 4 carbon atoms; The alkynyl that contains 3 to 4 carbon atoms; The isocyclic aryl that does not replace or replaced by the substituting group γ 1 that defines below at least that contains 6 to 10 ring carbon atoms; Or contain the heterocyclic radical of 3 to 6 annular atomses, and wherein having a heteroatoms at least is nitrogen-atoms and/or Sauerstoffatom and/or sulphur atom, described heterocyclic radical is not replace or replaced by a substituting group γ who defines below 1 at least; R
5Expression hydrogen atom or contain the alkyl of 1 to 3 carbon atom; R
6Expression hydrogen atom or contain the alkyl of 1 to 4 carbon atom; R
7Expression contains the alkyl of 1 to 6 carbon atom or contains the unsubstituted isocyclic aryl of 6 to 10 ring carbon atoms; Y is Sauerstoffatom or sulphur atom; R is 1,2 or 3; Q is methylene radical or carbonyl; R
8Expression contains the alkyl of 1 to 4 carbon atom; Substituents alpha
1Be selected from: halogen atom; Cyano group; The alkoxyl group that contains 1 to 3 carbon atom; The alkylthio that contains 1 to 3 carbon atom; The alkanoyloxy that contains 2 to 5 carbon atoms; The carbalkoxy that contains 2 to 4 carbon atoms; The carbocyclic ring aryloxy that contains 6 to 10 ring carbon atoms; The carbocyclic ring arylthio that contains 6 to 10 ring carbon atoms; Amino; The alkanoyl amido that contains 2 to 5 carbon atoms; The alkoxycarbonyl amido that contains 2 to 4 carbon atoms; N-(C
2-C
5Carbalkoxy)-N-(C
1-C
3Alkyl) amino; The haloalkoxy carbonylamino that contains 2 to 5 carbon atoms; The isocyclic aryl carbonylamino, wherein aryl moiety contains 6 to 10 ring carbon atoms; Aromatic alkyl carbonyl amino, wherein aryl moiety is to contain the carbocyclic ring of 6 to 10 ring carbon atoms and moieties contains 1 to 2 carbon atom; Contain the not replacement of 6 to 10 ring carbon atoms or at least by a γ
1The isocyclic aryl that substituting group replaces; Formula R
h-S-group, wherein R
hBe the heterocyclic radical that contains 3 to 6 annular atomses, having a heteroatoms at least is nitrogen-atoms and/or Sauerstoffatom and/or sulphur atom, and this heterocyclic radical does not replace; With the alkanoyl that contains 2 to 5 carbon atoms; Substituting group γ
1Be selected from: halogen atom; Cyano group; Nitro; The alkyl that contains 1 to 4 carbon atom; The alkoxyl group that contains 1 to 4 carbon atom; With the carbalkoxy that contains 2 to 5 carbon atoms.
9. according to each the compound of claim 1-3, R wherein
3Expression is amino, methylamino-, ethylamino contain the alkoxyl group of 1 to 3 carbon atom, or formula is (iii), (v) or (vi) group:
Wherein: R
4Expression contains the alkyl of 1-4 carbon atom; Contain 1 to 3 carbon atom at least by the α that defines below
2The substituted alkyl that substituting group replaces; The cycloalkyl that contains 3 to 6 carbon atoms; The alkenyl that contains 3 to 4 carbon atoms; The alkynyl that contains 3 to 4 carbon atoms; Contain 6 to 10 ring carbon atoms do not replace or at least by the γ that defines below
1The isocyclic aryl that substituting group replaces; Or contain the heterocycle of 3 to 6 annular atomses, and wherein having a heteroatoms at least is nitrogen-atoms and/or Sauerstoffatom and/or sulphur atom, described heterocycle does not replace or at least by a γ who defines below
1Substituting group replaces; R
5Expression hydrogen atom or contain the alkyl of 1 to 3 carbon atom; R is 1,2 or 3; Q is methylene radical or carbonyl; Substituents alpha
2Be selected from: halogen atom; Cyano group; Methoxyl group; Oxyethyl group; Methylthio group; Ethylmercapto group; The alkanoyloxy that contains 2 to 3 carbon atoms; The carbalkoxy that contains 2 to 3 carbon atoms; Phenoxy group; Thiophenyl; Amino; The alkanoyl amido that contains 2 to 5 carbon atoms; The alkoxycarbonyl amido that contains 2 to 4 carbon atoms; N-(C
2-C
5Carbalkoxy)-N-(C
1-C
3Alkyl) amino; The isocyclic aryl carbonylamino, wherein aryl moiety contains 6 to 10 ring carbon atoms; Aromatic alkyl carbonyl amino, wherein aryl moiety is to contain the carbocyclic ring of 6 to 10 ring carbon atoms and moieties contains 1 to 2 carbon atom; Do not replace or at least by a γ
2The phenyl that substituting group replaces; With formula R
h-S-group, wherein R
hBe the heterocyclic radical that contains 3 to 6 annular atomses, wherein having a heteroatoms at least is nitrogen-atoms and/or Sauerstoffatom and/or sulphur atom, and this heterocyclic radical is not substituted;
Substituting group γ
2Be selected from halogen atom; Cyano group; Nitro; Methyl; Ethyl; Methoxyl group; Oxyethyl group; With the carbalkoxy that contains 2 to 3 carbon atoms.
10. according to the compound of claim 9, R wherein
3Expression is amino, methylamino-, ethylamino, or formula (iii) or (vi) group:
Wherein: R
4Expression contains the alkyl of 1-4 carbon atom; Contain 1-3 carbon atom at least by a α who defines below
3The substituted alkyl that substituting group replaces; The cycloalkyl that contains 5 to 6 carbon atoms; Do not replace or by at least a γ that defines below
3The phenyl that substituting group replaces; Or contain the heterocyclic radical of 5 to 6 annular atomses, and wherein having a heteroatoms at least is nitrogen-atoms and/or Sauerstoffatom and/or sulphur atom, this heterocyclic radical does not replace or by at least one γ that defines below
3Substituting group replaces; R
5Expression hydrogen atom or contain the alkyl of 1-3 carbon atom; R is 2; Q is methylene radical or carbonyl; Substituents alpha
3Be selected from: halogen atom; Cyano group; Methoxyl group; Oxyethyl group; The alkanoyloxy that contains 2 to 3 carbon atoms; The carbalkoxy that contains 2 to 3 carbon atoms; Phenoxy group; Amino; The alkanoyl amido that contains 2 to 3 carbon atoms; The alkoxycarbonyl amido that contains 2 to 4 carbon atoms; With the benzoyl carbonylamino; Substituting group γ
3Be selected from: halogen atom; Cyano group; Nitro; Methyl; Ethyl; Methoxyl group; And oxyethyl group.
11. according to each the compound of claim 1-3, wherein n is 0.
12. according to the compound of claim 1, this compound is 13-[2-(4-cyanoacetamide base-phenyl)-2-methyl-prop acyloxy]-5-oximido-milbemycin A
4
13. according to the compound of claim 1, this compound is 13-{2-[4-(N-ethanoyl glycyl)-aminophenyl]-2-methyl-prop acyloxy]-5-oximido-milbemycin A
4
14. according to the compound of claim 1, this compound is 13-{2-[4-(N-methoxycarbonyl glycyl) methylamino-phenyl]-2-methyl-prop acyloxy }-5-oximido-milbemycin A
4
15. according to the compound of claim 1, this compound is 13-[2-(4-methoxycarbonyl-aminophenyl)-2-methyl-prop acyloxy]-5-oximido-milbemycin A
4
16. according to the compound of claim 1, this compound is 13-{2-[4-(N-phenyl amino formyl radical-amino) phenyl]-2-methyl-prop acyloxy }-5-oximido-milbemycin A
4
17. according to the compound of claim 1, this compound is 13-{2-[4-(2-Yang Za oxazoline-3-yl) phenyl]-2-methyl-prop acyloxy }-5-oximido-milbemycin A
4
18. according to the compound of claim 1, this compound is 13-[1-(4-aminophenyl)-pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4
19. according to the compound of claim 1, this compound is 13-[1-(4-acetylamino phenyl)-pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4
20. according to the compound of claim 1, this compound is a 13-[1-4-acetoxyl group acetylamino phenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4
21. according to the compound of claim 1, this compound is 13-[1-(4-methanesulfonamido phenyl) pentamethylene carbonyl oxygen base]-5-oximido-milbemycin A
4
22. according to the compound of claim 1, this compound is 13-[1-(4-acetylamino phenyl)-1-ethyl butyryl acyloxy]-5-oximido-milbemycin A
4
23. according to the compound of claim 1, this compound is 13-[1-(4-acetylamino phenyl)-tetramethylene carbonyl oxygen base]-5-oximido-milbemycin A
4
24. an insect-killing composition contains insecticidal effective dose and compound acceptable carrier or mixing diluents, wherein this compound is selected from formula (I) compound or its salt that defines in aforementioned arbitrary claim.
25. protective plant avoids being selected from the method for the parasite harm of acarid, worm and insect; this method comprises active compound is applied on the breeding thing of the part of described plant or described plant or described plant or is applied to and comprises described plant; or the location of the breeding thing of part of described plant or described plant, wherein active compound is selected from formula (I) compound or its salt that defines in arbitrary claim of claim 1-23.
26. a purposes, wherein the formula of each definition of claim 1-23 (I) compound or its salt is in production be used for the watching for animals purposes of medicine of the parasite harm of avoiding being selected from acarid, worm and insect.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2529695A JPH08223902A (en) | 1995-02-14 | 1995-02-14 | Disk-shaped mhd generator |
| JP252965/1995 | 1995-09-29 | ||
| JP252965/95 | 1995-09-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1153177A CN1153177A (en) | 1997-07-02 |
| CN1077110C true CN1077110C (en) | 2002-01-02 |
Family
ID=12162065
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96119229A Expired - Fee Related CN1077110C (en) | 1995-02-14 | 1996-09-29 | 13-substituted milbemycin 5-oxime derivatives their preparation and their use against insects and other pests |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPH08223902A (en) |
| CN (1) | CN1077110C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106059244B (en) * | 2016-06-21 | 2018-06-05 | 南京航空航天大学 | A kind of Hall type Magnetohydrodynamic(MHD) generator |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4936582A (en) * | 1989-02-24 | 1990-06-26 | Kenneth Bernstein | Golf club |
| CN1112119A (en) * | 1994-04-01 | 1995-11-22 | 三共株式会社 | 13-substituted milbemycin derivatives, their preparation and use |
-
1995
- 1995-02-14 JP JP2529695A patent/JPH08223902A/en not_active Withdrawn
-
1996
- 1996-09-29 CN CN96119229A patent/CN1077110C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4936582A (en) * | 1989-02-24 | 1990-06-26 | Kenneth Bernstein | Golf club |
| CN1112119A (en) * | 1994-04-01 | 1995-11-22 | 三共株式会社 | 13-substituted milbemycin derivatives, their preparation and use |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH08223902A (en) | 1996-08-30 |
| CN1153177A (en) | 1997-07-02 |
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